WO2007075468A1 - Imidazoquinoléines, imidazonaphtyridines et imidazopyridines substituées, compositions et procédés correspondants - Google Patents

Imidazoquinoléines, imidazonaphtyridines et imidazopyridines substituées, compositions et procédés correspondants Download PDF

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Publication number
WO2007075468A1
WO2007075468A1 PCT/US2006/048017 US2006048017W WO2007075468A1 WO 2007075468 A1 WO2007075468 A1 WO 2007075468A1 US 2006048017 W US2006048017 W US 2006048017W WO 2007075468 A1 WO2007075468 A1 WO 2007075468A1
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group
alkyl
pyran
tetrahydo
pharmaceutical composition
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PCT/US2006/048017
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English (en)
Inventor
Bryon A. Merrill
Chad A. Haraldson
Ryan B. Prince
Karl J. Manske
Tushar A. Kshirsagar
Philip D. Heppner
Luke T. Dressel
Larry R. Krepski
Michael J. Rice
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Coley Pharmaceutical Group, Inc.
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Priority to JP2008545861A priority Critical patent/JP2009519955A/ja
Priority to AU2006332000A priority patent/AU2006332000A1/en
Priority to CA002634017A priority patent/CA2634017A1/fr
Priority to EP06845602A priority patent/EP1968587A1/fr
Priority to MX2008007864A priority patent/MX2008007864A/es
Publication of WO2007075468A1 publication Critical patent/WO2007075468A1/fr
Priority to IL191846A priority patent/IL191846A0/en
Priority to NO20082757A priority patent/NO20082757L/no
Priority to AU2011201519A priority patent/AU2011201519A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula I, II, Ua, III, IV, IVa, V, or Va:
  • compositions comprising compounds or salts of Formulas I, II, Ha, III, IV, IVa, V, or Va are useful for modulating cytokine biosynthesis (e.g., inducing the biosynthesis or production of one or more cytokines) and otherwise modulate the immune response when administered to animals.
  • cytokine biosynthesis e.g., inducing the biosynthesis or production of one or more cytokines
  • the ability to modulate cytokine biosynthesis makes the compositions useful in the treatment of a variety of conditions such as viral diseases and neoplastic diseases that are responsive to such changes in the immune response.
  • the present invention also provides compounds of the Formulas Ha, III, IVa, and Va, and pharmaceutically acceptable salts thereof.
  • the present invention provides methods of inducing cytokine biosynthesis in animal cells, treating a viral disease in an animal, and/or treating a neoplastic disease in an animal by administering to the animal a compound or salt of Formulas Ha, III, IVa, and/or Va, or a pharmaceutical composition comprising one or more compounds of the Formulas I, II, Ha, III, IV, IVa, V, and/or Va, and/or pharmaceutically acceptable salts thereof.
  • the invention provides methods of synthesizing the compounds of Formulas I, II, Ha, III, IV, IVa, V, and Va and intermediate compounds useful in the synthesis of these compounds.
  • the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula I, II, Ha, III, IV, IVa, V, or Va:
  • R, R 1 , R la , R 2 , R 3 , R 3a , R A , RB, RA', RB', X', X", X'", n, and m are as defined below; or pharmaceutically acceptable salts thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula I:
  • X' is selected from the group consisting Of -CH 2 -, -CH(CH 3 )-, -NH-, and -O-;
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl. tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran- 3-yl, tetrahydo-2//-pyran-4-yl, tetrahydo-2//-thiopyran-4-yl, and 1 ,1-dioxidotetrahydo- 2H-thiopyran-4-yl;
  • R 2 is selected from the group consisting of -TSfflb, -CH 3 , -CHa-Ci ⁇ alkyl, -CH 2 -CL 2 alkylenyl-O-Ci-2 alkyl, -CH 2 -O-CL 3 alkyl, -CH 2 -OH, -CH 2 -CL 3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, Ci-4 alkyl, C1-4 alkoxy, hydroxy, haloCi-4 alkyl, and hydroxyCi-4 alkyl;
  • R A is alkyl
  • R B is hydrogen or alkyl
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, and -N(Re) 2 ;
  • R 3 is selected from the group consisting of: -Z-R 4 , -Z-X-R 4 , -Z-X-Y-R 4 , -Z-X-Y-X-Y-R 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;
  • 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;
  • 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_io alkyl, C 2- Io alkenyl, hydroxy-Ci-io alkylenyl, Ci.io alkoxy-Ci-ioalkylenyl, aryl-Ci-to alkylenyl, and heteroary 1-C i . i o alky leny 1;
  • R 9 is selected from the group consisting of hydrogen and alkyl;
  • A is selected from the group consisting Of-CH 2 -, -O-, -C(O)-, -S(0)o-2-, and -NC-Q-R 4 )-;
  • A' is selected from the group consisting of -O-, -S(0)o- 2 -, -NC-Q-R 4 )-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R O )-C(RO)-,
  • V is selected from the group consisting Of-C(R 6 )-, -0-C(R O )-, -N(RS)-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 1 is selected from the group consisting Of-CH 2 -, -NH-, and
  • R 3 is at the 7- or 8-position.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula II:
  • X' is selected from the group consisting of -CH 2 -, -CH(CH 3 )-, -NH-, and -O-;
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran- 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo-
  • R 2 is selected from the group consisting Of -NH 2 , -CH 3 , -CH 2 -Ci ⁇ alky 1, -CH 2 -C 2 alkylenyl-O-Ci. 2 alkyl, -CH 2 -O-C L3 alkyl, -CH 2 -OH, -CH 2 -Ci -3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen,
  • R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, and
  • R 3 is selected from the group consisting of: -Z-R 4 , -Z-X-R 4 , -Z-X-Y-R 4 , -Z-X-Y-X-Y-R 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;
  • Y is selected from the group consisting of:
  • Z is a bond or -O-
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen;
  • R.5 is selected from the group consisting of:
  • R 7 is C 2-7 alkylene
  • R 8 is selected from the group consisting of hydrogen, Ci. io alkyl, C2-joalkenyl, hydroxy-Ci-ioalkylenyl, Ci-io alkoxy-Ci.ioalkylenyl, aryl-Cuioalkylenyl, and heteroaryl-C i_ ⁇ o alkyleny I;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • Rio is C3.8 alkylene; A is selected from the group consisting Of-CH 2 -, -O-, -C(O)-, -S(0)o- 2 -, and
  • A' is selected from the group consisting of -O-, -S(0)o-2-, -NC-Q-R 4 )-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(R O )-C(R 6 )-, -S(O) 2 -, -C(Re)-N(Rs)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Rs)-S-, and -C(R 6 )-N(OR 9 )-;
  • V is selected from the group consisting Of-C(R 6 )-, -0-C(R 6 )-, -N(Rs)-C(R 6 )-, and
  • 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 1 is selected from the group consisting Of-CH 2 -, -NH-, and
  • R 3 is at the 7- or 8-position.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula III:
  • X 1 is selected from the group consisting Of-CH 2 -, -CH(CHa)-, -NH-, and -O-;
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran-
  • R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C 1-4 alkyl, -CH 2 -CL 2 alkylenyl-O-Ci -2 alkyl, -CH 2 -O-CL 3 alkyl, -CH 2 -OH, -CH 2 -C L3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, C i-4 alkyl, Ci -4 alkoxy, hydroxy, 1IaIoCi -4 alkyl, and hydroxyCi- 4 alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, and n is 0, 1 , or 2; and
  • R 9 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.
  • X 1 is selected from the group consisting Of -CH 2 -, -NH-, and
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula IV:
  • X' is selected from the group consisting Of -CH 2 -, -CH(CH 3 )-, -NH-, and -O-;
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2//-pyran- 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2//-thiopyran-4-yl, and 1,1-dioxidotetrahydo- 2//-thiopyran-4-yl;
  • R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -Ci -4 alkyl, -CH 2 -C 1-2 alkylenyl-O-Ci.2 alkyl, -CH 2 -O-C 3 alkyl, -CH 2 -OH, -CH 2 -C 1-3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CM alkyl, C M alkoxy, hydroxy, haloCi-4 alkyl, and hydroxyCi_4 alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, and
  • R. 3 is selected from the group consisting of:
  • 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;
  • 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;
  • R.5 is selected from the group consisting of:
  • R 7 is C2- 7 alkylene
  • Rs is selected from the group consisting of hydrogen, C 1-1 O alkyl, C 2-1 O alkenyl, hydroxy-Ci-ioalkylenyl, Ci- t oalkoxy-Ci-ioalkylenyl, aryl-Q.ioalkylenyl, and heteroaryl-C i .i o alky leny 1;
  • R 9 is selected from the group consisting of hydrogen and alkyl
  • A is selected from the group consisting Of-CH 2 -, -O-, -C(O)-, -S(0)o- 2 -, and -NC-Q-R 4 )-;
  • A' is selected from the group consisting of -O-, -S(0)o -2 -, -N(-Q-R4)-, and -CH 2 -;
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Re)-C(R ⁇ )-, -S(O) 2 -, -C(R ⁇ )-N(Rg)-W-, -S(O) 2 -N(R 8 )-, -C(Re)-O-, -C(Re)-S-, and -C(Re)-N(OR 9 )-;
  • V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(Rs)-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 selected from the group consisting Of-CH 2 -, -NH-, and -O-; and R 3 is at the 7- or 8- ⁇ osition.
  • the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier in combination with a therapeutically effective amount of a compound of Formula V: wherein:
  • X' is selected from the group consisting Of-CH 2 -, -CH(CHa)-, -NH-, and -O- ;
  • R 1 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2 ⁇ -pyran- 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo- 2H-thiopyran-4-y 1 ;
  • R 2 is selected from the group consisting Of -NH 2 , -CH 3 , -CH 2 -C] -4 alky 1, -CH 2 -Ci -2 alkylenyl-O-C,.2 alkyl, -CH 2 -O-C -3 alkyl, -CH 2 -OH, -CH 2 -C -3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, Ci-4 alkyl, C 1-4 alkoxy, hydroxy, haloC ⁇ alkyl, and hydroxyC-4 alkyl;
  • R A - is alkyl
  • R B 1 is hydrogen or alkyl
  • X' is selected from the group consisting Of-CH 2 -, -NH-, and -O-.
  • the present invention provides a compound of Formula Ha:
  • X" is selected from the group consisting Of-CH 2 -, -CH(CHa)-, and -O-;
  • Ri a is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo- 2H-pyran-3-yl, tetrahydo-2//-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1- dioxidotetrahydo-2H-thiopyran-4-yl; and
  • R 2 is selected from the group consisting of -C ⁇ 3 , -CH 2 -C -4 alkyl, -CH 2 -CL 2 alkylenyI-O-Cj. 2 alkyl, -CH 2 -O-C 1-3 alkyl, -CH 2 -OH, -CH 2 -C 1-3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CM alkyl, C 1-4 alkoxy, hydroxy, haloCi-4 alkyl, and hydroxyd.4 alkyl; or a pharmaceutically acceptable salt thereof.
  • X" is -CH 2 -.
  • the present invention provides a compound of Formula III:
  • X' is selected from the group consisting Of -CH 2 -, -CH(CHs)-, -NH-, and -O-;
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2//-pyran-2-yl, tetrahydo-2//-pyran- 3-yl, tetrahydo-2if-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo- 2H-thiopyran-4-yl;
  • R 2 is selected from the group consisting Of-NH 2 , -CH 3 , -CH 2 -Ci -4 alkyl, -CH 2 -Ci -2 alkylenyl-O-C 1-2 alkyl, -CH 2 -O-C 1-3 alkyl, -CH 2 -OH, -CH 2 -C 1-3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, Ci- 4 alkyl, Ci -4 alkoxy, hydroxy, haloCi- 4 alkyl, and hydroxyd ⁇ alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, and -N(R 9 ) 2 ; n is O, 1, or 2; and R 9 is selected from the group consisting of hydrogen
  • the present invention provides a compound of Formula IVa:
  • X 1 " is selected from the group consisting Of-CH 2 - and -CH(CH 3 )-; Ri a is selected from the group consisting of tetrahydo-2//-pyran-2-yl, tetrahydo-
  • R 2 is selected from the group consisting Of-NH 2 , -CH 3 , -CH 2 -CM alkyl, -CH 2 -C 2 alkylenyl-O-C,- 2 alkyl, -CH 2 -O-C 1-3 alkyl, -CH 2 -OH, -CH 2 -C 1-3 alkylenyl-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, Ci-4 alkyl, Ci -4 alkoxy, hydroxy, haloCi-4 alkyl, and hydroxyCi-4 alkyl; R is selected from the group consisting of: halogen, hydroxy, alkyl, haloalkyl, alkoxy, and -N(Rg) 2 ; n is O or l;
  • R 3a is selected from the group consisting of: -Z-R 4 , and -Z-X-R 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; Z is a bond or -O-;
  • R 4 is selected from the group consisting of hydrogen, alkyl, alkenyU 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 9 is selected from the group consisting of hydrogen and alkyl; or a pharmaceutically acceptable salt thereof.
