JP2009519955A - Substituted imidazoquinolines, imidazonaphthyridines and imidazopyridines, compositions and methods - Google Patents

Abstract

  Certain 1H-imidazo [4,5-c] quinolines substituted in the 1- and 2-positions, 6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolines, 1H -Imidazo [4,5-c] [1,5] naphthyridines, 6,7,8,9-tetrahydro-1H-imidazo [4,5-c] [1,5] naphthyridines, and 1H-imidazo [ 4,5-c] pyridines, pharmaceutical compositions containing these compounds, methods for making these compounds, and these compounds as immunomodulators for inducing cytokine biosynthesis in animals, and Disclosed are methods for use in treating diseases, including viral diseases and neoplastic diseases.

Description

REFERENCE TO RELATED APPLICATIONS This invention claims priority based on US Provisional Patent Application No. 60 / 751,392 (filed December 16, 2005), which is incorporated herein by reference.

Background Certain compounds have been found to be useful as immune response modifiers (IRMs), thus making them useful in the treatment of a variety of disorders. However, compounds that have the ability to modulate the immune response by inducing cytokine biosynthesis or other means are still of interest and need.

SUMMARY OF THE INVENTION Certain substituted 1H-imidazo [4,5-c] quinolines, 6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinolines, 1H-imidazo [4,5 -c] [1,5] naphthyridines, 6,7,8,9-tetrahydro-1H-imidazo [4,5-c] [1,5] naphthyridines, and 1H-imidazo [4,5-c] It has now been found that pyridines can regulate cytokine biosynthesis. In one aspect, the invention provides a therapeutically effective amount of a compound of formula I, II, IIa, III, IV, IVa, V, or Va:

Or a pharmaceutical composition comprising it in combination with pharmaceutically acceptable salts thereof, wherein R, R ₁ , R _1a , R ₂ , R ₃ , R _3a , R _A , R _B , R _{A ′} , R _{B ′} , X ′, X ″, X ″ ′, n, and m are as defined below].

  A composition comprising a compound or salt of formula I, II, IIa, III, IV, IVa, V, or Va, when administered to an animal, modulates cytokine biosynthesis (eg, biosynthesis of one or more cytokines or Inducing production) and other ways to modulate the immune response. Because of their ability to modulate cytokine biosynthesis, the compositions of the present invention are useful for the treatment of a variety of conditions, such as viral and neoplastic diseases, in response to such changes in immune response.

In another aspect, the present invention also provides compounds of formula IIa, III, IVa, and Va or pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides an animal by administering a compound of formula IIa, III, IVa, and / or Va or a salt thereof, or one or more of formula I, II, IIa, III, IV, IVa, A method of inducing cytokine biosynthesis in animal cells by administering a composition comprising a compound of V and / or Va and / or a pharmaceutically acceptable salt thereof, a method of treating a viral disease in an animal, and / or Alternatively, a method of treating neoplastic disease in an animal is provided.

In another aspect, the present invention provides methods for synthesizing compounds of Formulas I, II, IIa, III, IV, IVa, V, and Va and intermediate compounds useful in the synthesis of these compounds.
As used herein, article, definite article, “at least one”, and “one or more” are used interchangeably.

The terms “comprising” and variations thereof do not have a limiting meaning where these terms appear in the specification and claims.
The above summary of the present invention is not intended to describe each disclosed embodiment or every embodiment of the present invention. Specific embodiments will be illustrated in more detail by the following description. Reference is also provided herein by listing the examples; these can be used in various combinations. In each case, the listed list is only representative and should not be interpreted as a full list.

Detailed Description of Exemplary Embodiments of the Invention In one aspect, the invention provides a therapeutically effective amount of a compound of formula I, II, IIa, III, IV, IVa, V, or Va:

Or a pharmaceutical composition comprising it in combination with a pharmaceutically acceptable salt thereof, wherein R, R ₁ , R _1a , R ₂ , R ₃ , R _3a , R _A , R _B , R _{A ′} , R _{B ′} , X ′, X ″, X ″ ′, n, and m are as defined below].

  In one embodiment, the present invention provides a therapeutically effective amount of a compound of formula I:

Or a pharmaceutical composition comprising in combination with a pharmaceutically acceptable salt thereof:
In the formula:
X ′ is selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R _A and R _B together form a fused benzene ring or fused pyridine ring, which is unsubstituted or substituted with 1 or 2 R groups, or 1 R ₃ Substituted with a group or substituted with one R ₃ group and one R group; the fused pyridine ring is

Where the highlighted bond in the formula indicates the position where the ring is fused; or
R _A and R _B together form a fused cyclohexane ring or fused tetrahydropyridine ring, which is unsubstituted or substituted with one or more R groups at carbon atoms; Ring

Where the highlighted bond in the formula indicates the position where the ring is fused; or
R _A is alkyl and R _B is hydrogen or alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
R ₃ is selected from the group consisting of:
-ZR ₄ ,
-ZXR ₄ ,
-ZXYR ₄ ,
-ZXYXYR ₄ ,
-ZXR ₅ and
-NH-QR ₄ ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Y is selected from the group consisting of:

Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, in which alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; Hydroxy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; Optionally substituted with one or more selected substituents; in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, optionally substituted with one or more oxo;
R ₅ is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;
R ₇ is C _2-7 alkylene;
R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, and heteroaryl- Selected from the group consisting of C _1-10 alkylenyl;
R ₉ is selected from the group consisting of hydrogen and alkyl;
R ₁₀ is C _3-8 alkylene;
A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —;
A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —;
Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group consisting of:
V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;
W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —;
a and b are each independently an integer of 1 to 6, provided that a + b is ≦ 7. In other embodiments of this pharmaceutical composition, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—; R ₃ is in the 7- or 8-position.

  In another embodiment, the present invention provides a therapeutically effective amount of a compound of formula II:

Or a pharmaceutical composition comprising in combination with a pharmaceutically acceptable salt thereof:
In the formula:
X ′ is selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₃ is selected from the group consisting of:
-ZR ₄ ,
-ZXR ₄ ,
-ZXYR ₄ ,
-ZXYXYR ₄ ,
-ZXR ₅ and
-NH-QR ₄ ;
m is 0 or 1; provided that when m is 1, 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 are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Y is selected from the group consisting of:

Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; nitro; Xy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; In the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo;
R ₅ is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;
R ₇ is C _2-7 alkylene;
R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, and heteroaryl- Selected from the group consisting of C _1-10 alkylenyl;
R ₉ is selected from the group consisting of hydrogen and alkyl;
R ₁₀ is C _3-8 alkylene;
A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —;
A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —;
Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group consisting of:
V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;
W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —;
a and b are each independently an integer of 1 to 6, provided that a + b is ≦ 7. In other embodiments of this pharmaceutical composition, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—; R ₃ is in the 7- or 8-position.

  In another embodiment, the present invention provides a therapeutically effective amount of a compound of formula III:

Or a pharmaceutical composition comprising in combination with a pharmaceutically acceptable salt thereof:
In the formula:
X ′ is selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₉ is selected from the group consisting of hydrogen and alkyl. In other embodiments of this pharmaceutical composition, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—.

  In another embodiment, the invention provides a therapeutically effective amount of a compound of formula IV:

Or a pharmaceutical composition comprising in combination with a pharmaceutically acceptable salt thereof:
In the formula:
X ′ is selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₃ is selected from the group consisting of:
-ZR ₄ ,
-ZXR ₄ ,
-ZXYR ₄ ,
-ZXYXYR ₄ ,
-ZXR ₅ and
-NH-QR ₄ ;
m is 0 or 1; provided that when m is 1, 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 are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Y is selected from the group consisting of:

Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; nitro; Xy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; In the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo;
R ₅ is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;
R ₇ is C _2-7 alkylene;
R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, and heteroaryl- Selected from the group consisting of C _1-10 alkylenyl;
R ₉ is selected from the group consisting of hydrogen and alkyl;
R ₁₀ is C _3-8 alkylene;
A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —;
A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —;
Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group consisting of:
V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;
W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —;
a and b are each independently an integer of 1 to 6, provided that a + b is ≦ 7. In other embodiments of this pharmaceutical composition, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—; R ₃ is in the 7- or 8-position.

  In another embodiment, the present invention provides a therapeutically effective amount of a compound of formula V:

Or a pharmaceutical composition comprising in combination with a pharmaceutically acceptable salt thereof:
In the formula:
X ′ is selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R _{A ′} is alkyl and R _{B ′} is hydrogen or alkyl. In other embodiments of this pharmaceutical composition, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—.

  In another embodiment, the invention provides a compound of formula IIa:

Or a pharmaceutically acceptable salt thereof:
In the formula:
X _{"is, -CH 2 -, - CH (} CH 3) - is selected from and -O- the group consisting;
R _1a is tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-di Selected from the group consisting of oxide tetrahydro-2H-thiopyran-4-yl;
R ₂ is —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH ₂ —OH, -CH ₂ -C _1-3 alkylenyl-OH, and selected from the group consisting of benzyl, the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C _1-4 alkoxy Substituted with one or more substituents selected from the group consisting of: hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl. In other embodiments of the compounds of formula IIa, or pharmaceutically acceptable salts thereof, X ″ is —CH ₂ —.

  In another embodiment, the invention provides a compound of formula III:

Or a pharmaceutically acceptable salt thereof:
In the formula:
X ′ is selected from the group consisting of —CH ₂ —, —CH (CH ₃ ) —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₉ is selected from the group consisting of hydrogen and alkyl. In another embodiment of the compound of formula III, or a pharmaceutically acceptable salt thereof, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—.

  In another embodiment, the invention provides a compound of formula IVa:

Or a pharmaceutically acceptable salt thereof:
In the formula:
X ″ ′ is selected from the group consisting of —CH ₂ — and —CH (CH ₃ ) —;
R _1a is tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-di Selected from the group consisting of oxide tetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R _3a is selected from the group consisting of:
-ZR ₄ , and
-ZXR ₄ ;
m is 0 or 1; provided that when m is 1, 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 are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; nitro; Xy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; In the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo;
R ₉ is selected from the group consisting of hydrogen and alkyl. In other embodiments of compounds of Formula IVa, or pharmaceutically acceptable salts thereof, X ″ ′ is —CH ₂ —; R ₃ is in the 7- or 8-position.

  In another embodiment, the invention provides a compound of formula Va:

Or a pharmaceutically acceptable salt thereof:
In the formula:
X _{"is, -CH 2 -, - CH (} CH 3) - is selected from and -O- the group consisting;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R _{A ′} is alkyl and R _{B ′} is hydrogen or alkyl. In other embodiments of the compounds of formula Va, or pharmaceutically acceptable salts thereof, X ″ is —CH ₂ —.

As will be appreciated by those skilled in the art, for any compound shown herein, the following variables in any of its embodiments (eg, R, R ₁ , R _1a , R ₂ , R ₃ , R _3a , R _A , R _B , R _{A ′} , R _{B ′} , R ₄ , X, X ′, X ″, X ″ ′, Y, Z, A, Q, etc.), each of those embodiments and the present specification Can be combined with one or more of the other variables associated with any of the formulas described in the document. Each resulting combination of variables represents one or more compounds that are embodiments of the present invention, or one or more compounds that are compositions that are embodiments of the present invention in combination with a pharmaceutically acceptable carrier.

For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof,
R _A and R _B together form a fused benzene ring or fused pyridine ring, which is unsubstituted or substituted with 1 or 2 R groups, or 1 R ₃ Substituted with a group or substituted with one R ₃ group and one R group; the fused pyridine ring is

Where the highlighted bond in the formula indicates the position where the ring is fused; or
R _A and R _B together form a fused cyclohexane ring or fused tetrahydropyridine ring, which is unsubstituted or substituted with one or more R groups at carbon atoms; Ring

Where the highlighted bond in the formula indicates the position where the ring is fused; or
R _A is alkyl and R _B is hydrogen or alkyl.
For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, R _A and R _B together form a fused benzene ring or fused pyridine ring, which is substituted Or substituted with 1 or 2 R groups, or substituted with 1 R ₃ group, or substituted with 1 R ₃ group and 1 R group; The pyridine ring

Where the highlighted bond in the formula indicates the position at which this ring is fused. For certain of these embodiments, R _A and R _B together form a fused benzene ring, which is unsubstituted, substituted with 1 or 2 R groups, or 1 It substituted with pieces of is substituted with R ₃ groups, or one R ₃ group and one R group. For certain of these embodiments, the fused benzene ring is not substituted. Alternatively, for some of these embodiments, R _A and R _B together form a fused pyridine ring, which is unsubstituted or substituted with 1 or 2 R groups; Or substituted with one R ₃ group, or substituted with one R ₃ group and one R group. For certain of these embodiments, the fused pyridine ring is not substituted.

For example, for certain embodiments of pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof, R _A and R _B together form a fused cyclohexane ring or fused tetrahydropyridine ring, which is substituted Or substituted at the carbon atom with one or more R groups; the fused tetrahydropyridine ring is

Where the highlighted bond in the formula indicates the position at which this ring is fused. For certain of these embodiments, R _A and R _B together form a fused cyclohexane ring, which is unsubstituted or substituted with one or more R groups. For certain of these embodiments, the fused cyclohexane ring is not substituted. Alternatively, for some of these embodiments, R _A and R _B together form a fused tetrahydropyridine ring, which is unsubstituted or substituted with one or more R groups at a carbon atom. ing. For certain of these embodiments, the fused tetrahydropyridine ring is not substituted.

For example, for certain embodiments of the pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, R _A is alkyl and R _B is hydrogen or alkyl. For certain of these embodiments, R _A and R _B are both methyl.

For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula V or a pharmaceutically acceptable salt thereof, R _{A ′} is alkyl and R _{B ′} is hydrogen or alkyl. For certain of these embodiments, R _{A ′} and R _{B ′} are both methyl.

For example, Formula I, II or certain aspects or for any of the aspects of the containing R _3, a compound or pharmaceutical composition comprising a salt that can be pharmaceutically acceptable IV,, R ₃ is -ZR _4, -ZXR ₄ , -ZXYR ₄ , -ZXYXYR ₄ , -ZXR ₅ , and -NH-QR ₄ . For certain of these embodiments, R ₃ is —ZR ₄ . For certain of these embodiments, R ₄ is selected from the group consisting of aryl, arylalkylenyl, and heteroarylalkenyl, wherein the aryl, arylalkylenyl, and heteroarylalkenyl groups are substituted. Optionally or independently substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino and dialkylamino Z is a bond. For certain of these embodiments, R ₃ is selected from the group consisting of hydroxyphenyl, (hydroxymethyl) phenyl, 4- (aminomethyl) phenyl, pyridin-3-yl, and pyridin-4-yl. Alternatively, for certain of these embodiments, R ₃ is —ZR ₄ and R ₄ is a heterocyclyl group, which contains one or more ring nitrogen atoms and includes a ring oxygen atom or a ring sulfur atom. The point of attachment of the heterocyclyl group is one of the nitrogen atoms, the heterocyclyl group is unsubstituted or independently selected from the group consisting of oxo, alkyl, aryl, and arylalkylenyl Substituted with one or more substituents; Z is a bond. For certain of these embodiments, the heterocyclyl group is monocyclic and contains 4 to 6 ring atoms. For certain of these embodiments, the heterocyclyl group is unsubstituted or independently substituted with one or more substituents selected from the group consisting of oxo, alkyl, and arylalkylenyl. Yes. For certain of these embodiments, the heterocyclyl group is unsubstituted or substituted independently with one or more substituents selected from the group consisting of oxo and alkyl. For certain of these embodiments, the heterocyclyl group is selected from the group consisting of:

In these formulas, R ′ is alkyl. For certain of these embodiments, the heterocyclyl group is selected from the group consisting of:

In these formulas, R ′ is alkyl. For certain of these embodiments, the heterocyclyl group is selected from the group consisting of:

For certain of these embodiments, the heterocyclyl group is:

For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula I, II, or IV or a pharmaceutically acceptable salt thereof, or any of the foregoing embodiments comprising R ₃ , wherein R ₃ is —ZR ₄ R ₃ is -ZXYR ₄ except. For certain of these embodiments, R ₄ is selected from the group consisting of hydrogen, alkyl, and heterocyclyl; Y is —S (O) ₂ —, —C (O) —, —C (O) —NH Selected from the group consisting of-, and -NH-S (O) _2- ; X is phenylene; Z is a bond. For certain of these embodiments, R ₃ is (methylsulfonylamino) phenyl (eg, R ₄ is methyl and Y is —NH—S (O) ₂ —). Alternatively, for certain of these embodiments, R ₄ is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroaryl, each of which is unsubstituted or independently halogen, hydroxy, And Y is substituted with one or more substituents selected from the group consisting of alkyl; Y is —S (O) ₂ —, —C (O) —, —C (O) —NH—, and —NH Selected from the group consisting of -S (O) _2- ;

Z is a bond. Alternatively, for certain of these embodiments, wherein R ₃ is —ZXYR ₄ , R ₄ is hydrogen or alkyl; Y is —C (O) —N (R ₈ ) — or —C (O) —O R ₈ is C _1-4 alkyl; X is alkylene or alkenylene; Z is a bond. For certain of these embodiments, for certain of these embodiments, R ₄ is C _1-4 alkyl; Y is —C (O) —N (R ₈ ) —; X is alkylene is there. Alternatively, for certain of these embodiments, wherein R ₃ is —ZXYR ₄ , R ₄ is alkyl substituted with maleimidyl; Y is —NHC (O) —, and X is one — An alkylene with an O-group; Z is -O-;

For example, for certain embodiments of the pharmaceutical composition comprising a compound of Formula I or II or a pharmaceutically acceptable salt thereof, R ₃ is hydroxyphenyl, (hydroxymethyl) phenyl, 4- (aminomethyl) phenyl, 3- (methyl Selected from the group consisting of sulfonylamino) phenyl, pyridin-3-yl, and pyridin-4-yl.

For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula I or IV, or a pharmaceutically acceptable salt thereof, R ₃ is selected from the group consisting of hydroxyphenyl, (hydroxymethyl) phenyl, and (methylsulfonylamino) phenyl Is done.

For example, Formula I, II or certain aspects or for any of the aspects of the containing R _3, a compound or pharmaceutical composition comprising a salt that can be pharmaceutically acceptable IV,, R ₃ is -ZR ₄ or -ZXYR Except when it is ₄ , R ₃ is -ZX _f -Y _a -X _g -Y _b -R ₄ . For certain of these embodiments, R ₃ is —ZX _f —Y _a —X _g —Y _b —R ₄ , wherein R ₄ is hydrogen or C _1-4 alkyl, and Y _b is —C (O) —O—, X _g is alkylene, Y _a is —NHC (O) —, X _f is alkylene with one —O— group in the middle; Z is —O -That's it.

For example, aspects of the compounds or pharmaceutical compositions comprising a pharmaceutically acceptable salt of Formula I, II or IV, or for any of the aspects of the containing R _3,, R ₃ is -ZR _4, -ZXYR R ₃ is —NH—QR ₄ except where ₄ , or —ZX _f —Y _a —X _g —Y _b —R ₄ . For certain of these embodiments, Q is —C (O) —, —C (O) —O—, —C (O) —N (R ₈ ) —, or —S (O) ₂ —. , R ₄ is alkyl, aryl, arylalkylenyl or heteroaryl, each of which is unsubstituted or independently selected from one or more substituents selected from the group consisting of halogen, hydroxy, and alkyl Has been replaced by For certain of these embodiments, R ₈ is hydrogen or C _1-4 alkyl. For certain of these embodiments, Q is —C (O) — and R ₄ is alkyl or aryl. For certain of these embodiments, Q is —S (O) ₂ — and R ₄ is alkyl or aryl. Alternatively, for certain of these embodiments, Q is —C (O) — and R ₄ is heterocyclyl, which is unsubstituted or independently selected from the group consisting of alkyl and oxo. Substituted with one or more selected substituents; where heterocyclyl is a heterocyclyl group containing one or more ring nitrogen atoms, and the point of attachment of the heterocyclyl group is one of the nitrogen atoms It is. For certain of these embodiments, the heterocyclyl group is monocyclic and contains 5 or 6 ring atoms. For certain of these embodiments, R ₄ is piperidin-1-yl.

For example, for certain embodiments of a pharmaceutical composition comprising a compound of formula I, II, or IV, or a pharmaceutically acceptable salt thereof, or any of the foregoing embodiments comprising R ₃ (or R _3a ), R ₃ (or R _3a ) is in the 7- or 8-position. For certain of these embodiments, R ₃ (or R _3a ) is in the 7-position. Alternatively, for some of these embodiments, R ₃ (or R _3a ) is in the 8-position. The 7- and 8-positions are shown in the following equation.

For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula II, III, or IV or a pharmaceutically acceptable salt thereof, or any of the preceding embodiments comprising n, n is 0.
For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula II, III, or IV or a pharmaceutically acceptable salt thereof, R is from halogen, hydroxy, alkyl, haloalkyl, alkoxy, and —N (R ₉ ) ₂ Selected from the group consisting of For certain of these embodiments, R is hydroxy or —N (R ₉ ) ₂ . For certain of these embodiments, R is —N (R ₉ ) ₂ . For certain of these embodiments, R is hydrogen. Alternatively, for certain of these embodiments, R ₉ is alkyl. For certain of these embodiments, m is 0 and n is 1. For certain of these embodiments, R is in the 7-position. For certain of these embodiments, R is in the 8-position.

For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula II or IV, or a pharmaceutically acceptable salt thereof, m is 0.
For example, for certain embodiments of the pharmaceutical composition comprising a compound of formula II or IV, or a pharmaceutically acceptable salt thereof, m and n are both 0.

For certain embodiments, including any of the above embodiments, R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, — Selected from the group consisting of CH ₂ —OC _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 independently Substituted with one or more substituents selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl . For certain of these embodiments, R ₂ is —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —OC _1-3 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1— Selected from the group consisting of ₂ alkyl, —CH ₂ —OH, and —CH ₂ —C _1-3 alkylenyl-OH. For certain of these embodiments, R ₂ consists of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. Selected from the group. For certain of these embodiments, R ₂ is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl. For certain of these embodiments, R ₂ is selected from the group consisting of n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.

For certain embodiments, including any of the foregoing embodiments, R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran- Selected from the group consisting of 3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl. For certain of these embodiments, R ₁ is tetrahydro-2H-thiopyran-4-yl.

For certain embodiments, including any of the above embodiments wherein X ′ is present, X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—. Alternatively, for certain of these embodiments, X ′ is —CH ₂ —. Alternatively, for certain of these embodiments, X ′ is —NH—. Alternatively, for certain of these embodiments, X ′ is —O—.

For example, for certain embodiments of formula Va, R _{A ′} is alkyl and R _{B ′} is hydrogen or alkyl. For certain of these embodiments, R _{A ′} and R _{B ′} are both methyl.
For example, for any of the aspects of the embodiments or formula Va of Formula IIa, X "is -CH ₂ - except where, X" is _{-CH 2 -, - CH (CH} 3) -, and Selected from the group consisting of -O-. For certain of these embodiments, X ″ is —CH ₂ —.

For example, for certain embodiments of formula IVa, X ″ ′ is —CH ₂ —.
For certain embodiments, including any of the above embodiments of Formula IVa, m is 1 and R _3a is selected from the group consisting of —ZR ₄ and —ZXR ₄ . For certain of these embodiments, R _3a is selected from the group consisting of hydroxyphenyl and (hydroxymethyl) phenyl.

For certain embodiments, including any of the foregoing embodiments of Formula III or IVa, R is selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, alkoxy, and —N (R ₉ ) ₂ . For certain of these embodiments, R is hydroxy. For certain of these embodiments, n is 1.

For certain embodiments, including any of the foregoing embodiments of Formula III or IVa, n is 0, except where n is 1.
For certain embodiments, including any of the above embodiments of Formula IVa, except that m is 1, m is 0.

For certain embodiments, including any of the foregoing embodiments of Formula IVa, except that m or n is 1, both m and n are 0.
For certain embodiments, including any of the foregoing embodiments of Formula IIa or IVa, R _1a is tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl , Tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl. For certain of these embodiments, R _1a is tetrahydro-2H-thiopyran-4-yl.

For certain embodiments, including any of the foregoing embodiments of Formula III or Va, R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, From the group consisting of tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl Selected. For certain of these embodiments, R ₁ is tetrahydro-2H-thiopyran-4-yl.

For certain embodiments, including any of the above embodiments of Formula IIa, III, IVa, or Va, R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1— Selected from the group consisting of ₂ alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH ₂ —OH, —CH ₂ —C _1-3 alkylenyl-OH, and benzyl; The ring is unsubstituted or independently selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl Substituted with one or more substituents. For certain of these embodiments, R ₂ consists of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. Selected from the group. For certain of these embodiments, R ₂ is selected from the group consisting of n-propyl, n-butyl, methoxymethyl, ethoxymethyl, and 2-methoxyethyl.

For certain embodiments, R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkyl Selected from the group consisting of heteroarylenyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylene Nyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; Nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy It may be substituted with one or more substituents selected from the group; in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo.

For certain embodiments, R ₄ is selected from the group consisting of alkyl, aryl, heteroaryl, and arylalkylenyl, wherein the aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl groups are substituted. Or independently substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino and dialkylamino Good.

For certain embodiments, R ₄ is selected from the group consisting of aryl and heteroaryl, each of which is unsubstituted or substituted with hydroxy, hydroxyalkyl, or aminoalkyl.

For certain embodiments, R ₄ is selected from the group consisting of hydroxyphenyl, (hydroxymethyl) phenyl, (aminomethyl) phenyl, pyridin-3-yl, and pyridin-4-yl.

For certain embodiments, R ₄ is alkyl, aryl, arylalkylenyl, or heteroaryl, each of which is unsubstituted or independently selected from the group consisting of halogen, hydroxy, and alkyl Substituted with the above substituents.

For certain embodiments, R ₄ is alkyl or aryl.
For certain embodiments, R ₄ is selected from the group consisting of hydrogen, alkyl, and heterocyclyl.

For certain embodiments, R ₄ is hydrogen.
For certain embodiments, R ₄ is alkyl.
For certain embodiments, R ₄ is a heterocyclyl group, which contains one or more ring nitrogen atoms, may contain a ring oxygen atom or a ring sulfur atom, and the point of attachment of the heterocyclyl group is one of the nitrogen atoms. Wherein the heterocyclyl group is unsubstituted or independently substituted with one or more substituents selected from the group consisting of oxo, alkyl, aryl, and arylalkylenyl. For certain embodiments, the heterocyclyl group is monocyclic and contains 4 to 6 ring atoms. For certain of these embodiments, the heterocyclyl group is unsubstituted or independently substituted with one or more substituents selected from the group consisting of oxo, alkyl, and arylalkylenyl. Yes. For certain of these embodiments, the heterocyclyl group is unsubstituted or substituted independently with one or more substituents selected from the group consisting of oxo and alkyl.

For certain embodiments, R ₄ is a heterocyclyl group selected from the group consisting of:

In these formulas, R ′ is alkyl.
For certain embodiments, R ₄ is a heterocyclyl group selected from the group consisting of:

In these formulas, R ′ is alkyl.
For certain embodiments, R ₄ is a heterocyclyl group selected from the group consisting of:

For certain embodiments, R ₄ is:

For certain embodiments, R ₄ is piperidin-1-yl.
For certain embodiments, R ₅ is selected from the group consisting of:

For certain embodiments, R ₅ is:

For certain embodiments, R ₆ is selected from the group consisting of ═O and ═S.
For certain embodiments, R ₆ is ═O.
For certain embodiments, R ₆ is ═S.

For certain embodiments, R ₇ is C _2-7 alkylene.
For certain embodiments, R ₇ is C _2-4 alkylene.
For certain embodiments, R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, And selected from the group consisting of heteroaryl-C _1-10 alkylenyl.

For certain embodiments, R ₈ is hydrogen, C _1-10 alkyl, or hydroxy-C _1-10 alkylenyl.
For certain embodiments, R ₈ is C _1-4 alkyl.

For certain embodiments, R ₈ is hydrogen.
For certain embodiments, R ₉ is selected from the group consisting of hydrogen and alkyl.
For certain embodiments, R ₉ is hydrogen.

For certain embodiments, R ₉ is alkyl.
For certain embodiments, R ₁₀ is C _3-8 alkylenyl.
For certain embodiments, R ₁₀ is pentylene.

For certain embodiments, R ′ is hydrogen, alkyl, or aryl.
For certain embodiments, R ′ is alkyl.
For certain embodiments, R ′ is hydrogen.

For certain embodiments, A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —.
For certain embodiments, A is selected from the group consisting of —CH ₂ —, —O—, and —N (alkyl)-.

For certain embodiments, A is —O—.
For certain embodiments, A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —.

For certain embodiments, Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W-, -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ ) Selected from the group consisting of:

For certain embodiments, Q is, -C (O) -, - S (O) 2 -, - C (R 6) -N (R 8) -, - S (O) 2 -N (R 8) -, Selected from the group consisting of -C (O) -O- and -C (O) -S-.
For certain embodiments, Q is -C (O)-, -S (O) _2- , -C (R ₆ ) -N (R ₈ )-, or -S (O) ₂ -N (R ₈ )- It is.

For certain embodiments, Q is —C (R ₆ ) —.
For certain embodiments, Q is a bond.
For certain embodiments, V is selected from the group consisting of C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2-. The

For certain embodiments, V is —N (R ₈ ) —C (O) —.
For certain embodiments, W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —.
For certain embodiments, W is a bond.

  For certain embodiments, X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are mid- or terminally arylene, heteroarylene, or There may be heterocyclylene and there may be one or more -O- groups in the middle.

For certain embodiments, X is phenylene.
For certain embodiments, X is:

For certain embodiments, X is C _1-4 alkylene.
For certain embodiments, X is methylene.
For certain embodiments, Y is selected from the group consisting of:

For certain embodiments, Y is —N (R ₈ ) —Q—.
For certain embodiments, Y is -N (R ₈ ) -C (O)-, -N (R ₈ ) -S (O) _2- , -N (R ₈ ) -C (R ₆ ) -N (R ₈ )-, -N (R ₈ ) -S (O) ₂ -N (R ₈ )-, -N (R ₈ ) -C (R ₆ ) -O-, and -N (R ₈ ) -C ( Selected from the group consisting of R ₆ ) -S-.

For certain embodiments, Y is selected from the group consisting of —S (O) ₂ —, —C (O) —, —C (O) —NH—, and —NH—S (O) ₂ —.
For certain embodiments, Y is selected from the group consisting of S (O) ₂ —, —C (O) —, and —N (R ₈ ) —C (O) —.

For certain embodiments, Z is a bond or —O—.
For certain embodiments, Z is a bond.
For certain embodiments, Z is —O—.

  For certain embodiments, a and b are independently an integer from 1 to 6, where a + b is ≦ 7. For certain embodiments, a and b are each independently 1, 2 or 3. For certain embodiments, a and b are each 2.

For certain embodiments, m is 0 or 1; provided that when m is 1, n is 0 or 1.
For certain embodiments, m is 1 and n is 0 or 1.

For certain embodiments, m is 1 and n is 0.
For certain embodiments, m is 0.
For certain embodiments, n is 0, 1 or 2.

For certain embodiments, n is 1.
For certain embodiments, n is 0.
For certain embodiments, m is 0 and n is 0.

For example, certain embodiments of a pharmaceutical composition comprising a compound of formula I, II, III, IV, IVa, V, or Va or a pharmaceutically acceptable salt thereof, or certain embodiments of a compound of formula III, IVa, or Va, Alternatively, for any of the above embodiments wherein the formula includes a —NH ₂ group, eg, an embodiment wherein R ₂ is —NH ₂ , the —NH ₂ group is substituted with a —NH—G ₁ group to form a prodrug. May be. In such embodiments, G ₁ is —C (O) —R ″, α-aminoacyl, α-aminoacyl-α-aminoacyl, —C (O) —OR ″, —C (O) —N (R ″ ′ ) R ", -C (= NY ₂ ) -R", -CH (OH) -C (O) -OY ₂ , -CH (OC _1-4 alkyl) Y ₀ , -CH ₂ Y ₁ , and -CH (CH ₃ ) Y ₁ is selected from the group consisting of: For certain embodiments, G ₁ is —C (O) —R ″, α-aminoacyl, α-aminoacyl-α-aminoacyl, and —C (O) —OR “Selected from the group consisting of. Preferably, R” and R ″ ′ are independently selected from the group consisting of C _1-10 alkyl, C _3-7 cycloalkyl, phenyl, and benzyl, each of which is substituted Not or independently halogen, hydroxy, nitro, cyano, carboxy, C _1-6 alkyl, C _1-4 alkoxy, aryl, heteroaryl, aryl C _1-4 alkylenyl, heteroaryl C _1-4 alkylenyl , halo C _1-4 alkylenyl, halo C _1-4 Al _{Alkoxy, -OC (O) -CH 3,} -C (O) -O-CH 3, -C (O) -NH 2, -O-CH 2 -C (O) -NH 2, -NH 2, and It may be substituted with one or more substituents selected from the group consisting of —S (O) ₂ —NH ₂ ; provided that R ″ ′ may be hydrogen. Preferably the α-aminoacyl is an acyl group derived from an amino acid selected from the group consisting of racemic, D- and L-amino acids. Preferably Y ₂ is selected from the group consisting of hydrogen, C _1-6 alkyl, and benzyl. Preferably, Y ₀ is C _1-6 alkyl, carboxy C _1-6 alkylenyl, amino C _1-4 alkylenyl, mono-NC _1-6 alkylamino C _1-4 alkylenyl, and di-N, NC _1-6 alkyl. Selected from the group consisting of amino C _1-4 alkylenyl. Preferably, Y ₁ is a mono -NC _1-6 alkylamino, di -N, NC _1-6 alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and 4-C _1- Selected from the group consisting of ₄ alkylpiperazin-1-yl.

For certain embodiments, including any of the previous embodiments wherein G ₁ is present, G ₁ is selected from the group consisting of —C (O) —R ′, α-aminoacyl, and —C (O) —O—R ′. The
For certain embodiments, including any of the previous embodiments wherein G ₁ is present, G ₁ is —C (O) —R ′, α-amino-C _2-11 acyl, and —C (O) —O—R ′. Selected from the group consisting of: α-amino-C _2-11 acyl contains at least 2 carbon atoms, at most 11 carbon atoms in total, and one or more heteroatoms selected from the group consisting of O, S, and N Α-amino acids that may also contain are included.

For example, certain embodiments of a pharmaceutical composition comprising a compound of formula I, II, IIa, III, IV, IVa, V, or Va or a pharmaceutically acceptable salt thereof, or a compound of formula IIa, III, IVa, or Va Embedded image or any of the foregoing embodiments wherein the formula contains an —OH group, eg, an embodiment wherein R ₂ is —CH ₂ OH, the —OH group is substituted with an —OG ₂ group to form a prodrug May be. In such embodiments, G ₂ is —X ₂ —C (O) —R ″, α-aminoacyl, α-aminoacyl-α-aminoacyl, —X ₂ —C (O) —OR ″, —C (O) —N (R ″ ′) R ″ and —S (O) ₂ —R ″ are selected. For certain of these embodiments, X ₂ is a bond; —CH ₂ —O—; CH (CH ₃ ) —O—; selected from the group consisting of —C (CH ₃ ) ₂ —O—; in the case of —X ₂ —C (O) —OR ”, selected from —CH ₂ —NH— . Preferably, R ″ and R ″ ′ are independently selected from the group consisting of C _1-10 alkyl, C _3-7 cycloalkyl, phenyl, and benzyl, each of which is unsubstituted or independently Halogen, hydroxy, nitro, cyano, carboxy, C _1-6 alkyl, C _1-4 alkoxy, aryl, heteroaryl, aryl C _1-4 alkylenyl, heteroaryl C _1-4 alkylenyl, halo C _1-4 alkylenyl, halo C _1-4 alkoxy, -OC (O) -CH ₃ , -C (O) -O-CH ₃ , -C (O) -NH ₂ , -O-CH ₂ -C (O) -NH ₂ ,- May be substituted with one or more substituents selected from the group consisting of NH ₂ and —S (O) ₂ —NH ₂ ; provided that R ″ ′ may be hydrogen. α-Aminoacyl is an α-aminoacyl group derived from an amino acid selected from the group consisting of racemic, D- and L-amino acids.

  For certain embodiments, including any of the foregoing embodiments comprising an α-aminoacyl group, the α-aminoacyl is an α-aminoacyl group derived from a natural amino acid selected from the group consisting of racemic, D-, and L-amino acids. .

  For certain embodiments, including any of the foregoing embodiments comprising an α-aminoacyl group, the α-aminoacyl is an α-aminoacyl group derived from an amino acid found in a protein, wherein the amino acid is racemic, D-and Selected from the group consisting of L-amino acids.

For certain embodiments, including any of the foregoing embodiments wherein G ₂ is present, G ₂ is α-amino-C _2-5 alkanoyl, C _2-6 alkanoyl, C _1-6 alkoxycarbonyl, and C _1-6 alkylcarbamoyl. Selected from the group consisting of:

  For certain embodiments, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any of the above embodiments of Formula IIa, III, IVa, or Va in combination with a pharmaceutically acceptable carrier.

  For certain embodiments, the present invention provides an effective amount of a pharmaceutical composition of any of the preceding embodiments, or a compound or salt of any of the aforementioned embodiments of Formulas I, II, IIa, III, IV, IVa, V, or Va. Provided is a method for inducing cytokine biosynthesis in an animal comprising administering to the animal. For certain of these embodiments, the cytokine is selected from the group consisting of IFN-α, TNF-α, IL-6, IL-10, and IL-12. For certain of these embodiments, the cytokine is IFN-α or TNF-α. For certain of these embodiments, the cytokine is IFN-α.

  For certain embodiments, the present invention provides a therapeutically effective amount of a pharmaceutical composition of any of the preceding embodiments, or a compound or salt of any of the above embodiments of Formula I, II, IIa, III, IV, IVa, V, or Va. A method of treating a viral disease in an animal in need thereof is provided.

  For certain embodiments, the present invention provides a therapeutically effective amount of a pharmaceutical composition of any of the preceding embodiments, or a compound or salt of any of the above embodiments of Formula I, II, IIa, III, IV, IVa, V, or Va. A method of treating a neoplastic disease in an animal in need thereof is provided.

  As used herein, the terms “alkyl”, “alkenyl”, “alkynyl”, and the prefix “alk-” include both straight and branched groups, as well as cyclic groups such as cycloalkyl. And cycloalkenyl. Unless otherwise specified, these groups contain 1-20 carbon atoms, alkenyl groups contain 2-20 carbon atoms, and alkynyl groups contain 2-20 carbon atoms. In some embodiments, these groups have up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups may be monocyclic or bicyclic and preferably have from 3 to 10 ring carbon atoms. Examples of cyclic groups include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.

  Unless otherwise specified, “alkylene”, “-alkylene-”, “alkenylene”, “-alkenylene-”, “alkynylene”, and “-alkynylene-” are defined as “alkyl”, “alkenyl”, and A divalent form of an “alkynyl” group. The terms “alkylenyl”, “alkenylenyl”, and “alkynylenyl” are used when “alkylene”, “alkenylene”, and “alkynylene”, respectively, are substituted. For example, arylalkylenyl groups include those having an aryl group attached to an “alkylene” moiety.

  The term “haloalkyl” includes alkyl groups substituted with one or more halogen atoms and includes perhalogenated groups. This is also true for other groups containing the prefix “halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl and the like.

  As used herein, the term “aryl” includes carbocyclic aromatic rings or ring systems. Examples of the aryl group include phenyl, naphthyl, biphenyl, fluorenyl, and indenyl.

Unless otherwise specified, the term “heteroatom” refers to the atoms O, S, or N.
The term “heteroaryl” includes aromatic rings or ring systems that contain at least one ring heteroatom (eg, O, S, N). In certain embodiments, the term “heteroaryl” includes 2 to 12 ring carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and / or N as heteroatoms. Rings or ring systems are included. 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-oxidepyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl and the like.

  The term “heterocyclyl” includes non-aromatic rings or ring systems that contain at least one ring heteroatom (eg, O, S, N), such as fully saturated and partially saturated heteroaryl groups listed above. All unsaturated derivatives are included. In certain embodiments, the term “heterocyclyl” includes 2 to 12 ring carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and / or N as heteroatoms. Includes rings or ring systems. Examples of suitable 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- (1H) -yl, octahydroisoquinolin- (1H) -yl, dihydroquinoline- (2H ) -Yl, octahydroquinolin- (2H) -yl, dihydro-1H-imidazolyl, 3-azabicyclo [3.2.2] non-3-yl and the like.

  The term “heterocyclyl” includes bicyclic and tricyclic heterocyclic ring systems. Such ring systems include fused and / or bridged rings and spiro rings. In addition to saturated or partially saturated rings, fused rings can include aromatic rings such as benzene rings. Spiro rings include two rings connected by one spiro atom and three rings connected by two spiro atoms.

When “heterocyclyl” contains a nitrogen atom, the point of attachment of the heterocyclyl group may be a nitrogen atom.
The terms “arylene”, “heteroarylene”, and “heterocyclylene” are the divalent forms of the “aryl”, “heteroaryl”, and “heterocyclyl” groups defined above. The terms “arylenyl”, “heteroarylenyl”, and “heterocyclylenyl” are used when “arylene”, “heteroarylene”, and “heterocyclylene” are substituted, respectively. For example, an alkylarylenyl group includes those in which an alkyl group is bonded to an arylene moiety.

When more than one group (or substituent or variable) is present in any of the above formulas, each group (or substituent or variable), regardless of whether or not explicitly stated, Independently selected. For example, for —N (R ₉ ) —, each R ₉ group is independently selected. In other examples, when more than one Y group is present, each Y group is independently selected. In other examples, when more than one -N (R ₈ ) -QR ₄ group is present (eg, more than one -YR ₄ group is present, both containing -N (R ₈ ) -Q- groups ), Each R ₈ group is independently selected, each Q group is independently selected, and each R ₄ group is independently selected.

  The present invention includes any pharmaceutically acceptable form of the compounds (including intermediates) described herein, including isomers (eg, diastereomers and enantiomers), salts, solvates. , Polymorphs, prodrugs, etc. In particular, when a compound is optically active, the present invention specifically includes each enantiomer of the compound and a racemic mixture of the enantiomers. The term “compound” should be understood to include any or all of such forms, whether or not explicitly stated (sometimes “salts” are explicitly stated).

  The term “prodrug” means a compound that can be converted in vivo to become a compound of any of the aforementioned salts, solvates, polymorphs, or isomers that modulate the immune response. The prodrug itself may be a compound in any of the aforementioned salts, solvates, polymorphs, or isomers that modulate the immune response. This conversion can occur by a variety of mechanisms, such as chemical (eg solvolysis, eg in the blood) or enzymatic biotransformation. For a discussion of the use of prodrugs, see T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series, and Bioreversible Carriers in Drug Design, Editor Edward B. Roche, American Pharmaceutical. It is shown in Association and Pergamon Press, 1987.

The compounds of the present invention (including intermediates) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The term “tautomer” or “tautomeric form” refers to structural isomers with different energies that can be interconverted through a low energy barrier. For example, proton tautomers (prototropic tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. When the compound or the compound in the composition of the present invention has an amino group for the R ₂ group, proton transfer may occur between the nitrogen atom of this amino group and the 3-position nitrogen atom. For example, the following formulas _Ia and _Ib are tautomeric forms.

Manufacture of a compound The compound of the present invention can be synthesized by a synthetic route including a method similar to a method well known in the art, particularly in consideration of the description contained in the present specification. Starting materials are generally available from vendors such as Aldrich Chemicals (Milwaukee, Wis., USA) or can be readily prepared by methods well known to those skilled in the art (eg, generally prepared by the methods described below: Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York, (1967-1999); Alan R. Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive Organic Functional Group Transformations, v. 1-6 , Pergamon Press, Oxford, UK (1995); Barry M. Trost and Ian Fleming, Comprehensive Organic Synthesis, v. 1-8, Pergamon Press, Oxford, UK (1991); or Beilsteins Handbuch der organischen Chemie, 4, Aufl. Ed. Springer-Verlag, Germany, Berlin, including supplements (also available in the Beilstein online database)).

  For purposes of illustration, the reaction scheme described below shows possible routes for the synthesis of the compounds of the invention and key intermediates. See the examples below for a more detailed description of the individual reaction steps. Those skilled in the art will recognize that other synthetic routes can be used to produce the compounds of the invention. Although certain starting materials and reagents are described in the reaction scheme and discussed below, other starting materials and reagents can be used instead to obtain a variety of derivatives and / or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified using routine methods well known to those skilled in the art in view of this description.

  In preparing the compounds of the present invention, it may sometimes be necessary to protect certain functional groups upon reaction of other functional groups on the intermediate. The need for such protection will vary depending on the nature of the particular functional group and the conditions of the reaction process. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc). Suitable hydroxy protecting groups include acetyl and silyl groups such as t-butyldimethylsilyl group. For a general description of protecting groups and their use, see T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

  The general methods and techniques for separation and purification can be used to isolate the compounds of the present invention and various intermediates associated therewith. These methods include, for example, all types of chromatography (high performance liquid chromatography (HPLC), column chromatography with common adsorbents such as silica gel, and thin layer chromatography), recrystallization, and fractionation (ie liquid- Liquid) extraction methods can be included.

For certain embodiments of the present invention, compounds can be prepared according to Reaction Scheme I; R, R ₁ , R ₂ , X ″ ′, and n are as defined above, and E is carbon (imidazoquinolines) Or nitrogen (imidazonaphthyridines).

In step (1) of Reaction Scheme I, 4-chloro-3-nitroquinoline or 4-chloro-3-nitro [1,5] naphthyridine of formula XX is converted to an amine of formula R ₁ -X "'-NH ₂ . To give a compound of formula XXI, which is carried out by adding the amine to a solution of the compound of formula XX in a suitable solvent such as anhydrous tetrahydrofuran in the presence of a base such as triethylamine. This reaction can be carried out at ambient temperature, subambient temperature, eg 0 ° C., or elevated temperature, eg 45 ° C. Numerous compounds of formula XX are known or using known synthetic methods USP No. 4,689,338 (Gerster), 5,268,376 (Gerster), 5,389,640 (Gerster et al.), 6,194,425 (Gerster et al.), 6,331,539 (Crooks et al.), 6,451,810 (Coleman et al.), 6,541,485 (Crooks et al.), 6,660,747 (Crooks et al.) Et al.), 6,683,088 (Crooks et al.), 6,656,938 (Crooks et al.) And U.S. Patent Application Publication No. US 2004/0147543 see (Hays et al.) An expression R ₁ -X "'- amine NH ₂ are commercially available;. Others can be prepared using known synthetic methods.

  In step (2) of Reaction Scheme I, the compound of formula XXI is reduced to give the compound of formula XXII. This reduction can be carried out using a common heterogeneous hydrogenation catalyst such as platinum on carbon. This reaction can be conveniently carried out in a suitable solvent such as acetonitrile, toluene, ethanol, methanol and / or isopropanol by means of a Parr apparatus.

  Other reduction methods can be used for the reduction in step (2). For example, an aqueous sodium dithionite solution can be added to a solution or suspension of the compound of formula XXI in a suitable solvent, such as ethanol or isopropanol. The reaction can be carried out at an elevated temperature, such as reflux temperature or ambient temperature.

In step (3) of Reaction Scheme I, 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 give 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula XXIII. In part (i), the acyl halide is added to a solution of the compound of formula XXII in a suitable solvent such as acetonitrile or anhydrous dichloromethane, optionally in the presence of a base such as triethylamine. This reaction can be carried out at a reduced temperature, for example, 0 ° C., or ambient temperature. In part (ii), the product of part (i) is heated in an alcoholic solvent in the presence of a base. For example, the product of part (i) is refluxed in ethanol in the presence of excess triethylamine or heated with methanolic ammonia.

Alternatively, step (3) can be performed by reacting a compound of formula XXII with a carboxylic acid or equivalent thereof. Suitable carboxylic acid equivalents include orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that the desired R ₂ substituent is obtained in the compound of formula XXIII. For example, triethyl orthovalerate would produce a compound where R ₂ is butyl. This reaction can be carried out in the absence of a solvent or in an inert solvent such as anhydrous toluene. This reaction is carried out at an elevated temperature. Optionally, a catalyst such as pyridine hydrochloride can be used.

Alternatively, when R ₂ is —NH ₂ , this reaction can be carried out by reacting the compound of formula XXII with cyanogen bromide in a suitable solvent such as ethanol. This reaction can be carried out at an elevated temperature, for example at reflux temperature.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme II; R, R ₁ , R ₂ , E, X ″ ′, and m are as defined above, and R _3d is as defined below. 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula XXIV can be prepared according to Reaction Scheme I.

Compounds of formula XXIV can be treated by known palladium-catalyzed coupling reactions, such as Suzuki coupling and Heck reactions. For example, a compound of formula XXIV can be converted to a boronic acid of formula R _3d —B (OH) ₂ , its anhydride, or a boronic ester of formula R _3d —B (O-alkyl) ₂ [wherein R _3d is —R _4b, -X _a -R _4, be -X _b -YR ₄ or -X _b -R _5,; in these X _a is an alkenylene; X _b is arylene, heteroarylene, and alkenylene, they Arylene or heteroarylene may be present in the middle or at the end; R _4b is aryl or heteroaryl, where the aryl or heteroaryl group is unsubstituted or substituted as defined for R ₄ above And R ₄ , R ₅ , and Y are as defined above] to obtain a compound of formula XXV. Many boronic acids of the formula R _3d —B (OH) ₂ , their anhydrides or boronic esters of the formula R _3d —B (O-alkyl) ₂ are commercially available; others are readily available using known synthetic methods Can be manufactured.

The Heck reaction can also be used in Reaction Scheme II to provide compounds of formula XXV where R _3d is —X _a —R _4b and —X _a —YR ₄ . The Heck reaction is performed by coupling a compound of formula XXIV with a compound of formula H ₂ C═C (H) —R _4b or H ₂ C═C (H) —YR ₄ . Some of these vinyl substituted compounds are commercially available; others can be prepared by known methods. The Suzuki reaction and the Heck reaction can be carried out according to any method described in US Patent Application Publication No. 2004/0147543 (Hays et al.).

Compounds of the formula XXV in which R _3d is —X _c —R ₄ , X _c is alkylene and R ₄ is as defined above are palladium-catalyzed coupling reactions such as Stille linkages or Sonogashira It can also be produced by bonding. These reactions are carried out by combining a compound of formula XXIV with a compound of formula (alkyl) ₃ Sn—C≡CR ₄ , (alkyl) ₃ Si—C≡CR ₄ , or HC≡CR ₄ .

Prepared by palladium mediated binding reaction as described above, R _3d is -X _a -R ₄ , -X _a -YR ₄ , -X _b2 -YR ₄ , -X _b2 -R ₅ , or -X _c -R ₄ An alkenylene present in a compound of formula XXV, wherein X _b2 is an alkylene with an arylene or heteroarylene in the middle or terminal and X _a , X _c , Y, R ₄ and R ₅ are as defined above, or Reduction of the alkynylene group to a compound of formula XXV where R _3d is -X _d -R ₄ , -X _d -YR ₄ , -X _e -YR ₄ , or -X _e -R ₅ (X _d is alkylene and There; X _e is alkylene with arylene or heteroarylene in the middle or end; R _4, R _5, and Y can be obtained in which) as defined above. This reduction can be carried out by hydrogenation according to the method described in US Patent Application Publication No. 2004/0147543 (Hays et al.).

A copper mediated binding reaction can be used to produce compounds of formula XXV where R _3d is —NH—C (R ₆ ) —R ₄ , —NH—SO ₂ —R ₄ . This reaction comprises a compound of formula XXIV and an amide or sulfonamide of formula -NH-C (R ₆ ) -R ₄ or -NH-SO ₂ -R ₄ , copper (I) iodide, potassium phosphate, and racemic Can be carried out by coupling in a suitable solvent such as 1,4-dioxane in the presence of the trans-1,2-diaminocyclohexane. This reaction can be carried out at an elevated temperature, for example 110 ° C. Many amides and sulfonamides of these formulas are commercially available; others can be prepared by conventional methods. Using these reaction conditions, a compound of formula XXIV can be coupled with a variety of nitrogen-containing heterocyclyl compounds so that R _3d is -heterocyclyl, -heterocyclylene-R ₄ , or -heterocyclylene-YR ₄ Or a compound of formula XXV, where heterocyclyl or heterocyclylene is attached to the quinoline or naphthyridine ring via a nitrogen atom.

Further, those compounds of formula XXV, wherein R _3d is -heterocyclyl, -heterocyclylene-R ₄ , or -heterocyclylene-YR ₄ (heterocyclyl or heterocyclylene is a quinoline ring through the nitrogen atom Or (which are attached to the naphthyridine ring) can be prepared using a palladium-mediated linkage method; this involves the compound of formula XXIV and a nitrogen-containing heterocyclyl compound, tris (dibenzylideneacetone) Conveniently performed by conjugation in the presence of dipalladium, (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, sodium t-butoxide, and a suitable solvent such as toluene Is done. This reaction can be carried out at an elevated temperature, for example 80 ° C. The synthesis method described in International Patent Application Publication No. WO 05/123080 (Merrill et al.) Can also be used. Using these reaction conditions, a compound in which R _3d is —NH—R ₄ can also be produced.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme III; R, R ₁ , R ₂ , E, X ″ ′, and m are as defined above, Bn is benzyl, R _3e is defined below.

  In step (1) of Reaction Scheme III, benzyloxyaniline or benzyloxyaminopyridine of formula XXVI is converted to 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid) and Treatment with a condensate formed from triethylorthoformate gives the imine of formula XXVII. This reaction can be carried out by adding a solution of the compound of formula XXVI to a heated mixture of Meldrum acid and triethyl orthoformate and heating the reaction to an elevated temperature, for example 45 ° C. Many anilines and aminopyridines of formula XXVI are commercially available; others can be prepared by known synthetic methods. For example, benzyloxyaminopyridine of formula XXVI can be prepared using the method of Holladay et al., Biorg. Med. Chem. Lett., 8, pp. 2797-2802, (1998).

  In step (2) of Reaction Scheme III, the imine of formula XXVII is pyrolyzed and cyclized to give the compound of formula XXVIII. This reaction is conveniently carried out at a temperature of 200 to 250 ° C. in a medium such as the heat transfer liquid DOWTHERM A.

  In step (3) of Reaction Scheme III, a compound of formula XXVIII is nitrated under general nitration conditions to yield a benzyloxy-3-nitroquinolin-4-ol or benzyloxy-3-nitro [ 1,5] Naphthyridin-4-ol is obtained. This reaction is conveniently carried out by adding nitric acid to a compound of formula XXVIII in a suitable solvent, for example propionic acid, and heating the mixture to an elevated temperature, for example 125 ° C.

  In step (4) of Reaction Scheme III, benzyloxy-3-nitroquinolin-4-ol or benzyloxy-3-nitro [1,5] naphthyridin-4-ol of formula XXIX is a common chlorination chemical reaction. To give benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4-chloro-3-nitro [1,5] naphthyridine of formula XXX. This reaction is conveniently carried out by treating the compound of formula XXIX with a suitable solvent such as phosphorus oxychloride in DMF. This reaction can be carried out at an elevated temperature, for example 100 ° C.

Steps (5), (6) and (7) of Reaction Scheme III can be carried out according to steps (1), (2) and (3) of Reaction Scheme I, respectively.
In step (8) of Reaction Scheme III, the benzyloxy-1H-imidazo [4,5-c] quinoline of formula XXXI or the benzyloxy-1H-imidazo [4,5-c] [1,5] naphthyridine The group is cleaved to give 1H-imidazo [4,5-c] quinolinol or 1H-imidazo [4,5-c] [1,5] naphthyridinol of formula XXXII. This cleavage can be carried out in a solvent such as ethanol in a Pal apparatus under hydrocracking conditions using a suitable heterogeneous catalyst such as palladium on carbon. Alternatively, this reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst. 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. This reaction is carried out at an elevated temperature, for example the reflux temperature of the solvent.

In step (9) of Reaction Scheme III, 1H-imidazo [4,5-c] quinolinol or 1H-imidazo [4,5-c] [1,5] naphthyridinol of formula XXXII is used as a Williamson type Is converted to ether substituted 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula XXXIII. This reaction involves halogenation of a compound of formula XXXII in the presence of a base of the formula halogenated-R _4b , halogenated-alkylene-R ₄ , halogenated-alkylene-YR ₄ , or halogenated-alkylene-R ₅ This is done by treatment with a selected aryl, alkyl, or arylalkylenyl. This reaction can be carried out by combining these halides 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 ° C or 85 ° C. A number of halogenated alkyls, arylalkylenyls, and aryls of these formulas are commercially available, including substituted and unsubstituted benzyl bromides, substituted or unsubstituted bromides and alkyl chlorides or -Arylalkylenyl, as well as substituted fluorobenzenes are included. Other halides of these formulas can be prepared using common synthetic methods. The methods described in International Patent Application Publication Nos. WO 2005/020999 (Lindstrom et al.) And WO 2005/032484 (Lindstrom et al.) Can be used.

For certain embodiments of the invention, the compound can be prepared according to Reaction Scheme IV; R, R ₁ , R ₂ , E, X ″ ′, and n are as defined above. In Reaction Scheme IV, Reduction of 1H-imidazo [4,5-c] quinoline of formula XXXIII or 1H-imidazo [4,5-c] [1,5] naphthyridine yields a compound of formula XXXIV, which comprises a compound of formula XXIII Can be suspended or dissolved in trifluoroacetic acid and hydrogenated by adding platinum (IV) oxide.This reaction can be carried out in a PAL apparatus.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme V; R ₁ , R ₂ , R _{A ′} , R _{B ′} , and X ″ ′ are as defined above.
In steps (1)-(3) of Reaction Scheme V, 2,4-dichloro-3-nitropyridine of formula XXXV is converted to 4-chloro-1H-imidazo [4,5-c] pyridine of formula XXXVI To do. These steps can be performed according to the general method of steps (1) to (3) of Reaction Scheme I. 2,4-Dichloro-3-nitropyridine of formula XXXV is known or can be prepared using known synthetic methods; see for example USP No. 6,525,064 (Dellaria, et al.) And references cited therein. I want to be.

  In step (4) of Reaction Scheme V, the chloro group is removed from 4-chloro-1H-imidazo [4,5-c] pyridine of formula XXXVI to yield 1H-imidazo [4,5-c] of formula Vc. Pyridine is obtained. This reaction can be carried out in a solvent mixture containing ethanol and methanol using ammonium formate and a heterogeneous catalyst such as palladium on carbon. This reaction is carried out at an elevated temperature, for example the reflux temperature of the solvent system.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme VI; R, R ₁ , R ₂ , E, and n are as defined above.
In step (1) of Reaction Scheme VI, 1H-imidazo [4,5-c] quinolin-1-amine or 1H-imidazo [4,5-c] [1,5] naphthyridin-1-amine of formula XXXVII And a ketone of formula R ₁ ═O are reacted under acidic conditions to give a hydrazone of formula XXXVIII. This 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. This reaction is carried out at an elevated temperature, for example 110 ° C. Compounds of formula XXXVII are known or can be prepared using known synthetic methods; for example, US Patent Application Publication No. 2005/0054640 (Griesgraber et al.) And International Patent Application Publication No. WO 06/026760 (Stoermer et al.). As well as the references cited therein.

  In step (2) of Reaction Scheme VI, the hydrazone of formula XXXVIII is reduced to give 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] of formula XXXIX. Obtain naphthyridine. This reaction can be carried out by adding sodium borohydride to a solution of the compound of formula XXXVIII in a suitable solvent such as methanol. This reaction can be carried out at ambient or sub-ambient temperature, eg 0 ° C.

For certain embodiments of the invention, the compound can be prepared according to Reaction Scheme VII; R, R ₁ , R ₂ , R _3d , E, and m are as defined above.
In steps (1) and (2) of Reaction Scheme VII, a bromo-substituted 1H-imidazo [4,5-c] quinolin-1-amine or 1H-imidazo [4,5-c] [1 , 5] naphthyridin-1-amine according to the method of steps (1) and (2) of Reaction Scheme VI, 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] of formula XLI Convert to [1,5] naphthyridine. Compounds of formula XL are known or can be prepared using known synthetic methods; for example, US Patent Application Publication No. 2005/0054640 (Griesgraber et al.) And International Patent Application Publication No. WO 06/026760 (Stoermer et al.). As well as the references cited therein.

  In step (3) of Reaction Scheme VII, a method wherein 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula XLI is described in Reaction Scheme II To 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula XLII.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme VIII; R, R ₁ , R ₂ , R _3e , Bn, E, and m are as defined above.
In steps (1) and (2) of Reaction Scheme VIII, a benzyl substituted 1H-imidazo [4,5-c] quinolin-1-amine or 1H-imidazo [4,5-c] [1 , 5] Naphthyridin-1-amine is converted to 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] of formula XLIV by the method of steps (1) and (2) of Reaction Scheme VI. Convert to [1,5] naphthyridine. Compounds of formula XLIII are known or can be prepared using known synthetic methods; for example, US Patent Application Publication No. 2005/0054640 (Griesgraber et al.) And International Patent Application Publication No. WO 06/026760 (Stoermer et al.). As well as the references cited therein.

  In steps (3) and (4) of Reaction Scheme VIII, 1H-imidazo [4,5-c] quinoline of formula XLIV or 1H-imidazo [4,5-c] [1,5] naphthyridine is reacted respectively. Convert to 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula XLV by the method described in steps (8) and (9) of Scheme III .

For certain embodiments of the invention, the compound can be prepared according to Reaction Scheme IX; R, R ₁ , R ₂ , E, and n are as defined above. In Reaction Scheme IX, 1H-imidazo [4,5-c] quinolin-1-amine or 1H-imidazo [4,5-c] [1,5] naphthyridin-1-amine of formula XXXIX is reduced, 1H-imidazo [4,5-c] quinolin-1-amine or 1H-imidazo [4,5-c] [1,5] naphthyridin-1-amine of formula XLVI is obtained. This reduction can be carried out as described in Reaction Scheme IV.

For certain embodiments of the invention, the compound can be prepared according to Reaction Scheme X; R ₁ , R ₂ , R _{A ′} , and R _{B ′} are as defined above.
In steps (1) and (2) of Reaction Scheme X, 4-chloro-1H-imidazo [4,5-c] pyridin-1-amine of formula XLVII is converted to steps (1) and (2) of Reaction Scheme VI. ) To 4-chloro-1H-imidazo [4,5-c] pyridin-1-amine of formula XLVIII. Compounds of formula XLVII are known or can be prepared using known synthetic methods; see, eg, International Patent Application Publication No. WO 06/026760 (Stoermer et al.) And references cited therein.

  In step (3) of Reaction Scheme X, the chloro group is removed from 4-chloro-1H-imidazo [4,5-c] pyridin-1-amine of formula XLVIII to yield 1H-imidazo [4, 5-c] pyridin-1-amine is obtained. This reaction can be carried out as described in step (4) of Reaction Scheme V.

For certain embodiments of the invention, the compound can be prepared according to Reaction Scheme XI; R, R ₁ , R ₂ , E, m, and n are as defined above and D is bromo or benzyloxy. .

In Reaction Scheme XI, N- (4-chloroquinolin-3-yl) amide or N- (4-chloro [1,5] naphthyridin-3-yl) amide of formula XLIX is represented by the formula R ₁ ONH ₂ .HCl React with hydroxylamine hydrochloride and cyclize to give 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula L. This reaction can be carried out by adding hydroxylamine hydrochloride to a solution of a compound of formula XLIX in an alcoholic solvent such as ethanol. This reaction can be carried out at an elevated temperature, for example the reflux temperature of the solvent. N- (4-Chloroquinolin-3-yl) amide or N- (4-chloro [1,5] naphthyridin-3-yl) amide of formula XLIX is known or prepared using known synthetic methods See, eg, International Patent Application Publication No. WO 06/028962 (Krepski et al.).