  • X"' is -CH2-; and R 3 is at the 7- or 8-position.
  • the present invention provides a compound of Formula Va:
  • X" is selected from the group consisting Of-CH 2 -, -CH(CHs)-, and -O-;
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran- 3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo- 2#-thiopyran-4-yl;
  • R 2 is selected from the group consisting Of-NH 2 , -CH 3 , -CHa-C 1-4 alkyl, -CH 2 -CL 2 alkylenyI-O-Ci.2 alkyl,
  • RA 1 is alkyl, and RB 1 is hydrogen or alkyl; or a pharmaceutically acceptable salt thereof.
  • X" is -CH 2 -.
  • R A is alkyl
  • R B is hydrogen or alkyl
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, RA and RB taken 48017
  • fused benzene or pyridine ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; wherein the fused pyridine ring is
  • R A and R B taken together form the fused benzene ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group.
  • the fused benzene ring is unsubstituted.
  • R A and R B taken together form the fused pyridine ring which is unsubstituted or substituted by one or two R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group.
  • the fused pyridine ring is unsubstituted.
  • R A and RB taken together form a fused cyclohexene or tetrahydropyridine ring which is unsubstituted or substituted at a carbon atom by one or more R groups; wherein the fused tetrahydropyridine ring is
  • RA and R B taken together form a fused cyclohexene ring which is unsubstituted or substituted by one or more R groups.
  • the fused cyclohexene ring is unsubstituted.
  • R A and R B taken together form the fused tetrahydropyridine ring which is unsubstituted or substituted at a carbon atom by one or more R groups.
  • the fused tetrahydropyridine ring is unsubstituted.
  • R A is alkyl
  • R B is hydrogen or alkyl.
  • R A and RB are both methyl.
  • RA 1 is alkyl
  • R B is hydrogen or alkyl.
  • RA- and RB- are both methyl.
  • R 3 is selected from the group consisting Of -Z-R 4 , -Z-X-R 4 , -Z-X-Y-R 4 , -Z-X-Y-X-Y-R 4 , -Z-X-R 5 , and -NH-Q-R 4 .
  • R 3 is -Z-R 4 .
  • R 4 is selected from the group consisting of aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl wherein the aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino, and dialkylamino; and Z is a bond.
  • R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, (aminomethyl)phenyl, pyridin-3-yl, and pyridin-4-yl.
  • R 4 is a heterocyclyl group which contains one or more nitrogen atoms and optionally a ring oxygen or ring sulfur atom, wherein the point of attachment of the heterocyclyl group is one of the nitrogen atoms, and wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, aryl, and arylalkylenyl; and Z is a bond.
  • the heterocyclyl group is monocyclic and contains 4 to 6 ring atoms.
  • the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, and arylalkylenyl.
  • the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo and alkyl.
  • the heterocyclyl group is selected from the group consisting of:
  • R' is alkyl
  • the heterocyclyl group is selected from the group consisting of:
  • heterocyclyl group is selected from the group consisting of:
  • R 3 is -Z-X-Y-R 4 , except where R 3 is -Z-R 4 .
  • R 4 is selected from the group consisting of hydrogen, alkyl, and heterocyclyl;
  • Y is selected from the group consisting Of -S(O) 2 -,
  • R 3 is (methylsulfonylamino)phenyl (e.g., R 4 is methyl and Y is -NH-S(O) 2 -).
  • R4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroaryl, each of which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, and alkyl; Y is selected from the group consisting
  • R 3 is -Z-X- Y-R 4
  • R 4 is hydrogen or alkyl
  • Y is -C(O)-N(R 8 )- or -C(O)-O-
  • R 8 is Q -4 alkyl
  • X is alkylene or alkenylene
  • Z is a bond.
  • R 4 is Ci -4 alkyl; Y is -C(O)-N(R 8 )-; and X is alkylene.
  • R 3 is -Z-X-Y-R 4
  • R 4 is alkyl substituted by maleimidyl; Y is -NHC(O)-; X is alkylene interrupted by one -O- group; and Z is -O-.
  • R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, 4-
  • R 3 is selected from the group consisting of hydroxyphenyl, (hydroxymethyl)phenyl, and (methy lsulfonylamino)pheny 1.
  • R 3 is -Z-X-Y-X-Y-R 4 except where R 3 is -Z-R4 or -Z-X- Y-R4.
  • R 3 is -Z-Xf ⁇ Y a -Xg-Yb-R4 wherein R 4 is hydrogen or Cj -4 alkyl, Y b is -C(O)-O-, X g is alkylene, Y a is -NHC(O)-, Xf is alkylene interrupted by one -O- group, and Z is -O-.
  • R 3 is -NH-Q-R 4 except where R 3 is -Z-R 4 , -Z-X-Y-R 4 , or -Z-X-Y-X-Y-R 4 .
  • Q is -C(O)-
  • R 4 is alkyl, aryl, arylalkylenyl or heteroaryl, each of which is unsubstituted or substituted by one or more substiruents independently selected from halogen, hydroxy, and alkyl.
  • R 8 is hydrogen or Ci -4 alkyl.
  • Q is -C(O)-
  • R 4 is alkyl or aryl.
  • Q is -S(O) 2 -, and R 4 is alkyl or aryl.
  • Q is -C(O)- and R 4 is heterocyclyl which is unsubstituted or substituted by one or more substituents independently selected form the group consisting of alkyl and oxo; and wherein heterocyclyl is a heterocyclyl group which contains one or more nitrogen atoms, wherein the point of attachment of the heterocyclyl group is one of the nitrogen atoms.
  • the heterocyclyl group is monocyclic and contains 5 or 6 ring atoms.
  • R 4 is piperidin-1-yl.
  • R 3 (or R 33 ) is at the 7- or 8- position.
  • R 3 (or R 33 ) is at the 7-position.
  • R 3 (or R 33 ) is at the 8-position. The locations of the 7- and 8-positions are shown in the following formulas:
  • n 0.
  • R is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, and -N(Rs) 2 .
  • R is hydroxy or -N(Rg) 2 .
  • R is -N(Rg) 2 .
  • R9 is hydrogen.
  • R 9 is alkyl.
  • m is 0 and n is 1.
  • R is at the 7-position.
  • R is at the 8-position.
  • m is 0.
  • n are both 0.
  • R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -C M alkyl,
  • -CH 2 -Ci -2 alkylenyl-O-C L a alkyl, -CH 2 -O-C 1-3 alkyl, -CH 2 -OH, -CH 2 -C L3 alky leny 1-OH, and benzyl wherein the phenyl ring of the benzyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, CM alkyl, Q -4 alkoxy, hydroxy, haloCi_4 alky I, and hydroxyCi-4 alkyl.
  • R 2 is selected from the group consisting of -CH 3 , -CH 2 -CM alkyl, -CH 2 -O-C 1-3 alkyl, -CH 2 -C 1-2 alkylenyl-O-Ci. 2 alkyl, -CH 2 -OH, and -CH 2 -C 1-3 alkylenyl-OH.
  • R 2 is selected from the group consisting of methyl, ethyl, ⁇ -propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.
  • R 2 is selected from the group consisting of methyl, ethyl, n-propyl, rc-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.
  • R 2 is selected from the group consisting of ⁇ -propyl, rc-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.
  • Ri is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2//-pyran-2-yl, tetrahydo-2H-pyran- 3-yl, tetrahydo-2/f-pyran-4-yl, tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo- 2H-thiopyran-4-yl.
  • Ri is tetrahydo-2H-pyran-4-yl.
  • X' is selected from the group consisting of -CH 2 -, -NH-, and -O-.
  • X 1 is -CH 2 -.
  • X ? is -NH-.
  • X' is -O-.
  • R A - is alkyl
  • R B 1 is hydrogen or alkyl.
  • R A 1 and R ⁇ > are both methyl.
  • X" is selected from the group consisting Of-CH 2 -, -CH(CH 3 )-, and -O- except where X" is -CH 2 -.
  • X" is -CH 2 -.
  • X'" is -CH 2 -.
  • m is 1, and R 39 is selected from the group consisting Of-Z-R 4 and -Z-X-R 4 .
  • R 3a is selected from the group consisting of hydroxyphenyl and (hydroxymethyl)phenyl.
  • R is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, and -N(R 9 ) 2 .
  • R is hydroxy.
  • n is 1.
  • n is 0 except where n is 1.
  • n is 1.
  • n and n are both 0 except where m or n is 1.
  • Ri a is selected from the group consisting of tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran-3-yl, tetrahydo-2H-pyran-4-yl, tetrahydo-2H r -thiopyran-4-yl, and 1,1- dioxidotetrahydo-2//-thiopyran-4-yl.
  • Ri 3 is tetrahydo- 2H-pyran-4-yl.
  • R 1 is selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydo-2H-pyran-2-yl, tetrahydo-2H-pyran- 3-yl, tetrahydo-2//-pyran-4-yl 3 tetrahydo-2H-thiopyran-4-yl, and 1,1-dioxidotetrahydo- 2H-thiopyran-4-yl.
  • R 1 is tetrahydo-2H-pyran-4-yl.
  • R 2 is selected from the group consisting of -NH 2 , -CH 3 , -CH 2 -Ci -4 alkyl, -CH 2 -C,. 2 alkylenyl-O-Ci.
  • R 2 is selected from the group consisting of methyl, ethyl, «-propyl, rc-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl.
  • R 2 is selected from the group consisting of ⁇ -propyl, n-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.
  • 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, aryloxyalkylenyU alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy;
  • R 4 is selected from the group consisting of alkyl, aryl, heteroaryl, and arylalkylenyl wherein the aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino, and dialkylamino.
  • R4 is selected from the group consisting of aryl and heteroaryl each of which is unsubstituted or substituted by hydroxy, hydroxyalkyl, or aminoalkyl.
  • R 4 is selected from the group consisting of hydroxyphenyl, (hydroxyrnethyl)phenyl, (aminomethyl)phenyl, pyridin-3-yl, and pyridin- 4-yl.
  • R 4 is alkyl, aryl, arylalkylenyl or heteroaryl, each of which is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxy, and alkyl.
  • R4 is alkyl or aryl.
  • R4 is selected from the group consisting of hydrogen, alkyl, and heterocyclyl.
  • R 4 is hydrogen.
  • R 4 is alkyl.
  • R4 is a heterocyclyl group which contains one or more ring nitrogen atoms and optionally a ring oxygen or ring sulfur atom, wherein the point of attachment of the heterocyclyl group is one of the nitrogen atoms, and wherein the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, aryl, and arylalkylenyl.
  • the heterocyclyl group is monocyclic and contains 4 to 6 ring atoms.
  • the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo, alkyl, and arylalkylenyl.
  • the heterocyclyl group is unsubstituted or substituted by one or more substituents independently selected from the group consisting of oxo and alkyl.
  • R 4 is a heterocyclyl group selected from the group consisting of:
  • R' is alkyl
  • R4 is a heterocyclyl group selected from the group consisting of:
  • R' is alkyl
  • R 4 is a heterocyclyl group selected from the group consisting of:
  • R4 is
  • R 4 is piperidin-1-yl.
  • Rs is selected from the group consisting of:
  • R 5 is
  • R 7 is C 2-7 alkylene.
  • R 7 is C 2 - 4 alkylene.
  • R 8 is selected from the group consisting of hydrogen, Ci-io alkyU C 2- Io alkenyl, hydroxy-Ci.io alkylenyl, Ci_io alkoxy-Ci-io alkylenyl, aryl-Ci.ioalkylenyl, and heteroaryl-Ci-io alkylenyl.
  • R 8 is hydrogen, Ci-ioalkyl, or hydroxy-Cj-io alkylenyl.
  • Rg is Ci -4 alkyl.
  • R 8 is hydrogen.
  • R 9 is selected from the group consisting of hydrogen and alkyl.