  Compounds of formula L where m is 1 and D is bromo can be further processed by the general methods described in Reaction Scheme II. Compounds where m is 1 and D is benzyloxy in Formula I can be further processed by the general methods described in Reaction Scheme III.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme XII; R, R ₁ , R ₂ , Bn, E, and n are as defined above.
In step (1) of Reaction Scheme XII, N- (4-chloroquinolin-3-yl) amide or N- (4-chloro [1,5] naphthyridin-3-yl) amide of formula LI is replaced with O- Reaction with benzylhydroxylamine hydrochloride and cyclization to form 1-benzyloxy-1H-imidazo [4,5-c] quinoline or 1-benzyloxy-1H-imidazo [4,5-c] [1 , 5] get naphthyridine. This reaction can be carried out by adding O-benzylhydroxylamine hydrochloride to a solution of a compound of formula LI in a solvent such as isopropanol. This reaction can be carried out at an elevated temperature, for example the reflux temperature of the solvent. N- (4-chloroquinolin-3-yl) amide or N- (4-chloro [1,5] naphthyridin-3-yl) amide of formula LI is known or prepared using known synthetic methods See, eg, International Patent Application Publication No. WO 06/028962 (Krepski et al.).

  In step (2) of Reaction Scheme XII, 1-benzyloxy-1H-imidazo [4,5-c] quinoline or 1-benzyloxy-1H-imidazo [4,5-c] [1,5 of formula LII The naphthyridine is cleaved to give 1H-imidazo [4,5-c] quinolin-1-ol or 1H-imidazo [4,5-c] [1,5] naphthyridin-1-ol of formula LIII. This cleavage can be carried out in a solvent such as ethanol in a Pal apparatus under hydrocracking conditions using a suitable heterogeneous catalyst such as palladium on carbon. Alternatively, this reaction can be carried out by transfer hydrogenation in the presence of a suitable hydrogenation catalyst. 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. This reaction is carried out at an elevated temperature, for example the reflux temperature of the solvent.

In step (3) of Reaction Scheme XII, 1H-imidazo [4,5-c] quinolin-1-ol or 1H-imidazo [4,5-c] [1,5] naphthyridin-1-ol of formula LIII Is converted to ether substituted 1H-imidazo [4,5-c] quinoline or 1H-imidazo [4,5-c] [1,5] naphthyridine of formula LIV. This reaction can be carried out by treating a compound of formula LIII with a halide of formula halogenated-R ₁ in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). This reaction can be carried out by heating a mixture of halide, compound of formula LIII and DBU to an elevated temperature, for example 120 ° C., in a sealed pressure vessel. Some of the halides of formula halide-R ₁ are commercially available; others can be prepared using known synthetic methods.

For certain embodiments of the invention, the compound can be prepared according to Reaction Scheme XIII; R, R ₁ , R ₂ , Bn, and n are as defined above.
In step (1) of Reaction Scheme XIII, N- (4-chloro-5,6,7,8-tetrahydroquinolin-3-yl) amide of formula LV is reacted with O-benzylhydroxylamine hydrochloride; Cyclization provides 1-benzyloxy-4-chloro-5,6,7,8-tetrahydro-1H-imidazo [4,5-c] quinoline of formula LVI. This reaction can be carried out as described in step (1) of Reaction Scheme XII. N- (4-Chloro-5,6,7,8-tetrahydroquinolin-3-yl) amide of formula LV is known or can be prepared using known synthetic methods; see, eg, International Patent Application Publication No. See WO 06/028962 (Krepski et al.).

  In step (2) of Reaction Scheme XIII, both the benzyl and chloro groups of 1-benzyloxy-4-chloro-5,6,7,8-tetrahydro-1H-imidazo [4,5-c] quinoline are removed. Cleavage to give 1H-imidazo [4,5-c] quinolin-1-ol of formula LVII. This cleavage can be carried out as described in step (2) of Reaction Scheme XII.

  In step (3) of Reaction Scheme XIII, 1H-imidazo [4,5-c] quinolin-1-ol of Formula LVII is converted to an ether substituted 1H of Formula IIIb by the method described in Step (3) of Reaction Scheme XII. -Convert to imidazo [4,5-c] quinoline.

For certain embodiments of the invention, the compounds can be prepared according to Reaction Scheme XIV; R _{A ′} , R _{B ′} , R ₁ , and R ₂ are as defined above.
In step (1) of Reaction Scheme XIV, 2,4-dichloro-3-nitropyridine of formula XXXV is reduced to give 2,4-dichloropyridin-3-amine of formula LVIII. This reduction can be performed by the method described in step (2) of Reaction Scheme I.

In step (2) of Reaction Scheme XIV, 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, N- (2,4-dichloropyridin-3-yl) amide of formula LIX is obtained. This reaction can be carried out by adding the acyl halide to a solution of 2,4-dichloropyridin-3-amine of formula LVIII in a suitable solvent such as anhydrous dichloromethane in the presence of a base such as triethylamine. This reaction can be carried out at a reduced temperature, for example, 0 ° C., or ambient temperature.

  In steps (3), (4) and (5) of Reaction Scheme XIV, N- (2,4-dichloropyridin-3-yl) amide of formula LIX is replaced with steps (1), ( Conversion to the ether substituted 1H-imidazo [4,5-c] pyridine of formula Ve by the method described in 2) and (3).

  The compounds useful in the compositions of the present invention and the compounds of the present invention can also be prepared using variations that are obvious to those skilled in the art in the synthetic routes shown in Reaction Schemes I-XI. The compounds useful for the composition of the present invention and the compounds of the present invention can also be produced using the synthetic routes described in the examples below.

Pharmaceutical Compositions and Biological Activity The pharmaceutical compositions of the present invention contain a therapeutically effective amount of the compound or salt in combination with a pharmaceutically acceptable carrier.

  The terms “therapeutically effective amount” and “effective amount” mean an amount of a compound or salt sufficient to induce a therapeutic or prophylactic effect, eg, cytokine induction, immunomodulation, antitumor activity, and / or antiviral activity. To do. The exact amount of the compound or salt used in the pharmaceutical composition of the invention will vary according to factors known to those skilled in the art, such as the physical and chemical properties of the compound or salt, the nature of the carrier, and the intended dosage regimen. I will.

  In certain embodiments, the composition of the present invention has a composition of about 100 nanograms / kilogram (ng / kg) to about 50 milligrams / kilogram (mg / kg), preferably about 10 micrograms / kilogram (μg / kg) to about 5 mg / kg. It will contain sufficient active ingredient or prodrug to supply the subject with a quantity of the compound or salt of the invention in kg.

In other embodiments, the composition of the invention contains sufficient active ingredient or prodrug to provide the subject with an amount of, for example, from about 0.01 to about 5.0 mg / m ² as calculated by the Dubois method. waxes; in this method, calculated by weight of the subject to the subject's body surface area ^{(m 2): m 2 =} ( weight kg ^0.425 × Height cm ^0.725) × 0.007184; however, in some embodiments in an amount outside this range the The methods of the invention can be practiced by administering an inventive compound or salt or composition to a subject. In some of these embodiments, the methods of the invention administer sufficient compound to provide the subject in an amount of about 0.1 to about 2.0 mg / m ² , eg, about 0.4 to about 1.2 mg / m ^2. Including that.

  Various dosage forms such as tablets, troches, capsules, parenteral preparations, syrups, creams, ointments, aerosol preparations, transdermal patches, transmucosal patches and the like can be used. These dosage forms can be prepared by conventional methods using common pharmaceutically acceptable carriers and additives, and these methods generally comprise the step of combining the active ingredient with a carrier. In general, the compositions according to the invention can be prepared by intimately combining the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then if necessary shaping the product into the intended dosage form.

  The pharmaceutically acceptable carrier may be a solid or liquid, or a gas that has been compressed into a liquid. Suitable pharmaceutical carriers for use in the formulations of the present invention are known. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, eg, systemic administration (oral, parenteral, intravenous, or intranasal) and topical administration.

  In preparing an oral dosage form, any conventional pharmaceutical carrier can be used: for example, oral liquid formulations (eg, emulsions, suspensions, elixirs, solutions, syrups) such as water, glycols In the case of oils and alcohols and oral solid preparations (eg pills, granules, powders, capsules, tablets) eg starches, sugars (including lactose, sucrose, glucose, mannitol), silicic acid, methylcellulose, Carboxymethylcellulose, alginate, pectin, dextrin, gelatin, polyvinylpyrrolidone, gum arabic, glycerol, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, sodium carbonate, low melting wax, cocoa butter, cetyl Alcohol, monos Alin glycerol, kaolin and bentonite clay, talc, calcium stearate, magnesium carbonate, magnesium stearate, solid polyethylene glycols, carrier, such as sodium lauryl sulfate, and mixtures thereof.

  Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, sweetening agents, solubilizing agents, and thickening agents thereto. Aqueous suspensions suitable for oral use include finely divided active ingredients, viscous materials or thickeners such as synthetic rubbers, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. It can be prepared by dispersing in water together with the agent.

  In the case of capsules, tablets and pills, these dosage forms can also contain buffering agents. Oral compositions can also contain adjuvants such as wetting, emulsifying and suspending agents, sweetening agents and flavoring agents.

  Parenteral injection pharmaceutical compositions are reconstituted into pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile injectable solutions or suspensions just prior to use. For aseptic powder. Suitable aqueous and non-aqueous carriers include water, aqueous solutions such as saline (isotonic sodium chloride solution), Ringer's solution, dextrose solution, and Hank's solution, ethanol, polyols (eg 1,3-butanediol, glycerol, propylene) Glycols, polyethylene glycols, etc.), and suitable mixtures thereof, vegetable oils such as 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 included. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

  These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the activity of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like. It may be desirable to include isotonic agents such as sugars, sodium chloride. Prolonged absorption of the injectable dosage form can be obtained by including a substance that delays absorption, for example, aluminum monostearate and gelatin.

  In some cases, it may be desirable to reduce the rate of drug absorption from subcutaneous or intramuscular injection in order to sustain the effect of the drug. This can be achieved using a suspension of crystalline or amorphous material with low water solubility. In so doing, the absorption rate of the drug will depend on its solubility, which will depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenteral dosage form is accomplished by dissolving or suspending the drug in an oil vehicle.

  Injectable depot forms can be made by forming drug microencapsulated matrices in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot forms can also be made by entrapping the drug in body tissue compatible liposomes or microemulsions.

  Injectables can be obtained, for example, by filtration through a bacteria capture filter or by including a bactericide in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile medium for injection just before use. Can be sterilized.

  Pharmaceutical compositions for topical administration can include the liquid dosage forms described above, as well as ointments, creams, lotions, aerosols, sprays, dusts and powders, which contain the active ingredient as a topical formulation. Prepared in combination with common pharmaceutically acceptable carriers commonly used in dry formulations, solutions, creams and aerosols. For example, an aqueous or oily base can be added to the ointment and cream together with a suitable thickener and / or gelling agent. Such bases can include, for example, water and / or oils such as mineral oil, liquid petrolatum, white petrolatum or vegetable oil. Thickeners that can be used according to the properties of the base include petrolatum (soft paraffin), aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, polyoxyethylene, polyoxypropylene, hydrogenated lanolin, beeswax, etc. It is. Alternatively, the active ingredients can be formulated, for example, as a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more of the following mixtures: 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 application by nasal passage or inhalation. The active ingredient is in the form of an aerosol from a pressurized pack or nebulizer, suitable propellant such as carbon dioxide, air, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2-tetrafluoroethane Or other suitable gas can be used for delivery. In the case of a pressurized aerosol, the dosage unit can be determined by installing a valve to deliver a metered amount. For example, capsules or cartridges made of gelatin for use in an inhaler or insufflator can be prepared to contain a powder mix of the active ingredient and a suitable powder base such as lactose or starch.

  The compounds and / or salts or compositions described herein can also be delivered in the form of transdermal patches, transmucosal patches, and the like. Matrix or reservoir type patches common in the art for transdermal or transmucosal delivery can be used for this purpose. In this case, a matrix, such as a pressure sensitive adhesive matrix, or a carrier in the reservoir acts as a pharmaceutically acceptable carrier.

  The compounds or salts described herein can be administered as a single therapeutic agent in a treatment regime. Alternatively, the compounds or salts described herein can be administered in combination with one or more other active agents, including additional immune response modifiers, antiviral agents, antibiotics, antibodies, proteins, peptides , Oligonucleotides and the like.

  It has been shown in experiments conducted according to the test methods described below that the compositions and compounds or salts of the present invention induce the production of certain cytokines. These results indicate that the compounds or salts or compositions of the invention are useful for modulating the immune response in a number of different ways, and thus they are useful for the treatment of a variety of disorders.

  Cytokines whose production is induced by administration of the compounds or salts or compositions described herein generally include interferon-α (IFN-α) and tumor necrosis factor-α (TNF-α) and certain types of interferons. Includes leukin (IL). Cytokines whose biosynthesis can be induced by the compounds or salts of the present invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and various other cytokines be able to. Among other effects, these and other cytokines can specifically inhibit virus production and tumor cell growth, so that the compounds or salts or compositions of the invention are useful in the treatment of viral and neoplastic diseases . Accordingly, the present invention provides a method of inducing cytokine biosynthesis in an animal comprising administering to the animal an effective amount of a compound or salt or composition of the present invention. An animal to which a compound or salt or composition of the present invention is administered for cytokine biosynthesis is an animal that may be associated with the aforementioned diseases, such as viral diseases or neoplastic diseases, and the compound or salt of the present invention or Administration of the composition can provide a therapeutic treatment. Alternatively, a compound or salt or composition of the invention may be administered to an animal before the animal suffers from the disease, whereby administration of the compound or salt or composition of the invention provides a prophylactic treatment. it can.

  The compounds or salts described herein can induce the production of cytokines and can act on other aspects of the innate immune response. For example, natural killer cell activity can be stimulated, which may be due to cytokine induction. The compounds or salts of the present invention can activate macrophages, which stimulate nitric oxide secretion and other cytokine production. Furthermore, the compounds or salts of the invention can cause proliferation and differentiation of B lymphocytes.

The compounds or salts described herein can also act on the acquired immune response. For example, administration of a compound or salt of the present invention indirectly induces the production of IFN-γ, a T helper type 1 (T _H 1) cytokine, and IL-, a T helper type 2 (T _H 2) cytokine. 4. Can inhibit the production of IL-5 and IL-13.

  Regardless of whether it is for prophylactic or therapeutic treatment of a disease, or to act on innate or acquired immunity, a compound or salt or composition of the invention alone or, for example, It can be administered in combination with one or more active ingredients in a vaccine adjuvant. When administered with other ingredients, the compound or salt or composition of the invention and one or more other ingredients are separately; either together but independently, such as in solution; or combined together, For example, it can be administered (a) covalently or (b) non-covalently, eg, in a colloidal suspension.

Conditions under which a compound or salt or composition as defined herein can be used for treatment include, but are not limited to:
(a) viral diseases such as those caused by infection with the following viruses: adenoviruses, herpes viruses (eg HSV-I, HSV-II, CMV, or VZV), pox viruses (eg orthopox viruses such as variola virus or vaccinia) Virus, or contagious molluscumoma virus), picornavirus (eg rhinovirus or enterovirus), orthomyxovirus (eg influenza virus), paramyxovirus (eg parainfluenza virus, mumps virus, measles) Viruses, and respiratory rash virus (RSV), coronavirus (e.g. SARS), papovavirus (e.g. papilloma virus, e.g. causing genital warts, common warts or plantar warts), hepadnavirus (e.g. hepatitis B Virus) Rabivirus (eg hepatitis C virus or dengue virus), or retrovirus (eg lentivirus, eg HIV);
(b) Bacterial diseases, such as those caused by infection with the following bacteria: Escherichia, Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria, Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas, Streptococcus, Chlamydia , Mycoplasma, Pneumococcus, Neisseria, Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter (Campylobacter), Vibrio, Serratia, Providencia (P rovidencia), Chromobacterium, Brucella, Yersinia, Haemophilus, or Bordetella;
(c) Other infectious diseases such as chlamydia diseases, fungal diseases, including but not limited to: candidiasis, aspergillosis, histoplasmosis, cryptococcal meningitis, or parasitic diseases: including But are not limited to: malaria, Pneumocystis carinii pneumonia, leishmaniasis, cryptosporidiosis, toxoplasmosis, and trypanosoma infection;
(d) Neoplastic diseases such as intraperitoneal neoplasia, cervical dysplasia, UV keratosis, basal cell carcinoma, squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemia, including but not limited to: Without limitation: acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, B-cell lymphoma, and hair Cellular leukemia, as well as other cancers;
(e) T _H 2-mediated atopic diseases such as atopic dermatitis or eczema, eosinophilia, asthma, allergies, allergic rhinitis, and Ommen's syndrome;
(f) certain autoimmune diseases such as systemic lupus erythematosus, essential thrombocythemia, multiple sclerosis, discoid lupus erythematosus, alopecia areata; and
(g) Prevention of wound repair related diseases such as keloid formation and other types of scar formation (eg, promoting healing of wounds, including chronic wounds).

  Furthermore, the compounds or salts or compositions defined herein can be used as vaccine adjuvants; any other substance that enhances humoral and / or cellular immune responses, such as live viral, bacterial or parasites Inactivated viral, tumor-derived, protozoan, organism-derived, fungal or bacterial immunogens; toxoid; toxin; autoantigen; polysaccharide; protein; glycoprotein; peptide; DNA vaccine; auto vaccine; combined with recombinant protein, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitis B, hepatitis C, influenza A, influenza B, parainfluenza, acute gray Myelitis, rabies, measles, mumps, rubella, yellow fever, tetanus, diphtheria, influenza b bacteria (hemophilus) influenza b), tuberculosis, meningococcal and pneumococcal vaccine, adenovirus, HIV, chickenpox, cytomegalovirus, dengue fever, feline leukemia, chicken plague, HSV-1 and HSV-2, swine cholera, Japanese encephalitis, Used for respiratory rash virus, rotavirus, papillomavirus, yellow fever, and Alzheimer's disease.

  The compounds or salts or compositions defined herein may be particularly beneficial for individuals with an infectious immune function. For example, the compounds or salts or compositions of the invention can be used for the treatment of opportunistic infections and tumors that occur after suppression of cellular immunity, for example in transplant patients, cancer patients and HIV patients.

  Thus, a therapeutically effective amount of a compound or salt of Formula I, II, IIa, III, IV, IVa, V, or Va, any embodiment described herein, or combinations thereof, By administering a compound or salt or composition to an animal, one or more of the aforementioned diseases or disease types, such as viral diseases or neoplastic diseases, can be treated in an animal in need thereof (with a disease). An effective amount of a compound or salt, comprising an effective amount of a compound or salt of Formula I, II, IIa, III, IV, IVa, V, or Va, any embodiment described herein, or combinations thereof An animal can also be vaccinated by administering the composition as a vaccine adjuvant to the animal. In one aspect, a method of vaccinating an animal is provided comprising administering to the animal an effective amount of a compound or salt or composition described herein as a vaccine adjuvant.

An amount of a compound or salt or composition of the invention effective to induce cytokine biosynthesis is in one or more cell types, such as monocytes, macrophages, dendritic cells and B cells, and one or more cytokines, such as In an amount sufficient to produce IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12 in increased (induced) amounts above their cytokine background levels is there. The exact amount will vary according to factors known in the art, but is expected to be from about 100 ng / kg to about 50 mg / kg, preferably from about 10 μg / kg to about 5 mg / kg. In other embodiments, the amount is expected to be, for example, from about 0.01 to about 5.0 mg / m ² (calculated according to the Dubois method above), but in some embodiments, the amount of compound or salt outside of this embodiment or Induction of cytokine biosynthesis can be performed by administration of the composition. In certain of these embodiments, the method in an amount of about 0.1 to about 2.0 mg / m ^2, for example, sufficient compound or salt or composition to provide the subject an amount of from about 0.4 to about 1.2 mg / m ² Administration of the product.

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 to the animal an effective amount of a compound or salt or composition of the invention. An amount effective to treat or prevent a viral infection reduces one or more symptoms of viral infection, such as viral lesions, viral load, viral growth rate and mortality, compared to untreated control animals. It is the amount to make. The exact amount effective for such treatment will vary according to factors known in the art, but from about 100 ng / kg to about 50 mg / kg, preferably from about 10 μg / kg to about 5 mg / kg. Expected to be. An amount of a compound or salt or composition that is effective in treating a neoplastic condition is an amount that results in a reduction in tumor size or a reduction in the number of tumor lesions. Again, the exact amount will vary according to factors known in the art, but is expected to be from about 100 ng / kg to about 50 mg / kg, preferably from about 10 μg / kg to about 5 mg / kg. Is done. In other embodiments, this amount is expected to be, for example, from about 0.01 to about 5.0 mg / m ² (calculated according to the DuBois method above), although in some of these embodiments, amounts outside the scope of this embodiment These methods can be practiced by administration of a compound or salt or composition. In certain of these embodiments, the method in an amount of about 0.1 to about 2.0 mg / m ^2, for example, sufficient compound or salt or composition to provide the subject an amount of from about 0.4 to about 1.2 mg / m ² Administration of the product.

  In addition to the formulations and uses detailed herein, other formulations, uses and administration devices suitable for the compounds of the present invention are described, for example, in International Patent Application Publications WO 03/077944 and WO 02/036592, USP No. 6,245,776, And US Patent Application Publication Nos. 2003/0139364, 2003/185835, 2004/0258698, 2004/0265351, 2004/076633 and 2005/0009858.

  The objects and advantages of this invention are further illustrated by the following examples, which are to be construed as unduly limiting the specific materials and amounts thereof and other conditions and details set forth in these examples. Not.

EXAMPLES In the following examples, conventional high-speed flash chromatography (preparative HPLC) was performed using the COMBIFLASH system (product for automated high-speed flash purification; obtained from Teledyne Isco, Inc., Lincoln, Nebraska, USA), HORIZON HPFC system (automated Product for high-speed flash purification; obtained from Biotage, Inc., Charlotteville, VA, USA) or INTELLIFLASH flash chromatography system (automatic high-speed flash purification system; obtained from AnaLogix, Inc., Burlington, Wis., USA) It was. The eluent used for each purification is shown in the examples. In some chromatographic separations, a solvent mixture 80/18/2 v / v / v chloroform / methanol / concentrated ammonium hydroxide (CMA) was used as the polar component of the eluent. During these separations, CMA was mixed with chloroform at the indicated ratio.

Example 1
2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine

Part A
Phosphorus oxychloride (2.55 mL, 27.5 mmol) suspended in 4-hydroxy-3-nitro [1,5] naphthyridine (5 g, 26.1 mmol) in N, N-dimethylformamide (DMF, 30 mL) The solution was added dropwise. The resulting mixture was heated to 60 ° C. to dissolve all solids. The reaction was held 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 solid was isolated by filtration, washed with water until the filtrate was neutral and then dried in vacuo for 30 minutes to give 4-chloro-3-nitro [1,5] naphthyridine. This material was mixed with tetrahydrofuran (THF, 30 mL). A mixture of triethylamine (7.32 mL, 52.5 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (4.17 g, 27.5 mmol) in THF was added dropwise to the slurry. The reaction mixture was stirred overnight and then diluted with water. The solid was isolated by filtration and dried in vacuo to give 6.8 g of 3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) [1,5] naphthyridin-4-amine.

Part B
3-Nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) [1,5] naphthyridin-4-amine (2.5 g, 8.67 mmol), 5% platinum on carbon (0.25 g) and acetonitrile (50 mL) Was placed under hydrogen pressure in a Pal apparatus. When the reaction was complete, the mixture was filtered through a layer of CELITE filter media. The filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to, 2.37 g of the crude N ⁴ - was obtained (tetrahydro -2H- pyran-4-ylmethyl) [1,5] naphthyridine-3,4-diamine as an oil of yellow-orange.

Part C
Under a nitrogen atmosphere, N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1,5] naphthyridine-3,4-diamine (1.19 g, 4.61 mmol) of a solution in anhydrous dichloromethane (25 mL) in Cooled in an ice bath for 10 minutes. Anhydrous triethylamine (1.0 mL, 6.92 mmol) was added in one portion. 3-Methoxypropionyl chloride (0.55 mL, 5.07 mmol) was added dropwise, and then the reaction mixture was stirred at ambient temperature until liquid chromatography (LC) analysis indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude 3-methoxy-N- {4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] [1,5] naphthyridin-3-yl} propanamide as an orange solid. It was. This material was suspended in absolute ethanol (25 mL) and admixed with anhydrous triethylamine (2.25 mL, 16.14 mmol). The mixture was placed under a nitrogen atmosphere and heated to 110 ° C. over the weekend. The reaction mixture was concentrated under reduced pressure and then diluted with dichloromethane (100 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-15% CMA in chloroform) to give 0.82 g of an off-white solid. This material was suspended in cold methyl t-butyl ether (MTBE, 10 mL), isolated by filtration, washed with cold MTBE, then dried at 80 ° C. to give 0.39 g of 2- (2-methoxyethyl) -1 -(Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine was obtained as a light gray solid. Melting point 124-126 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.23 (s, 1H), 8.99 (dd, J = 4.1, 1.6, 1H), 8.50 (dd, J = 8.5, 1.6, 1H), 7.73 (dd, J = 8.5, 4.7, 1H), 4.85 (d, J = 6.3, 2H), 3.91 (t, J = 6.7, 2H), 3.78 (dd, J = 11.0, 3.2, 2H), 3.29 (s, 3H) , 3.26 (t, J = 6.7, 2H), 3.14 (td, J = 11.3, 2.2, 2H), 2.24 (m, 1H), 1.50-1.35 (m, 4H); ¹³ C NMR (125 Hz, d ₆ -DMSO) δ 154.5, 149.1, 145.0, 138.8, 138.7, 137.5, 134.8, 133.0, 122.2, 69.6, 66.6, 58.1, 50.2, 36.0, 29.7, 27.2; Elemental analysis: calculated C ₁₈ H ₂₂ N ₄ O ₂ : C, 66.24; H, 6.79; N, 17.17. Measurements: C, 66.23; H, 6.99; N, 17.42.

Example 2
2- (Ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine

2- (Ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine is prepared in Part C according to the general procedure of Example 1. Ethoxyacetyl chloride was prepared in place of 3-methoxypropionyl chloride. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give 0.92 g of a brown solid. This material is suspended in cold diethyl ether (10 mL), isolated by filtration, washed with cold diethyl ether and then dried at 80 ° C. to give 0.46 g of 2- (ethoxymethyl) -1- (tetrahydro-2H -Pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine was obtained as a light gray solid. Mp 94-96 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.27 (s, 1H), 9.00 (dd, J = 4.1, 1.6, 1H), 8.52 (dd, J = 8.5, 1.6, 1H), 7.75 (dd, J = 8.5, 4.7, 1H), 4.88 (d, J = 6.3, 2H), 4.85 (s, 2H), 3.78 (dd, J = 11.0, 3.2, 2H), 3.60 (q, J = 6.9, 2H) , 3.14 (td, J = 11.3, 2.2, 2H), 2.36 (m, 1H), 1.50-1.35 (m, 4H), 1.16 (t, J = 6.9, 3H); ¹³ C NMR (125 Hz, d ₆ -DMSO) δ 152.4, 149.2, 145.6, 139.2, 138.4, 137.5, 135.0, 133.6, 122.6, 66.6, 65.6, 64.1, 50.7, 36.0, 29.8, 14.9; Elemental analysis: calculated C ₁₈ H ₂₂ N ₄ O ₂ : C, 66.24; H, 6.79; N, 17.17. Measurements: C, 65.96; H, 7.00; N, 17.15.

Example 3
[1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridin-2-yl] methanol

Under a nitrogen atmosphere, N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1,5] naphthyridine-3,4-diamine (1.57 g, 6.08 mmol) of a solution in anhydrous dichloromethane (30 mL) in Cooled in an ice bath for 10 minutes. Anhydrous triethylamine (1.30 mL, 9.12 mmol) was added in one portion. Acetoxyacetyl chloride (0.75 mL, 6.69 mmol) was added dropwise and then the reaction mixture was stirred at ambient temperature until liquid chromatography (LC) analysis indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude 2-oxo-2-({4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] [1,5] naphthyridin-3-yl} amino) ethyl acetate in orange Obtained as a solid. This material was suspended in absolute ethanol (35 mL) and mixed with anhydrous triethylamine (3.0 mL, 21.30 mmol). The mixture was placed under a nitrogen atmosphere and heated to 110 ° C. over the weekend. 50% sodium hydroxide (1 mL) was added and the reaction mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and then diluted with chloroform (100 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-25% CMA in chloroform) to give 1.00 g of an off-white solid. This material was suspended in cold diethyl ether (20 mL), isolated by filtration, washed with cold diethyl ether, then dried at 80 ° C. to give 0.94 g of [1- (tetrahydro-2H-pyran-4-ylmethyl ) -1H-imidazo [4,5-c] [1,5] naphthyridin-2-yl] methanol was obtained as a light gray solid. Melting point 186-188 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.25 (s, 1H), 9.00 (dd, J = 4.1, 1.6, 1H), 8.52 (dd, J = 8.5, 1.6, 1H), 7.75 (dd, J = 8.5, 4.7, 1H), 5.80 (t, J = 6.0, 1H), 4.90 (d, J = 6.3, 2H), 4.85 (d, J = 6.0, 2H), 3.78 (dd, J = 11.0, 3.2, 2H), 3.14 (td, J = 11.3, 2.2, 2H), 2.36 (m, 1H), 1.49-1.36 (m, 4H); ¹³ C NMR (125 Hz, d ₆ -DMSO) δ 155.4, 149.2 , 145.5, 139.1, 138.4, 137.5, 135.1, 133.6, 66.6, 56.4, 50.6, 36.0, 29.8; Elemental analysis: calculated C ₁₆ H ₁₈ N ₄ O ₂ : C, 64.41; H, 6.08; N, 18.78. Values: C, 64.40; H, 5.98; N, 19.11.

Example 4
2-Ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine

N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1,5] naphthyridine-3,4-diamine (1.25 g, 4.84 mmol), triethyl orthopropionate (1.20 mL, 5.81 mmol), pyridine hydrochloride (25 A mixture of mg, 0.22 mmol) and toluene (20 mL) was placed in a hot (130 ° C.) oil bath. After about 4 hours, more pyridine hydrochloride (25 mg) was added and the reaction mixture was heated overnight. Analysis by liquid chromatography / mass spectrometry (LC / MS) indicated that the reaction was incomplete. Additional toluene (50 mL) was added and the reaction flask was equipped with a Dean-Stark trap. After 3 hours, analysis by LC / MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-25% CMA in chloroform) to give an off-white solid. This material was suspended in hexane (20 mL), isolated by filtration, washed with hexane, then dried at 80 ° C. to give 458 mg of 2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine was obtained as a pale pink solid. Mp 132-134 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.23 (s, 1H), 8.98 (dd, J = 4.1, 1.6, 1H), 8.49 (dd, J = 8.5, 1.6, 1H), 7.71 (dd, J = 8.5, 4.7, 1H), 4.80 (d, J = 6.3, 2H), 3.78 (dd, J = 11.0, 3.2, 2H), 3.15 (td, J = 11.3, 2.2, 2H), 3.02 (q, J = 7.5, 2H), 2.36 (m, 1H), 1.49-1.36 (m, 7H); ¹³ C NMR (125 Hz, d ₆ -DMSO) δ 157.7, 149.0, 144.9, 138.8, 138.7, 137.4, 134.8, 133.2, 122.1, 66.6, 50.1, 35.9, 29.7, 20.0, 11.4; Elemental analysis: calculated C ₁₇ H ₂₀ N ₄ O: C, 68.91; H, 6.80; N, 18.90. Measured values: C, 68.69; H, 7.08; N, 18.81.

Example 5
2-propyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine

Dean - N ⁴ Stark trap with flask - (tetrahydro -2H- pyran-4-ylmethyl) [1,5] naphthyridine-3,4-diamine (1.46 g, 5.65 mmol), trimethyl orthobutyrate (1.2 mL, 6.78 mmol), pyridine hydrochloride (35 mg, 0.28 mmol) and toluene (60 mL) were placed in a hot (150 ° C.) oil bath. After 1 hour, analysis by LC / MS showed that the starting material was consumed and an amide intermediate was formed. Concentrated hydrochloric acid (3 drops) was added. After 2 hours, analysis by LC / MS indicated that the amide was cyclized. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-25% CMA in chloroform) to give 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 ° C. to give 0.55 g of 2-propyl-1- (tetrahydro-2H-pyran- 4-Ilmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine was obtained as an off-white solid. Melting point 122-125 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.23 (s, 1H), 8.98 (dd, J = 4.1, 1.6, 1H), 8.49 (dd, J = 8.5, 1.6, 1H), 7.71 (dd, J = 8.5, 4.7, 1H), 4.80 (d, J = 6.3, 2H), 3.78 (dd, J = 11.0, 3.2, 2H), 3.14 (td, J = 11.3, 2.2, 2H), 2.97 (q, J = 7.6, 2H), 2.24 (m, 1H), 1.93 (hexet, J = 7.6, 2H), 1.49-1.35 (m, 4H), 1.04 (t, J = 7.1, 3H); ¹³ C NMR (125 Hz, d ₆ -DMSO) δ 156.6, 149.0, 144.9, 138.79, 138.74, 137.4, 134.8, 133.0, 122.1, 66.6, 50.1, 36.0, 29.7, 28.3, 20.3, 13.8; Elemental analysis: calculated value C ₁₈ H ₂₂ N ₄ O: C, 69.65; H, 7.14; N, 18.05. Measurements: C, 69.52; H, 7.38; N, 17.95.

Example 6
8-Bromo-2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Part A
Phosphorus oxychloride (10.6 mL, 113.8 mmol) was added dropwise to a mixture of 6-bromo-4-hydroxy-3-nitroquinoline (30.00 g, 81.28 mmol) and DMF (250 mL). After 1.5 hours, the reaction mixture was poured into ice water (400 mL) with stirring. The solid was isolated by filtration, washed with water and dried overnight at high ambient temperature under high vacuum to give crude 6-bromo-4-chloro-3-nitroquinoline (> 32 g).

Part B
Under nitrogen atmosphere, THF (75 mL) and triethylamine (14.6 mL, 104.4 mmol) were added in turn to crude 6-bromo-4-chloro-3-nitroquinoline (15.0 g, 52.2 mmol) and 1-tetrahydro-2H- To a mixture of pyran-4-ylmethylamine hydrochloride (8.30 g, 54.8 mmol). The reaction mixture was placed in a 45 ° C. oil bath for 2 hours and then concentrated in vacuo. The residue was diluted with THF (30 mL) and water (200 mL). THF was removed under reduced pressure. The solid was isolated by filtration and dried to give 7.55 g of 6-bromo-3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine.

Part C
6-Bromo-3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine (7.56 g), 5% platinum on carbon (0.76 g), methanol (25 mL) and acetonitrile (95 mL) of the mixture was placed under hydrogen pressure in a Pal apparatus. When the reaction was complete, the mixture was filtered through a layer of celite filter media. The filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to, 6.94 g of 6-bromo -N ⁴ - was obtained (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine as an oil of yellow-orange.

Part D
6-Bromo -N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (6.94 g, 20.64 mmol) and ethoxyacetyl chloride (2.5 mL, 22.70 mmol) was reacted with, then cyclization the; according to example 1, the general method of Part C, 6- bromo -N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran -4 -Ylmethyl) [1,5] naphthyridine-3,4-diamine was used instead of ethoxyacetyl chloride instead of 3-methoxypropionyl chloride. The crude product was suspended in diethyl ether (20 mL), isolated by filtration, washed with diethyl ether and then dried at 80 ° C. to give 3.03 g of 8-bromo-2- (ethoxymethyl) -1- ( Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 136-139 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.22 (s, 1H), 8.46 (d, J = 2.2, 1H), 8.10 (d, J = 8.9, 1H), 7.85 (dd, J = 8.9, 2.2, 1H), 4.83 (s, 2H), 4.65 (d, J = 7.3, 2H), 3.81 (dd, J = 11.7, 2.5, 2H), 3.60 (q, J = 7.0, 2H), 3.15 (td , J = 11.6, 2.2, 2H), 2.16 (m, 1H), 1.54-1.42 (m, 4H), 1.16 (t, J = 6.9, 3H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 152.3, 145.4, 142.8, 136.5, 132.6, 132.4, 130.0, 123.3, 119.6, 118.8, 66.5, 65.6, 64.2, 50.4, 35.6, 29.9, 14.9; Elemental analysis: calculated C ₁₉ H ₂₂ N ₃ O ₂ Br: C , 56.40; H, 5.49; N, 10.39. Measurements: C, 56.30; H, 5.45; N, 10.26.

Example 7
2-Benzyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

  Under a nitrogen atmosphere, THF (90 mL) and triethylamine (17.5 mL, 125.6 mmol) were added sequentially to crude 4-chloro-3-nitroquinoline (13.10 g, 62.81 mmol) and 1-tetrahydro-2H-pyran-4- To a mixture of ylmethylamine hydrochloride (10.0 g, 65.95 mmol) was added. The reaction mixture was placed in a 45 ° C. oil bath for 1 hour and then concentrated in vacuo. The residue was diluted with THF (30 mL) and water (200 mL). THF was removed under reduced pressure. The solid was isolated by filtration and dried to give 16.10 g of 3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine as a pale yellow solid.

Part B
A mixture of 3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine (2.50 g), 10% palladium on carbon (0.25 g) and ethanol (40 mL) was charged with hydrogen on a PAL apparatus. Placed under pressure. When the reaction was complete, the mixture was filtered through a layer of celite filter media. The filter cake was washed with ethanol. The filtrate was concentrated under reduced pressure to, 2.23 g of N ⁴ - was obtained (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine as an oil of yellow-orange.

Part C
N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (2.23 g, 8.67 mmol) phenylacetyl chloride (1.25 mL, 9.54 mmol) was reacted with and then cyclized; Example 1, in accordance with the general method of Part C, N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1,5] Used in place of naphthyridine-3,4-diamine and phenylacetyl chloride was used in place of 3-methoxypropionyl chloride. The crude product was suspended in MTBE (20 mL), isolated by filtration, washed sequentially with MTBE and water, then dried at 80 ° C. to give 459 mg of 2-benzyl-1- (tetrahydro-2H-pyran. -4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 177-180 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.15 (s, 1H), 8.35 (m, 1H), 8.15 (m, 1H), 7.72-7.66 (m, 2H), 7.37-7.23 (m, 5H ), 4.54 (d, J = 7.2, 2H), 4.44 (s, 2H), 3.77 (dd, J = 10.6, 2.8, 2H), 3.07 (td, J = 11.6, 1.8, 2H), 2.05 (m, 1H), 1.55-1.38 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 154.5, 144.3, 144.1, 136.8, 136.3, 133.2, 130.3, 128.8, 128.5, 126.6, 126.5, 120.8, 117.5 , 66.5, 50.2, 35.7, 33.1, 29.5; Elemental analysis: calculated C ₂₃ H ₂₃ N ₃ O: C, 77.28; H, 6.49; N, 11.76. Measurements: C, 76.89; H, 6.44; N, 11.58 .

Example 8
2- (Methoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (1.37 g, 5.32 mmol) and methoxyacetyl chloride (0.55 mL, 5.85 mmol) was reacted with and then cyclized; Example 1, in accordance with the general method of Part C, N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1,5] Used in place of naphthyridine-3,4-diamine, and methoxyacetyl chloride was used in place of 3-methoxypropionyl chloride. The crude product was suspended in MTBE (20 mL), isolated by filtration, washed sequentially with MTBE and water, then dried at 80 ° C. to give 101 mg of 2- (methoxymethyl) -1- (tetrahydro- 2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 136-139 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.19 (s, 1H), 8.39-8.37 (m, 1H), 8.18-8.16 (m, 1H), 7.75-7.71 (m, 2H), 4.80 (s , 2H), 4.62 (d, J = 7.5, 2H), 3.79 (dd, J = 11.7, 2.5, 2H), 3.37 (s, 3H), 3.13 (td, J = 11.7, 1.9, 2H), 2.18 ( m, 1H), 1.52-1.41 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 154.5, 144.3, 144.1, 136.8, 136.3, 133.2, 130.3, 128.8, 128.5, 126.6, 126.5, 120.8 , 117.5, 66.5, 50.2, 35.7, 33.1, 29.5; Elemental analysis: calculated C ₁₈ H ₂₁ N ₃ O ₂ : C, 69.43; H, 6.80; N, 13.49. Measurements: C, 69.21; H, 6.77; N, 13.59.

Example 9
[1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-2-yl] methanol

The [1- (tetrahydro -2H- pyran-4-ylmethyl)-1H-imidazo [4,5-c] quinolin-2-yl] methanol according to the general procedure of Example 3, N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (prepared using in place of tetrahydro -2H- pyran-4-ylmethyl) [1,5] naphthyridine-3,4-diamine. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-25% CMA in chloroform) to give 1.47 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 ° C. to give 1.07 g of [1- (tetrahydro-2H-pyran-4-ylmethyl ) -1H-imidazo [4,5-c] quinolin-2-yl] methanol was obtained as an off-white solid. Mp 165-169 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.16 (s, 1H), 8.39-8.37 (m, 1H), 8.17-8.15 (m, 1H), 7.74-7.70 (m, 2H), 5.77 (t , J = 5.7, 1H), 4.84 (d, J = 6.0, 2H), 4.66 (d, J = 7.2, 2H), 3.79 (dd, J = 5.0, 2.5, 2H), 3.14 (td, J = 12.0 , 2.2, 2H), 2.19 (m, 1H), 1.51-1.40 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 154.7, 144.7, 144.2, 136.0, 133.5, 130.3, 126.8, 126.5 , 121.0, 117.6, 66.5, 56.6, 50.3, 35.6, 29.7; Elemental analysis: calculated C ₁₇ H ₁₉ N ₃ O ₂ : C, 68.67; H, 6.44; N, 14.13. Measurements: C, 68.32; H, 6.21; N, 13.86.

Example 10
2-propyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Dean - N ⁴ Stark trap with flask - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (2.20 g, 8.55 mmol), trimethyl orthobutyrate (1.9 mL, 10.69 mmol), pyridine hydrochloride A mixture of (50 mg, 0.43 mmol) and toluene (90 mL) was placed in a hot (150 ° C.) oil bath. After 3.5 hours, analysis by LC / MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give an off-white solid. This material was suspended in cold MTBE (20 mL), isolated by filtration, washed with cold MTBE, then dried at 80 ° C. to give 763 mg of 2-propyl-1- (tetrahydro-2H-pyran-4- (Ilmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 126-129 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.14 (s, 1H), 8.34-8.33 (m, 1H), 8.15-8.13 (m, 1H), 7.71-7.66 (m, 2H), 4.54 (d , J = 7.2, 2H), 3.79 (dd, J = 10.1, 2.95, 2H), 3.13 (td, J = 11.7, 2.3, 2H), 2.95 (t, J = 7.6, 2H), 2.12 (m, 1H ), 1.90 (hexet, J = 7.6, 2H), 1.53-1.45 (m, 4H), 1.04 (t, J = 7.2, 3H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 155.9, 144.2, 144.0, 136.3, 133.0, 130.3, 126.43, 126.40, 120.7, 117.5, 66.5, 49.9, 35.7, 29.6, 28.6, 20.3, 13.8; Elemental analysis: calculated value C ₁₉ H ₂₃ N ₃ O ・ 1.0 H ₂ O: C, 69.71; H, 7.70; N, 12.84. Measurements: C, 69.73; H, 7.64; N, 12.85.

Example 11
2-Methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

2-Methyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was used according to the general procedure of Example 10 using triethyl orthoacetate instead of trimethyl orthobutyrate. Manufactured. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give an off-white solid. This material was recrystallized from boiling MTBE (50 mL), isolated by filtration, washed with cold MTBE, then dried at 80 ° C. to give 763 mg of 2-methyl-1- (tetrahydro-2H-pyran-4 -Ilmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 159-162 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.10 (s, 1H), 8.35-8.33 (m, 1H), 8.15-8.13 (m, 1H), 7.72-7.66 (m, 2H), 4.52 (d , J = 7.6, 2H), 3.80 (dd, J = 11.0, 2.5, 2H), 3.16 (td, J = 11.6, 2.5, 2H), 2.66 (s, 3H), 2.15 (m, 1H), 1.53- 1.45 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 152.8, 143.99, 143.95, 136.2, 133.0, 130.3, 126.45, 126.42, 120.6, 117.4, 66.5, 50.4, 35.7, 29.7, 14.2; calcd _{C 17 H 19 N 3 O:} . C, 72.57; H, 6.81; N, 14.93 measurements: C, 72.84; H, 6.96 ; N, 15.06.

Example 12
2- (4-Ethoxybenzyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (2.75 g, 10.69 mmol) of 4-ethoxyphenyl chloride (2.1 mL, 11.76 mmol) was reacted with and then cyclized ; example 1, in accordance with the general method of Part C, N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1 , 5] naphthyridin-3,4-diamine, 4-ethoxyphenylacetyl chloride was used instead of 3-methoxypropionyl chloride. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-30% CMA in chloroform) to give an off-white solid. This material was recrystallized from boiling MTBE (40 mL), isolated by filtration, washed with cold MTBE, then dried at 80 ° C. to give 1.30 g of 2- (4-ethoxybenzyl) -1- (tetrahydro- 2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Mp 162-166 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.15 (s, 1H), 8.36-8.33 (m, 1H), 8.16-8.12 (m, 1H), 7.71-7.66 (m, 2H), 7.25-7.23 (d, J = 8.7, 2H), 6.90-6.85 (d, J = 8.8, 2H), 4.52 (d, J = 7.3, 2H), 4.35 (s, 2H), 3.97 (q, J = 6.9, 2H ), 3.77 (dd, J = 11.3, 3.2, 2H), 3.07 (td, J = 11.7, 1.6, 2H), 2.05 (m, 1H), 1.52-1.43 (m, 2H), 1.42-1.32 (m, 2H), 1.29 (t, J = 6.9, 3H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 157.3, 154.8, 144.3, 144.1, 136.3, 133.2, 130.3, 129.8, 128.4, 126.6, 126.4, 120.8 , 117.5, 114.4, 66.6, 62.9, 50.2, 35.7, 32.3, 29.5, 14.6; Elemental analysis: calculated C ₂₅ H ₂₇ N ₃ O ₂ : C, 74.79; H, 6.78; N, 10.47. 74.49; H, 6.65; N, 10.47.

Example 13
6- (Benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Part A
Under a nitrogen atmosphere, a mixture of isopropylidene malonate (72 g) and triethyl orthoformate (220 mL) was heated in a 100 ° C. oil bath for 3 hours. The reaction mixture was cooled to 60 ° C. and 2-benzyloxyaniline (114 g) was added in small portions. The reaction mixture was allowed to cool to ambient temperature overnight and then diluted with diethyl ether. The solid was isolated by filtration, washed with diethyl ether and 129 g of 5-{[(2-benzyloxy) phenylimino] methyl} -2,2-dimethyl- [1,3] -dioxane-4,6 -I got a dione.

Part B
The material from Part A was added slowly to hot (200 ° C.) DOWTHERM A heat transfer liquid (600 mL). The mixture was heated to 210 ° C. until reflux ceased. The reaction mixture was cooled to ambient temperature. The solid was isolated by filtration and washed with diethyl ether to give 67 g of 8-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 to 120 ° C. for 3 hours and then allowed to cool to ambient temperature. The precipitate was isolated by filtration and washed with water (100 mL) to give 9.7 g of 8-benzyloxy-3-nitroquinolin-4-ol.

Part D
Phosphorus oxychloride (3.3 mL, 35.72 mmol) was added dropwise to a suspension of 8-benzyloxy-3-nitroquinolin-4-ol (7.56 g, 25.52 mmol) in DMF (250 mL). The reaction mixture was stirred overnight and then poured into ice water (150 mL) with stirring. The solid was isolated by filtration, washed with water and dried under high vacuum at ambient temperature to give 8.03 g of 8-benzyloxy-4-chloro-3-nitroquinoline as a yellow solid.

Part E
8-Benzyloxy-4-chloro-3-nitroquinoline (8.03 g, 25.51 mmol) and 1-tetrahydro-2H-pyran-4-ylmethylamine hydrochloride (4.06 mmol, 26.79 mmol) were added to Example 7, Part According to the general procedure of A, 8-benzyloxy-4-chloro-3-nitroquinoline is reacted instead of 4-chloro-3-nitroquinoline and 7.88 g of 8-benzyloxy-3-nitro-N- (Tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine was obtained as a light brown solid.

Part F
8-Benzyloxy-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 in a Pal apparatus. When the reaction was complete, the mixture was filtered through a layer of celite filter media. The filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure of 1.85 g 8- benzyloxy -N ⁴ - was obtained (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine as an oil of yellow-orange.

Part G
8-benzyloxy -N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (1.85 g, 5.09 mmol) ethoxy acetyl chloride (0.60 mL, 5.60 mmol) was reacted with, then ring phased; example 1, in accordance with the general method of Part C, 8- benzyloxy -N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran -4-ylmethyl) [1,5] naphthyridine-3,4-diamine was used instead of ethoxyacetyl chloride instead of 3-methoxypropionyl chloride. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give 758 mg of 6- (benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H -Pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 106-109 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.14 (s, 1H), 7.94 (d, J = 8.8, 1H), 7.62 (t, J = 8.2, 1H), 7.57-7.56 (m, 2H) , 7.43-7.40 (m, 2H), 7.36-7.33 (m, 1H), 7.31 (d, J = 7.8, 1H), 5.33 (s, 2H), 4.82 (s, 2H), 4.61 (d, J = 7.3, 2H), 3.80 (dd, J = 12.0, 4.4, 2H), 3.58 (q, J = 6.9, 2H), 3.11 (td, J = 11.7, 1.6, 2H), 2.2 (m, 1H), 1.52 -1.43 (m, 2H), 1.42-1.32 (m, 2H), 1.29 (t, J = 6.9, 3H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 155.2, 151.9, 142.9, 137.2, 136.3 , 135.9, 133.6, 128.4, 127.8, 127.0, 118.8, 113.0, 108.8, 70.0, 66.6, 65.5, 64.3, 50.5, 35.7, 29.7, 14.9; Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37 ; H, 6.77; N, 9.74. Measurements: C, 72.12; H, 6.86; N, 9.72.

Example 14
2- (2-Methoxyethyl) -8-phenyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Part A
6-Bromo -N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (10.53 g, 31.32 mmol) of 3-methoxy-propionyl chloride (3.7 mL, 34.45 mmol) was reacted with, then was cyclized; example 1, in accordance with the general method of Part C, 6- bromo -N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran Used instead of -4-ylmethyl) [1,5] naphthyridine-3,4-diamine. The crude product was suspended in diethyl ether (20 mL), isolated by filtration, washed with cold ethyl ether and then dried at 80 ° C. to give 8.59 g of 8-bromo-2- (2-methoxyethyl)- 1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a white solid.

Part B
8-bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol), phenylboronic acid ( 0.22 g, 1.78 mmol), triphenylphosphine (12 mg, 0.044 mmol), palladium acetate (4 mg, 0.0148 mmol), 1-propanol (10 mL), sodium carbonate (0.19 g, 1.78 mmol) and water (2 mL) ) Was degassed and backfilled with nitrogen three times. This yellow solution was placed in a hot (100 ° C.) oil bath for about 18 hours. 1-propanol was removed under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with water (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow solid. This material was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling 2-propanol (20 mL), isolated by filtration, washed with cold 2-propanol, dried at 60 ° C., and 375 mg of 2- (2-methoxyethyl) -8- Phenyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Mp 204-208 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.15 (s, 1H), 8.44 (d, J = 1.9, 1H), 8.23 (d, J = 8.9, 1H), 8.00 (dd, J = 8.8, 1.9, 1H), 7.84-7.83 (m, 2H), 7.56-7.53 (m, 2H), 7.45-7.42 (m, 1H), 4.66 (d, J = 6.9, 2H), 3.92 (t, J = 6.6 , 2H), 3.83 (dd, J = 11.1, 2.5, 2H), 3.30 (s, 3H), 3.26 (t, J = 6.6, 2H), 3.19 (td, J = 11.7, 1.9, 2H), 2.28 ( m, 1H), 1.58-1.54 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 153.8, 144.3, 143.3, 140.0, 138.0, 136.6, 133.0, 130.9, 129.1, 127.8, 127.2, 125.7 , 118.5, 117.7, 69.7, 66.4, 58.1, 50.1, 35.8, 29.9, 27.4, 25.5; Elemental analysis: calculated values C ₂₅ H ₂₇ N ₃ O ₂ · 0.25 H ₂ O: C, 73.94; H, 6.83; N, 10.35. Measurements: C, 73.98; H, 6.76; N, 10.10.

Example 15
8- (3-Chlorophenyl) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 3-chlorophenylboron The acid (0.28 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling propyl acetate (10 mL), isolated by filtration, washed with cold propyl acetate, dried at 60 ° C., and 75 mg of 8- (3-chlorophenyl) -2- (2- Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 161-164 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.17 (s, 1H), 8.44 (d, J = 1.6, 1H), 8.23 (d, J = 8.9, 1H), 8.02 (dd, J = 8.8, 1.0, 1H), 7.87 (s, 1H), 7.82 (dd, J = 7.6, 0.9, 1H), 7.58 (t, J = 7.9, 1H), 7.50 (d, J = 8.2, 1H), 4.66 (d , J = 5.1, 2H), 3.91 (t, J = 6.6, 2H), 3.85 (d, J = 10.7, 2H), 3.30 (m, 3H), 3.27-3.21 (m, 4H), 2.29 (m, 1H), 1.58-1.51 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 153.9, 144.6, 143.5, 142.1, 136.7, 136.4, 133.9, 133.1, 130.9, 127.6, 127.1, 125.9, 125.5 , 119.1, 117.6, 69.7, 66.4, 58.1, 50.0, 35.7, 29.9, 27.4; Elemental analysis: calculated C ₂₅ H ₂₆ N ₃ O ₂ Cl: C, 68.88; H, 6.01; N, 9.64. 68.80; H, 5.84; N, 9.41.

Example 16
{3- [2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-8-yl] phenyl} methanol

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 3- (hydroxy Methyl) phenylboronic acid (0.27 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 5-30% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling acetonitrile (20 mL), isolated by filtration, washed with cold acetonitrile, dried at 60 ° C., and 344 mg of {3- [2- (2-methoxyethyl) -1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-8-yl] phenyl} methanol was obtained as an off-white solid. Mp 171-173 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.15 (s, 1H), 8.42 (d, J = 1.6, 1H), 8.23 (d, J = 8.5, 1H), 8.00 (dd, J = 8.8, 1.9, 1H), 7.77 (s, 1H), 7.70 (dd, J = 7.6, 0.9, 1H), 7.49 (t, J = 7.6, 1H), 7.37 (d, J = 7.6, 1H), 5.26 (t , J = 5.7, 1H), 4.62 (d, J = 6.3, 2H), 4.60 (d, J = 5.7, 2H), 3.91 (t, J = 6.6, 2H), 3.84 (d, J = 11.3, 2H ), 3.30 (m, 3H), 3.27-3.19 (m, 4H), 2.29 (m, 1H), 1.56-1.52 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 153.8, 144.3 , 143.5, 143.3, 139.7, 138.1, 136.6, 133.0, 130.9, 128.9, 125.9, 125.6, 125.5, 125.2, 118.4, 117.7, 69.7, 66.5, 62.8, 58.1, 50.1, 35.8, 29.8, 27.4; Elemental analysis: calculated values C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37; H, 6.77; N, 9.74. Measurements: C, 72.57; H, 6.61; N, 9.68.

Example 17
2- (2-methoxyethyl) -8- (2-methoxyphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 2-methoxyphenyl Boronic acid (0.27 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 5-30% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling hexane / ethyl acetate (20 mL), isolated by filtration, washed with cold hexane, dried at 60 ° C., and 362 mg of 2- (2-methoxyethyl) -8- ( 2-Methoxyphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 165-168 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.14 (s, 1H), 8.37 (d, J = 1.9, 1H), 8.15 (d, J = 8.8, 1H), 7.81 (dd, J = 8.6, 1.5, 1H), 7.46 (dd, J = 7.5, 1.6, 1H), 7.47 (td, J = 8.5, 1.6, 1H), 7.20 (d, J = 8.2, 1H), 7.09 (t, J = 7.2, 1H), 4.55 (d, J = 7.3, 2H), 3.91 (t, J = 6.7, 2H), 3.83-3.81 (m, 5H), 3.30 (m, 3H), 3.25-3.19 (m, 4H), 2.29 (m, 1H), 1.56-1.32 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 156.3, 153.6, 144.1, 143.0, 136.4, 136.0, 133.0, 130.8, 129.7, 129.4, 129.3 , 128.3, 121.0, 120.9, 117.2, 112.0, 69.7, 66.4, 58.1, 55.8, 50.1, 35.7, 29.7, 27.3; Elemental analysis: calculated values C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37; H, 6.77; N , 9.74. Measurements: C, 72.14; H, 6.63; N, 9.54.

Example 18
2- (2-methoxyethyl) -8- (2-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 2-methylphenyl Boronic acid (0.24 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling hexane / ethyl acetate (20 mL), isolated by filtration, washed with cold hexane, dried at 60 ° C., and 408 mg of 2- (2-methoxyethyl) -8- ( 2-Methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 180-183 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.17 (s, 1H), 8.17 (d, J = 8.5, 1H), 8.15 (d, J = 1.9, 1H), 7.70 (dd, J = 8.5, 1.6, 1H), 7.38-7.30 (m, 4H), 4.55 (d, J = 7.3, 2H), 3.90 (t, J = 7.0, 2H), 3.81 (dd, J = 11.4, 3.2, 2H), 3.29 (m, 3H), 3.24 (t, J = 6.6, 2H), 3.16 (t, J = 10.4, 2H), 2.35 (s, 3H), 2.21 (m, 1H), 1.47 (qd, J = 12.0, 4.4, 2H), 1.35-1.33 (m, 2H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 153.8, 144.3, 142.9, 141.0, 139.2, 136.6, 134.9, 132.9, 130.5, 129.99, 129.95, 128.1 , 127.7, 126.1, 120.7, 117.3, 69.7, 66.4, 58.1, 50.0, 35.6, 29.7, 27.4, 20.2; Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₂ : C, 75.15; H, 7.03; N, 10.11 Measurements: C, 74.84; H, 6.98; N, 10.08.

Example 19
2- (2-Methoxyethyl) -8- (3-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 3-methylphenyl Boronic acid (0.24 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling hexane / ethyl acetate (20 mL), isolated by filtration, washed with cold hexane, dried at 60 ° C., and 410 mg of 2- (2-methoxyethyl) -8- ( 3-Methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 138-141 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.14 (s, 1H), 8.41 (d, J = 1.9, 1H), 8.21 (d, J = 8.5, 1H), 7.99 (dd, J = 8.8, 1.9, 1H), 7.63-7.61 (m, 2H), 7.42 (t, J = 7.5, 1H), 7.25 (d, J = 7.2, 1H), 4.62 (d, J = 6.0, 2H), 3.91 (t , J = 7.0, 2H), 3.85 (d, J = 10.7, 2H), 3.30 (m, 3H), 3.27-3.21 (m, 4H), 2.40 (s, 3H), 2.21 (m, 1H), 1.57 -1.52 (m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 153.8, 144.2, 143.3, 139.9, 138.3, 138.1, 136.6, 133.0, 130.8, 129.0, 128.4, 128.0, 125.6, 124.3, 118.5 , 117.6, 69.7, 66.4, 58.1, 50.1, 35.7, 29.8, 27.4, 21.1; Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₂ : C, 75.15; H, 7.03; N, 10.11. Measured: C, 75.25; H, 6.92; N, 10.00.

Example 20
2- (2-Methoxyethyl) -8- (4-methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 4-methylphenyl Boronic acid (0.24 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling hexane / ethyl acetate (20 mL), isolated by filtration, washed with cold hexane, dried at 60 ° C., and 410 mg of 2- (2-methoxyethyl) -8- ( 3-Methylphenyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 150-153 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.13 (s, 1H), 8.40 (d, J = 1.9, 1H), 8.20 (d, J = 8.8, 1H), 7.97 (dd, J = 8.5, 1.9, 1H), 7.72 (d, J = 7.9, 2H), 7.35 (d, J = 7.9, 2H), 4.64 (d, J = 6.4, 2H), 3.91 (t, J = 6.9, 2H), 3.83 (d, J = 12.0, 2H), 3.27 (s, 3H), 3.25 (t, J = 7.0, 2H), 3.19 (t, J = 11.6, 2H), 2.38 (s, 3H), 2.26 (m, 1H), 1.54 (qd, J = 12.9, 4.4, 2H), 1.47 (m, 2H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 153.7, 144.1, 143.2, 137.9, 137.3, 137.1, 136.6, 133.0, 130.8, 129.7, 127.0, 125.5, 118.0, 117.7, 69.7, 66.4, 58.1, 50.1, 35.8, 29.9, 27.4, 20.7; Elemental analysis: calculated values C ₂₆ H ₂₉ N ₃ O ₂ : C, 75.15; H, 7.03; N, 10.11. Measurements: C, 75.02; H, 6.92; N, 10.03.

Example 21
3- [2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-8-yl] phenol

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 3-hydroxyphenyl Boronic acid (0.25 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-30% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling ethanol (20 mL), isolated by filtration, washed with cold ethanol, dried at 60 ° C., and 150 mg of 3- [2- (2-methoxyethyl) -1- ( Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-8-yl] phenol was obtained as an off-white solid. Melting point 256-259 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.61 (s, 1H), 9.14 (s, 1H), 8.38 (d, J = 1.6, 1H), 8.20 (d, J = 8.5, 1H), 7.92 (dd, J = 8.5, 1.9, 1H), 7.32 (t, J = 7.8, 1H), 7.23 (d, J = 7.9, 1H), 7.18 (t, J = 2.2, 1H), 6.83 (dd, J = 7.9, 1.5, 1H), 4.62 (d, J = 7.0, 2H), 3.91 (t, J = 6.6, 2H), 3.83 (d, J = 10.8, 2H), 3.30 (m, 3H), 3.25 ( t, J = 6.7, 2H), 3.20 (t, J = 11.3, 2H), 2.25 (m, 1H), 1.54 (qd, J = 12.9, 3.5, 2H), 1.53-1.49 (m, 2H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 158.0, 153.8, 144.2, 143.3, 141.4, 138.1, 136.6, 133.0, 130.8, 130.1, 125.6, 118.3, 117.9, 117.6, 114.8, 114.1, 69.7, 66.4, 58.1, 50.1, 35.8, 29.8, 27.4; Elemental analysis: Calculated value C ₂₅ H ₂₇ N ₃ O ₃ · 0.25 H ₂ O: C, 71.16; H, 6.57; N, 9.96. Measured value: C, 71.42; H, 6.32; N, 9.90.