  • R 9 is hydrogen
  • R 9 is alkyl
  • R 1O is C 3 - 8 alkylene.
  • R ⁇ is pentylene.
  • R 1 is hydrogen, alkyl, or aryl.
  • R 1 is alkyl
  • R' is hydrogen
  • A is selected from the group consisting of -CH2-, -O-, -C(O)-, -S(0)o- 2 -, and -NC-Q-R 4 )-.
  • A is selected from the group consisting Of -CH 2 -, -O-, and-N(alkyl)-.
  • A is -O-.
  • A' is selected from the group consisting of -O-, -S(0)o -2 -, -NC-Q-R 4 )-, and -CH 2 -.
  • Q is selected from the group consisting of a bond, -C(R 6 )-, -C(Re)-C(R 6 )-, -S(O) 2 -, -C(R ⁇ )-N(Rs)-W-, -S(O) 2 -N(R 8 )-, -C(Rn)-O-, -C(R 6 )S-, and -C(Rs)-N(OR 9 )-.
  • Q is selected from the group consisting of -C(O)-, -S(O) 2 -, -C(Re)-N(R 8 )-, -S(O) 2 -N(R 8 )-, -C(O)-O-, and -C(O)-S-.
  • Q is -C(O)-, -S(O) 2 -, -C(R ⁇ )-N(R 8 )-, or -S(O) 2 -N(R 8 )-.
  • Q is -C(R 6 )-.
  • Q is a bond
  • V is selected from the group consisting of -C(R 6 )-, -0-C(R 6 )-, -N(Rs)-C(R 6 )-, and -S(O) 2 -.
  • 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 a bond.
  • X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more -O- groups.
  • X is phenylene
  • X is
  • X is CM alkylene.
  • X is methylene.
  • Y is -NCRs)-Q-.
  • Y is selected from the group consisting of - N(R 8 )-CCO)-, -NCRs)-S(O) 2 -, -N(Rs)-CCRe)-NCR 8 )-, -NCRs)-S(O) 2 -NCR 8 )-, -NCRs)-CCRa)-O-, and
  • Y is selected from the group consisting Of -S(O) 2 -, - CCO)-, -CCO)-NH-, and -NH-SCO) 2 -.
  • Y is selected from the group consisting Of -SCO) 2 -, -CCO)-, and -NCRg)-C(O)-.
  • Z is a bond or -0-.
  • 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 independently 1 , 2, or 3.
  • a and b are each 2.
  • n is O or l.
  • n is O or 1.
  • n is O.
  • n is O.
  • n is O, 1, or 2.
  • n is 1.
  • n is O.
  • m is O, and n is O.
  • a pharmaceutical composition comprising a compound of Formula I, II, III, IV, IVa, V, or Va, or a pharmaceutically acceptable salt thereof, or of a compound or salt of Formula III, IVa, or Va, or of any one of the above embodiments which includes an -NH 2 group in a Formula, for example when R 2 is -NH 2 , the -NH 2 group can be replaced by an -NH-G 1 group, to form prodrugs.
  • G 1 is selected from the group consisting of -C(O)-R", ⁇ -aminoacyl, ⁇ -aminoacyl- ⁇ -aminoacyl, and -C(O)-O-R".
  • R" and R 1 " are independently selected from the group consisting of Ci-io alkyl, C 3-7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, Ci- ⁇ alkyl, Ci- 4 alkoxy, aryl, heteroaryl, arylCi-4 alkylenyl, heteroarylCi- 4 alkylenyl, haloCi.
  • ⁇ -aminoacyl is an acyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids.
  • Y 2 is selected from the group consisting of hydrogen, Ci. 6 alkyl, and benzyl.
  • Y 0 is selected from the group consisting of Cj -6 alkyl, carboxyCi- 6 alkylenyl, aminoCi - 4 alkylenyl, mono- N-Ci- 6 alkylaminod- 4 alkylenyl, and di-iV, JV-C 1-6 alkylaminoCi -4 alkylenyl.
  • Yi is selected from the group consi sting of mono-N-C 1 .6 alky lamino , di-N, N-Ci -6 alky lamino, morpholin-4-yi, piperidin-1-yl, pyrrolidin-1-yl, and 4-Ci -4 alky lpiperazin-1-yl.
  • Gi is selected from the group consisting of -C(O)-R 1 , ⁇ -aminoacyl, and -C(O)-O-R'.
  • G 1 is selected from the group consisting of -C(O)-R', ⁇ -amino-C 2- i 1 acyl, and -C(O)-O-R'.
  • ⁇ -Amino-C 2- ⁇ acyl includes ⁇ -amino acids containing a total of at least 2 carbon atoms and a total of up to 11 carbon atoms, and may also include one or more heteroatoms selected from the group consisting of O, S, and N.
  • a pharmaceutical composition comprising a compound of Formula I, II, Ha, III, IV, IVa, V, or Va, or a pharmaceutically acceptable 2006/048017
  • G 2 is selected from the group consisting Of -X 2 -C(O)-R", ⁇ -arninoacyl, ⁇ - aminoacyl- ⁇ -aminoacyl, -X 2 -C(O)-O-R", -C(O)-N(R'")R", and -S(O) 2 -R".
  • X 2 is selected from the group consisting of a bond; -CH 2 -O-; -CH(CH 3 )-O-; -C(CHa) 2 -O-; and, in the case Of-X 2 -C(O)-O-R", -CH 2 -NH-.
  • R" and R"' are independently selected from the group consisting of Ci -10 alkyl, C 3 - 7 cycloalkyl, phenyl, and benzyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxy, Ci-e alkyl, C M alkoxy, aryl, heteroaryl, aryl-Ci- 4 alkylenyl, heteroaryl-Ci .
  • ⁇ -aminoacyl is an ⁇ - aminoacyl group derived from an amino acid selected from the group consisting of racemic, D-, and L-amino acids.
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from a naturally occuring amino acid selected from the group consisting of racemic, D-, and L- amino acids.
  • ⁇ -aminoacyl is an ⁇ -aminoacyl group derived from an amino acid found in proteins, wherein the the amino acid is selected from the group consisting of racemic, D-, and L-amino acids.
  • G 2 is selected from the group consisting of ⁇ -amino-C 2- 5 alkanoyl, C 2-6 alkanoyl, Ci. 6 alkoxycarbonyl, and Ci- ⁇ alkylcarbamoyl.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of the above embodiments of Formulas Ha, IVa, or Va in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of any one of the above embodiments of a pharmaceutical composition or a compound or salt of any one of the above embodiments of Formulas I, II, Ha, III, IV, IVa, V, or Va to the animal.
  • the cytokine is selected from the group consisting of IFN- ⁇ , TNF- ⁇ , IL-6, IL-IO, and IL- 12.
  • the cytokine is IFN- ⁇ or TNF- ⁇ .
  • the cytokine is IFN- ⁇ .
  • the present invention provides a method of treating a viral disease in an animal in need thereof comprising administering a therapeutically effective amount of any one of the above embodiments of a pharmaceutical composition or a compound or salt of any one of the above embodiments of Formulas I, II, Ha, III, IV, IVa, V, or Va to the animal.
  • the present invention provides method of treating a neoplastic disease in an animal in need thereof comprising administering a therapeutically effective amount of any one of the above embodiments of a pharmaceutical composition or a compound or salt of any one of any one of the above embodiments of Formulas I, II, Ha, III, IV, IVa, V, or Va to the animal.
  • alkyl As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, e.g., cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groups containing from 2 to 20 carbon atoms. In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.
  • alkylene "-alkylene-”, “alkenylene”, “-alkenylene-”, “alkynylene”, and “-alkynylene-” are the divalent forms of the "alkyl”,
  • alkenyl and “alkynyl” groups defined above.
  • alkylenyl alkenylenyl
  • alkynylenyl alkynylenyl
  • an arylalkylenyl group comprises an "alkylene" moiety to which an aryl group is attached.
  • haloalkyl is inclusive of alkyl groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • aryl as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • heteroatom refers to the atoms O, S, or N.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N).
  • heteroaryl includes a ring or ring system that contains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and/or N as the heteroatoms.
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
  • heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • heterocyclyl includes a ring or ring system that contains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and N as the heteroatoms.
  • heterocyclyl groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl (azepanyl), 1 ,4- oxazepanyl, homopiperazinyl (diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl, dihydroisoquinolin-(lH)-yl, octahydroisoquinolin-(l H)-y ⁇ , dihydroquinolin- ⁇ i ⁇ -yl, octahydroquinolin-(2H)-yl, dihydro-ll
  • heterocyclyl includes bicylic and tricyclic heterocyclic ring systems. Such ring systems include fused and/or bridged rings and spiro rings. Fused rings can include, in addition to a saturated or partially saturated ring, an aromatic ring, for example, a benzene ring. Spiro rings include two rings joined by one spiro atom and three rings joined by two spiro atoms.
  • heterocyclyl contains a nitrogen atom
  • the point of attachment of the heterocyclyl group may be the nitrogen atom
  • arylene is the divalent forms of the "aryl”, “heteroaryl”, and “heterocyclyl” groups defined above.
  • arylenyl is used when “arylene”, “heteroarylene,” and “heterocyclylene”, respectively, are substituted.
  • an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached.
  • each group is independently selected, whether explicitly stated or not.
  • each R 9 group is independently selected.
  • each Y group is independently selected.
  • each Y group is independently selected.
  • -N(Re)-Q-R 4 group is present (e.g., more than one -Y-R 4 group is present, and both contain a -N(Rs)-Q- group) each Rg group is independently selected, each Q group is independently selected, and each R 4 group is independently selected.
  • the invention is inclusive of the compounds described herein (including intermediates) in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymorphs, prodrugs, and the like.
  • isomers e.g., diastereomers and enantiomers
  • salts e.g., sodium bicarbonate
  • solvates e.g., sodium bicarbonate
  • polymorphs e.g., sodium bicarbonate
  • prodrugs e.g., sodium bicarbonate
  • the term “compound” includes any or all of such forms, whether explicitly stated or not (although at times, “salts" are explicitly stated).
  • prodrug means a compound that can be transformed in vivo to yield an immune response modifying compound in any of the salt, solvated, polymorphic, or isomeric forms described above.
  • the prodrug itself, may be an immune response modifying compound in any of the salt, solvated, polymorphic, or isomeric forms described above.
  • the transformation may occur by vaious mechanisms, such as through a chemical (e.g., solvolysis or hydrolysis, for example, in the blood) or enzymatic biotransformation.
  • a discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • tautomer or tautomeric form
  • proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.
  • compounds or compounds in compositions of the present invention have an amino group for the R 2 group, proton migration between the nitrogen atom of the amino group and the nitrogen atom at the 3-position may occur.
  • Formulas I a and I b are tautomeric forms of each other:
  • Compounds of the invention may be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wisconsin, USA) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R. Katritsky, Otto Meth- Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. 1 - 6, Pergamon Press, Oxford, England, (1995); Barry M.
  • Suitable amino protecting groups include acetyl, trifluoroacetyl, rer ⁇ -butoxycarbonyl (Boc), benzyloxycarbonyl, and 9- fluorenylmethoxycarbonyl (Fmoc).
  • Suitable hydroxy protecting groups include acetyl and silyl groups such as the t erf-butyl dimethylsilyl group.
  • compounds can be prepared according to Reaction Scheme I wherein R, Rj, R 2 , X'", and n are as defined above and E is carbon (imidazoquinolines) or nitrogen (imidazonaphthyridines).
  • step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline or 4-chloro-3- nitro[l ,5]naphthyridine of Formula XX is reacted with an amine of Formula Ri-X"'-NH2 to provide a compound of Formula XXI.
  • the reaction can be carried out by adding the amine to a solution of a compound of Formula XX in a suitable solvent such as anhydrous tetrahydrofuran in the presence of a base such as triethylamine.
  • the reaction can be run at ambient temperature, at a sub-ambient temperature such as, for example 0 0 C, or at an elevated temperature such as, for example, 45 0 C.
  • step (2) of Reaction Scheme I a compound of Formula XXI is reduced to provide a compound of Formula XXII.
  • the reduction can be carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon.
  • the reaction can be conveniently carried out on a Parr apparatus in a suitable solvent such as acetonitrile, toluene, ethanol, methanol, and/or isopropanol.
  • step (2) an aqueous solution of sodium dithionite can be added to a solution or suspension of the compound of Formula XXI in a suitable solvent such as ethanol or isopropanol.