Example 22
8- (3,4-Dichlorophenyl) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 3,4- Dichlorophenylboronic acid (0.25 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling acetonitrile (20 mL), isolated by filtration, washed with cold acetonitrile, dried at 60 ° C., and 357 mg of 8- (3,4-dichlorophenyl) -2- (2- Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. 192-195 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.17 (s, 1H), 8.43 (d, J = 1.8, 1H), 8.23 (d, J = 8.8, 1H), 8.08 (d, J = 2.2, 1H), 8.02 (dd, J = 8.5, 1.9, 1H), 7.86 (dd, J = 8.2, 2.2, 1H), 7.80 (d, J = 8.5, 1H), 4.66 (d, J = 5.4, 2H) , 3.91 (t, J = 6.6, 2H), 3.83 (d, J = 11.0, 2H), 3.30 (m, 3H), 3.27-3.20 (m, 4H), 2.27 (m, 1H), 1.58-1.50 ( m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 154.0, 144.7, 143.6, 140.6, 136.7, 135.3, 133.0, 131.9, 131.1, 131.0, 130.6, 129.2, 127.3, 125.4, 119.2, 117.5, 69.7, 66.4, 58.1, 50.0, 35.6, 29.9, 27.4; Elemental analysis: calculated values C ₂₅ H ₂₅ N ₃ O ₂ Cl ₂ : C, 63.83; H, 5.36; N, 8.93. Measured values: C, 63.63; H , 5.07; N, 8.92.

Example 23
8- (4-Fluorophenyl) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.60 g, 1.48 mmol) and 4-fluorophenyl Boronic acid (0.25 g, 1.78 mmol) was coupled according to the general method of Example 14, Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 0-20% CMA in chloroform) to give a pale yellow solid. This material was recrystallized from boiling hexane / ethyl acetate (20 mL), isolated by filtration, washed with cold hexane, dried at 60 ° C., and 267 mg of 8- (4-fluorophenyl) -2- ( 2-Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 181-184 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.15 (s, 1H), 8.40 (d, J = 1.9, 1H), 8.21 (d, J = 8.9, 1H), 7.98 (dd, J = 8.8, 1.9, 1H), 7.90-7.87 (m, 2H), 7.40-7.36 (m, 2H), 4.65 (d, J = 6.7, 2H), 3.91 (t, J = 6.9, 2H), 3.82 (d, J = 11.3, 1.9, 2H), 3.30 (s, 3H), 3.26 (t, J = 6.7, 2H), 3.18 (td, J = 11.4, 2.2, 2H), 2.24 (m, 1H), 1.56-1.44 ( m, 4H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 163.1, 161.1, 153.9, 144.3, 143.2, 136.7 (d, J = 36.4), 136.4 (d, J = 3.9), 133.0, 130.9, 129.23, 129.16, 125.6, 118.4, 117.6, 115.9 (d, J = 22.1), 69.7, 66.4, 58.1, 50.0, 35.7, 29.9, 27.4; Elemental analysis: calculated values C ₂₅ H ₂₆ N ₃ O ₂ F: C, 71.58; H, 6.25; N, 10.02. Measurements: C, 71.51; H, 5.98; N, 9.91.

Example 24
2- (Cyclopropylmethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (2.23 g, 8.67 mmol) and cyclopropyl-acetyl chloride (1.1 mL, 9.54 mmol) was reacted with and then cyclized; exemplary example 1, in accordance with the general method of Part C, N ⁴ - a (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) [1,5 It was used in place of naphthyridine-3,4-diamine and cyclopropylacetyl chloride was used in place of 3-methoxypropionyl chloride. The crude product was suspended in MTBE (20 mL), isolated by filtration and washed sequentially with MTBE and water. The resulting solid was recrystallized from boiling hexane / ethyl acetate (20 mL), isolated by filtration, washed with cold hexane, dried at 80 ° C., and 572 mg of 2- (cyclopropylmethyl) -1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as an off-white solid. Melting point 190-193 ° C. ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.16 (s, 1H), 8.35-8.33 (m, 1H), 8.15-8.13 (m, 1H), 7.72-7.67 (m, 2H), 4.53 (d , J = 7.3, 2H), 3.79 (dd, J = 11.1, 3.1, 2H), 3.13 (td, J = 11.7, 1.9, 2H), 2.95 (d, J = 6.6, 2H), 2.12 (m, 1H ), 1.48 (qd, J = 12.6, 4.1, 2H), 1.43-1.35 (m, 2H), 1.34-1.27 (m, 1H), 0.58-0.54 (m, 2H), 0.32-0.29 (m, 2H) ; ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 155.7, 144.3, 144.0, 136.4, 133.0, 130.3, 126.46, 124.40, 120.7, 117.5, 66.5, 50.0, 35.7, 31.4, 29.5, 9.2, 4.7; elemental analysis : calculated _{C 20 H 23 N 3 O:} . C, 74.74; H, 7.21; N, 13.07 measurements: C, 74.51; H, 7.48 ; N, 13.11.

Example 25
2-Methyl-N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] quinolin-1-amine

Part A
Glacial acetic acid (2 mL) was added to a suspension of 2-methyl-1H-imidazo [4,5-c] quinolin-1-amine (2.00 g, 10.1 mmol) in acetonitrile (20 mL). 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 ° C. The progress of the reaction was monitored by HPLC. After 3 days, the reaction mixture was cooled to ambient temperature, neutralized with 5% sodium carbonate solution (10 mL) and then concentrated in vacuo. The residue was partitioned between chloroform (40 mL) and water (10 mL). The organic layer was washed sequentially with water (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to give 2.82 g of 2-methyl-N- (tetrahydro-4H-pyran. -4-Ilidene) -1H-imidazo [4,5-c] quinolin-1-amine was obtained as a tan solid.

Part B
A solution of the material from Part A (2.82 g, 10.1 mmol) in methanol (40 mL) was cooled in an ice bath. Sodium borohydride (0.764 g, 20.2 mmol) was added in small portions over 5 minutes. The reaction mixture was raised to ambient temperature over 1.5 hours. The reaction mixture was quenched by the slow addition of 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 give a tan foam. This material was recrystallized twice from acetonitrile to give 308 mg of 2-methyl-N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] quinolin-1-amine. Obtained as tan crystals. Melting point 209-211 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.07 (s, 1 H), 8.90-8.87 (m, 1 H), 8.12-8.07 (m, 1 H), 7.70-7.65 (m, 2 H), 7.28 (d, J = 2.2 Hz, 1 H), 3.83-3.79 (m, 2 H), 3.52-3.42 (m, 1 H), 3.29-3.20 (m, 2 H), 2.68 (s, 3 H), 1.66-1.42 (m, 4 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 152.5, 143.3, 132.7, 132.5, 129.0, 126.2, 125.2, 120.7, 116.5, 64.5 , 55.4, 30.2, 12.6; MS (APCI) m / z 283.04 (M + H) ⁺ ; Elemental analysis: calculated C ₁₆ H ₁₈ N ₄ O: C, 68.06; H, 6.43; N, 19.84; C, 67.85; H, 6.44; N, 20.12.

Example 26
2- (Ethoxymethyl) -N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] quinolin-1-amine

2- (Ethoxymethyl) -N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] quinolin-1-amine is prepared according to the general procedure of Example 25 and 2- (ethoxy Prepared using methyl) -1H-imidazo [4,5-c] quinolin-1-amine instead of 2-methyl-1H-imidazo [4,5-c] quinolin-1-amine. The crude product was recrystallized from acetonitrile to give 415 mg of 2- (ethoxymethyl) -N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] quinolin-1-amine Was obtained as white crystals. Melting point 113-116 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1 H), 8.97-8.94 (m, 1 H), 8.15-8.12 (m, 1 H), 7.73-7.70 (m, 2 H), 7.30 (d, J = 2.2 Hz, 1 H), 4.85 (s, 2 H), 3.85-3.81 (m, 2 H), 3.68-3.59 (m, 1 H), 3.67 ( q, J = 7.0 Hz, 2 H), 3.25-3.17 (m, 2 H), 1.68-1.42 (m, 4 H), 1.18 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (75 MHz , DMSO-d ₆ ) δ 152.5, 145.1, 144.6, 133.7, 133.5, 130.1, 127.6, 126.4, 121.9, 117.7, 65.9, 65.6, 63.2, 57.0, 31.1, 15.4; MS (ESI) m / z 327.28 (M + H) ⁺ ; Elemental analysis: calculated C ₁₈ H ₂₂ N ₄ O ₂ : C, 66.24; H, 6.79; N, 17.16; measured values: C, 65.92; H, 6.90; N, 17.19.

Example 27
2- (Ethoxymethyl) -1-[(2S) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline

Part A
Under a nitrogen atmosphere, triethylamine (2.51 mL, 18.0 mmol) was added to a suspension of 4-chloro-3-nitroquinoline (1.87 g, 8.99 mmol) in dichloromethane (30 mL). The resulting solution was cooled in an ice bath and then (S)-(+)-tetrahydrofurfurylamine (1.02 mL, 9.89 mmol) was added. The reaction was gradually raised to ambient temperature overnight. The reaction mixture was partitioned between chloroform (30 mL) and water (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 give 2.36 g of 3-nitro-N-[(2S) -tetrahydrofuran. -2-ylmethyl] quinolin-4-amine was obtained as a yellow / orange solid.

Part B
Platinum on carbon (0.24 g of 5%) was added to a solution of the material from Part A in acetonitrile (100 mL). The mixture was placed under hydrogen pressure (50 psi, 3.4 × 10 ⁵ Pa) for 4 hours. The reaction mixture was filtered through a layer of celite filter media. The filter cake was rinsed with acetonitrile until the filtrate was clear. The filtrate was concentrated in vacuo to give 2.08 g of N ⁴ -[(2S) -tetrahydrofuran-2-ylmethyl] quinoline-3,4-diamine as an orange oil.

Part C
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 cooled in an ice-water bath. Ethoxyacetyl chloride (1.10 g, 8.98 mmol) was added dropwise over 2 minutes. The reaction mixture was gradually raised to ambient temperature. After 1.5 hours, more ethoxyacetyl chloride (0.50 mL) was added. The reaction was stirred for 30 minutes and then concentrated in vacuo to give the intermediate amide as an orange oil. This 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 to 100 ° 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 give an orange oil. It was. The oil was purified by preparative HPLC (silica gel, eluting with a gradient of 1-20% CMA in chloroform) to give an orange oil. The oil was triturated with MTBE (ca. 40 mL) first at ambient temperature and then in an ice-water bath for 1 hour. The solid was isolated by filtration and dried in vacuo at 50 ° C. overnight to give 2.10 g of 2- (ethoxymethyl) -1-[(2S) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c Quinoline was obtained as a white solid. Melting point 92-94 ° C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.18 (s, 1 H), 8.45-8.43 (m, 1 H), 8.17-8.15 (m, 1 H), 7.73-7.68 (m, 2 H), 4.94-4.90 (m, 2 H), 4.79-4.72 (m, 2 H), 4.33-4.27 (m, 1 H), 3.80-3.76 (m, 1 H), 3.61-3.55 (m, 3 H), 2.18-2.12 (m, 1 H), 1.97-1.90 (m, 1 H), 1.88-1.74 (m, 2 H), 1.17 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 152.3, 145.1, 144.7, 136.2, 134.2, 130.6, 127.3, 126.7, 121.7, 118.1, 77.9, 67.9, 65.9, 64.9, 49.9, 29.0, 25.7, 15.3; MS (APCI) m / z 312.18 (M + H) ⁺ ; Elemental analysis: calculated C ₁₈ H ₂₁ N ₃ O ₂ : C, 69.43; H, 6.80; N, 13.49; measured values: C, 69.39; H, 6.87 N, 13.62.

Example 28
2- (Ethoxymethyl) -1-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline

2- (Ethoxymethyl) -1-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline was prepared according to the general method of Example 27 using (R)-(−)- Tetrahydrofurfurylamine was prepared in place of (S)-(+)-tetrahydrofurfurylamine. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 1-20% CMA in chloroform) to give an orange oil. This oil was crystallized twice from MTBE to give 2- (ethoxymethyl) -1-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline as white crystals. Melting point 89-92 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.18 (s, 1 H), 8.46-8.43 (m, 1 H), 8.18-8.15 (m, 1 H), 7.75-7.67 (m, 2 H), 4.95-4.89 (m, 2 H), 4.80-4.70 (m, 2 H), 4.34-4.26 (m, 1 H), 3.82-3.75 (m, 1 H), 3.62-3.55 (m, 3 H), 2.21-2.10 (m, 1 H), 1.98-1.72 (m, 3 H), 1.17 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 152.2, 145.1, 144.7, 136.2, 134.2, 130.6, 127.3, 126.7, 121.7, 118.1, 77.8, 67.9, 65.9, 64.9, 49.9, 29.0, 25.7, 15.3; MS (APCI) m / z 312.19 (M + H) ⁺ ; Elemental analysis: calculated C ₁₈ H ₂₁ N ₃ O ₂ : C, 69.43; H, 6.80; N, 13.49; measured values: C, 69.31; H, 6.98; N, 13.68.

Example 29
2- (Ethoxymethyl) -1-[(2S) -tetrahydrofuran-2-ylmethyl] -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinoline hydrochloride

Platinum (IV) oxide (0.430 g, 1.89 mmol) was added to 2- (ethoxymethyl) -1-[(2S) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline (0.590 g, 1.89 mmol) was added to a solution in trifluoroacetic acid (25 mL). The mixture was placed in a Pal apparatus under hydrogen pressure (50 psi, 3.4 × 10 ⁵ Pa) for 24 hours. The reaction mixture was diluted with chloroform (20 mL) and methanol (5 mL) and filtered through a layer of celite filter media. The filter cake was rinsed with additional solvent and the filtrate was concentrated in vacuo to give a clear and colorless oil. This oil was suspended in water (15 mL) and the pH of the mixture was adjusted to 13 by dropwise addition of 10% sodium hydroxide, which was then extracted with dichloromethane (4 times, 15 mL). The combined extracts were washed with brine (15 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to give a clear colorless oil. The oil was purified by preparative HPLC (silica gel, eluting with a gradient of 5-20% CMA in chloroform) to give a clear and colorless oil. This oil was mixed with diethyl ether (15 mL) and a hydrochloric acid solution in ethanol was added dropwise until a precipitate formed. The solid was triturated and cooled in an ice bath for 30 minutes. The solid was isolated by filtration and dried overnight in a vacuum desiccator to give 108 mg of 2- (ethoxymethyl) -1-[(2S) -tetrahydrofuran-2-ylmethyl] -6,7,8,9-tetrahydro- 1H-imidazo [4,5-c] quinoline hydrochloride was obtained as a white solid. Melting point 156-159 ° C; ¹ H NMR (300 MHz, D ₂ O) δ 8.83 (s, 1 H), 4.98-4.83 (m, 2 H), 4.64 (d, J = 2.4 Hz, 1 H), 4.54 -4.45 (m, 1 H), 4.31-4.22 (m, 1 H), 3.89-3.82 (m, 1 H), 3.74-3.62 (m, 3 H), 3.35-3.28 (m, 1 H), 3.13 -3.08 (m, 3 H), 2.24-2.14 (m, 1 H), 2.04-1.85 (m, 6 H), 1.78-1.66 (m, 1 H), 1.18 (t, J = 7.1 Hz, 3 H ); ¹³ C NMR (75 MHz, D ₂ O) δ 159.6, 145.0, 144.8, 137.1, 131.4, 121.9, 79.1, 69.1, 67.7, 64.6, 50.4, 28.9, 27.7, 25.8, 24.2, 21.1, 20.6, 14.4; MS (APCI) m / z 316.18 (M + H) ⁺ ; Elemental analysis: Calculated C ₁₈ H ₂₆ ClN ₃ O ₂ · 0.5 H ₂ O: C, 59.91; H, 7.54; N, 11.64; Measurement: C , 59.52; H, 7.57; N, 11.52.

Example 30
2- (Ethoxymethyl) -1-[(2R) -tetrahydrofuran-2-ylmethyl] -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinoline hydrochloride

2- (Ethoxymethyl) -1-[(2R) -tetrahydrofuran-2-ylmethyl] -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinoline hydrochloride was obtained as described in Example 29. According to the method, 2- (ethoxymethyl) -1-[(2R) -tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline is converted to 2- (ethoxymethyl) -1-[(2S)- Prepared and purified in place of tetrahydrofuran-2-ylmethyl] -1H-imidazo [4,5-c] quinoline. The product was obtained as a white solid. Melting point 153-155 ° C; ¹ H NMR (300 MHz, D ₂ O) δ 8.83 (s, 1 H), 4.90 (q, J = 16.5 Hz, 2 H), 4.64 (d, J = 13.3 Hz, 1 H ), 4.49 (dd, J = 15.6, 9.8 Hz, 1 H), 4.31-4.22 (m, 1 H), 3.89-3.81 (m, 1 H), 3.73-3.62 (m, 3 H), 3.35-3.28 (m, 1 H), 3.14-3.07 (m, 3 H), 2.24-2.13 (m, 1 H), 2.02-1.85 (m, 6 H), 1.78-1.67 (m, 1 H), 1.18 (t , J = 7.0 Hz, 3 H); ¹³ C NMR (75 MHz, D ₂ O) δ 159.6, 145.0, 144.8, 137.0, 131.4, 121.9, 79.1, 69.1, 67.7, 64.6, 50.4, 28.9, 27.7, 25.8, 24.2, 21.1, 14.4; MS (APCI) m / z 316.19 (M + H) ⁺ ; Elemental analysis: calculated C ₁₈ H ₂₆ ClN ₃ O ₂ • 0.7 H ₂ O: C, 59.32; H, 7.58; N, 11.53; found: C, 59.17; H, 7.80; N, 11.46.

Example 31
1-cyclohexylmethyl-2- (2-methoxyethyl) -1H-imidazo [4,5-c] quinoline

1-Cyclohexylmethyl-2- (2-methoxyethyl) -1H-imidazo [4,5-c] quinoline is prepared according to the general procedure of Example 27, with cyclohexanemethylamine in part A as (S)-(+)- Prepared in place of tetrahydrofurfurylamine and in Part C using 3-methoxypropionyl chloride in place of ethoxyacetyl chloride. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 1-12% CMA in chloroform) to give a yellow solid. This solid was recrystallized twice from acetonitrile and dried in a vacuum oven at 80 ° C. to give 1-cyclohexylmethyl-2- (2-methoxyethyl) -1H-imidazo [4,5-c] quinoline as white crystals Got as. Melting point 129-131 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.15 (s, 1 H), 8.32-8.29 (m, 1 H), 8.17-8.14 (m, 1 H), 7.74-7.66 (m, 2 H), 4.49 (d, J = 7.4 Hz, 2 H), 3.90 (t, J = 6.8 Hz, 2 H), 3.31 (s, 3 H), 3.23 (t, J = 6.7 Hz, 2 H), 1.92-1.80 (m, 1 H), 1.67-1.54 (m, 5 H), 1.26-0.99 (m, 5 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 154.0, 144.6 , 144.4, 136.6, 133.3, 130.7, 126.9, 126.8, 121.0, 117.9, 70.1, 58.5, 51.0, 38.6, 30.0, 27.8, 26.1, 25.7; MS (ESI) m / z 324.23 (M + H) ⁺ ; Elemental analysis : calculated _{C 20 H 25 N 3 O:} C, 74.27; H, 7.79; N, 12.99; measurements: C, 74.08; H, 7.82 ; N, 12.77.

Example 32
2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-2-ylmethyl) -1H-imidazo [4,5-c] quinoline

Part A
Under a nitrogen atmosphere, sodium azide (2.18 g, 33.5 mmol) was added to a solution of 2- (bromomethyl) tetrahydro-2H-pyran (5.00 g, 27.9 mmol) in DMF. The mixture was heated to 50 ° C. After 24 hours, more sodium azide (1.5 g) was added. After a total of 3 days, the reaction mixture was cooled to ambient temperature, diluted with diethyl ether (90 mL) and filtered. The organic portion was washed sequentially with water (twice, 30 mL) and brine (30 mL), dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 3.88 g of 2- (azidomethyl) tetrahydro-2H- Pyran was obtained as a yellow oil.

Part B
Palladium on carbon (0.39 g of 10%) was added to a solution of the material from Part A in ethanol (30 mL). The mixture was placed in a Pal apparatus under hydrogen pressure (50 psi, 3.4 × 10 ⁵ Pa) for 15 hours. The reaction mixture was filtered through a layer of celite filter media. The filter cake was rinsed with 1: 1 methanol: ethanol. The filtrate was concentrated without heating to give 2.41 g of 1-tetrahydro-2H-pyran-2-ylmethylamine as a clear light oil.

Part C
2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-2-ylmethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general method of Example 27 in 1-tetrahydro Prepared using -2H-pyran-2-ylmethylamine in place of (S)-(+)-tetrahydrofurfurylamine and in Part C using 3-methoxypropionyl chloride in place of ethoxyacetyl chloride. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 1-15% CMA in chloroform) to give a yellow oil. This oil was crystallized and then recrystallized from MTBE / hexane to give 2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-2-ylmethyl) -1H-imidazo [4,5-c] Quinoline was obtained as white crystals. Melting point 108-110 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.14 (s, 1 H), 8.35-8.32 (m, 1 H), 8.16-8.13 (m, 1 H), 7.70-7.67 (m, 2 H), 4.75 (dd, J = 5.7, 3.0 Hz, 1 H), 4.59 (dd, J = 15.8, 9.0 Hz, 1 H), 3.88 (t, J = 7.0 Hz, 2 H), 3.77-3.69 (m, 2 H), 3.32 (s, 3 H), 3.28-3.24 (m, 2 H), 3.16-3.08 (m, 1 H), 1.92-1.82 (m, 2 H), 1.50- 1.41 (m, 4 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 154.5, 144.5, 136.5, 133.5, 130.6, 126.9, 126.7, 121.2, 117.8, 76.5, 70.0, 68.0, 58.4, 55.3, 50.2 , 29.0, 27.8, 25.7, 22.8; MS (APCI) m / z 326.20 (M + H) ⁺ ; Elemental analysis: calculated C ₁₉ H ₂₃ N ₃ O ₂ : C, 70.13; H, 7.12; N, 12.91; Measurements: C, 70.31; H, 7.16; N, 13.08.

Example 33
2- [1- (Tetrahydro-2H-pyran-2-ylmethyl) -1H-imidazo [4,5-c] quinolin-2-yl] ethanol

2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-2-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.54 g, 1.66 mmol) in dichloromethane (17 mL) The solution was placed under a nitrogen atmosphere and cooled in an ice-water bath. Boron trifluoride (1.74 mL of 1 M in dichloromethane) was added dropwise. The reaction mixture was gradually warmed to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to give a tan solid. This solid was mixed with an ammonia solution in methanol (20 mL of 7 N) and stirred for 2 hours. Silica gel (5 g) was added and the mixture was concentrated in vacuo to a fine powder. This material was loaded onto a preparative HPLC column (100 g silica gel) and the column was eluted with a gradient of 1-20% CMA in chloroform. Fractions containing product were combined and concentrated in vacuo to give a white foam. The foam was triturated with diethyl ether (10-15 mL) for 2 hours. The solid was isolated by filtration and dried overnight in a vacuum oven to give 57 mg of 2- [1- (tetrahydro-2H-pyran-2-ylmethyl) -1H-imidazo [4,5-c] quinoline-2- Il] ethanol was obtained as an off-white solid. Melting point 151-153 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.14 (s, 1 H), 8.36-8.33 (m, 1 H), 8.17-8.13 (m, 1 H), 7.71-7.67 (m, 2 H), 4.87 (t, J = 5.4 Hz, 1 H), 4.76 (dd, J = 15.6, 3.0 Hz, 1 H), 4.62 (dd, J = 15.7, 6.8 Hz, 1 H), 3.96-3.90 (m, 2 H), 3.78-3.69 (m, 2 H), 3.21-3.09 (m, 3 H), 1.93-1.90 (m, 1 H), 1.84 (br, 1 H), 1.51- 1.41 (m, 4 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 155.2, 144.5, 136.5, 133.4, 130.6, 126.9, 126.7, 121.2, 117.9, 76.5, 68.0, 59.6, 50.3, 31.0, 29.1 , 25.7, 22.8; MS (APCI) m / z 312.20 (M + H) ⁺ ; Elemental analysis: calculated C ₁₈ H ₂₁ N ₃ O ₂ : C, 69.43; H, 6.80; N, 13.49; measured: C 69.08; H, 6.76; N, 13.28.

Example 34
1-Cyclopentylmethyl-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline

1-Cyclopentylmethyl-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline is prepared according to the general procedure of Example 27, in part A with cyclopentylmethylamine hydrochloride (S)-(+)- Prepared using instead of tetrahydrofurfurylamine. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 1-15% CMA in chloroform) to give a tan solid. This material was recrystallized from n-propyl acetate to give 1-cyclopentylmethyl-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline as light brown crystals. Melting point 95-98 ° C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.19 (s, 1 H), 8.40-8.38, 1 H), 8.18-8.16 (m, 1 H), 7.75-7.71 (m , 2 H), 4.84 (s, 2 H), 4.68 (d, J = 7.6 Hz, 2 H), 3.59 (q, J = 7.0 Hz, 2 H), 2.55-2.50 (m, 1 H), 1.69 -1.56 (m, 4 H), 1.51-1.44 (m, 2 H), 1.43-1.36 (m, 2 H), 1.16 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (125 MHz, DMSO -d ₆ ) δ 151.7, 145.2, 144.7, 136.4, 133.8, 130.7, 127.4, 127.0, 121.5, 118.0, 65.9, 64.8, 50.0, 40.5, 29.8, 24.7, 15.3; MS (ESI) m / z 310.32 (M + H) ⁺ ; Elemental analysis: calculated C ₁₉ H ₂₃ N ₃ O: C, 73.76; H, 7.49; N, 13.58; measured values: C, 73.83; H, 7.42; N, 13.61.

Example 35
[1- (Cyclopentylmethyl) -1H-imidazo [4,5-c] quinolin-2-yl] methanol

A solution of 1-cyclopentylmethyl-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline (120 mg, 0.39 mmol) in dichloromethane (20 mL) was placed under a nitrogen atmosphere and placed in an ice-water bath. Cooled in. Boron trifluoride (0.58 mL of 1 M in dichloromethane) was added dropwise. The reaction mixture was gradually warmed to ambient temperature overnight. The reaction mixture was quenched with methanol (5 mL) and then concentrated under reduced pressure to give an orange solid. This solid was mixed with an ammonia solution in methanol (10 mL of 7 N) and stirred for 30 minutes. Silica gel (3 g) was added and the mixture was concentrated in vacuo to a fine powder. This material was loaded onto a preparative HPLC column (40 g silica gel) and the column was eluted with a gradient of 1-25% CMA in chloroform. Fractions containing product were combined and concentrated under reduced pressure to give an off-white solid. The solid was recrystallized from acetonitrile, dried in a vacuum oven at 80 ° C. for 3 hours, and 46 mg of [1- (cyclopentylmethyl) -1H-imidazo [4,5-c] quinolin-2-yl] methanol Was obtained as white crystals. Melting point 168-170 ° C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.17 (s, 1 H), 8.40-8.38 (m, 1 H), 8.17-8.15 (m, 1 H), 7.74-7.70 (m, 2 H), 5.79 (t, J = 5.8 Hz, 1 H), 4.84 (d, J = 5.9 Hz, 2 H), 4.72 (d, J = 7.7 Hz, 2 H), 2.54-2.49 ( m, 1 H), 1.70-1.58 (m, 4 H), 1.52-1.44 (m, 2 H), 1.42-1.35 (m, 2 H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 154.4 , 144.6, 144.1, 135.9, 133.3, 130.2, 126.7, 126.4, 121.0, 117.6, 56.6, 49.4, 40.1, 29.4, 24.2; MS (APCI) m / z 282.11 (M + H) ⁺ ; Elemental analysis: calculated value C ₁₇ H ₁₉ N ₃ O: C, 72.57; H, 6.81; N, 14.93; found: C, 72.60; H, 6.72; N, 15.02.

Example 36
2- (Ethoxymethyl) -6,7-dimethyl-N- (tetrahydro-2H-thiopyran-4-yl) -1H-imidazo [4,5-c] pyridin-1-amine

Part A
2,4-dichloro-5,6-dimethyl-3-nitropyridine (40 g, 1 eq), triethylamine (50.4 mL, 2.0 eq), t-butyl carbazate (47.8 g, 2.0 Eq.), And anhydrous DMF (400 mL) were heated to 65 ° C. for 2 days under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 10% sodium carbonate (500 mL) and dichloromethane (500 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (500 mL). The organic layers were combined and concentrated under reduced pressure to give a dark brown solid. The solid was purified by preparative HPLC (silica gel, eluting with a gradient of 40-60% ethyl acetate in hexane) to give a light brown oil. The oil was stirred with toluene and then concentrated in vacuo to give 43.5 g of t-butyl 2- (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl) hydrazinecarboxylate as tan crystals. Obtained.

Part B
Mixture of t-butyl 2- (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl) hydrazinecarboxylate (39.1 g), 5% platinum on carbon (4.0 g) and toluene (800 mL) Was placed in a Pal apparatus under hydrogen pressure (50 psi, 3.4 × 10 ⁵ Pa) for 16 hours. The reaction mixture was filtered through a layer of celite filter media. The filter cake was washed with methanol and dichloromethane. The filtrate was concentrated under reduced pressure to give 32.8 g of t-butyl 2- (3-amino-2-chloro-5,6-dimethylpyridin-4-yl) hydrazinecarboxylate as a tan solid.

Part C
2- (3-Amino-2-chloro-5,6-dimethylpyridin-4-yl) hydrazinecarboxylate t-butyl (24.75 g, 86.3 mmol), triethylamine (18.0 mL, 129 mmol) and dichloromethane (500 mL) The mixture was cooled in an ice bath. Ethoxyacetyl chloride (11.6 g, 94.9 mmol) was added dropwise. The reaction mixture was allowed to cool for 1 hour and then allowed to rise to ambient temperature overnight. More ethoxyacetyl chloride (0.3 eq) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was washed with water (100 mL). The organic layer was filtered and then concentrated in vacuo to give the amide intermediate. This material was dissolved in ethanol (175 mL) and water (50 mL). Sodium hydroxide (10.4 g, 259 mmol) was added and the reaction mixture was stirred for 2 hours. The pH of the reaction mixture was adjusted to 11 with hydrochloric acid and sodium carbonate. The reaction mixture was diluted with water (300 mL) and then extracted with dichloromethane (3 times 100 mL). The combined organic layers were filtered, concentrated under reduced pressure, and 27.2 g of 4-chloro-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-ylcarbamic acid t-Butyl was obtained as an orange solid.

Part D
Under a nitrogen atmosphere, trifluoroacetic acid (50 mL) was added over 5 minutes to the cooled (ice bath) solution of the material from Part C in dichloromethane (200 mL). The reaction mixture was allowed to cool for 1 hour and then raised to ambient temperature. The reaction mixture was concentrated under reduced pressure to give a light brown oil. The oil was partitioned between dichloromethane (250 mL) and water (250 mL). The pH of the aqueous layer was adjusted to about 12 with sodium carbonate, and then the aqueous layer was extracted with dichloromethane (3 times 250 mL). The organic layers were combined and concentrated under reduced pressure to give a light brown oil. Trituration of this oil with ethyl acetate yielded 5 g of 4-chloro-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-amine as tan crystals. Obtained. The mother liquor was purified by preparative HPLC (silica gel, eluting with a gradient of 0-10% methanol in dichloromethane) to give 10.8 g of 4-chloro-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4, 5-c] pyridin-1-amine was obtained as a light brown oil that solidified gradually on standing.

Part E
4-chloro-2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-amine (5.95 g, 23.4 mmol), tetrahydrothiopyran-4 under nitrogen atmosphere A mixture of -one (5.43 g, 46.7 mmol), acetonitrile (60 mL) and glacial acetic acid (20 mL) was heated to reflux for 48 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated under reduced pressure to give a brown oil. The oil was partitioned between dichloromethane (100 mL) and 10% sodium carbonate (100 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 × 100 mL). The organic layers were combined and concentrated under reduced pressure to give a brown oil. The oil was purified by preparative HPLC (silica gel, eluting with a gradient of 0-7% methanol in dichloromethane) to yield 6.2 g of 4-chloro-2- (ethoxymethyl) -6,7-dimethyl-N- (tetrahydro -4H-thiopyran-4-ylidene) -1H-imidazo [4,5-c] pyridin-1-amine was obtained as a yellow solid.

Part F
Under a nitrogen atmosphere, sodium borohydride (2.0 g, 52.7 mmol) was added over 5 minutes to a solution of the material from Part E (17.6 mmol) in methanol (120 mL). After 2 hours, the reaction was quenched with saturated ammonium chloride (40 mL) and then stirred for 5 minutes. Methanol was removed under reduced pressure. The remaining aqueous layer was mixed with sodium carbonate (5 g) and water (100 mL) and then extracted with dichloromethane (3 times 100 mL). The organic layers were combined and concentrated under reduced pressure to give a light brown oil. The oil was purified by preparative HPLC (silica gel, eluting with a gradient of 0-6% methanol in dichloromethane) to yield 4.96 g of 4-chloro-2- (ethoxymethyl) -6,7-dimethyl-N- (tetrahydro -2H-thiopyran-4-yl) -1H-imidazo [4,5-c] pyridin-1-amine was obtained as a pale yellow solid.

Part G
4-Chloro-2- (ethoxymethyl) -6,7-dimethyl-N- (tetrahydro-2H-thiopyran-4-yl) -1H-imidazo [4,5-c] pyridin-1-amine (0.5 g, 1.41 mmol), ammonium formate (0.9 g, 14.8 mol), ethanol (50 mL) and methanol (25 mL) were flushed with nitrogen. 10% palladium on carbon (0.5 g) was added and the reaction mixture was heated to 80 ° C. After 3 hours, the reaction mixture was cooled to ambient temperature and more ammonium formate (0.9 g) and 10% palladium on carbon (0.5 g) were added, then the reaction mixture was heated to reflux for an additional 3 hours. The reaction mixture was cooled to ambient temperature and then filtered through a layer of celite filter media. The filtrate was concentrated under reduced pressure to give 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 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure to give 0.45 g of a clear oil. This material was purified by preparative HPLC (silica gel, eluting with a gradient of 0-7% methanol in dichloromethane) to give a clear oil (0.34 g). The oil was crystallized and then recrystallized from ethyl acetate and then dried under high vacuum at 50 ° C. for 16 hours to give 0.16 g of 2- (ethoxymethyl) -6,7-dimethyl-N- (tetrahydro- 2H-thiopyran-4-yl) -1H-imidazo [4,5-c] pyridin-1-amine was obtained as white crystals. Melting point 109-111 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 6.71 (d, J = 1.6 Hz, 1H), 4.71 (s, 2H), 3.61 (q, J = 7.0 Hz, 2H) , 3.14 (m, 1H), 2.61 (s, 3H), 2.61-2.53 (m, 4H), 2.50 (s, 3H), 1.84 (m, 2H), 1.49 (m, 2H), 1.15 (t, J = 7.0 Hz, 3H); MS (ESI) m / z 321 (M + H) ⁺ ; Elemental analysis: calculated C ₁₆ H ₂₄ N ₄ OS · 0.50 H ₂ O: C, 58.33; H, 7.65; N, 17.01. Measurements: C, 58.18; H, 7.63; N, 16.91.

Example 37
N- (1,1-Dioxidetetrahydro-2H-thiopyran-4-yl) -2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-amine

Part A
Under a nitrogen atmosphere, 4-chloro-2- (ethoxymethyl) -6,7-dimethyl-N- (tetrahydro-2H-thiopyran-4-yl) -1H-imidazo [4,5-c] pyridine-1- A mixture of amine (1.00 g, 2.82 mol) and dichloromethane (20 mL) was cooled in an ice bath. 3-Chloroperbenzoic acid (60% of 1.78 g, 6.20 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. Analysis by HPLC showed the reaction was complete after 1 hour. The reaction was repeated with 3.46 g of starting material. The two reaction mixtures were combined and washed with 5% sodium carbonate and then concentrated in vacuo to give 4.2 g of crude 4-chloro-N- (1,1-dioxidetetrahydro-2H-thiopyran-4-yl) -2. -(Ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-amine was obtained as a pale orange solid.

Part B
4-Chloro-N- (1,1-dioxidetetrahydro-2H-thiopyran-4-yl) -2- (ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridine-1 A mixture of amine (0.5 g, 1.28 mmol), ammonium formate (0.85 g, 13.5 mol), ethanol (40 mL) and methanol (20 mL) was flushed with nitrogen. 10% palladium on carbon (0.5 g) was added and the reaction mixture was heated to 80 ° C. for 3 hours. The reaction mixture was cooled to ambient temperature and then filtered through a layer of celite filter media. The filtrate was concentrated under reduced pressure to give a white solid. This 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 × 100 mL). The combined organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure to give 0.40 g of a white solid. This material was purified by preparative HPLC (silica gel, eluting with a gradient of 0-10% methanol in dichloromethane) to give a white solid (0.34 g). The oil was recrystallized from ethyl acetate / methanol and then dried under high vacuum at 80 ° C. for 16 hours to give 0.23 g of N- (1,1-dioxidetetrahydro-2H-thiopyran-4-yl) -2 -(Ethoxymethyl) -6,7-dimethyl-1H-imidazo [4,5-c] pyridin-1-amine was obtained as white crystals. Melting point 194-196 ° C. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 6.94 (d, J = 1.3 Hz, 1H), 4.72 (s, 2H), 3.62 (q, J = 7.0 Hz, 2H) , 3.44 (m, 1H), 3.21-2.95 (m, 4H), 2.62 (s, 3H), 2.51 (s, 3H), 1.96-1.76 (m, 4H), 1.16 (t, J = 7.0 Hz, 3H ); MS (ESI) m / z 353 (M + H) ⁺ ; Elemental analysis: calculated C ₁₆ H ₂₄ N ₄ O ₃ S: C, 54.53; H, 6.86; N, 15.90. Measured values: C, 54.54 H, 7.05; N, 15.90.

Example 38
2-Ethyl-1- (tetrahydro-2H-pyran-4-yl-methyl) -1H-imidazo [4,5-c] quinoline

Triethyl orthopropionate (0.938 mL, 4.66 mmol) and pyridine hydrochloride (50 mg, 0.47 mmol), and sequentially, N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (1.2 g, 4.66 mmol) was added to a solution in toluene (40 mL). The mixture was heated to reflux for 4 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane and then washed with water. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The resulting solid was dissolved in refluxing acetonitrile. The solution was allowed to cool and then it was concentrated under reduced pressure. The residue mass was redissolved in refluxing acetonitrile (a small amount of solid remained) and the mixture was allowed to cool. The solid was isolated by filtration, washed with acetonitrile, dried in vacuo for 2 hours, and 1.05 g of 2-ethyl-1- (tetrahydro-2H-pyran-4-yl-methyl) -1H-imidazo [4,5 -c] quinoline was obtained as pale green crystals. Melting point 169-170 ° C. MS (ESI) m / z 296.33 (M + H) ⁺ ; Elemental analysis: calculated C ₁₈ H ₂₁ N ₃ O: C, 73.19; H, 7.17; N, 14.23. Measured values: C, 72.99; H, 7.21 N, 14.39.

Example 39
2- (Ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Ethoxy chloride (0.476 g, 3.89 mmol) and, N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (1.0 g, 3.89 mmol) in dichloromethane (40 mL) and triethylamine ( 0.540 mL, 3.89 mmol) was added dropwise to the solution in the mixture. After 30 minutes, dichloromethane was removed under reduced pressure. The crude amine intermediate was dissolved in ethanol (40 mL). Triethylamine (2.6 mL) was added and the reaction mixture was heated to reflux. After 4 hours, more triethylamine (1 mL) was added and the reaction mixture was heated to reflux overnight. Further triethylamine (1 mL) was added and the reaction mixture was heated to reflux for an additional 2 hours. The reaction mixture was allowed to cool to ambient temperature and then ethanol was removed under reduced pressure. The residue was dissolved in dichloromethane and then washed with water. The organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC (silica gel, eluting with a linear gradient of 2-15% CMA in chloroform) followed by treatment with refluxing acetonitrile. The solid was isolated by filtration and then dried in vacuo overnight to give 0.97 g of 2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline. Obtained as an off-white solid. Melting point 123.5-125 ° C. MS (ESI) m / z 326.24 (M + H) ⁺ ; Elemental analysis: calculated C ₁₉ H ₂₃ N ₃ O ₂ : C, 70.13; H, 7.12; N, 12.91. Measured values: C, 70.25; H, 7.25; N, 13.00.

Example 40
2-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

2-Butyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general procedure of Example 38 except that trimethyl orthoformate was replaced by triethyl orthopropionate. Manufactured. The crude product was purified by preparative HPLC (silica gel, eluting with a linear gradient of 2-15% CMA in chloroform) followed by crystallization from acetonitrile to give 2-butyl-1- (tetrahydro-2H-pyran-4- (Ilmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a white solid. Melting point 135-136.5 ° C. MS (ESI) m / z 324.05 (M + H) ⁺ ; Elemental analysis: Calculated value C ₂₀ H ₂₅ N ₃ O: C, 74.27; H, 7.79; N, 12.99. Measured value: C, 74.25; H, 7.91 ; N, 13.00.

Example 41
2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline hydrochloride

2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline hydrochloride was prepared according to the general procedure of Example 39 and 3-methoxypropionyl. Prepared using chloride instead of ethoxyacetyl chloride. The crude product was purified by preparative HPLC (silica gel, eluting with a linear gradient of 2-15% CMA in chloroform) followed by treatment with refluxing acetonitrile. The resulting oil was diluted with diethyl ether and then admixed with a solution of hydrogen chloride in diethyl ether (1.0 mL of 1.0 M). The resulting solid was isolated by filtration, washed with diethyl ether, dried and 0.550 g 2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline hydrochloride was obtained as an off-white solid. Melting point 217 ° C, decomposition. MS (ESI) m / z 326.19 (M + H) ⁺ ; Elemental analysis: Calculated C ₁₉ H ₂₃ N ₃ O ₂ · 1.0HCl: C, 63.06; H, 6.68; N, 11.61; Cl, 9.80. : C, 62.84; H, 6.57; N, 11.33; Cl, 9.55.

Example 42
2-Ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -6,7,8,9-tetrahydro-1H-imidazo [4,5-c] quinoline dihydrochloride

A solution of 2-ethyl-1- (tetrahydro-2H-pyran-4-yl-methyl) -1H-imidazo [4,5-c] quinoline (0.400 g, 1.36 mmol) in trifluoroacetic acid was added to trifluoroacetic acid. A Pal reactor containing platinum oxide IV (0.300 g, 1.25 mmol) moistened with acetic acid was added. The reactor was placed under hydrogen pressure over the weekend. The reaction mixture was filtered through a layer of celite filter media. The filter cake was rinsed with 10% methanol in dichloromethane. The filtrate was concentrated under reduced pressure. The residue was basified with saturated aqueous sodium carbonate and a small amount of 50% sodium hydroxide and extracted with dichloromethane (2 × 50 mL). The organic layers were combined, washed sequentially with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative HPLC (silica gel, eluting with a gradient of 5-25% methanol in dichloromethane) 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. The solid was mixed with acetonitrile and heated to reflux. The mixture was allowed to cool with stirring. The solid was isolated by filtration, washed with acetonitrile and then dried in vacuo to give 0.224 g of 2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -6,7,8,9-tetrahydro-1H -Imidazo [4,5-c] quinoline dihydrochloride was obtained as a white powder. 251-252.5 ° C. MS (ESI) m / z 300.21 (M + H) ⁺ ; Elemental analysis: Calculated C ₁₈ H ₂₅ N ₃ O · 2.0 HCl · 1.0 H ₂ O: C, 55.39; H, 7.49; N, 10.77; Cl, 18.17. Measurements: C, 55.42; H, 7.87; N, 10.73; Cl, 18.26.

Example 43
N- [2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] -2-methylpropanamide

Dioxane (1.3 mL) was added to 7-bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5 in a vial equipped with a stir bar. -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) were added. The vial was flushed with nitrogen, sealed with a TEFLON (lined cap, then heated overnight at 80 ° C. The reaction mixture was diluted with chloroform containing a trace amount of methanol and then preparative HPLC ( The resulting foamy residue (0.476 g) was dissolved in acetonitrile and then allowed to stand overnight.The solid was isolated by filtration and dissolved in acetonitrile. 0.129 g N- [2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl ] -2-Methylpropanamide was obtained as a white solid, mp 203-204.5 ° C. MS (ESI) m / z 411.28 (M + H) ⁺ ; Elemental analysis: calculated C ₂₃ H ₃₀ N ₄ O ₃ : C , 67.29; H, 7.37; N, 13.65. Measurements: C, 67.28; H, 7.45; N, 13.57.

Example 44
{5- [2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] pyridin-3-yl} methanol

1,2-Dimethoxyethane (5 mL) and water (2.5 mL) were added to 7-bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline (0.500 g, 1.24 mmol), 5- (t-butyldimethylsilanyloxymethyl) pyridine-3-boronic acid (0.398 g, 1.49 mmol) and potassium carbonate (0.598 g, 4.34 mmol) It was added to the mixture and nitrogen was bubbled through the resulting slurry. Dichlorobis (triphenylphosphine) palladium (II) (0.043 g, 0.062 mmol) was added. Nitrogen was bubbled through the mixture and then heated to reflux for 1 hour. The organic layer was purified by preparative HPLC (silica gel, eluting with a linear gradient of 2-10% CMA in chloroform). The resulting solid was added to a mixture of THF (10 mL) and water (5 mL). Acetic acid (5 mL) was added and the mixture was stirred overnight. The reaction was basified with 2M aqueous sodium carbonate and the THF was removed under reduced pressure. The solid was isolated by filtration, washed with water and dried to give 0.368 g of {5- [2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [ 4,5-c] quinolin-7-yl] pyridin-3-yl} methanol was obtained as a white powder. Melting point 218-220 ° C. MS (ESI) m / z 433.20 (M + H) ⁺ ; Elemental analysis: Calculated value C ₂₅ H ₂₈ N ₄ O ₃・ 1.0H ₂ O: C, 66.65; H, 6.71; N, 12.43. Measured value: C 66.51; H, 6.39; N, 12.34.

Example 45
2- (2-Methoxyethyl) -7-pyridin-3-yl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

1,2-Dimethoxyethane (5 mL) and water (2.5 mL) were added to 7-bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline (0.500 g, 1.24 mmol), pyridin-3-ylboronic acid (0.183 g, 1.49 mmol) and potassium carbonate (0.598 g, 4.34 mmol) are added to the resulting slurry and nitrogen is added to the resulting slurry. Infused. Dichlorobis (triphenylphosphine) palladium (II) (0.043 g, 0.062 mmol) was added. Nitrogen was bubbled through the mixture and then heated to reflux for 1 hour. The organic layer was purified by preparative HPLC (silica gel, eluting with a linear gradient of 2-15% CMA in chloroform). The resulting oil was dissolved in dichloromethane and then the solvent was removed under reduced pressure. Repeating this procedure with acetonitrile yielded 0.474 g of a pale yellow oil. The oil was triturated with diethyl ether and then left overnight. The solid was isolated by filtration, washed with diethyl ether, dried and 0.345 g of 2- (2-methoxyethyl) -7-pyridin-3-yl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a white solid. Melting point 150-151 ° C. MS (ESI) m / z 403.25 (M + H) ⁺ ; Elemental analysis: calculated C ₂₄ H ₂₆ N ₄ O ₂ : C, 71.62; H, 6.51; N, 13.92. Measured values: C, 71.90; H, 6.85; N, 14.09.

Compound 1
7-Benzyloxy-2-ethyl-1- (tetrahydro-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Part A
Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (20 mL, 150 mmol) in methanol (500 mL) and the reaction was stirred overnight at ambient temperature. . More ammonium hydroxide (500 mL) was added and the reaction was stirred for an additional 4 days. Methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3 times, 150 mL). The extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure to give 11.4 g of tetrahydro-2H-pyran-4-carboxamide as a white solid.

Part B
A solution of tetrahydro-2H-pyran-4-carboxamide (11.4 g, 88.3 mmol) in THF (441 mL) was cooled to 0 ° C. Lithium aluminum hydride (10.0 g, 265 mmol) was added in 6 portions and added over 10 minutes. The reaction flask was purged with nitrogen between these additions. When the reaction mixture no longer foamed, it was heated to reflux for 6 hours. The reaction was then cooled to 0 ° C. and ethyl acetate was added dropwise until bubbling ceased. Methanol was then added dropwise until bubbling ceased. Water (10 mL), 15% aqueous sodium hydroxide solution (10 mL) and water (30 mL) were added sequentially. The organic fraction was decanted and the remaining gray solid was washed with chloroform. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give tetrahydro-2H-pyran-4-ylmethylamine.

Part C
7- (Benzyloxy) -3-nitroquinolin-4-ol (12.3 g, 41.6 mmol) was suspended in DMF (83 mL). Phosphorous oxychloride (4.2 mL, 45 mmol) was added in one portion and the mixture was heated to 100 ° C. for 5 minutes. The solution was allowed to cool to 40 ° C. and then poured into ice water (total volume 400 mL) resulting in the formation of a tan precipitate. The precipitate was filtered and washed with water. After drying, the solid was dissolved in dichloromethane and the remaining water was separated. The organic fraction was dried over anhydrous sodium sulfate and anhydrous magnesium sulfate (about 50/50 mixture). The organic fraction was filtered into a reaction flask (total volume of organic fraction containing 7- (benzyloxy) -3-chloro-4-nitroquinoline was about 425 mL). The flask was cooled to 8 ° C. and triethylamine (11.6 mL, 83.0 mmol) was added. (Tetrahydro-2H-pyran-4-yl) methylamine (6.0 g, 52 mmol) in dichloromethane (50 mL) was added dropwise to the mixture. The cooling bath was removed and the reaction was stirred for 16 hours. Water (200 mL) was added and stirred for 30 minutes. The layers were separated and the organic fraction was washed successively with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Recrystallization from 2-propanol gave 14.1 g of 7- (benzyloxy) -3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine as a yellow powder.

Part D
PAL reactor with 7- (benzyloxy) -3-nitro-N- (tetrahydro-2H-pyran-4-ylmethyl) quinolin-4-amine (14.1 g, 35.6 mmol) and 5% platinum on carbon (2.0 g) Added to. These solids were covered with acetonitrile (200 mL) and placed on a hydrogenator. The reactor was degassed three times, charged with 50 psi (3.4 × 10 ⁵ Pa) of hydrogen, and shaken for 3 hours, refilling with hydrogen as needed. After 6 hours, the catalyst was removed by filtration through a celite filter medium. Celite was washed with acetonitrile (about 300 mL) until a clear filtrate flowed out. The solvent was evaporated under reduced pressure to about 1/2 volume and cooled to 8 ° C. To this solution was added propionyl chloride (3.15 mL, 35.6 mmol) dropwise over 3 minutes. The cooling bath was removed and the reaction was stirred for 16 hours. The resulting precipitate was filtered and washed with acetonitrile. Vacuum drying for 1 hour gave 14.2 g of N- {7- (benzyloxy) -4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] quinolin-3-yl} propanamide dihydrochloride as tan Obtained as a solid.

Part E
N- {7- (Benzyloxy) -4-[(tetrahydro-2H-pyran-4-ylmethyl) amino] quinolin-3-yl} propanamide dihydrochloride (14.2 g, 31.1 mmol) in ethanol (150 mL) And diluted with water (50 mL). Potassium carbonate (12.3 g, 89 mmol) in water (15 mL) was added and stirred until the reaction was dissolved (about 30 minutes). The reaction was then heated to 60 ° C. for 16 hours. Ethanol was evaporated under reduced pressure and residual water was extracted with dichloromethane. The organic fraction was washed sequentially with water followed by saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give a brown viscous oil. This oil was crystallized from acetonitrile (ca. 200 mL) to give 8.4 g of 7- (benzyloxy) -2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5 -c] Quinoline was obtained as a white solid. Melting point: 143-145 ° C. Elemental analysis: Calculated value C ₂₅ H ₂₇ N ₃ O ₂ : C, 74.79; H, 6.78; N, 10.47. Measurement value: C, 74.58; H, 7.05; N, 10.50.

Compound 2
2-Ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-ol

7- (Benzyloxy) -2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (8.3 g, 20.7 mmol) was moistened with acetonitrile. A Pal reactor containing 10% palladium on carbon (1.5 g) was added. Methanol (160 mL) was added and the reactor was placed on a hydrogenator. The reactor was degassed three times and charged with 50 psi (3.4 × 10 ⁵ Pa) of hydrogen. The reactor was shaken for 16 hours, refilling with hydrogen as needed. The catalyst was filtered off with glass fiber filter paper. The catalyst was washed with 3: 1 chloroform / methanol. The filtrates were combined and concentrated under reduced pressure to give 6.1 g of a gray solid. A small amount of this material was purified by preparative HPLC (silica gel, eluting with a linear gradient of 2-25% CMA in chloroform). The residue was suspended in methanol. The mixture was heated to reflux and then allowed to cool to ambient temperature overnight. The solid was isolated by filtration, washed with methanol, dried and 110 mg 2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline-7 -Ole was obtained as a white solid. Melting point 318 ° C, decomposition. MS (ESI) m / z 312.07 (M + H) ⁺ ; Elemental analysis: Calculated value C ₁₈ H ₂₁ N ₃ O ₂ : C, 69.43; H, 6.80; N, 13.49. Measured value: C, 69.42; H, 6.89; N, 13.45.

Example 46
2-Ethyl-7- (tetrahydrofuran-2-ylmethoxy) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

2-Ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-ol (0.800 g, 2.57 mmol), tetrahydrofurfuryl chloride (0.293 mL, 2.70 mmol), cesium carbonate (1.67 g, 5.14 mmol) and DMF (20 mL) were mixed and then heated to 65 ° C. After 3 hours, analysis by LC / MS showed no product. An additional equivalent of acid chloride was added and the reaction mixture was heated to 100 ° C. overnight. 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 × 50 mL). The dichloromethane extract was washed with water (3 times 50 mL). The combined organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified twice by preparative HPLC (silica gel, eluted with a linear gradient of 2-20% CMA in chloroform; then eluted with a linear gradient of 1-20% CMA in silica gel, chloroform). The residue was dissolved in a small amount of refluxing ethyl acetate. The solution was diluted with hexane until cloudy and then allowed to stand. The solid was isolated by filtration and dried to give 0.214 g of 2-ethyl-7- (tetrahydrofuran-2-ylmethoxy) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- c] Quinoline was obtained as a white solid. Melting point 146-147.5 ° C. MS (ESI) m / z 396.07 (M + H) ⁺ ; Elemental analysis: calculated C ₂₃ H ₂₉ N ₃ O ₃ : C, 69.85; H, 7.39; N, 10.62. Measured values: C, 69.75; H, 7.43; N, 10.50.

Example 47
2-Ethoxymethyl-7- (morpholin-4-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Under nitrogen atmosphere, toluene (2.50 mL) was added to 7-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.50 g, 1.24 mmol), morpholine (0.11 mL, 1.49 mmol), tris (dibenzylideneacetone) dipalladium (39 mg, 0.037 mmol), (±) -2,2'-bis (diphenylphosphino) -1,1'- Binaphthyl (46 mg, 0.074 mmol) and sodium t-butoxide (0.17 g, 1.74 mmol) were added to a vial. Nitrogen was bubbled through the mixture. The vial was sealed with a Teflon lined cap and then heated to 80 ° C. for 15 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to give an orange solid. The solid was purified by preparative HPLC (silica gel, eluting with a gradient of 1-15% CMA in chloroform) to give a yellow solid. This material was recrystallized from n-propyl acetate to give 150 mg of 2-ethoxymethyl-7- (morpholin-4-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline was obtained as white crystals. Melting point 197-199 ° C; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.04 (s, 1 H), 8.22 (d, J = 9.2 Hz, 1 H), 7.53 (d, J = 9.2 Hz, 1 H), 7.47 (d, J = 2.6 Hz, 1 H), 4.79 (s, 2 H), 4.56 (d, J = 7.4 Hz, 2 H), 3.82-3.80 (m, 6 H), 3.58 (q , J = 7.0 Hz, 2 H), 3.31-3.29 (m, 4 H), 3.19-3.10 (m, 2 H), 2.23-2.14 (m, 1 H), 1.52-1.44 (m, 2 H), 1.42-1.35 (m, 2 H), 1.16 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 151.1, 150.2, 146.6, 145.1, 135.1, 134.4, 122.0, 117.9, 112.5, 111.0, 67.0, 66.5, 65.8, 64.7, 50.7, 48.5, 35.9, 30.1, 15.3; MS (APCI) m / z 411.10 (M + H) ⁺ ; Elemental analysis: calculated value C ₂₃ H ₃₀ N ₄ O ₃ : C, 67.29; H, 7.37; N, 13.65; found: C, 67.18; H, 7.70; N, 14.00.

Example 48
1- [2-Ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] pyrrolidin-2-one

Under nitrogen atmosphere, toluene (2.50 mL) was added to 7-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-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) -1,1 '-Binaphthyl (46 mg, 0.074 mmol) and sodium t-butoxide (0.17 g, 1.74 mmol) were added to a vial. Nitrogen was bubbled through the mixture. The vial was capped with a Teflon lined cap and then heated to 80 ° C. for 15 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to give a green solid. This solid was purified by preparative HPLC (silica gel, eluting with a gradient of 1-15% CMA in chloroform) to give a yellow solid. This material was recrystallized from n-propyl acetate / heptane to give 0.114 g of 1- [2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] Quinolin-7-yl] pyrrolidin-2-one was obtained as white crystals. Melting point: 145-147 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.16 (s, 1 H), 8.39 (d, J = 9.2 Hz, 1 H), 8.30 (dd, J = 9.2, 2.3 Hz , 1 H), 8.22 (d, J = 2.3 Hz, 1 H), 4.82 (s, 2 H), 4.61 (d, J = 7.4 Hz, 2 H), 4.02 (t, J = 7.0 Hz, 2 H ), 3.85-3.75 (m, 2 H), 3.59 (q, J = 7.0 Hz, 2 H), 3.20-3.08 (m, 2 H), 2.59 (t, J = 8.0 Hz, 2 H), 2.29- 2.09 (m, 3 H), 1.56-1.35 (m, 4 H), 1.17 (t, J = 7.0 Hz, 3 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ174.7, 151.8, 145.7 , 145.2, 138.8, 135.9, 134.0, 121.8, 119.8, 118.8, 114.2, 67.0, 65.9, 64.7, 48.5, 36.0, 32.8, 30.1, 17.8, 15.3; MS (APCI) m / z 409.08 (M + H) ⁺ ; calcd _{C 23 H 28 N 4 O 3} : C, 67.63; H, 6.91; N, 13.72; measurements: C, 67.45; H, 7.10 ; N, 13.46.

Example 49
N- (Cyclopropylmethyl) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-amine

Under nitrogen atmosphere, toluene (2.50 mL) was added to 7-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.50 g, 1.24 mmol), cyclopropylmethylamine (0.13 mL, 1.49 mmol), tris (dibenzylideneacetone) dipalladium (39 mg, 0.037 mmol), (±) -2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl (46 mg, 0.074 mmol) and sodium t-butoxide (0.17 g, 1.74 mmol) were added to a vial. Nitrogen was bubbled through the mixture. The vial was capped with a Teflon lined cap and then heated to 80 ° C. for 15 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to give an orange solid. This solid was purified by preparative HPLC (silica gel, eluting with a gradient of 1-15% CMA in chloroform) to give a yellow solid. This material was recrystallized from acetonitrile to give 0.26 g of N- (cyclopropylmethyl) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- c] Quinolin-7-amine was obtained as yellow crystals. Melting point 161-163 ° C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.92 (s, 1 H), 8.05 (d, J = 7.1 Hz, 1 H), 7.16 (dd, J = 9.0, 2.3 Hz , 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 6.22 (t, J = 5.4 Hz, 1 H), 4.75 (s, 2 H), 4.50 (d, J = 7.4 Hz, 2 H ), 3.85-3.75 (m, 2 H), 3.56 (q, J = 7.0 Hz, 2 H), 3.20-3.07 (m, 2 H), 3.03 (t, J = 6.0 Hz, 2 H), 2.24- 2.09 (m, 1 H), 1.53-1.33 (m, 4 H), 1.18-1.08 (m, 4 H), 0.55-0.49 (m, 2 H), 0.30-0.25 (m, 2 H); ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 150.4, 148.5,147.4, 144.5, 134.8, 134.2, 121.7, 117.6, 108.8, 106.8, 67.0, 65.7, 64.7, 50.6, 47.7, 35.9, 30.1, 15.3, 10.8, 4.0 MS (APCI) m / z 395.09 (M + H) ⁺ ; Elemental analysis: calculated C ₂₃ H ₃₀ N ₄ O ₂ : C, 70.02; H, 7.66; N, 14.20; measured: C, 69.81; H , 7.65; N, 14.17.

Compound 3
8- (Benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8- (Benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general method of Example 13 Prepared using 4-benzyloxyaniline instead of 2-benzyloxyaniline in A. The crude product was purified by recrystallization from heptane / ethyl acetate to give 8- (benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline was obtained as an off-white solid. Mp 105-108 ° C. Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37; H, 6.77; N, 9.74. Measured values: C, 72.50; H, 6.60; N, 9.70.

Compound 4
7- (Benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

7- (Benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general method of Example 13 Prepared in A using 3-benzyloxyaniline instead of 2-benzyloxyaniline. The crude product was purified by recrystallization from heptane / ethyl acetate to give 7- (benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline was obtained as an off-white solid. Melting point 136-139 ° C. Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37; H, 6.77; N, 9.74. Measured values: C, 72.27; H, 7.05; N, 9.76.

Example 50
8- (Benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

8- (Benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general procedure of Example 13. In Part A, 4-benzyloxyaniline was used in place of 2-benzyloxyaniline, and in Part G, 3-methoxypropionyl chloride was used in place of ethoxyacetyl chloride. The crude product was purified by recrystallization from heptane / ethyl acetate to give 8- (benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a beige solid. Melting point 133-136 ° C. Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37; H, 6.77; N, 9.74. Measured values: C, 72.05; H, 6.99;

Example 51
7- (Benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

7- (Benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general procedure of Example 13. In Part A, 3-benzyloxyaniline was used in place of 2-benzyloxyaniline, and in Part G, 3-methoxypropionyl chloride was used in place of ethoxyacetyl chloride. The crude product was purified by recrystallization from heptane / ethyl acetate to give 7- (benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a pale orange solid. Melting point 119-122 ° C. Elemental analysis: calculated C ₂₆ H ₂₉ N ₃ O ₃ : C, 72.37; H, 6.77; N, 9.74. Measured values: C, 72.26; H, 7.06; N, 9.80.

Example 52
7-Bromo-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-2-amine

Part A
Triethylamine (43 mL, 0.31 mol) was added at once to a cooled (ice bath) suspension of 7-bromo-4-chloro-3-nitroquinoline (60 g, 0.21 mol) in DMF (200 mL). Addition to give a solution. A solution of 1-tetrahydro-2H-pyran-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 cooled in an ice bath and then quenched with water (150 mL) and then stirred for 30 minutes. The solid was isolated by filtration, washed sequentially with water and diethyl ether and then dried in a 65 ° C. vacuum oven to give 36.2 g of (7-bromo-3-nitroquinolin-4-yl) (tetrahydro-2H— Pyran-4-ylmethyl) amine was obtained as a yellow solid.

Part B
A Pal reactor was charged sequentially with the material from Part A, acetonitrile (1 L), and platinum on carbon (3.7 g). The reactor was placed under hydrogen pressure until analysis by LC / MS indicated that the reaction was complete. Magnesium sulfate was added to the reaction mixture and then filtered through a layer of celite filter media. The filtrate was concentrated under reduced pressure to, 35 g of crude 7-bromo -N ⁴ - was obtained (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine as a light brown oil.