  • a suitable solvent such as ethanol or isopropanol.
  • the reaction can be carried out at an elevated temperature, for example, at reflux, or at ambient temperature.
  • a compound of Formula XXII is (i) reacted with an acyl halide of Formula R 2 C(O)Cl or R 2 C(O)Br and then (ii) cyclized to provide a IH- imidazo[4,5-c]quinoline or lH-imidazo[4,5-c][l,5]naphthyridine of Formula XXIII.
  • the acyl halide is added to a solution of a compound of Formula XXII in a suitable solvent such as acetonitrile or anhydrous dichloromethane optionally in the presence of a base such as triethylamine.
  • step (3) can be carried out by reacting a compound of Formula XXII with a carboxylic acid or an equivalent thereof. Suitable equivalents to carboxylic acid include orthoesters and 1,1-dialkoxyalkyl alkanoates.
  • the carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XXIIL
  • triethyl orthovalerate will provide a compound where R 2 is butyl.
  • the reaction can be run in the absence of solvent or in an inert solvent such as anhydrous toluene.
  • the reaction is run at an elevated temperature.
  • a catalyst such as pyridine hydrochloride can be utilized.
  • the reaction can be carried out by reacting a compound of Formula XXII with cyanogen bromide in a suitable solvent such as ethanol.
  • a suitable solvent such as ethanol.
  • the reaction can be run at an elevated temperature, for example, at reflux.
  • compounds can be prepared according to Reaction Scheme II wherein R, R], R 2 , E, X 1 ", and m are as defined above and R 3( j is as defined below.
  • R, R], R 2 , E, X 1 ", and m are as defined above and R 3( j is as defined below.
  • Compounds of Formula XXIV can undergo known palladium-catalyzed coupling reactions such as the Suzuki coupling and the ⁇ eck reaction.
  • a compound of Formula XXIV undergoes Suzuki coupling with a boronic acid of Formula R 3 J-B(OH) 2 , an anhydride thereof, or a boronic acid ester of Formula R 3 d-B(O-alkyl) 2 ; wherein R 3c j is -R4t>, -X a -R 4 , -X b -Y-R 4 , or -X b -R 5 ; where X a is alkenylene; Xb is arylene, heteroarylene, and alkenylene interrupted or terminated by arylene or heteroarylene; R4 b is aryl or heteroaryl where the aryl or heteroaryl groups can be unsubstituted or substituted as defined in R 4 above; and R4, R 5 , and Y are as defined above;
  • boronic acids of Formula R 3 ⁇ -B(OH) 2 anhydrides thereof, and boronic acid esters of Formula R 3 ⁇ 1 -B(O-alkyl) 2 are commercially available; others can be readily prepared using known synthetic methods.
  • the Heck reaction can also be used in Reaction Scheme II to provide compounds of Formula XXV, wherein R3d is -X a -R4 b and -Xa-Y-R 4 .
  • the Suzuki coupling and Heck reaction can be carried out according to any of the methods described in U. S. Patent Application Publication No. 2004/0147543 (Hays et al.).
  • a copper-mediated coupling reaction can be used to prepare compounds of Formula XXV, wherein R 3d is -NH-C(Re)-R 4 , -NH-SO 2 -R 4 .
  • the reaction can be carried out by combining a compound of Formula XXIV and an amide or sulfonamide of formula -NH-C(RO)-RJ or -NH-SO 2 -R 4 in the presence of copper (I) iodide, potassium phosphate, and racemic trans- 1,2-diaminocyclohexane in a suitable solvent such as 1,4-dioxane.
  • the reaction can be carried out at an elevated temperature such as 110 0 C.
  • certain of these compounds of Formula XXV wherein R 31J is -heterocyclyl, -heterocyclylene-R 4 , or -heterocyclylene- Y-R 4 , wherein the heterocyclyl or heterocyclylene is attached to the quinoline or naphthyridine ring through a nitrogen atom can be prepared using a palladium-mediated coupling, which is conveniently carried out by combining a compound of the Formula XXIV and the nitrogen-containing heterocyclyl compound in the presence of tris(dibenzylideneacetone)dipalladium, ( ⁇ )-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl, sodium ter ⁇ -butoxide, and a suitable solvent such as toluene.
  • the reaction can be carried out at an elevated temperature such as 80 0 C.
  • the synthetic methods described in International Publication No. WO 05/123080 can also be used. These reaction conditions can also be used to prepare compounds wherein R 3 a is -NH-R 4 .
  • compounds can be prepared according to Reaction Scheme III wherein R, Rj, R 2 , E, X" 1 , and m are as defined above, Bn is benzyl, and R 3e is as defined below.
  • step (1) of Reaction Scheme III a benzyloxyaniline or benzyloxyaminopyridine of Formula XXVI 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 XXVII.
  • the reaction can be carried out by adding a solution of a compound of Formula XXVI to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature such as 45 0 C.
  • a solution of a compound of Formula XXVI to a heated mixture of Meldrum's acid and triethyl orthoformate and heating the reaction at an elevated temperature such as 45 0 C.
  • Many anilines and aminopyridines of Formula XXVI are commercially available; others can be prepared by known synthetic methods.
  • benzyloxypyridines of Formula XXVI can be prepared using the method of Holladay et al., Biorg. Med. Chem. Lett, 8, pp. 2797-2802,
  • step (2) of Reaction Scheme III an imine of Formula XXVII undergoes thermolysis and cyclization to provide a compound of Formula XXVIII.
  • the reaction is conveniently carried out in a medium such as DOWTHERM A heat transfer fluid at a temperature in the range of 200 to 250 0 C.
  • step (3) of Reaction Scheme III a compound of Formula XXVIII is nitrated under conventional nitration conditions to provide a benzyloxy-3-nitroquinolin-4-ol or benzyloxy-3-nitro[l,5]naphthyridin-4-ol of Formula XXIX.
  • the reaction is conveniently carried out by adding nitric acid to the compound of Formula XXVIII in a suitable solvent such as propionic acid and heating the mixture at an elevated temperature such as 125 0 C.
  • a benzyloxy-3-nitroquinolin-4-ol or benzyloxy- 3-nitro[l,5]naphthyridin-4-ol of Formula XXIX is chlorinated using conventional chlorination chemistry to provide a benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4- chloro-3-nitro[l,5]naphthyridine of Formula XXX.
  • the reaction is conveniently carried out by treating the compound of Formula XXIX with phosphorous oxychloride in a suitable solvent such as DMF.
  • the reaction can be carried out at an elevated temperature such as 100 0 C.
  • Steps (5), (6), and (7) of Reaction Scheme HI can be carried out according to the methods of steps (1), (2), and (3), respectively, of Reaction Scheme I.
  • step (8) of Reaction Scheme III the benzyl group of a benzyloxy-lH- imidazo[4,5-c]quinoline or benzyloxy-lH-imidazo[4,5-c][l,5]naphthyridine of Formula XXXI is cleaved to provide a lH-imidazo[4,5-c]quinolinol or lH-imidazo[4,5- c][l,5]naphthyridinol of Formula XXXII.
  • the cleavage can be carried out on a Parr apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium on carbon in a solvent such as ethanol.
  • the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst.
  • the transfer hydrogenation can be carried out by adding ammonium formate to a solution of a compound of Formula XXXI 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 reflux temperature of the solvent.
  • step (9) of Reaction Scheme III a lH-imidazo[4,5-c]quinolinol or IH- imidazo[4,5-c][l,5]naphthyridinol of Formula XXXII is converted to an ether-substituted lH-imidazo[4,5-c]quinoline or lH-imidazo[4,5-cj[l,5]naphthyridine of Formula XXXIII using a Williamson-type ether synthesis.
  • the reaction is carried out by treating a compound of Formula XXXII with an aryl, alkyl, or arylalkylenyl halide of Formula halide-IL t b, halide-alkylene-R 4 , halide-alkylene-Y-OPU, or halide-alkylene-Rs in the presence of a base.
  • the reaction can be carried out by combining the halide with a compound of Formula XXXII in a solvent such as DMF in the presence of a suitable base such as cesium carbonate.
  • the reaction can be carried out at ambient temperature or at an elevated temperature, for example 65 0 C or 85 0 C.
  • 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 methods described in International Publication Nos. WO2005/020999 (Lindstrom et al.) and WO2005/032484 (Lindstrom et al.) can be used.
  • compounds can be prepared according to Reaction Scheme IV wherein R, Rj, R 2 , E, X'", and n are as defined above.
  • Reaction Scheme IV a l/f-Imidazo[4.5-c]quinoline or lH-imidazo[4,5-c][l,5]naphthyridine of Formula XXIII is reduced to provide a compound of Formula XXXIV.
  • the reaction can be carried out by suspending or dissolving a compound of Formula XXIII in trifluoroacetic acid, adding platinum (IV) oxide, and hydrogenating.
  • the reaction can be carried out on a Parr apparatus.
  • compounds can be prepared according to Reaction Scheme V wherein R 1 , R 2 , R A -, R B 1 , and X'" are as defined above.
  • steps (1) through (3) of Reaction Scheme V a 2,4-dichloro-3-nitropyridine of Formula XXXV is converted to a 4-chloro-lH-imidazo[4,5-c]pyridine of Formula XXXVI.
  • the steps can be carried out according to the general methods of steps (1) through (3) of Reaction Scheme I.
  • 2,4-Dichloro-3-nitropyridines of Formula XXXV are known or can be prepared using known synthetic methods, see for example, U.S. Patent
  • step (4) of Reaction Scheme V the chloro group is removed from a 4-chloro- lH-imidazo[4,5-c]pyridine of Formula XXXVI to provide a lH-imidazo[4,5-c]pyridine of Formula Vc.
  • the reaction can be carried out using ammonium formate and a heterogeneous catalyst such as palladium on carbon in a solvent mixture comprised of ethanol and methanol.
  • the reaction is carried out at an elevated temperature, such as for example, the reflux temperature of the solvent system.
  • compounds can be prepared according to Reaction Scheme VI wherein R, Ri, R 2 , E, and n are as defined above.
  • step (1) of Reaction Scheme VI a l//-Imidazo[4,5-c]quinolin-l -amine or IH- imidazo[4,5-c][l,5]naphthyridin-l -amine of Formula XXXVII is reacted with a ketone of the Formula under acidic conditions to provide a hydrazone of Formula XXXVIII.
  • the reaction can be carried out by adding the ketone to a solution of a compound of Formula XXXVII in a suitable solvent such as acetonitrile in the presence of an acid such as glacial acetic acid.
  • a suitable solvent such as acetonitrile
  • the reaction is run at an elevated temperature, such as for example, at 110 0 C.
  • Compounds of Formula XXXVII are known or can be prepared using known synthetic methods, see for example, U.S. Patent Application Publication No. 2005/0054640 (Griesgraber et al.) and International Publication No. WO 06/026760 (Stoermer et al.) and the references cited therein.
  • a hydrazone of Formula XXXVIII is reduced to provide a lH-imidazo[4,5-c]quinoline or lH-imidazo[4,5-c][l,5]naphthyridine of Formula XXXIX.
  • the reaction can be carried out by adding sodium borohydride to a solution of a compound of Formula XXXVIII in a suitable solvent such as methanol.
  • the reaction can be run at ambient temperature or at a sub-ambient temperature, such as for example, 0 °C.
  • a bromo substituted lH-imidazo[4,5- c]quinolin-l -amine or l/7-imidazo[4,5-c][l,5]naphthyridin-l-amine of Formula XL is converted to a l/f-imidazo[4,5-c]quinoline or lH-imidazo[4,5-c][l,5]naphthyridine of Formula XLI using the methods of steps (1) and (2) of Reaction Scheme VI.
  • Compounds of Formula XL are known or can be prepared using known synthetic methods, see for example U.S. Patent Application Publication No.
  • step (3) of Reaction Scheme VII a lH-imidazo[4,5-c]quinoline or IH- imidazo[4,5-c][l,5]naphthyridine of Formula XLI is converted to a lH-imidazo[4,5- c]quinoline or lH-imidazo[4,5-c][l,5]naphthyridine of Formula XLII using the methods described in Reaction Scheme II.
  • compounds can be prepared according to Reaction Scheme VIII wherein R, Rj, R 2 , R 3e , Bn, E, and m are as defined above.
  • a benzyloxy substituted IH- imidazo[4,5-c]quinolin-l -amine or lH-imidazo[4,5-c][l,5]naphthyridin-l-amine of Formula XLIII is converted to a lH-imidazo[4,5-c]quinoline or lH-imidazo[4,5- c][l,5]naphthyridine of Formula XLIV using the methods of steps (1) and (2) of Reaction Scheme VI.