Part C
7-Bromo -N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (3 g, 9 mmol), cyanogen bromide (1.4 g, 13 mmol) and ethanol (100 mL) The mixture was heated to reflux overnight. Analysis by LC / MS indicated that the reaction was incomplete. Two more equivalents of cyanogen bromide were added. Heating was continued until analysis by LC / MS showed about 80% completion of the reaction. The reaction mixture was concentrated under reduced pressure to give a viscous brown oil. This oil was dissolved in dichloromethane and washed with water. The precipitate that formed in the aqueous layer was isolated by filtration. This material was converted to the free base by stirring with 2N sodium hydroxide (200 mL) at ambient temperature for 2 hours. The free base was purified by preparative HPLC (silica gel, eluting with 6.7% methanol in dichloromethane containing 0.4% ammonium hydroxide), washed with diethyl ether, dried and 300 mg 7-bromo-1- (tetrahydro -2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-2-amine was obtained as a reddish brown solid. Melting point> 275 ° C. Elemental analysis: calculated C1 ₆ H ₁₇ BrN ₄ O 0.20 HBr: C, 50.95; H, 4.54; N, 14.85. Found: C, 50.58; H, 4.38; N, 14.66.

Examples 53-92
8-Bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (20 mg, 0.10 mmol), 7: 3 capacity: capacity ( v: v) A solution in chloroform: methanol (2 mL) was added to the test tube and the solvent was removed by vacuum centrifugation. Boronic acid (0.11 mmol) and n-propanol (1.6 mL) shown in the following table were added sequentially. The test tube was purged with nitrogen. Palladium (II) acetate (4 mg / mL solution in toluene 150 μL, 0.0026 mmol), 2 M aqueous sodium carbonate solution (600 μL), deionized water (113 μL), and 0.15 mol% triphenylphosphine solution in n-propanol ( 53 μL, 0.0078 mmol) was added sequentially. The test tube was purged with nitrogen, capped, and then heated to 80 ° C. overnight in a sand bath. For Example 92, glacial acetic acid (500 μL), tetrahydrofuran (500 μL) and deionized water (500 μL) were added to the test tube. The reaction was heated to 60 ° C. for 2 hours.

  The contents of each tube were passed through a Waters Oasis Sample 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 a 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. The 1% ammonia in methanol (2 × 5 mL) was then passed through the cartridge, optionally using light nitrogen pressure, and the eluate was collected and concentrated by vacuum centrifugation.

  The compound was purified by preparative high performance liquid chromatography using Waters FractionLynx automated purification system. Fractions were analyzed by Waters LC / TOF-MS, and appropriate fractions were centrifuged and evaporated to give the target compound trifluoroacetate. Reverse phase preparative liquid chromatography was performed with a non-linear gradient elution of 5-95% B; A is 0.05% trifluoroacetic acid / water and B is 0.05% trifluoroacetic acid / acetonitrile. Fractions were collected by mass-selective triggering. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 93-128
Part A
8-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline is prepared according to the general procedure of Example 6 and Part D In which 3-methoxypropionyl chloride was used in place of ethoxyacetyl chloride. The crude product was triturated with diethyl ether, isolated by filtration, dried and 8-bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a white solid.

Part B
The compounds in the table below were prepared and purified according to the methods of Examples 53-92 except that the reaction was heated for 4 hours instead of overnight to give 8-bromo-2- (2-methoxyethyl) -1- (tetrahydro -2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline to 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline was used instead. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 129-157
Part A
7-Bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline is prepared according to the general method of Example 6 in Part B Prepared using 4-chloro-3-nitroquinoline instead of 6-bromo-4-chloro-3-nitroquinoline. The crude product was triturated with diethyl ether and then recrystallized twice from acetonitrile to give the product as a white crystalline solid.

Part B
The compounds in the table below were prepared and purified according to the methods of Examples 53-92 except that the reaction was heated for 4 hours instead of overnight to give 7-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran. -4-ylmethyl) -1H-imidazo [4,5-c] quinoline to 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c Used in place of quinoline. Example 156 was prepared according to the method used in Example 92, but heated for 4 hours instead of 2 hours. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 158-204
Part A
7-Bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine was prepared according to the general method of Example 6 Prepared in A using 7-bromo-4-hydroxy-3-nitro [1,5] naphthyridine instead of 6-bromo-4-hydroxy-3-nitroquinoline. The crude product was triturated with diethyl ether, isolated by filtration, rinsed with diethyl ether and dried to give the product as a white solid.

Part B
The compounds in the table below were prepared and purified according to the methods of Examples 53-92 except that the reaction was heated for 4 hours instead of overnight to give 7-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran. -4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine with 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [ Used in place of 4,5-c] quinoline. Example 204 was prepared according to the method used in Example 92 except that the reaction was heated for 4 hours instead of 2 hours. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 205-240
Part A
7-Bromo-2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine was obtained as described in Example 6 According to the method, 7-bromo-4-hydroxy-3-nitro [1,5] naphthyridine is used in place of 6-bromo-4-hydroxy-3-nitroquinoline in part A and 3-methoxypropionyl chloride is used in part D. Prepared by using in place of ethoxyacetyl chloride. The crude product was triturated with MTBE, isolated by filtration, rinsed with MTBE and dried to give the product as a beige solid.

Part B
The compounds in the table below were prepared and purified according to the methods of Examples 53-92 except that the reaction was heated for 4 hours instead of overnight to give 7-bromo-2- (2-methoxyethyl) -1- (tetrahydro -2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] [1,5] naphthyridine into 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl)- Used in place of 1H-imidazo [4,5-c] quinoline. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 241-277
Part A
3-methoxy propionyl chloride (4.37 g, 35.7 mmol) of a solution in dichloromethane (25 mL), the crude 7-bromo -N ⁴ - (tetrahydro -2H- pyran-4-ylmethyl) quinoline-3,4-diamine (32.5 mmol) was added to a solution in dichloromethane (350 mL). The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The resulting amide intermediate was suspended in ethanol (300 mL). A solution of potassium carbonate (6.73 g, 49 mmol) in water (100 mL) was added and completely dissolved. The solution was heated to reflux overnight and then cooled to ambient temperature. Ethanol was removed under reduced pressure and the resulting aqueous slurry was extracted with dichloromethane (2 × 350 mL). The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to give a red purple solid. This material was purified by preparative HPLC (silica gel, eluting with a gradient of 1-10% CMA in chloroform) and recrystallized from acetonitrile to give 6.5 g of 7-bromo-2- (2-methoxyethyl) -1- (Tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline was obtained as a tan crystalline solid.

Part B
The compounds in the table below were prepared and purified according to the methods of Examples 53-92 except that the reaction was heated for 4 hours instead of overnight to give 7-bromo-2- (2-methoxyethyl) -1- (tetrahydro -2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline to 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline was used instead. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 278-285
7-Bromo-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-2-amine (18 mg, 0.10 mmol) in 7: 3 volume: volume (v : v) A solution in chloroform: methanol (2 mL) was added to the test tube and the solvent was removed by vacuum centrifugation. Boronic acid (0.11 mmol) and n-propanol (1.6 mL) shown in the following table were added sequentially. The test tube was purged with nitrogen. Palladium (II) acetate (4 mg / mL solution in toluene 150 μL, 0.0026 mmol), 2 M aqueous sodium carbonate solution (600 μL), deionized water (63 μL), and 0.15 mol% triphenylphosphine solution in n-propanol ( 53 μL, 0.0078 mmol) was added sequentially. The test tube was purged with nitrogen, capped, and then heated to 80 ° C. overnight in a sand bath. Palladium (II) acetate (4 mg / mL solution in toluene 150 μL, 0.0026 mmol) was added and the test tube was heated for an additional 4 hours. For Example 285, glacial acetic acid (500 μL), trifluoroacetic acid (500 μL) and deionized water (500 μL) were added to the test tube. The reaction was heated to 60 ° C. for 4 hours. The reaction mixture was purified according to the methods of Examples 53-92. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Compound 5
2-Ethoxymethyl-6,7-dimethyl-N- (tetrahydropyran-4-yl) -1H-imidazo [4,5-c] pyridin-1-amine

Under a nitrogen atmosphere, 4-chloro-2-ethoxymethyl-6,7-dimethyl-N- (tetrahydropyran-4-yl) -1H-imidazo [4,5-c] pyridin-1-amine (1.00 g, 1 eq) was mixed with ammonium formate (1.94 g, 10.5 eq), methanol (40 mL) and ethanol (80 mL). The mixture was flushed with nitrogen for several minutes, 10% palladium on carbon (1.00 g) was added, and then the reaction mixture was heated to 80 ° C. for 3 hours. The reaction mixture was allowed to cool to ambient temperature and then filtered through a layer of celite filter media. The filtrate was concentrated under reduced pressure. The residue was partitioned between 5% sodium hydroxide (100 mL) and dichloromethane (100 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 3% methanol in chloroform) to give 0.52 g of a clear oil that gradually solidified. This material was vacuum dried at 40 ° C. for 16 hours to give 0.52 g of 2-ethoxymethyl-6,7-dimethyl-N- (tetrahydropyran-4-yl) -1H-imidazo [4,5-c] pyridine The 1-amine was obtained as a white solid. Mp 94-97 ° C. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 5.46 (d, J = 3.2 Hz, 1H), 4.87 (br s, 2H), 4.00 (m, 2H), 3.63 (q, J = 7.0 Hz, 2H), 3.45-3.25 (m, 3H), 2.68 (s, 3H), 2.60 (s, 3H), 1.77-1.44 (m, 4H), 1.26 (t, J = 7.0 Hz, 3H) ; MS (APCI) m / z 305 (M + H) ⁺ ; Elemental analysis: calculated C ₁₆ H ₂₄ N ₄ O ₂ · 0.50H ₂ O: C, 61.32; H, 8.04; N, 17.88. C, 60.92; H, 7.93; N, 17.75.

Compound 6
2-Ethoxymethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] [1,5] naphthyridin-1-amine

  2-Ethoxymethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5-c] [1,5] naphthyridin-1-amine is disclosed in International Patent Application No. WO 06 / Prepared as described in Example 36 of 026760.

Compound 7
[1- (Tetrahydro-2H-pyran-4-yl) amino-1H-imidazo [4,5-c] [1,5] naphthyridin-2-yl] methanol

Under nitrogen atmosphere, boron trifluoride (2.00 mL of 1 M in dichloromethane, 2 equivalents) was added 2-ethoxymethyl-N- (tetrahydro-2H-pyran-4-yl) -1H-imidazo [4,5 -c] [1,5] naphthyridin-1-amine (0.327 g, 1 eq) was added dropwise to cooling (ice water bath) in dichloromethane (10 mL). The reaction was gradually allowed to reach ambient temperature and stirred overnight. After 18 hours, the reaction was quenched by the dropwise addition of water (2 mL) and methanol (10 mL) was added. Dichloromethane and methanol were removed under reduced pressure to give an aqueous slurry. A solution of ammonia in methanol (7 M, 10 mL) was added and the mixture was stirred for 1 hour. Silica gel (3 g) was added and the slurry was loaded onto a preparative HPLC column, which was then eluted with a gradient of 1-30% CMA in chloroform to give a yellow solid. The solid was purified by preparative HPLC (40 g silica gel, eluting with a gradient of 1-25% CMA in chloroform) to give 15 mg of a pale yellow solid. This material was recrystallized from acetonitrile to give 5 mg of [1- (tetrahydro-2H-pyran-4-yl) amino-1H-imidazo [4,5-c] [1,5] naphthyridin-2-yl] Methanol was obtained as pale yellow crystals. Melting point 203-205 ° C. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.26 (s, 1 H), 9.04 (dd, J = 4.2, 1.6 Hz, 1 H), 8.53 (dd, J = 8.5, 1.6 Hz, 1 H) , 7.76 (dd, J = 8.5, 4.2 Hz, 1 H), 6.96 (d, J = 2.5 Hz, 1 H), 5.56 (t, J = 6.1 Hz, 1 H), 4.83 (d, J = 6.1 Hz , 2 H), 3.88-3.82 (m, 2 H), 3.82-3.75 (m, 1 H), 3.24-3.20 (m, 2 H), 1.65 (br, 2 H), 1.57-1.50 (m, 2 H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 156.1, 149.6, 145.5, 138.7, 137.3, 137.1, 134.3, 132.1, 122.5, 65.2, 56.4, 54.7, 30.6; MS (APCI) m / z 300.17 (M + H) ^+; elemental analysis: calculated _{C 15 H 17 N 5 O 2} : C, 60.19; H, 5.72; N, 23.40; measurements: C, 59.91; H, 5.41 ; N, 23.05.

Example 286
2- (Ethoxymethyl) -8-morpholin-4-yl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline

Under nitrogen atmosphere, toluene (2.50 mL) was added to 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.45 g, 1.11 mmol), morpholine (0.12 mL, 1.33 mmol), tris (dibenzylideneacetone) dipalladium (35 mg, 0.033 mmol), (±) -2,2'-bis (diphenylphosphino) -1,1'- Binaphthyl (42 mg, 0.0664 mmol) and sodium t-butoxide (0.15 g, 1.55 mmol) were added to a vial. Nitrogen was bubbled through the mixture. The vial was sealed with a Teflon liner cap and then heated to 80 ° C. for 20 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to give an orange solid. This solid was purified by preparative HPLC (silica gel, eluting with a gradient of 0-25% CMA in chloroform) to give an off-white solid. This material was recrystallized from ethyl acetate / heptane to give 178 mg of 2-ethoxymethyl-8- (morpholin-4-yl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinoline was obtained as an off-white solid. Melting point 167-170 ° C; ¹ H NMR (500 MHz, d ₆ -DMSO) δ 8.94 (s, 1H), 8.00 (d, J = 9.2, 1H), 7.54 (dd, J = 9.1, 2.9, 1H), 7.43 (d, J = 2.8, 1H), 4.80 (s, 2H), 4.62 (d, J = 7.3, 2H), 3.81 (m, 6H), 3.57 (q, J = 6.9, 2H), 3.32 (m , 4H), 3.16 (td, J = 11.3, 1.9, 2H), 2.25 (m, 1H), 1.50 (qd, J = 12.9, 4.4, 2H), 1.47 (m, 2H), 1.15 (t, J = 7.0, 3H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 151.4, 149.0, 141.6, 139.1, 136.4, 132.8, 130.9, 118.4, 102.5, 66.5, 66.0, 65.4, 64.3, 50.5, 48.4, 36.0, 29.9, 14.9; elemental analysis: calculated _{C 23 H 30 N 4 O 3} :. C, 67.29; H, 7.37; N, 13.65 measurements: C, 67.46; H, 7.19 ; N, 13.78.

Example 287
1- [2- (Ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-8-yl] pyrrolidin-2-one

Under nitrogen atmosphere, toluene (2.50 mL) was added to 8-bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.45 g, 1.11 mmol), 2-pyrrolidinone (0.10 mL, 1.33 mmol), tris (dibenzylideneacetone) dipalladium (35 mg, 0.033 mmol), (±) -2,2'-bis (diphenylphosphino) -1,1 '-Binaphthyl (42 mg, 0.0664 mmol) and sodium t-butoxide (0.15 g, 1.55 mmol) were added to a vial. Nitrogen was bubbled through the mixture. The vial was capped with a Teflon liner cap and then heated to 80 ° C. for 20 hours. The reaction mixture was diluted with chloroform (2 mL) and then filtered through a cotton plug. The filtrate was concentrated under reduced pressure to give a green solid. This solid was purified by preparative HPLC (silica gel, eluting with a gradient of 0-25% CMA in chloroform) to give an off-white solid. This material was recrystallized from ethyl acetate / heptane to give 65 mg of 1- [2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline- 8-yl] pyrrolidin-2-one was obtained as an off-white solid. Melting point 152-155 ° C; ¹ H NMR (500 MHz, d ₆ -DMSO) δ 9.10 (s, 1H), 8.90 (d, J = 2.2, 1H), 8.16 (d, J = 9.1, 1H), 7.90 ( d, J = 9.2, 2.2, 1H), 4.80 (s, 2H), 4.58 (d, J = 7.6, 2H), 4.04 (t, J = 7.2, 2H), 3.81 (t, J = 11.1, 2H) , 3.59 (q, J = 6.9, 2H), 3.16 (m, 2H), 2.60 (t, J = 8.2, 2H), 2.34 (m, 1H), 2.14 (quintet, J = 7.6, 2H), 1.49 (m, 4H), 1.16 (t, J = 6.9, 3H); ¹³ C NMR (125 MHz, d ₆ -DMSO) δ 174.5, 151.7, 143.8, 140.8, 137.6, 136.2, 133.2, 130.6, 119.2, 117.5 , 109.5, 66.6, 65.5, 64.3, 50.6, 48.2, 35.5, 32.5, 29.7, 17.4, 14.9; Elemental analysis: calculated C ₂₃ H ₂₈ N ₄ O ₃ : C, 67.63; H, 6.91; N, 13.72. Values: C, 67.47; H, 6.87; N, 13.62.

Example 288
2-propyl-1- (tetrahydro-2H-pyran-4-yloxy) -1H-imidazo [4,5-c] quinoline

Part A
Mix N- (4-chloroquinolin-3-yl) butyric acid amide (8.4 g, 33.8 mmol), O-benzylhydroxylamine hydrochloride (7.0 g, 43.9 mmol) and isopropanol (100 mL), then bring to 60 ° C. Heated for 7 hours. The reaction mixture was allowed to cool to ambient temperature and a precipitate formed. The supernatant was decanted off. The precipitate was partitioned between dichloromethane (100 mL) and saturated aqueous sodium carbonate (50 mL). The layers were separated and the organic layer was washed with water (2 × 25 mL), dried over potassium carbonate, filtered, and concentrated in vacuo to give 7.3 g of 1-benzyloxy-2-propyl-1H-imidazo [ 4,5-c] quinoline was obtained as a dark oil that began to crystallize on standing.

Part B
A mixture of the material from Part A (23 mmol), 10% palladium on carbon (0.50 g) and ethanol (90 mL) was placed under hydrogen pressure (30 psi, 2.1 × 10 ⁵ Pa) for 3 hours. The reaction mixture was filtered through a layer of celite filter media. The filtrate was diluted with dichloromethane (25 mL) and a precipitate formed. The precipitate was isolated by filtration to give 1.6 g of 2-propyl-1H-imidazo [4,5-c] quinolin-1-ol. The filtrate was concentrated under reduced pressure to give more product.

Part C
2-propyl-1H-imidazo [4,5-c] quinolin-1-ol (0.4 g, 1.8 mmol), 4-chlorotetrahydropyran (0.4 g, 3.3 mmol) and 1,8-diazabicyclo [5.4.0] Undec-7-ene (0.4 g, 2.6 mmol) was mixed in a pressure vessel. The vessel was sealed and then heated in an oven at 120 ° C. for 22 hours. This reaction was repeated on a large scale (8 times). The small and large reaction mixtures were combined and then partitioned between dichloromethane (150 mL) and saturated aqueous sodium carbonate (25 mL). The organic layer was separated, washed with water (3 times 25 mL), dried over potassium carbonate, filtered and then concentrated in vacuo to give 4.8 g of crude product as a brown oil. This material was purified by column chromatography (silica gel, eluting with 5% methanol in dichloromethane containing 5 mL of ammonium hydroxide per L of dichloromethane) to give 0.98 g of 2-propyl-1- (tetrahydro-2H- Pyran-4-yloxy) -1H-imidazo [4,5-c] quinoline was obtained as a yellow oil. HRMS (ESI) calcd _{C 18 H 21 N 3 O 2} + H +: 312.1712, measured 312.1712.

Example 289
2- (Ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-6-ol

6- (Benzyloxy) -2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (407 mg, 0.943 mmol) (Example 13 Solution in 45% HBr (10 mL) in acetic acid was heated to 65 ° C. for 1.5 hours. The reaction mixture was cooled in an ice bath and gradually adjusted to pH 7 with 50% aqueous sodium hydroxide. The light brown precipitate was isolated by filtration, washed and dried. This solid was recrystallized from boiling hexane / ethyl acetate (15 mL) to give 117 mg of 2- (ethoxymethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- c] Quinolin-6-ol was obtained as gray needles. Melting point 173-177 ° C. Calcd _{C 19 H 23 N 3 O 3} · 0.20H 2 O:. C, 66.15; H, 6.84; N, 12.18 measurements: C, 66.13; H, 6.84 ; N, 12.02.

Example 290
2- (2-Methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-ol

7- (Benzyloxy) -2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (1.00 g, 2.32 mmol, Examples 51), a mixture of 10% palladium on carbon (0.1 g) and ethanol (20 mL) was hydrogenated on a Pal apparatus for 18 hours. The mixture was filtered through a celite filter medium, and the filtrate was concentrated under reduced pressure. The resulting oil was purified by preparative HPLC (silica gel, eluting with a gradient of 0-35% CMA in chloroform) to give an off-white solid. This solid was suspended in boiling acetonitrile (20 mL), filtered, washed with cold acetonitrile, dried and 0.429 g of 2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl). ) -1H-imidazo [4,5-c] quinolin-7-ol was obtained as white needles. Mp 242-245 ° C. Calcd _{C 19 H 23 N 3 O 3} :. C, 66.84; H, 6.79; N, 12.31 measurements: C, 66.72; H, 6.68 ; N, 12.22.

Examples 291-293
2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-ol (0.75 g, 2.2 mmol, description of Example 290) ), Cesium carbonate (3.59 g, 11 mmol) and DMF (20 mL) were heated to 75 ° C. for 30 min. The reagents from the table below (2.75 mmol) were added to the mixture, which was then heated for 17-23 hours. DMF was removed at 65 ° C. under reduced pressure. The residue was partitioned between chloroform (100 mL) and water (100 mL). 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 preparative HPLC (silica gel, eluting with a gradient of 10-35% CMA in chloroform) to give a pale yellow solid. This solid was dissolved in ethanol (10 mL) and anhydrous hydrogen chloride in ethanol (3.0 M, ca. 5 mL) was added. 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 give the hydrochloride salt with the structure shown in the table below.

Example 291: 576 mg of 2- (2-methoxyethyl) -7- (2-morpholin-4-ylethoxy) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- c] Quinoline was isolated as beige needles. Melting point 220-224 ° C. Elemental analysis: calculated value C ₂₅ H ₃₄ N ₄ O ₄ 2.40HCl: C, 55.39; H, 6.77; N, 10.34. Measured value: C, 55.41; H, 6.97; N, 10.19;
Example 292: 273 mg of 2- (2-methoxyethyl) -7- (2-pyrrolidin-1-ylethoxy) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- c] Quinoline was isolated as brown needles. Mp 205-209 ° C. Elemental analysis: calculated C ₂₆ H ₃₆ N ₄ O ₃ 3.25HCl: C, 54.68; H, 6.93; N, 9.81. Measured values: C, 54.68; H, 6.84; N, 9.66;
Example 293: 401 mg of 2- (2-methoxyethyl) -7- (2-piperidin-1-ylethoxy) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- c] Quinoline was isolated as brown needles. Mp 205-209 ° C. Elemental analysis: calculated C ₂₆ H ₃₆ N ₄ O ₃ 3.25HCl: C, 54.68; H, 6.93; N, 9.81. Measured values: C, 54.68; H, 6.84; N, 9.66.

Example 294
1- (Cycloheptylmethyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline

  Cycloheptyl cyanide (3.00 mL, 22.5 mmol), 10% palladium on carbon (0.42 g), and 3 M hydrogen chloride in ethanol (45 mL) were hydrogenated on a Pal apparatus overnight. Platinum oxide (0.10 g) was added to the reaction mixture and then hydrogenated on a Pal apparatus for 4 hours. The reaction mixture was filtered through celite filter medium and then rinsed with ethanol. Concentration of the filtrate gave a solid that was treated with diethyl ether (50 mL). The white solid was isolated by filtration and dried to give 1.57 g of 1-cycloheptylmethanamine hydrochloride.

1- (Cycloheptylmethyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline was prepared according to the general procedure of Example 27, with 1-cycloheptylmethanamine hydrochloride (S )-(+)-Tetrahydrofurfurylamine was used instead of palladium on carbon as catalyst (10% w / w) and methanol / acetonitrile as solvent in Part B. The crude product was purified by preparative HPLC (silica gel, eluting with a gradient of 1-15% CMA in chloroform) to give a yellow oil. This oil was dissolved in methanol / chloroform and treated with about 0.25 g of activated carbon for 2 hours. The mixture was filtered through a celite filter medium, and the filtrate was concentrated and dried to give 1- (cycloheptylmethyl) -2- (ethoxymethyl) -1H-imidazo [4,5-c] quinoline as a yellow oil. Calcd _{C 21 H 27 N 3 O ·} 0.2 CH 4 O: C, 74.05; H, 8.15; N, 12.22; measurements: C, 73.84; H, 8.13 ; N, 12.17.

Examples 295-320
8-Bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-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 equiv) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (7.6 mg, 0.12 equiv) The contained toluene solution (250 μmL) was added to a test tube containing 1 M potassium t-butoxide in THF (150 μL) and one of the reagents listed in the table below (1.5 eq). The test tube was purged with nitrogen, capped, and then heated to 80 ° C. overnight in a sand bath. The solvent was removed in a vacuum centrifuge and the product was purified as described in Examples 53-92 above. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Examples 321 to 350
7-Bromo-2-ethoxymethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (prepared as described in Examples 129-157) (40 mg, 0.10 mmol), tris (dibenzylideneacetone) dipalladium (0) (3.3 mg, 0.03 equiv) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (4.0 mg, 0.06 equiv) ) Was added to a test tube containing 1 M potassium t-butoxide (150 μL) in THF and one of the reagents listed in the table below (1.2 eq). The test tube was purged with nitrogen, capped, and then heated to 80 ° C. overnight in a sand bath. Contains tris (dibenzylideneacetone) dipalladium (0) (3.3 mg, 0.03 eq) and (±) -2,2'-bis (diphenylphosphino) -1,1'-binaphthalene (4.0 mg, 0.06 eq) Toluene solution (250 μL) was added to each tube. The test tube was purged with nitrogen, capped, and then heated to 80 ° C. overnight in a sand bath. The solvent was removed in a vacuum centrifuge and the product was purified as described in Examples 53-92 above. The following table shows the exact measured mass for the reagents used in each example, the structure of the resulting compound, and the isolated trifluoroacetate salt.

Example 351
5-{[2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] Oxy} ethoxy) ethyl] amino} -5-oxopentanoic acid

Part A
2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-ol (2.00 g, 5.86 mmol), 2- (2 A stirred solution of t-butyl-hydroxyethoxy) ethylcarbamate (1.38 g, 6.74 mmol) and triphenylphosphine (1.77 g, 6.74 mmol) in tetrahydrofuran (40 mL) was placed under a nitrogen atmosphere and brought to 0 ° C. Cooled down. Diisopropyl azodicarboxylate (1.3 mL, 6.74 mmol) was added dropwise via syringe over 5 minutes. The resulting solution was raised to ambient temperature and stirred overnight. After 26 hours, volatile components were removed under reduced pressure and the resulting residue was purified by column chromatography on a HORIZON HPFC system (silica cartridge, eluting with 0-35% CMA-80 / chloroform). Fractions containing product were combined and concentrated under reduced pressure to give 2.77 g of 2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H- The t-butyl imidazo [4,5-c] quinolin-7-yl] oxy} ethoxy) ethylcarboxylate was obtained as a light brown solid.

Part B
3 M HCl in ethanol (5.1 mL, 15.2 mmol) was added to 2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4 , 5-c] quinolin-7-yl] oxy} ethoxy) ethyl carboxylate (2.67 g, 5.05 mmol) was added dropwise to a stirred solution in ethanol (25 mL). The resulting solution was stirred at reflux for 2 hours, cooled to ambient temperature and concentrated in vacuo to give 2.54 g of 2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran. -4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] oxy} ethoxy) ethanamine hydrochloride was obtained as a brown foam.

Part C
Glutaric anhydride (0.14 g, 1.20 mmol) was added to 2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5- To a stirred solution of c] quinolin-7-yl] oxy} ethoxy) ethanamine hydrochloride (0.50 g, 0.997 mmol) in pyridine (2 mL) at ambient temperature. After 18 hours, the solution was concentrated under reduced pressure, and the resulting residue was dissolved in water (10 mL). The pH was adjusted to 10 with 1 M sodium carbonate (aq) and the mixture was transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (1 × 20 mL) and ethyl acetate (2 × 20 mL), and the organic layer was discarded. The pH of the aqueous layer was adjusted to 4 with 6 M HCl (aq) and extracted with dichloromethane (2 × 30 mL) and ethyl acetate (1 × 30 mL). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 332 mg of 5-{[2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H- Pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] oxy} ethoxy) ethyl] amino} -5-oxopentanoic acid was obtained as a tan foam. Calcd _{C 28 H 38 N 4 O 7} · 0.8H 2 O:. C, 60.37; H, 7.17; N, 10.06 measurements: C, 60.49; H, 6.96 ; N, 9.77.

Example 352
3- (2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl) -N- [2- (2-{[2- (2-methoxyethyl) -1- (tetrahydro-2H- Pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] oxy} ethoxy) ethyl] propanamide

1- {3-[(2,5-Dioxopyrrolidin-1-yl) oxy] -3-oxopropyl} -1H-pyrrole-2,5-dione (0.156 g, 0.588 mmol) was replaced with 2- (2 -{[2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] oxy} ethoxy) ethanamine (0.229 g , 0.534 mmol) in dichloromethane (6 mL) at ambient temperature. After 21 hours, the solution was placed on a 2 mm silica gel plate and purified by radial chromatography; eluting with 5% methanol in dichloromethane. Fractions containing product were combined and concentrated to give 200 mg of 3- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) -N- [2- (2- { [2- (2-methoxyethyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] oxy} ethoxy) ethyl] propanamide Obtained as a yellow foam. Calcd _{C 30 H 37 N 5 O 7} · H 2 O:. C, 60.29; H, 6.58; N, 11.72 measurements: C, 59.94; H, 6.73 ; N, 12.03.

Example 353
3- [2-Ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] -N, N-dimethylpropanamide

Part A
In a thick glass vessel equipped with a stir bar, 7-bromo-2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (0.56 g, 1.5 mmol) ) In N, N-dimethylformamide (10 mL). To this solution, in turn, palladium acetate (0.1 eq, 37 mg, 0.15 mmol) and tri-ortho-tolylphosphine (0.2 eq, 91 mg, 0.3 mmol) in N, N-dimethylformamide (5 mL). A solution of triethylamine (3.0 eq, 0.6 mL); and N, N-dimethylacrylamide (1.2 eq, 178 mg, 1.8 mmol) in N, N-dimethylformamide (2 mL) was added. The reaction mixture was purged with nitrogen, the vessel was sealed and heated to 120 ° C. for 18 hours. The reactor was cooled to ambient temperature. The reaction mixture was transferred to a round bottom flask and concentrated to dryness under reduced pressure. The residue was treated with water and 10% NaOH to pH = 12. The mixture was then extracted with dichloromethane. The organic fractions were combined, dried (MgSO ₄ ) and concentrated to dryness. The residue was purified by HORIZON HPFC system (silica cartridge, 0-15% CMA / chloroform) followed by recrystallization from acetonitrile to give 0.54 g of (2E) -3- [2-ethyl-1- (tetrahydro -2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] -N, N-dimethylprop-2-enamide was obtained as a white crystalline solid. Melting point 235-237 ° C. MS (APCI) m / z 393 (M + H) ⁺ ; Elemental analysis: calculated C ₂₃ H ₂₈ N ₄ O ₂ : C, 70.38; H, 7.19; N, 14.27. Measured values: C, 70.29; H, 7.12; N, 14.28.