  • Compounds of Formula XLIII are known or can be prepared using known synthetic methods, see for example, U.S. Patent Application Publication No. 2005/0054640 (Griesgraber et al.) and International Publication No. WO 06/026760 (Stoermer et al. ' ) and the references cited therein.
  • compounds can be prepared according to Reaction Scheme IX wherein R, Rj, R 2 , E, and n are as defined above.
  • Reaction Scheme IX lH-imidazo[4,5-e]quinoline or lH-imidazo[4,5-c][l,5]naphthyridine of Formula XXXIX is reduced to provide a l//-imidazo[4,5-e]quinoline or lH-imidazo[4,5- e][l ,5]naphthyridine of Formula XLVL
  • the reduction can be carried out as described in Reaction Scheme IV.
  • compounds can be prepared according to Reaction Scheme X wherein R 1 , R 2 , R A 1 , and R B 1 are as defined above.
  • a 4-chloro-lH-imidazo[4,5-c]pyridin-l- amine of Formula XLVII is converted to a 4-chloro-lH-imidazo[4,5-c]pyridin-l-amine of Formula XLVIII using the methods of steps (1) and (2) of Reaction Scheme VI.
  • Compounds of Formula XLVII are known or can be prepared using known synthetic methods, see for example, International Publication No. WO 06/026760 (Stoermer et al.) and the references cited therein.
  • step (3) of Reaction Scheme X the chloro group is removed from a 4-chloro- lH-imidazo[4,5-c]pyridin-l -amine of Formula XLVIII to provide a lH-imidazo[4,5- c]pyridin-l -amine of Formula Vd.
  • the reaction can be carried out as described in step (4) of Reaction Scheme V.
  • reaction Scheme XI an iV-(4-chloroquinolin-3-yl)amide or N-(4- chloro[l,5]napthyridin-3-yl)amide of Formula XLIX is reacted with a hydroxylamine hydrochloride of Formula R 1 ONH 2 ⁇ CI and cyclized to provide a l/f-imidazo[4,5- c]quinoline or l//-imidazo[4,5-c][l,5]naphthyridine of Formula L.
  • the reaction can be carried out by adding the hydroxylamine hydrochloride to a solution of a compound of Formula XLIX in an alcoholic solvent such as ethanol.
  • the reaction can be carried out at an elevated temperature, such as for example, the reflux temperature of the solvent.
  • an elevated temperature such as for example, the reflux temperature of the solvent.
  • XLIX are known or can be prepared using known synthetic methods, see for example, International Publication No. WO 06/028962 (Krepski et al.).
  • compounds can be prepared according to Reaction Scheme XII wherein R, Rj, R2, Bn, E, and n are as defined above.
  • step (1) of Reaction Scheme XII an -V- ⁇ -chloroquinolin-S-ytyarnide or N-(A- chloro[l,5]napthyridin-3-yl)amide of Formula LI is reacted with O-benzylhydroxylamine hydrochloride and cyclized to provide a l-benzylox-lH-imidazo[4,5-e]quinoline or 1- benzyloxy-l//-imidazo[4,5-c][l,5]naphthyridine of Formula LII.
  • the reaction can be carried out by adding the ⁇ 9-benzylhydroxylamine hydrochloride to a solution of a compound of Formula LI in an alcoholic solvent such as isopropanol.
  • the reaction can be carried out at an elevated temperature, such as for example, the reflux temperature of the solvent.
  • JV-(4-Chloroquinolin-3-yl)amides and iV-(4-chloro[l,5]napthyridin-3-yl)amides of Formula LI are known or can be prepared using known synthetic methods, see for example, International Publication No. WO 06/028962 (Krepski et al.).
  • step (2) of Reaction Scheme XII the benzyl group of a 1-benzyloxy-lH- imidazo[4,5-c]quinoline or l-benzyloxy-lH-imidazo[4,5-c][l,5]naphthyridine of Formula LII is cleaved to provide a lH-imidazo[4,5-c]quinolin-l-ol or l//-imidazo[4,5- c][l ,5] ⁇ aphthyridin-l -ol of Formula LIII.
  • the cleavage can be carried out on a Parr apparatus under hydrogenolysis conditions using a suitable heterogeneous catalyst such as palladium on carbon in a solvent such as ethanol.
  • the reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst.
  • the transfer hydrogenation can be carried out by adding ammonium formate to a solution of a compound of Formula LII 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 reflux temperature of the solvent.
  • step (3) of Reaction Scheme XII a lH-imidazo[4,5-c]quinolin-l-ol or IH- imidazo[4,5-c][l,5]naphthyridin-l-ol of Formula LIII is converted to an ether-substituted lH-imidazo[4 3 5-c]quinoline or l//-imidazo[4,5-c][l,5]naphthyridine of Formula LIV.
  • the reaction can carried out by treating a compound of Formula LIII with a halide of Formula halide-Rj in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • the reaction can be carried out by heating a mixture of the halide, a compound of Formula LIII, and the DBU in a sealed pressure vessel at an elevated temperature, for example 120 °C.
  • compounds can be prepared according to Reaction Scheme XIII wherein R 3 Ri, R 2 , Bn, and n are as defined above.
  • step (1) of Reaction Scheme XIII an N-(4-chloro-5,6,7,8-tetrahydroquinolin-3- yl)amide of Formula LV is reacted with 0-benzylhydroxylamine hydrochloride and cyclized to provide a l-benzyloxy-4-chloro-5,6,7,8-tetrahydro-lH-imidazo[4,5- c]quinoline of Formula LVI.
  • the reaction can be carried out as described in step (1) of Reaction Scheme XII.
  • N-(4-Chloro-5 3 6,7,8-tetrahydroqumolin-3-yl)amides of Formula LV are known or can be prepared using known synthetic methods, see for example, International Publication No. WO 06/028962 (Krepski et al.).
  • step (2) of Reaction Scheme XIII 3 both the benzyl group and the chloro group of a l-benzyloxy-4-chloro-5,6,7 3 8-tetrahydro-lH-imidazo[4,5-c]quinoline are cleaved to provide a lH-imidazo[4,5-c]quinolin-l-ol of Formula LVII.
  • the cleavage can be carried out as described in step (2) of Reaction Scheme XII.
  • step (3) of Reaction Scheme XIII a l//-imidazo[4,5-c]quinolin-l-ol of Formula LVII is converted to an ether-substituted lH-imidazo[4,5-c]quinoline of Formula UIb using the method described in step (3) of Reaction Scheme XII.
  • Reaction Scheme XIV wherein RA 1 , RB S RI, and R 2 are as defined above.
  • step (1) of Reaction Scheme XIV a 2,4-dichloro-3-nitropyridine of Formula XXXV is reduced to provide a 2,4-dichloropyridin-3 -amine of Formula LVIII.
  • the reduction can be carried out using the methods described in step (2) of Reaction Scheme I.
  • step (2) of Reaction Scheme XIV a 2,4-dichloropyridin-3-amine of Formula
  • LVIII is reacted with an acyl halide of Formula R 2 C(O)Cl or R 2 C(O)Br to provide an N- (2,4-dichloropyridin-3-yl)amide of Formula LIX.
  • the reaction can be carried out by adding the acyl halide to a solution of the 2,4-dichloropyridin-3-amine of Formula LVIII in a suitable solvent such anhydrous dichloromethane optionally in the presence of a base such as triethylamine.
  • the reaction can be run at a reduced temperature, for example, 0 0 C, or at ambient temperature.
  • compositions of the invention and compounds of the invention can also be prepared using variations in the synthetic routes shown in Reaction
  • compositions of the invention contain a therapeutically effective amount of a compound or salt described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount and “effective amount” mean an amount of the compound or salt sufficient to induce a therapeutic or prophylactic effect, such as cytokine induction, immunomodulation, antitumor activity, and/or antiviral activity.
  • cytokine induction cytokine induction
  • immunomodulation antitumor activity
  • antiviral activity cytokine induction
  • amount of compound or salt used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound or salt, the nature of the carrier, and the intended dosing regimen.
  • compositions of the invention will contain sufficient active ingredient or prodrug to provide a dose of about 100 nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram (mg/kg), preferably about 10 micrograms per kilogram ( ⁇ g/kg) to about 5 mg/kg, of the compound or salt to the subject.
  • the method includes administering sufficient compound to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • dosage forms such as tablets, lozenges, capsules, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
  • These dosage forms can be prepared with conventional pharmaceutically acceptable carriers and additives using conventional methods, which generally include the step of bringing the active ingredient into association with the carrier.
  • the compositions may be prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired dosage form.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas that has been compressed to form a liquid.
  • Suitable pharmaceutical carriers for use in the present pharmaceutical formulations are known.
  • the carrier may take a wide variety of forms, depending on the form of preparation desired for administration, for example, such as systemic administration (including but not limited to oral, parenteral, intravenous, or nasal) and topical administration.
  • any of the usual pharmaceutical carriers may be employed, such as, for example, water, glycols, oils, and alcohols in the case of oral liquid preparations (e.g., emulsions, suspensions, elixirs, solutions, syrups), and carriers such as, for example, starches, sugars (including lactose, sucrose, glucose, mannitol), silicic acid, methylcellulose, carboxymethylcellulose, alginates, pectin, dextrin, gelatin, polyvinylpyrrolidone, acacia, glycerol, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, low melting waxes, cocoa butter, cetyl alcohol, glycerol monostearate, kaolin and bentonite clay, talc, calcium stearate, magnesium carbonate, magnesium stearate, solid polyethylene glycols, sodium
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding thereto suitable colorants, flavors, stabilizing, sweetening, solubilizing and thickening agents.
  • Aqueous suspensions suitable for oral use can be made by dispersing the active component in finely divided form in water with viscous materials or thickening agents such as, for example, synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well known suspending agents.
  • the dosage form may also comprise buffering agents.
  • Oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • aqueous and nonaqueous carriers examples include water, aqueous solutions, such as saline (sotinic sodium chloride solution), Ringer's solution, dextrose solution, and Hanks' solution, ethanol, polyols (such as 1,3-butanediol, glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as, for example, olive oil, corn oil, cottonseed oil, sesame oil, and castor oil, synthetic mono- or di-glyceride oils, and organic esters such as ethyl oleate and isopropyl myristate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • Injectable depot forms may be made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Pharamaceutical compositions for topical application may include the above liquid forms, as well as ointments, creams, lotions, aerosols, sprays, dusts, and powders, which are prepared by combining an active component according with conventional pharmaceutically acceptable carriers commonly used in topical, dry, liquid, cream, and aerosol formulations.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • bases may include, for example, water and/or oil such as mineral oil, liquid petrolatum, white petrolatum, or a vegetable oil.
  • Thickening agents which may be used according to the nature of the base, include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycols, polyoxyethylene, polyoxypropylene, hydrogenated lanolin, beeswax, and the like.
  • the active component can be formulated into suitable lotions or creams containing the active component suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Administration of the pharmaceutical compositions and compounds and/or salts of the invention may be in the form of an aerosol, for example, for nasal or inhalation applications.
  • the active component may be delivered in the form of an aerosol from a pressurized pack or nebulizer with the use of a suitable propellant such as, for example, carbon dioxide, air, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, or other suitable gas.
  • a suitable propellant such as, for example, carbon dioxide, air, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane, or other suitable gas.
  • a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds and/or salts or compositions described herein may also be delivered in the form of transdermal patches, transmucosal patches, and the like.
  • Matrix or reservoir type patches that are conventional in the art for transdermal or transmucosal delivery may be used for this purpose.
  • the matrix such as a pressure sensitive adhesive matrix, or the carrier in the reservoir act as the pharmaceutically acceptable carrier.
  • the compounds or salts described herein can be administered as the single therapeutic agent in the treatment regimen, or the compounds or salts described herein may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, antibodies, proteins, peptides, oligonucleotides, etc.
  • Compositions and compounds or salts of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds or salts or compositions are useful for modulating 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 or compositions described herein generally include interferon- ⁇ (IFN- ⁇ ) and tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (IL).
  • Cytokines whose biosynthesis may be induced by compounds or salts of the invention include IFN- ⁇ , TNF- ⁇ , IL- 1 , IL-6, IL- 10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds or salts or compositions useful in the treatment of viral diseases and neoplastic diseases.
  • 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 or composition may provide therapeutic treatment.
  • the compound or salt or composition may be administered to the animal prior to the animal acquiring the disease so that administration of the compound or salt or composition may provide a prophylactic treatment.
  • compounds or salts described herein can affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds or salts may also activate macrophages, which in turn stimulate secretion of nitric oxide and the production of additional cytokines. Further, the compounds or salts may cause proliferation and differentiation of B-lymphocytes.
  • T H I T helper type 1
  • cytokine IFN- ⁇ T helper type 2
  • TH2 T helper type 2
  • IL- 4 T helper type 4
  • IL-5 T helper type 13
  • the compound or salt or composition may be administered alone or in combination with one or more active components as in, for example, a vaccine adjuvant.
  • the compound or salt or composition and other component or components may be administered separately; together but independently such as in a solution; or together and associated with one another such as (a) covalently linked or (b) non-covalently associated, e.g., in a colloidal suspension.
  • Conditions for which compounds or salts or compositions identified herein may be used as treatments include, but are not limited to:
  • viral diseases such as, for example, diseases resulting from infection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, or VZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum), a picornavirus (e.g., rhinovirus or enterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus (e.g., parainfluenzavirus, mumps virus, measles virus, and respiratory syncytial virus
  • a herpesvirus e.g., HSV-I, HSV-II, CMV, or VZV
  • a poxvirus e.g., an orthopoxvirus such as variola or vaccinia, or molluscum contagiosum
  • a picornavirus e.g., rhinovirus or enterovirus
  • RSV coronavirus
  • a coronavirus e.g., SARS
  • apapovavirus 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
  • 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
  • neoplastic diseases such as intraepithelial neoplasias, cervical dysplasia, actinic keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemias including but not limited to acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lympho
  • atopic diseases such as atopic dermatitis or eczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen's syndrome;
  • diseases associated with wound repair such as, for example, inhibition of keloid formation and other types of scarring (e.g., enhancing wound healing, including chronic wounds).
  • a compound or salt or composition identified herein may be useful as a vaccine adjuvant for use in conjunction with any material that raises either humoral and/or cell mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens; toxoids; toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; autologous vaccines; recombinant proteins; and the like, for use in connection with, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilus influenza b, tuberculosis, men
  • Compounds or salts or compositions identified herein may be particularly helpful in individuals having compromised immune function.
  • compounds or salts or compositions may be used for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • one or more of the above diseases or types of diseases for example, a viral disease or a neoplastic disease may be treated in an animal in need thereof (having the disease) by administering a therapeutically effective amount of a compound or salt of or a composition comprising a therapeutically effective amount of a compound or salt of Formula I, H, Ha, III, IV, IVa, V, Va, any one of the embodiments described herein, or a combination thereof to the animal.
  • An animal may also be vaccinated by administering an effective amount of a compound or salt of or a composition comprising an effective amount of a compound or salt of Formula I, II, Ila, III, IV, IVa, V, Va, any one of the embodiments described herein, or a combination thereof to the animal as a vaccine adjuvant.
  • a method of vaccinating an animal comprising administering an effective amount of a compound or salt or composition described herein to the animal as a vaccine adjuvant.
  • An amount of a compound or salt or composition effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-I, IL-6, IL-IO and IL- 12 that is increased (induced) over a background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments the induction of cytokine biosynthesis may be performed by administering a compound or salt or composition in a dose outside this range.
  • the method includes administering sufficient compound or salt or composition to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m to about 1.2 mg/m .
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or salt or composition of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • the precise amount that is effective for such treatment will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • An amount of a compound or salt or composition effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg. preferably about 10 ⁇ g/kg to about 5 mg/kg. In other embodiments, the amount is expected to be a dose of, for example, from about 0.01 mg/m 2 to about 5.0 mg/m 2 , (computed according to the Dubois method as described above) although in some embodiments either of these methods may be performed by administering a compound or salt or composition in a dose outside this range.
  • the method includes administering sufficient compound or salt or composition to provide a dose of from about 0.1 mg/m 2 to about 2.0 mg/ m 2 to the subject, for example, a dose of from about 0.4 mg/m 2 to about 1.2 mg/m 2 .
  • pre HPLC normal high performance flash chromatography
  • COMBIFLASH an automated high-performance flash purification product available from Teledyne Isco, Inc., Lincoln, California, USA
  • HORIZON HPFC an automated high-performance flash purification product available from Biotage, Inc, Charlottesville, Virginia, USA
  • INTELLIFLASH Flash Chromatography System an automated flash purification system available from AnaLogix, Inc, Burlington, Wisconsin, USA.
  • the eluent used in each purification is given in the example.
  • the solvent mixture 80/18/2 v/v/v chloroform/methanol/concentrated ammonium hydroxide (CMA) was used as the polar component of the eluent.
  • CMA was mixed with chloroform in the indicated ratio.
  • Phosphorous oxychloride (2.55 mL, 27.5 mmol) was added dropwise to a suspension of 4-hydroxy-3-nitro[l ,5]naphthyridine (5 g, 26.1 mmol) in N,N- dimethylformamide (DMF, 30 mL). The resulting mixture was heated to 60 0 C to dissolve all of the solids. The reaction was maintained at 60 °C for 10 minutes and then allowed to cool to ambient temperature. The solution was poured into ice water (150 mL) and then stirred for 1 hour.
  • the reaction mixture was concentrated under reduced pressure to provide crude 3-methoxy-iV- ⁇ 4-[(tetrahydro-2H-pyran-4- ylmethyl)amino][l,5]naphthyridin-3-yl ⁇ propanamide as an orange solid.
  • This material was suspended in anhydrous ethanol (25 mL) and combined with anhydrous triethylamine (2.25 mL, 16.14 mmol). The mixture was placed under a nitrogen atmosphere and heated at 110 °C over the weekend. The reaction mixture was concentrated under reduced pressure and then diluted with dichloromethane (100 mL).
  • This material was suspended in cold methyl tert-butyl ether (MTBE, 10 mL), isolated by filtration, washed with cold MTBE, and then dried at 80 0 C to provide 0.39 g of 2-(2-methoxyethy I)-I -(tetrahydro-2H-pyran-4-ylmethyl)- IH- imidazo[4,5-c][l,5]naphthyridine as a light grey solid, mp 124-126 0 C.
  • MTBE cold methyl tert-butyl ether
  • the reaction mixture was concentrated under reduced pressure to provide crude 2-oxo-2-( ⁇ 4-[(tetrahydro-2H-pyran-4- ylmethyl)amino][l,5]naphthyridin-3-yl ⁇ amino)ethyl acetate as an orange solid.
  • This material was suspended in anhydrous ethanol (35 mL) and combined with anhydrous triethylamine (3.0 mL, 21.30 mmol). The mixture was placed under a nitrogen atmosphere and heated at 110 0 C over the weekend. 50% Sodium hydroxide (1 mL) was added and the reaction mixture was stirred at 100 0 C for 1 hour. The reaction mixture was concentrated under reduced pressure and then diluted with chloroform (100 mL).
  • This material was suspended in hexanes (20 mL), isolated by filtration, washed with hexanes, and then dried at 80 0 C to provide 458 mg of 2-ethyl-l-(tetrahydro-2H-pyran-4- ylmethyl)-lH-imidazo[4,5-c][l,5]naphthyridine as a light pink solid, mp 132-134 0 C.
  • the crude product was purified by prep HPLC (silica gel eluted with a gradient of 0-25% CMA in chloroform) to provide 0.97 g of an off-white solid.
  • This material was suspended in cold diethyl ether (20 mL), isolated by filtration, washed with cold diethyl ether, and then dried at 80 0 C to provide 0.55 g of 2-propyl-l-(tetrahydro-2//-pyran-4-ylmethyl)-lH- imidazo[4,5-c][l,5]naphthyridine as an off-white solid, mp 122-125 0 C.
  • 6-Bromo--V 4 -(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3 ,4-diamine (6.94 g, 20.64 mmol) was reacted with ethoxyacetyl chloride (2.5 mL, 22.70 mmol) and then cyclized according to the general method of Example 1 Part C using 6-bromo-iV 4 - (tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine in lieu of ⁇ -(tetrahydro-2H- pyran-4-ylmethyl)[l ,5]naphthyridine-3 ,4-diamine and ethoxyacetyl chloride in lieu of 3- methoxypropionyl chloride.
  • iV 4 -(Tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (2.75 g, 10.69 mmol) was reacted with 4-ethoxyphenylacetyl chloride (2.1 mL, 11.76 mmol) and then cyclized according to the general method of Example 1 Part C using 7V 4 -(tetrahydro-2H-pyran-4- ylmethyl)quinoline-3,4-diamine in lieu of ⁇ ' 4 -(tetrahydro-2H-pyran-4- ylmethyl)[l,5]naphthyridine-3,4-diamine and 4-ethoxyphenylacetyl chloride in lieu of 3- methoxypropionyl chloride.
  • the crude product was purified by prep ⁇ PLC (silica gel eluted with a gradient of 0-30% CMA in chloroform) to provide an off-white solid.
  • This material was recrystallized from boiling MTBE (40 mL), isolated by filtration, washed with cold MTBE, and then dried at 80 0 C to provide 1.30 g of 2-(4-ethoxybenzy I)-I- (tetrahydro-2H-pyran-4-ylmethyl)-l//-imidazo[4,5-c]quinoline as an off-white solid, mp 162-166 0 C.
  • Part B The material from Part A was slowly added to hot (200 0 C) DOWTHERM A heat transfer fluid (600 mL). The mixture was heated at 210 0 C until refluxing ceased. The reaction mixture was cooled to ambient temperature. A solid was isolated by filtration and washed with diethyl ether to provide 67 g of S-benzyloxyquinolin-4-ol.
  • Part C Nitric acid (3.7 mL, 1.5 eq) was added to a hot (120 °C) solution of 8- benzyloxyquinolin-4-ol (10 g, 1 eq) in propionic acid (100 mL). The reaction mixture was heated at 120 0 C for 3 hours and then allowed to cool to ambient temperature. A precipitate was isolated by filtration and washed with water (100 mL) to provide 9.7 g of 8-benzyloxy-3 -nitroquinolin-4-ol . Part D
  • Part F A mixture of 8-ben2yloxy-3-nitro-N-(tetrahydro-2H : -pyran-4-ylmethyl)quinolin-4- amine (2.00 g), 5% platinum on carbon (0.2 g), methanol (8 mL), and acetonitrile (28 mL) was placed under hydrogen pressure on a Parr apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter agent. The filter cake was washed with acetonitrile.
  • the crude product was purified by prep ⁇ PLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide 758 mg of 6-(benzyloxy)- 2-(ethoxymethyl)-l-(tetrahydro-2H-pyran-4-ylmethyl)-li/-imidazo[4,5-c]quinoline as an off-white solid, mp 106-109 0 C.
  • Example 14 Part B (0.25 g, 1.78 mmol) according to the general method of Example 14 Part B.
  • the crude product was purified by prep ⁇ PLC (silica gel eluted with a gradient of 0-20% CMA in chloroform) to provide a light yellow solid.
  • iV 4 -(Tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (2.23 g, 8.67 mmol) was reacted with cyclopropylacetyl chloride (1.1 mL, 9.54 mmol) and then cyclized according to the general method of Example 1 Part C using N 4 -(tetrahydro-2H-pyran-4- ylmethyl)quinoline-3,4-diamine in lieu of ⁇ ?4 -(tetrahydro-2H-pyran-4- ylmethyl)[l,5]naphthyridine-3,4-diamine and cyclopropylacetyl chloride in lieu of 3- methoxypropionyl chloride.
  • Glacial acetic acid (2 mL) was added to a suspension of 2-methyl-lH-imidazo[4,5- c]quinolin-l -amine (2.00 g, 10.1 m ⁇ iol) in acetonitrile (20 mL) and a solution was obtained. Tetrahydro-4H-pyran-4-one (1.86 mL, 20.2 mmol) was added.
  • the reaction mixture was placed under a nitrogen atmosphere and heated to 110 0 C. The progress of the reaction was monitored by ⁇ PLC. After 3 days the reaction mixture was cooled to ambient temperature, neutralized with 5% sodium carbonate solution (10 mL), and then concentrated under reduced pressure. The residue was partitioned between chloroform (40 mL) and water (10 mL).
  • reaction mixture was quenched by slowly adding saturated ammonium chloride solution (5 mL) and then concentrated under reduced pressure.