Part B
A glass par bottle (500 mL) was charged with 10% palladium on carbon (0.1 g) moistened with ethanol (5 mL), and (2E) -3- [2-ethyl-1- (tetrahydro-2H-pyran-4 A solution of (-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] -N, N-dimethylprop-2-enamide (0.5 g, 1.27 mmol) in methanol (250 mL) did. The vessel was placed on a Pal device, evacuated and charged with hydrogen (approximately 50 psi). The mixture was shaken for 24 hours at ambient temperature and then monitored for completion by HPLC / mass spectrometry. The reaction was further reloaded with catalyst and hydrogen and held at ambient temperature for an additional 24 hours. The reaction mixture was passed through a 0.2 micron PTFE membrane filter and the filtrate was concentrated to dryness under reduced pressure. Purification by HORIZON HPFC system (silica cartridge, 0-10% CMA / chloroform), followed by recrystallization from acetonitrile, 0.16 g of 3- [2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] -N, N-dimethylpropanamide was obtained as a white crystalline solid. 176-178 ° C. MS (APCI) m / z 395 (M + H) ⁺ ; Elemental analysis: calculated C ₂₃ H ₃₀ N ₄ O ₂ : C, 70.02; H, 7.66; N, 14.20. Measured values: C, 69.83; H, 7.62; N, 14.26.

Example 354
3- [2-Ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] propanoic acid

Part A
In a thick glass vessel equipped with a stir bar, 7-bromo-2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline (3.7 g, 10.0 mmol) ) In N, N-dimethylformamide (70 mL). To this solution was sequentially added palladium acetate (224 mg, 1.0 mmol) and tri-ortho-tolylphosphine (608 mg, 2.0 mmol) in N, N-dimethylformamide (10 mL); triethylamine (4.2 mL, 30.0 mmol); and ethyl acrylate (1.2 g, 12.0 mmol) in N, N-dimethylformamide (2 mL) was added. The reaction mixture was purged with nitrogen, the vessel was sealed and heated to 120 ° C. for 18 hours. The reactor was cooled to ambient temperature. The reaction mixture was transferred to a round bottom flask and concentrated to dryness under reduced pressure. The resulting solid was dissolved in dichloromethane (150 mL) and washed with saturated potassium carbonate solution. Fractions were separated. The organic fraction was dried (MgSO ₄ ) and concentrated. Purification by HORIZON HPFC system (silica cartridge, 0-12% CMA / chloroform) followed by recrystallization from acetonitrile gave 2.5 g of (2E) -3- [2-ethyl-1- (tetrahydro-2H-pyran- Ethyl 4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] prop-2-enoate was obtained as a white solid. Melting point 210-212 ° C. MS (APCI) m / z 394 (M + H) ⁺ ; Elemental analysis: Calculated value C ₂₃ H ₂₇ N ₃ O ₃ : C, 70.21; H, 6.92; N, 10.68. Measured value: C, 70.19; H, 6.93; N, 10.67.

Part B
A glass par bottle (500 mL) was charged with 10% palladium on carbon (0.25 g) moistened with ethanol (5 mL), and (2E) -3- [2-ethyl-1- (tetrahydro-2H-pyran-4 A slurry of ethyl -ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] prop-2-enoate (2.4 g, 6.1 mmol) in methanol (250 mL) was charged. The vessel was placed on a Pal device, evacuated and charged with hydrogen (approximately 50 psi). The mixture was then shaken at ambient temperature for 48 hours. The reaction was monitored by HPLC / mass spectrometry and found complete. The reaction mixture was passed through a 0.2 micron PTFE membrane filter and the filtrate was concentrated to dryness under reduced pressure. Purification by HORIZON HPFC system (silica cartridge, 0-11% CMA / chloroform), followed by recrystallization from 60:30 hexane / ethyl acetate (30 mL) gave 1.9 g of 3- [2-ethyl-1- ( Ethyl tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] propanoate was obtained as a white crystalline solid. Melting point 113-115 ° C. MS (APCI) m / z 396 (M + H) ⁺ ; Elemental analysis: Calculated value C ₂₃ H ₂₉ N ₃ O ₃・ 0.75 H ₂ O: C, 67.54; H, 7.52; N, 10.27. Measured value: C 67.25; H, 7.67; N, 10.26.

Part C
Ethyl 3- [2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinolin-7-yl] propanoate (1.8 g) in methanol (3 mL Claisen's alkali (5 mL) was added to the stirred solution in). The reaction mixture was heated to 70 ° C. and held for 18 hours. The reaction mixture was removed from heating and treated with citric acid to adjust pH = 5. The mixture was then concentrated to dryness under reduced pressure. The resulting solid was charged into water and neutralized with saturated potassium carbonate solution to pH = 7. A white crystalline solid was formed. The crystalline solid was collected by vacuum filtration, air dried and 1.4 g 3- [2-ethyl-1- (tetrahydro-2H-pyran-4-ylmethyl) -1H-imidazo [4,5-c] quinoline -7-yl] propanoic acid was obtained as a white solid. Melting point 198-200 ° C. MS (APCI) m / z 368 (M + H) ⁺ ; Elemental analysis: Calculated value C ₂₁ H ₂₅ N ₃ O ₃ : C, 68.64; H, 6.86; N, 11.44. Measured value: C, 68.42; H, 6.67; N, 11.35.

Certain exemplary compounds, including some of those described in the Examples illustrate compounds and pharmaceutical compositions wherein the following formula shown in the table below (IIb, IIIa, IVb, Vb or VIa), and X _'a group and R _2a Each column in the table corresponds to the formula (IIb, IIIa, IVb, Vb or VIa) and represents a compound of the present invention (or a pharmaceutically acceptable salt thereof) or a pharmaceutically acceptable carrier. Represents a particular embodiment of a pharmaceutical composition of the invention comprising a therapeutically effective amount of a particular embodiment of the compound of the invention (or a pharmaceutically acceptable salt thereof) in combination.

Certain exemplary compounds, including some described in the above examples, have the following formula (IIc) shown in the table below, and R _2a and R _3b substituents; Consistent with formula (IIc) representing a particular embodiment, a therapeutically effective amount of these compounds (or pharmaceutically acceptable salts thereof) in combination with a pharmaceutically acceptable carrier is specific for the pharmaceutical composition of the invention It is an aspect.

Certain exemplary compounds, including some described in the above examples, have the following formula (IId), as shown in the table below, and R _2b and R _3c substituents; Consistent with formula (IId) representing a particular embodiment, a therapeutically effective amount of these compounds (or pharmaceutically acceptable salts thereof) in combination with a pharmaceutically acceptable carrier is a specification of the pharmaceutical composition of the invention It is an aspect.

  The compounds described herein modulate cytokine biosynthesis by inducing production of interferon alpha and / or tumor necrosis factor alpha in human cells when tested using any of the methods described below. Was found.

Cytokine induction in human cells In vitro-human blood cell system is used to evaluate cytokine induction. Activity is based on the measurement of interferon (α) and / or tumor necrosis factor (α) secreted into the medium (IFN-α and TNF-α, respectively); Testerman et. Al. “Immunemod (Imiquimod) And S-27609 ", Journal of Leukocyte Biology, 58, 365-372 (September 1995).

Blood cell preparation for culture Whole blood is collected from a healthy human donor by venipuncture into a suction tube or syringe containing EDTA. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham Biosciences, Piscataway, NJ). The blood is diluted 1: 1 with Dulbecco's phosphate buffered saline (DPBS) or Hanks buffered saline (HBSS). Alternatively, whole blood is placed in an Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL) centrifugal frit tube containing density gradient media. PBMC layers are collected, washed twice with DPBS or HBSS, and resuspended in complete RPMI at 4 × 10 ⁶ cells / mL. This PBMC suspension is added to a 96 well flat bottom sterile tissue culture plate containing an equal volume of RPMI complete medium containing the test compound.

Compound Preparation The compound of the present invention is dissolved in dimethyl sulfoxide (DMSO). DMSO concentration should not exceed 1% final concentration for addition to culture wells. The compounds of the invention are generally tested at a concentration of 30-0.014 μM. Controls include a cell sample containing media only, a cell sample containing DMSO only (no compound), and a cell sample containing a reference compound.

Incubation Add a solution of test compound at 60 μM to the first well containing complete RPMI, and perform serial 3-fold dilution in the well. The PBMC suspension is then added to the wells in equal volumes to bring the test compound concentration to the target range (usually 30-0.014 μM). The final concentration of PBMC suspension is 2 × 10 ⁶ cells / mL. Cover the plate with a sterile plastic lid, mix gently, and then incubate at 37 ° C. in a 5% carbon dioxide atmosphere for 18-24 hours.

Separation Following incubation, the plate is centrifuged at 1000 rpm (approximately 200 × g) at 4 ° C. for 10 minutes. Cell-free culture supernatant is separated and transferred to a sterile polypropylene tube. Keep sample at -30 to -70 ° C until analysis. Samples are analyzed by ELISA for IFN-α and by IGEN / BioVeris assay for TNF-α.

Analysis of interferon (α) and tumor necrosis factor (α)
IFN-α concentration is measured by a human multi-subtype colorimetric sandwich ELISA (Cat # 41105) from PBL Biomedical Laboratories (Piscataway, NJ). Results are expressed in pg / mL.

  TNF-α concentrations are measured by the ORIGEN M-series-immunoassay from BioVeris Corporation (formerly known as IGEN International; Geysersburg, MD) and read on an IGEN M-8 analyzer. The immunoassay uses a human TNF-α capture antibody and detection antibody pair (Catalog Numbers AHC3419 and AHC3712) from Biosource International (Camarillo, Calif.). Results are expressed in pg / mL.

Assay Data and Analysis Overall, the assay data output consists of TNF-α and IFN-α concentration values (y-axis) as a function of compound concentration (x-axis).

  There are two stages to data analysis. First, the greater of average DMSO (DMSO control well) or experimental background (usually 20 pg / mL for IFN-α, 40 pg / mL for TNF-α) is subtracted from each reading. If a negative number is obtained by background subtraction, the reading is reported as “*” to indicate that it cannot be reliably detected. In subsequent calculations and statistical processing, “*” is treated as zero. Second, all background subtraction values are multiplied by a single adjustment ratio to reduce variation between experiments. This match ratio is the area of the reference compound in the new experiment divided by the expected area of the reference compound based on the past 61 experiments (non-match reading). This scales the reading (y-axis) for new data without changing the shape of the dose-response curve. The reference compound used was 2- [4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethanol Hydrate (USP No. 5,352,784; Example 91), the expected area is the sum of the median dose values obtained in the past 61 experiments.

  The minimum effective concentration is calculated based on the experiment and the background matched reference match results for the compound. The minimum effective concentration (μmolar) is the concentration of test compound that induces a response that exceeds the fixed cytokine concentration for the cytokine tested (usually 20 pg / mL for IFN-α and 40 pg / mL for TNF-α). The lowest concentration. The maximum response is the maximum amount of cytokine (pg / ml) produced in the dose-response.

Cytokine induction in human cells (high-throughput screening)
The cytokine induction test method in human cells was modified for high-throughput screening as follows.

Blood cell preparation for culture Whole blood is collected from a healthy human donor by venipuncture into a suction tube or syringe containing EDTA. Peripheral blood mononuclear cells (PBMC) are separated from whole blood by density gradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, MO) or Ficoll-Paque Plus (Amersham Biosciences, Piscataway, NJ). Whole blood is placed in an Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, FL) centrifugal frit tube containing density gradient media. PBMC layers are collected, washed twice with DPBS or HBSS, and resuspended in complete RPMI at 4 × 10 ⁶ cells / mL (2 times the final cell density). This PBMC suspension is added to a 96 well flat bottom sterile tissue culture plate.

Compound Preparation The compound of the present invention is dissolved in dimethyl sulfoxide (DMSO). The compounds of the invention are generally tested at a concentration of 30-0.014 μM. Controls include on each plate a cell sample containing medium only, a cell sample containing DMSO only (no compound), and the reference compound 2- [4-amino-2-ethoxymethyl-6,7,8,9- A cell sample containing tetrahydro-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethanol hydrate (USP No. 5,352,784; Example 91) is included. A solution of the test compound is added at 7.5 mM to the first well of the dosing plate, and serial 3-fold dilutions are made in DMSO to obtain 7 subsequent concentrations. RPMI complete medium is then added to the test compound dilutions to reach a final compound concentration (60-0.028 μM) that is twice as high as the final test concentration range.

Incubation The compound solution is then added to the wells containing the PBMC suspension to bring the test compound concentration to the target range (usually 30-0.014 μM) and the DMSO concentration to 0.4%. The final concentration of PBMC suspension is 2 × 10 ⁶ cells / mL. Cover the plate with a sterile plastic lid, mix gently, and then incubate at 37 ° C. in a 5% carbon dioxide atmosphere for 18-24 hours.

Separation Following incubation, the plate is centrifuged at 1000 rpm (approximately 200 g) at 4 ° C. for 10 minutes. Quad plate human panel MSD MULTI-SPOT 96 well plates are precoated with the appropriate capture antibody (MSD, Geysersburg, Md.) By MesoScale Discovery, Inc. Separate cell-free culture supernatant and transfer to MSD plate. In general, fresh samples are tested, but the samples may be held at -30 to -70 ° C until analysis.

Analysis of interferon-α and tumor necrosis factor-α
MSD MULTI-SPOT plates contain capture antibodies against human TNF-α and human IFN-α pre-coated on specific spots in each well. Each well contains 4 spots: 1 human TNF-α capture antibody (MSD) spot, 1 human IFN-α capture antibody (PBL Biomedical Laboratories, Piscataway, NJ) spot, and 2 not Active bovine serum albumin spot. The human TNF-α capture antibody and detection antibody pair is from MesoScale Discovery. Human IFN-α multi-subtype antibodies (PBL Biomedical Laboratories) capture all IFN-α subtypes except IFN-α F (IFNA21). Standards consist of recombinant human TNF-α (R & D Systems, Minneapolis, MN) and IFN-α (PBL Biomedical Laboratories). Samples and individual standards are added to each MSD plate for analysis. For the measurement of IFN-α concentration, two human IFN-α detection antibodies (Catalog Nos. 21112 and 21100, PBL) are used in a 2: 1 ratio (w: w) to each other. Cytokine-specific antibodies are labeled with SULFO-TAG reagent (MSD). After the detection antibody labeled with SULFO-TAG is added to the well, the electrochemiluminescence level of each well is read with the SECTOR HTS READER of MSD. Results are expressed in pg / mL based on calculations with known cytokine labeling substances.

Assay Data and Analysis Overall, the assay data output consists of TNF-α or IFN-α concentration values (y-axis) as a function of compound concentration (x-axis).

  In order to reduce the variation between the plates used in the same experiment, scaling is performed for each plate in the experiment. First, the greater of the central DMSO (DMSO control well) or experimental background (usually 20 pg / mL for IFN-α, 40 pg / mL for TNF-α) is subtracted from each reading. Background subtraction may give a negative number, which is set to zero. Each plate in the experiment contains a reference compound used as a control. This control is used to calculate the area under the median expected curve across all plates in the assay. For each plate, the scaling factor for each plate is calculated as the ratio of the area of the reference compound on a particular plate to the median expected area for the entire experiment. Then, for all plates, the data obtained from each plate is multiplied by the scaling factor for each plate. Only data from plates with a scaling factor of 0.5-2.0 (for both cytokines IFN-α, TNF-α) are reported. Data from plates with scaling factors outside this range are retested until they have scaling factors within this range. With the above method, y-value scaling is performed without changing the shape of the curve. The reference compound used was 2- [4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethanol Hydrate (USP No. 5,352,784; Example 91). The median expected area is the median area of all plates that are part of the experiment.

  A second scaling can also be performed to reduce variability between experiments (in many experiments). To reduce the variation between experiments, all background subtraction values are multiplied by a single matching ratio. This matching ratio is the area of the reference compound in a new experiment divided by the expected area of the reference compound based on the average of previous experiments (non-matching reading). This scales the reading (y-axis) for new data without changing the shape of the dose-response curve. The reference compound used was 2- [4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α, α-dimethyl-1H-imidazo [4,5-c] quinolin-1-yl] ethanol Hydrate (USP No. 5,352,784; Example 91), the expected area is the sum of the median dose values obtained from the average of previous experiments.

  The minimum effective concentration is calculated based on the experiment and the background matched reference match results for the compound. The minimum effective concentration (μmolar) is the concentration of test compound that induces a response that exceeds the fixed cytokine concentration for the cytokine tested (usually 20 pg / mL for IFN-α and 40 pg / mL for TNF-α). The lowest concentration. The maximum response is the maximum amount of cytokine (pg / ml) produced in the dose-response.

  The entire disclosures of the patents, patent documents and publications cited herein are incorporated by reference as if individually set forth. Those skilled in the art will readily be able to variously modify and change the present invention without departing from the scope and spirit of the present invention. The present invention is not limited by the specific embodiments and examples shown in the specification, which examples and embodiments are merely given as examples of the scope of the present invention, and the present invention is limited only by the claims. It should be understood that it is limited.

Claims (53)

A therapeutically effective amount of a compound of formula I in a pharmaceutically acceptable carrier:

Or a pharmaceutical composition comprising a combination thereof with a pharmaceutically acceptable salt thereof:
X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R _A and R _B together form a fused benzene ring or fused pyridine ring, which is unsubstituted or substituted with 1 or 2 R groups, or 1 R ₃ Substituted with a group or substituted with one R ₃ group and one R group; the fused pyridine ring is

The highlighted bond in the formula indicates the position at which this ring is fused; R ₃ is in the 7- or 8-position; or
R _A and R _B together form a fused cyclohexane ring or fused tetrahydropyridine ring, which is unsubstituted or substituted with one or more R groups at carbon atoms; Ring

Where the highlighted bond in the formula indicates the position where the ring is fused; or
R _A is alkyl and R _B is hydrogen or alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
R ₃ is selected from the group consisting of:
-ZR ₄ ,
-ZXR ₄ ,
-ZXYR ₄ ,
-ZXYXYR ₄ ,
-ZXR ₅ and
-NH-QR ₄ ;
X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Y is selected from the group consisting of:

Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, in which alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; Hydroxy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; Optionally substituted with one or more selected substituents; in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, optionally substituted with one or more oxo;
R ₅ is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;
R ₇ is C _2-7 alkylene;
R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, and heteroaryl- Selected from the group consisting of C _1-10 alkylenyl;
R ₉ is selected from the group consisting of hydrogen and alkyl;
R ₁₀ is C _3-8 alkylene;
A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —;
A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —;
Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group consisting of:
V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;
W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —;
a and b are each independently an integer from 1 to 6, where a + b is ≦ 7]. A therapeutically effective amount of a compound of formula II in a pharmaceutically acceptable carrier:

Or a pharmaceutical composition comprising a combination thereof with a pharmaceutically acceptable salt thereof:
X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₃ is selected from the group consisting of:
-ZR ₄ ,
-ZXR ₄ ,
-ZXYR ₄ ,
-ZXYXYR ₄ ,
-ZXR ₅ and
-NH-QR ₄ ;
R ₃ is in the 7- or 8-position;
m is 0 or 1; provided that when m is 1, 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 are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Y is selected from the group consisting of:

Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; nitro; Xy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; In the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo;
R ₅ is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;
R ₇ is C _2-7 alkylene;
R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, and heteroaryl- Selected from the group consisting of C _1-10 alkylenyl;
R ₉ is selected from the group consisting of hydrogen and alkyl;
R ₁₀ is C _3-8 alkylene;
A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —;
A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —;
Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group consisting of:
V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;
W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —;
a and b are each independently an integer from 1 to 6, provided that a + b is ≦ 7]. A therapeutically effective amount of a compound of formula III in a pharmaceutically acceptable carrier:

Or a pharmaceutical composition comprising a combination thereof with a pharmaceutically acceptable salt thereof:
X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₉ is selected from the group consisting of hydrogen and alkyl]. A therapeutically effective amount of a compound of formula IV in a pharmaceutically acceptable carrier:

Or a pharmaceutical composition comprising a combination thereof with a pharmaceutically acceptable salt thereof:
X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₃ is selected from the group consisting of:
-ZR ₄ ,
-ZXR ₄ ,
-ZXYR ₄ ,
-ZXYXYR ₄ ,
-ZXR ₅ and
-NH-QR ₄ ;
R ₃ is in the 7- or 8-position;
m is 0 or 1; provided that when m is 1, 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 are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Y is selected from the group consisting of:

Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; nitro; Xy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; In the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo;
R ₅ is selected from the group consisting of:

R ₆ is selected from the group consisting of = O and = S;
R ₇ is C _2-7 alkylene;
R ₈ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, hydroxy-C _1-10 alkylenyl, C _1-10 alkoxy-C _1-10 alkylenyl, aryl-C _1-10 alkylenyl, and heteroaryl- Selected from the group consisting of C _1-10 alkylenyl;
R ₉ is selected from the group consisting of hydrogen and alkyl;
R ₁₀ is C _3-8 alkylene;
A is selected from the group consisting of —CH ₂ —, —O—, —C (O) —, —S (O) _0-2 —, and —N (—QR ₄ ) —;
A ′ is selected from the group consisting of —O—, —S (O) _0-2 —, —N (—QR ₄ ) —, and —CH ₂ —;
Q is a bond, -C (R ₆ )-, -C (R ₆ ) -C (R ₆ )-, -S (O) _2- , -C (R ₆ ) -N (R ₈ ) -W- , -S (O) ₂ -N (R ₈ )-, -C (R ₆ ) -O-, -C (R ₆ ) -S-, and -C (R ₆ ) -N (OR ₉ )- Selected from the group consisting of:
V is selected from the group consisting of -C (R ₆ )-, -OC (R ₆ )-, -N (R ₈ ) -C (R ₆ )-, and -S (O) _2- ;
W is selected from the group consisting of a bond, —C (O) —, and —S (O) ₂ —;
a and b are each independently an integer from 1 to 6, where a + b is ≦ 7]. A therapeutically effective amount of a compound of formula V in a pharmaceutically acceptable carrier:

Or a pharmaceutical composition comprising a combination thereof with a pharmaceutically acceptable salt thereof:
X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R _{A ′} is alkyl and R _{B ′} is hydrogen or alkyl]. 6. The pharmaceutical composition of claim 5, wherein R _{A ′} and R _{B ′} are both methyl. R ₃ is -ZR _4, any one of the pharmaceutical composition according to claim 1, 2 and 4. R ₄ is selected from the group consisting of aryl, arylalkylenyl, heteroaryl and heteroarylalkylenyl, wherein the aryl, arylalkylenyl, heteroaryl and heteroarylalkylenyl groups are substituted Optionally or independently substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, aminoalkyl, halogen, hydroxy, cyano, amino, alkylamino and dialkylamino The pharmaceutical composition of claim 7, wherein Z is a bond. R ₄ is a 4- to 7-membered heterocyclyl group, which contains one or more ring nitrogen atoms, may contain a ring oxygen atom or a ring sulfur atom, and the point of attachment of the heterocyclyl group is one of the nitrogen atoms. The heterocyclyl group is unsubstituted or substituted independently with one or more substituents selected from the group consisting of oxo, alkyl and arylalkylenyl; Z is a bond The pharmaceutical composition of claim 7. A heterocyclyl group,

10. The pharmaceutical composition of claim 9, wherein R 'is alkyl selected from the group consisting of: R ₃ is -ZXYR _4, any one of the pharmaceutical composition according to claim 1, 2 and 4. R ₄ is selected from the group consisting of hydrogen, alkyl and heterocyclyl; Y is —S (O) ₂ —, —C (O) —, —C (O) —NH—, and —NH—S (O 12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition is selected from the group consisting of: _2- ; X is phenylene; and Z is a bond. R ₄ is selected from the group consisting of alkyl, aryl, arylalkylenyl, and heteroaryl, each of which is unsubstituted or independently selected from the group consisting of halogen, hydroxy, and alkyl And Y is selected from the group consisting of —S (O) ₂ —, —C (O) —, —C (O) —NH—, and —NH—S (O) ₂ —. Selected; X is

The pharmaceutical composition of claim 11, wherein Z is a bond. R ₄ is hydrogen or alkyl; Y is —C (O) —N (R ₈ ) — or —C (O) —O—; R ₈ is C _1-4 alkyl; X is alkylene or 12. The pharmaceutical composition of claim 11 which is alkenylene; Z is a bond. R ₄ is alkyl substituted by maleimidyl; Y is -NHC (O) - and; X is alkylene that is one -O- groups in the middle; Z is -O-, and claims Eleven pharmaceutical compositions. R ₃ is -ZX _f -Y _a -X _g -Y _b -R ₄ where R ₄ is hydrogen or C _1-4 alkyl, Y _b is -C (O) -O-; X _g is alkylene, Y _a is -NHC (O) - and, X _f is alkylene where there is one -O- groups in the middle; Z is -O-, and claim 1 5. The pharmaceutical composition according to any one of 4 and 4. R ₃ is hydroxyphenyl, (hydroxymethyl) phenyl, are selected from (aminomethyl) phenyl, pyridin-3-yl, and pyridin-4 group consisting yl, claims 1,2,4,7 and 8 A pharmaceutical composition according to any one of the above. R ₃ is (methylsulfonylamino) phenyl, any one of pharmaceutical composition according to claim 1, 2, 4 and 12. R ₃ is selected from the group consisting of hydroxyphenyl, (hydroxymethyl) phenyl, 4- (aminomethyl) phenyl, 3- (methylsulfonylamino) phenyl, pyridin-3-yl, and pyridin-4-yl; The pharmaceutical composition of claim 1 or 2. The pharmaceutical composition according to claim 1 or 4, wherein R ₃ is selected from the group consisting of hydroxyphenyl, (hydroxymethyl) phenyl, and (methylsulfonylamino) phenyl. R ₃ is in the 7-position, according to claim 1, 2, 4, and any one of the pharmaceutical compositions of 7-20. R ₃ is in the 8-position, according to claim 1, 2, 4, and any one of the pharmaceutical compositions of 7-20.   23. The pharmaceutical composition according to any one of claims 2, 3, 4, and 7-22, wherein n is 0, excluding those dependent on claim 1.   The pharmaceutical composition according to claim 2 or 4, wherein m is 0.   The pharmaceutical composition of claim 2 or 4, wherein m and n are both 0. R ₂ is —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —OC _1-3 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OH, and -CH ₂ -C _1-3 is selected from the group consisting of alkylenyl -OH, any one of the pharmaceutical composition according to claim 1 to 25. 27. R ₂ is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. Pharmaceutical composition. R ₂ is methyl, ethyl, n- propyl, n- butyl, cyclopropylmethyl, methoxymethyl, selected from ethoxymethyl, and the group consisting of 2-methoxyethyl, pharmaceutical composition according to claim 27. R ₂ is, n- propyl, n- butyl, methoxymethyl, selected from ethoxymethyl, and the group consisting of 2-methoxyethyl, pharmaceutical composition according to claim 28. R ₁ is tetrahydro -2H- thiopyran-4-yl, any one of the pharmaceutical composition according to claim 1 to 29. X 'is -CH ₂ -, any one of the pharmaceutical composition according to claim 1-30.   The pharmaceutical composition according to any one of claims 1 to 30, wherein X 'is -NH-.   The pharmaceutical composition according to any one of claims 1 to 30, wherein X 'is -O-. Compound of formula IIa:

Or a pharmaceutically acceptable salt thereof, wherein:
X ″ is —CH ₂ —;
R _1a is tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-di Selected from the group consisting of oxide tetrahydro-2H-thiopyran-4-yl;
R ₂ is —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH ₂ —OH, -CH ₂ -C _1-3 alkylenyl-OH, and selected from the group consisting of benzyl, the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C _1-4 alkoxy Substituted with one or more substituents selected from the group consisting of hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl]. Compound of formula III:

Or a pharmaceutically acceptable salt thereof, wherein:
X ′ is selected from the group consisting of —CH ₂ —, —NH—, and —O—;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R ₉ is selected from the group consisting of hydrogen and alkyl]. Compounds of formula IVa:

Or a pharmaceutically acceptable salt thereof, wherein:
X ″ ′ is —CH ₂ —;
R _1a is tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-di Selected from the group consisting of oxide tetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R is selected from the group consisting of:
halogen,
Hydroxy,
Alkyl,
Haloalkyl,
Alkoxy, and
-N (R ₉ ) ₂ ;
n is 0, 1 or 2;
R _3a is selected from the group consisting of:
-ZR ₄ , and
-ZXR ₄ ;
R _3a is in the 7- or 8-position;
m is 0 or 1; provided that when m is 1, 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 are arylene, heteroarylene, or heterocyclylene at the middle or terminal. May have one or more —O— groups in the middle;
Z is a bond or —O—;
R ₄ is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylene. Selected from the group consisting of nyl and heterocyclyl, wherein alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, hetero Aryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or independently alkyl; alkoxy; hydroxyalkyl; haloalkyl; haloalkoxy; halogen; nitro; Xy; mercapto; cyano; aryl; aryloxy; arylalkyleneoxy; heteroaryl; heteroaryloxy; heteroarylalkyleneoxy; heterocyclyl; amino; alkylamino; dialkylamino; In the case of alkyl, alkenyl, alkynyl, and heterocyclyl, it may be substituted with one or more oxo;
R ₉ is selected from the group consisting of hydrogen and alkyl]. Compound of formula Va:

Or a pharmaceutically acceptable salt thereof, wherein:
X ″ is —CH ₂ —;
R ₁ is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4 Selected from the group consisting of -yl, tetrahydro-2H-thiopyran-4-yl, and 1,1-dioxidetetrahydro-2H-thiopyran-4-yl;
R ₂ is —NH ₂ , —CH ₃ , —CH ₂ —C _1-4 alkyl, —CH ₂ —C _1-2 alkylenyl-OC _1-2 alkyl, —CH ₂ —OC _1-3 alkyl, —CH Selected from the group consisting of _2- OH, —CH ₂ -C _1-3 alkylenyl-OH, and benzyl, wherein the phenyl ring of the benzyl group is unsubstituted or independently halogen, C _1-4 alkyl, C Substituted with one or more substituents selected from the group consisting of _1-4 alkoxy, hydroxy, halo C _1-4 alkyl, and hydroxy C _1-4 alkyl;
R _{A ′} is alkyl and R _{B ′} is hydrogen or alkyl]. 38. The compound or salt of claim 37, wherein R _{A ′} and R _{B ′} are both methyl. X 'is -CH ₂ -, a compound or salt according to claim 35.   36. The compound or salt of claim 35, wherein X 'is -NH-.   36. The compound or salt of claim 35, wherein X 'is -O-. _37. The compound or salt of claim 36, wherein R3a is selected from the group consisting of hydroxyphenyl and (hydroxymethyl) phenyl.   43. A compound or salt according to any one of claims 35, 36 and 39 to 42, wherein n is 0.   37. The compound or salt of claim 36, wherein m is 0.   38. The compound or salt of claim 36, wherein m and n are both 0. 45. A compound or salt according to any one of claims 34, 36, 42, claim 36 or claim 43, dependent on claim 36 or claim 42, wherein R _1a is tetrahydro-2H-thiopyran-4-yl. And R ₁ is tetrahydro -2H- thiopyran-4-yl, any of claims 43 to claim 35,37,38,39,40,41, and depending on claim 35,39,40 or 41 Or a salt of 35. R ₂ is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, cyclopropylmethyl, methoxymethyl, ethoxymethyl, 2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. 48. A compound or salt according to any one of .about.47. R ₂ is, n- propyl, n- butyl, methoxymethyl, selected from ethoxymethyl, and the group consisting of 2-methoxyethyl, compound or salt according to claim 48.   50. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 34 to 49 or a salt thereof in combination with a pharmaceutically acceptable carrier.   51. Cytokine biosynthesis in an animal comprising administering to the animal an effective amount of the pharmaceutical composition of any one of claims 1-33 and 50 or the compound of any one of claims 34-49 or a salt thereof. How to guide.   50. An animal in need thereof comprising administering to the animal a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-33 and 50 or the compound of any one of claims 34-49 or a salt thereof. A method of treating a viral disease in   50. An animal in need thereof comprising administering to the animal a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-33 and 50 or the compound of any one of claims 34-49 or a salt thereof. Of treating neoplastic disease in a method.