  • the residue was partitioned between chloroform (75 mL) and 10% sodium carbonate solution (20 mL).
  • the organic layer was washed sequentially with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a tan foam.
  • Triethylamine (2.38 mL, 17.1 mmol) was added to a solution of the material from Part B (2.08 g, 8.55 mmol) in dichloromethane (45 mL). The solution was placed under a nitrogen atmosphere and chilled in an ice water bath. Ethoxyacetyl chloride (1.10 g, 8.98 mmol) was added dropwise over a period of 2 minutes. The reaction mixture was allowed to slowly warm to ambient temperature. After 1.5 hours additional ethoxyacetyl chloride (0.50 mL) was added. The reaction was stirred for 30 minutes and then concentrated under reduced pressure to provide the intermediate amide as an orange oil. The oil was dissolved in ethanol (50 mL).
  • Triethylamine (3.58 mL, 25.7 mmol) and concentrated hydrochloric acid (2 drops) were added and the reaction mixture was heated at 100 0 C for 3 hours.
  • the reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure.
  • the residue was dissolved in chloroform (60 mL).
  • the organic solution was washed sequentially with 10% sodium carbonate solution (20 mL), water (20 mL), and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an orange oil.
  • the oil was purified by prep HPLC (silica gel eluted with a gradient of 1-20% CMA in chloroform) to provide an orange oil.
  • the oil was suspended in water (15 mL), the pH of the mixture was adjusted to 13 by the dropwise addition of 10% sodium hydroxide, and then it was extracted with dichloromethane (4 x 15 mL). The combined extracts were washed with brine (15 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide a clear colorless oil.
  • the oil was purified by prep HPLC (silica gel eluted with a gradient of 5-20% CMA in chloroform) to provide a clear colorless oil.
  • the oil was combined with diethyl ether (15 mL) and a solution of hydrochloric acid in ethanol was added dropwise until a precipitate formed.
  • l-Cyclohexylmethyl-2-(2-methoxyethyl)-li-T-imidazo[4,5-c]quinoline was prepared according to the general methods of Example 27 using cyclohexanemethylamine in lieu of (iS)-(+)-tetrahydrofurfurylamine in Part A and 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part C.
  • the crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-12% CMA in chloroform) to provide a yellow solid.
  • 2-(2-Methoxyethyl)-l-(tetrahydro-2H-pyran-2-ylmethyl)-liy-imidazo[4,5- c]quinoline was prepared according to the general methods of Example 27 using 1- tetrahydro-2H-pyran-2-ylmethylamine in lieu of (S)-(+)-tetrahydrofurfurylamine in Part A and 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part C.
  • the crude product was purified by prep ⁇ PLC (silica gel eluted with a gradient of 1-15% CMA in chloroform) to provide a yellow oil.
  • Silica gel (5 g) was added and the mixture was concentrated under reduced pressure to a fine powder. This material was loaded onto a prep ⁇ PLC column (100 g of silica gel) and the column was eluted with a gradient of 1-20% CMA in chloroform. The fractions containing product were combined and concentrated under reduced pressure to provide a white foam. The foam was triturated with diethyl ether (10-15 mL) for 2 hours.
  • This material was loaded onto a prep HPLC column (40 g of silica gel) and the column was eluted with a gradient of 1-25% CMA in chloroform. The fractions containing product were combined and concentrated under reduced pressure to provide an off white solid.
  • the oil was triturated with ethyl acetate to provide 5 g of 4-chloro-2-(ethoxymethyl)-6,7- dimethyl-lH-imidazo[4,5-c]pyridin-l-amine as tan crystals.
  • the mother liquor was purified by prep HPLC (silica gel eluted with a gradient of 0-10% methanol in dichloromethane) to provide 10.8 g of 4-chloro-2-(ethoxymethyl)-6,7-dimethyl-l/f- imidazo[4,5-c]pyridin-l-amine as an amber oil which slowly solidified.
  • reaction mixture was cooled to ambient temperature, additional ammonium formate (0.9 g) and 10% palladium on carbon (0.5 g) were added, and then the reaction mixture was heated at reflux for an additional 3 hours.
  • the reaction mixture was cooled to ambient temperature and then filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure to provide a clear oil.
  • the oil was partitioned between 5% sodium hydroxide (100 mL) and dichloromethane (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 0.45 g of a clear oil.
  • the solid was partitioned between 5% sodium hydroxide (100 mL) and dichloromethane (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 0.40 g of a white solid.
  • This material was purified by prep ⁇ PLC (silica gel eluted with a gradient of 0-10% methanol in dichloromethane) to provide a white solid (0.34 g).
  • Triethyl orthopropionate (0.938 mL, 4.66 mmol) and pyridine hydrochloride (50 mg, 0.47 mmol) were added sequentially to a solution of iV 4 -(tetrahydro-2H-pyran-4- ylmethyl)quinoline-3,4-diamine (1.2 g, 4.66 mmol) in toluene (40 mL).
  • the mixture was heated at reflux for 4 hours and then concentrated under reduced pressure.
  • the residue was dissolved in dichloromethane and then washed with water.
  • the organic was dried over sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the resulting solid was dissolved in refluxing acetonitrile.
  • Ethoxyacetyl chloride (0.476 g, 3.89 mmol) was added dropwise to a solution of ⁇ -(tetrahydro-2H-py ⁇ an-4-ylmemyl)quinoline-3,4-diamine (1.0 g, 3.89 mmol) in a mixture of dichloromethane (40 mL) and triethylamine (0.540 mL, 3.89mmol). After 30 minutes the dichloromethane was removed under reduced pressure. The crude amide intermediate was dissolved in ethanol (40 mL). Triethylamine (2.6 mL) was added and the reaction mixture was heated to reflux. After 4 hours additional triethylamine (1 mL) was added and the reaction mixture was heated at reflux overnight.
  • 2-Butyl-l-(tetrahydro-2/ : /-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinoline was prepared according to the general method of Example 38 using trimethyl orthovalerate in lieu of triethyl orthopropionate.
  • the crude product was purified by prep ⁇ PLC (silica gel eluted with a linear gradient of 2-15% CMA in chloroform) followed by crystallization from acetonitrile to provide 2-butyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-imidazo[4,5- c]quinoline as a white solid, m.p. 135-136.5 0 C.
  • the residue was made basic with saturated aqueous sodium carbonate and a small amount of 50% sodium hydroxide and then extracted with dichloromethane (2 x 50 mL). The combined organics were washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the residue was purified by prep HPLC (silica gel eluted with a gradient of 5-25% methanol in chloroform) and then dissolved in dichloromethane. The solution was evaporated and the residue was dissolved in diethyl ether (5 mL) and treated with a solution of hydrogen chloride in diethyl ether (3.0 mL of 1.0 M). The resulting precipitate was isolated by filtration.
  • Ci 8 H25N 3 O-2.OHCl-l.OH2O C, 55.39; H, 7.49; N, 10.77; Cl, 18.17. Found: C, 55.42; H, 7.87; N, 10.73; Cl, 18.26.
  • Dioxane (1.3 mL) was added to a mixture of 7-bromo-2-(2-methoxyethyl)-l- (tetrahydro-2i ⁇ -pyran-4-ylmethyl)-l/f-imidazo[4,5-c]quinoline (0.500 g, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (32 mg, 0.031 mmol), cesium carbonate (0.560 g, 1.72 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54 mg, 0.093 mmol), and isobutyramide (0.127 g, 1.47 mmol) in a vial equipped with a stir bar.
  • the vial was flushed with nitrogen, sealed with a TEFLON lined cap, and then heated at 80 °C overnight.
  • the reaction mixture was diluted with chloroform containing a trace amount of methanol and then purified by prep HPLC (silica gel eluted with a linear gradient of 2- 15% CMA in chloroform).
  • the resulting foamy residue (0.476 g) was dissolved in acetonitrile and then allowed to stand over night.
  • Dichlorobis(triphenyIphosphine)palladium(II) (0.043 g, 0.062 mmol) was added. The mixture was sparged with nitrogen and then heated at reflux for 1 hour. The organic layer was purified by prep ⁇ PLC (silica gel eluted with a linear gradient of 2-10% CMA in chloroform). The resulting solid was dissolved in a mixture of T ⁇ F (10 mL) and water (5 mL). Acetic acid (5 mL) was added and the mixture was stirred overnight. The reaction was made basic with 2 M aqueous sodium carbonate and the T ⁇ F was removed under reduced pressure.
  • N- ⁇ 7-(Benzyloxy)-4-[(tetrahydro-2/f-pyran-4-ylmethyl)amino]quinolin-3-yl ⁇ propanamide dihydrochloride (14.2 g, 31.1 mmol) was slurried in ethanol (150 mL) and diluted with water (50 mL). Potassium carbonate (12.3 g, 89 mmol) in water (15 mL) was added and the reaction was stirred until dissolution ( ⁇ 30 minutes). The reaction was then heated to 60 0 C for 16 hours. The ethanol was evaporated under reduced pressure and the remaining water was extracted with dichloromethane.
  • the organic fraction was sequentially washed with water, followed by saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to provide a brown viscous oil.
  • the oil was crystallized from acetonitrile (about 200 mL) to provide 8.4 g of 7-(benzyloxy)-2-ethyl-l-(tetrahydro- 2H-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinoline as a white solid, m.p. 143-145 0 C.
  • the reaction mixture was allowed to cool to ambient temperature, diluted with water (80 mL), and then extracted sequentially with ethyl acetate, diethyl ether, and dichloromethane.
  • the ethyl acetate and diethyl ether extracts were combined and then washed with water (2 x 50 mL).
  • the dichloromethane extract was washed with water (3 x 50 mL).
  • the organics were combined, dried over sodium sulfate, filtered, and then concentrated under reduced pressure.
  • the residue was purified twice by prep ⁇ PLC (silica gel eluted with a linear gradient of 2-20% CMA in chloroform and then silica gel eluted with a linear gradient of 1-20% CMA in chloroform).
  • Example 48 1 -[2-Ethoxymethy- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- l//-imidazo[4,5-c]quinolin-7-yl]pyr ⁇ olidin-2-one
  • toluene (2.50 mL) was added to a vial containing 7- bromo-2-ethoxymethyl- 1 -(tetrahydro-2/- r -pyran-4-ylmethyl)- lH-imidazo[4,5-c]quinoline (0.50 g, 1.24 mmol), 2-pyrrolidinone (0.13 mL, 1.49 mmol), tris(dibenzylideneacetone)dipalladium (39 mg, 0.037 mmol), ( ⁇ )-2,2 - bis(diphenylphosphino)-l,r-binaphthyl (46 mg, 0.074 mmol), and sodium tert-butoxide (0.17 g, 1.74 mmol).
  • toluene (2.50 mL) was added to a vial containing 7- bromo-2-ethoxymethyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH " -imidazo[4,5-c]quinoline (0.50 g, 1.24 rrunol), cyclopropylmethylamine (0.13 mL, 1.49 mmol), tris(dibenzylideneacetone)dipalladium (39 mg, 0.037 mmol), ( ⁇ )-2,2'- bis(diphenylphos ⁇ hino)-l,r-binaphthyl (46 mg, 0.074 mmol), and sodium te/V-butoxide (0.17 g, 1.74 mmol).
  • Triethylamine 43 mL, 0.31 mol was added in a single portion to a chilled (ice bath) suspension of 7-bromo-4-chloro-3-nitroquinoline (60 g, (0.21 mol) in DMF (200 mL) to provide a solution.
  • a solution of 1 -tetrahydro-2H-py ⁇ an-4-ylmethylamine (36 g, 0.31 mole) in DMF (50 mL) was added dropwise. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was chilled in an ice bath, then quenched with water (150 mL), and then stirred for 30 minutes.
  • Extractions Cartridge MCX (6 cc) according to the following procedure. Hydrochloric acid (3 mL of 1 N) was added to adjust each example to pH ⁇ 5,- and the resulting solution was passed through the cartridge optionally using light nitrogen pressure. The cartridge was 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) was then passed through the cartridge optionally using light nitrogen pressure, and the eluent was collected and concentrated by vacuum centrifugation. The compounds were purified by preparative high performance liquid chromatography using a Waters FractionLynx automated purification system.
  • the fractions were analyzed using a Waters LC/TOF-MS, and the appropriate fractions were centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
  • Reversed phase preparative liquid chromatography was performed with non-linear gradient elution from 5-95% B where A is 0.05% trifluoroacetic acid/water and B is 0.05% trifluoroacetic acid/acetonitrile.
  • the fractions were collected by mass-selective triggering.
  • 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 93 - 128 Part A 8-Bromo-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)-l H- imidazo[4,5-c]quinoline was prepared according to the general methods of Example 6 using 3-methoxypropionyl chloride in lieu of ethoxyacetyl chloride in Part D.
  • the crude product was triturated with diethyl ether, isolated by filtration, and dried to provide 8- bromo-2-(2-methoxyethyl)- 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 H-imidazo [4,5 - e]quinoline as a white solid.
  • Example 156 was prepared according to the method used for Example 92, except that it was heated for 4 hours instead of 2 hours.
  • 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.
  • Palladium (II) acetate 150 ⁇ L of a 4 mg/mL solution in toluene, 0.0026 mmol
  • 2 M aqueous sodium carbonate solution 600 ⁇ L
  • deionized water 63 ⁇ L
  • a solution of 0.15 mol% triphenylphosphine in n-propanol 53 ⁇ L, 0.0078 mmol
  • the test tube was purged with nitrogen, capped, and then heated at 80 0 C overnight in a sand bath.
  • Palladium (II) acetate 150 ⁇ L of a 4 mg/mL solution in toluene, 0.0026 mmol
  • Example 285 glacial acetic acid (500 ⁇ L), trifluoroacetic acid (500 ⁇ L), and deionized water (500 ⁇ L) were added to the test tube. The reaction was heated for 4 hours at 60 0 C. The reaction mixtures were purified according to the methods of Examples 53 — 92. 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.
  • toluene (2.50 mL) was added to a vial containing 8- bromo-2-ethoxymethyl-l-(tetrahydro-2H-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinoline (0.45 g, 1.11 mmol), 2-pyrrolidinone (0.10 mL, 1.33 mmol), tris(dibenzylideneacetone)dipalladiurn (35 mg, 0.033 mmol), ( ⁇ )-2,2'- bis(diphenylphosphino)-l,l '-binaphthyl (42 mg, 0.066 mmol), and sodium /er/-butoxide (0.15 g, 1.55 mmol).
  • Part B A mixture of the material from Part A (23 mmol), 10% palladium on carbon (0.50 g), and ethanol (9OmL) was placed under hydrogen pressure (30 psi, 2.1 X 10 s Pa) for 3 hours. The reaction mixture was filtered through a layer of CELITE filter agent. The filtrate was diluted with dichloromethane (25 mL) and a precipitate formed. The precipitate was isolated by filtration to provide 1.6 g of 2-propyl-lH-imidazo[4,5- c]quinolin-l-ol. The filtrate was concentrated under reduced pressure to obtain additional product. Part C
  • the organic layer was separated and washed with brine (50 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the crude oil was purified by prep ⁇ PLC (silica gel eluted with 10-35% CMA in chloroform) to yield a pale yellow solid.
  • the solid was dissolved in eathanol (10 mL) and anhydrous hydrogen chloride in ethanol was added (3.0 M, about 5 mL). The solution was stirred at room temperature for 15 minutes. The solvent was removed under reduced pressure and the pale yellow solid was suspended in cold ethanol (about 15 mL). The solid was isolated by filtration, washed with cold ethanol, and dried to afford the hydrochloride salts of the structures shown in the Table below.
  • Example 291 576 mg of 2-(2-methoxyethyl)-7-(2-morpholin-4-ylethoxy)-l-(tetrahydro- 2H-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinoline was isolated as beige needles, mp 220-224 0 C. Anal, calcd for C 25 H 34 N 4 O 4 • 2.40 HCl: C, 55.39; H, 6.77; N, 10.34. Found: C, 55.41; H, 6.97; N, 10.19.
  • Example 292 273 mg of 2-(2-methoxyethyl)-7-(2-pyrrolidin-l-ylethoxy)-l-(tetrahydro- 2H-py ⁇ an-4-ylmethyl)-lH-imidazo[4,5-c]quinoline was isolated as brown needles, mp 205-209 0 C.
  • Example 293 401 mg of 2-(2-methoxyethyl)-7-(2-piperidin-l-ylethoxy)-l-(tetrahydro- 2H-pyran-4-ylmethyl)-l//-imidazo[4,5-c]quinoline was isolated as brown needles, mp 205-209 0 C.
  • ⁇ (Cycloheptylmethy ⁇ -CethoxymethyO-lH-imidazo ⁇ jS-cjquinoline was prepared according to the general methods of Example 27 using 1- cycloheptylmethanamine hydrochloride in lieu of (5)-(+)-tetrahydrofurfurylamine in Part A, and palladium on carbon (10% w/w) as the catalyst and methanol/acetontrile as the solvent in Part B.
  • the crude product was purified by prep HPLC (silica gel eluted with a gradient of 1-15%% CMA in chloroform) to provide a yellow oil. The oil was dissolved in methanol/chloroform and treated with about 0.25 g of activated carbon for 2 hours.
  • a toluene solution (250 ⁇ L) containing 8-bromo-2-ethoxymethyl-l-(tetrahydro- 2H-pyran-4-ylmethyl)-lH ' -imidazo[4,5-c]quinoline (prepared as described in Example 6) (40 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.6 mg, 0.06 equivalents), and (+/-)-2,2 > -bis(diphenylphosphino)-l,r-binapthalene (7.6 mg, 0.12 equivalents) was added to a test tube containing 1 M potassium ter/-butoxide in T ⁇ F (150 ⁇ L) and one of the reagents (1.5 equivalents) listed in the table below.
  • test tube was purged with nitrogen, capped, and then heated at 80 0 C overnight in a sand bath.
  • the solvent was removed on a vacuum centrifuge and the product was purified as described above in Examples 53-92.
  • 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.
  • a toluene solution 250 ⁇ L containing 7-bromo-2-ethoxy methyl- 1 -(tetrahydro- 2H-pyran-4-ylmethyl)-l//-imidazo[4,5-c]quinoline (prepared as described in Examples 129-157) (40 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.3 rag, 0.03 equivalents), and (+/-)-2,2'-bis(diphenylphosphino)-l,l '-binapthalene (4.0 mg, 0.06 equivalents) was added to a test tube containing 1 M potassium tert-bntoxide in T ⁇ F (150 ⁇ L) and one of the reagents (1.2 equivalents) listed in the table below.
  • test tube was purged with nitrogen, capped, and then heated at 80 0 C overnight in a sand bath.
  • a toluene solution 250 ⁇ L containing tris(dibenzylideneacetone)dipalladium(0) (3.3 mg, 0.03 equivalents) and (+/-)-2,2'-bis(diphenylphosphino)-l,l'-binapthalene (4.0 mg, 0.06 equivalents) was added to each test tube.
  • the test tube was purged with nitrogen, capped, and then heated at 80 0 C overnight in a sand bath.
  • the solvent was removed on a vacuum centrifuge and the product was purified as described above in Examples 53-92.
  • 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.
  • the aqueous layer was extracted with dichloromethane (1 x 20 mL) and ethyl acetate (2 x 20 mL) and the organic layers were discarded.
  • the p ⁇ of the aqueous layer was adjusted to 4 with 6 M HCl (aq) and extracted with dichloromethane (2 x 30 mL) and ethyl acetate (1 x 30 mL).
  • reaction was recharged with additional catalyst and hydrogen and maintained at ambient temperature for an additional 24 hours.
  • the reaction mixture was filtered through a 0.2 micron PTFE membrane filter and the filtrate was concentrated to dryness under reduced pressure.
  • Purification using a HORIZON HPFC system silica cartridge, 0- 10% CMA/chloroform) followed by recrystallization from acetonitrile provided 0.16 g of 3-[2-ethyl-l-(tetrahydro- 2H-pyran-4-ylmethyl)-lH-imidazo[4,5-c]quinolin-7-yl]-N r ⁇ '-dimethylpropanamide as a white crystalline solid, 176-178 0 C.

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Abstract

L'invention concerne certaines 1H-imidazo[4,5-c]quinoléines, 6,7,8,9-tétrahydro-1H-imidazo[4,5-c]quinoléines, 1H-imidazo[4,5-c][1,5]naphtyridines, 6,7,8,9-tétrahydro-1H-imidazo[4,5-c][1,5]naphtyridines et 1H-imidazo[4,5-c]pyridines substituées en positions 1 et 2, des compositions pharmaceutiques contenant ces composés, des procédés de préparation des composés et des procédés d'utilisation de ces composés comme immunomodulateurs, pour induire la biosynthèse de cytokines chez des animaux et dans le traitement de maladies, y compris de maladies virales et néoplasiques.
PCT/US2006/048017 2005-12-16 2006-12-15 Imidazoquinoléines, imidazonaphtyridines et imidazopyridines substituées, compositions et procédés correspondants WO2007075468A1 (fr)

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JP2008545861A JP2009519955A (ja) 2005-12-16 2006-12-15 置換されたイミダゾキノリン、イミダゾナフチリジンおよびイミダゾピリジン、組成物ならびに方法
AU2006332000A AU2006332000A1 (en) 2005-12-16 2006-12-15 Substituted imidazoquinolines, imidazonaphthyridines, and imidazopyridines, compositions, and methods
CA002634017A CA2634017A1 (fr) 2005-12-16 2006-12-15 Imidazoquinoleines, imidazonaphtyridines et imidazopyridines substituees, compositions et procedes correspondants
EP06845602A EP1968587A1 (fr) 2005-12-16 2006-12-15 Imidazoquinoléines, imidazonaphtyridines et imidazopyridines substituées, compositions et procédés correspondants
MX2008007864A MX2008007864A (es) 2005-12-16 2006-12-15 Imidazoquinolinas, imidazonaftiridinas, e imidazopiridinas sustituidas, composiciones y metodos.
IL191846A IL191846A0 (en) 2005-12-16 2008-05-29 Substituted imidazoquinolines imidazonaphthyridines, and imidazopyridines, compositions, and methods
NO20082757A NO20082757L (no) 2005-12-16 2008-06-18 Substituerte imidazoquinoliner, imidazonaftyridiner og imidazopyridiner, sammensetninger og fremgangsmater
AU2011201519A AU2011201519A1 (en) 2005-12-16 2011-04-04 Substituted imidazoquinolines, imidazonaphthyridines, and imidazopyridines, compositions, and methods

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WO2012143416A3 (fr) * 2011-04-21 2013-01-31 Glaxosmithkline Llc Nouveaux composés
US8846709B2 (en) 2011-04-21 2014-09-30 Glaxosmithkline Llc 7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1H-imidazo[4,5-C]quinoline derivatives
US9067936B2 (en) 2011-08-17 2015-06-30 Glaxosmithkline Llc 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-C]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor
US9416130B2 (en) 2011-08-17 2016-08-16 Glaxosmithkline Llc 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-C]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor
US9610284B2 (en) 2011-08-17 2017-04-04 Glaxosmithkline Llc 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor
US9861627B2 (en) 2011-08-17 2018-01-09 Glaxosmithkline Llc 4-(8-methoxy-1-((1-methoxypropan-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-C]quinolin-7-yl)-3,5-dimethylisoxazole and its use as bromodomain inhibitor
US9227969B2 (en) 2013-08-14 2016-01-05 Novartis Ag Compounds and compositions as inhibitors of MEK
US9629836B2 (en) 2013-08-14 2017-04-25 Novartis Ag Compounds and compositions as inhibitors of MEK
US10011599B2 (en) 2013-08-14 2018-07-03 Novartis Ag Compounds and compositions as inhibitors of MEK
EP3992191A1 (fr) 2020-11-03 2022-05-04 Deutsches Krebsforschungszentrum Dérivés d'imidazo[4,5-c]quinoline et leur utilisation en tant qu'inhibiteurs de kinase atm
WO2022096361A1 (fr) 2020-11-03 2022-05-12 Deutsches Krebsforschungszentrum Composés imidazo[4,5-c]quinoléine et leur utilisation en tant qu'inhibiteurs de kinase atm

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IL191846A0 (en) 2008-12-29
JP2009519955A (ja) 2009-05-21
AU2011201519A1 (en) 2011-04-21
MX2008007864A (es) 2009-03-04
CA2634017A1 (fr) 2007-07-05
CN101330916A (zh) 2008-12-24
NO20082757L (no) 2008-09-04
EP1968587A1 (fr) 2008-09-17
ZA200805105B (en) 2009-06-24
AU2006332000A1 (en) 2007-07-05

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