IP Library › Granted Patent US 7,897,767

Granted Patent B2

US 7,897,767 · App. 10/595,792 · Granted Mar 1, 2011

Oxime substituted imidazoquinolines

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Quick Facts

Patent No.: US 7,897,767
App. No.: 10/595,792
Granted: Mar 1, 2011
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

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

Claims (596)

1. A compound of the Formula II:

wherein:

X is C 1-10 alkylene or C 2-10 alkenylene;

R A1 and R B1 are taken together to form a fused 6-membered aryl ring, wherein the aryl ring is unsubstituted or substituted by one or more R groups, or substituted by one R 3 group, or substituted by one R 3 group and one R group; or a fused 6 membered saturated ring, wherein the saturated ring is unsubstituted or substituted by one or more R groups;

R is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

N(R 9 ) 2 ;

R 1 is selected from the group consisting of:

—R 4 ,

—X′—R 4 ,

—X′—Y—R 4 ,

—X′—Y—X′—Y—R 4 ,

—X′—R 5 ,

—X″—O—NR 1a —Y′—R 1b , and

—X″—O—N═C(R 1 ′)(R 1 ″);

R 2 , R″, R 1a , R 1b , R 1 ′, and R 1 ″ are independently selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

aryl,

arylalkylenyl,

heteroaryl,

heteroarylalkylenyl,

heterocyclyl,

heterocyclylalkylenyl, and

alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:

hydroxy,

alkyl,

haloalkyl,

hydroxyalkyl,

alkoxy,

amino,

dialkylamino,

—S(O) 0-2 -alkyl,

—S(O) 0-2 -aryl,

—NH—S(O) 2 -alkyl,

—NH—S(O) 2 -aryl,

haloalkoxy,

halogen,

cyano,

nitro,

aryl,

heteroaryl,

heterocyclyl,

aryloxy,

arylalkyleneoxy,

—C(O)—O-alkyl,

—C(O)—N(R 8 ) 2 ,

—N(R 8 )—C(O)-alkyl,

—O—(CO)-alkyl, and

—C(O)-alkyl;

or R 2 and R″ and/or R 1 ′ and R 1 ″ can join together to form a ring system selected from the group consisting of:

wherein the total number of atoms in the ring is 4 to 9, and

wherein the total number of atoms in the ring is 4 to 9;

or R 1a and R 1b together with the nitrogen atom and Y′ to which they are bonded can join to form a ring selected from the group consisting of:

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X′—R 4 ,

—Z—X′—Y—R 4 ,

—Z—X′—Y—X′—Y—R 4 , and

—Z—X′—R 5 ;

X′ is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;

X″ is selected from the group consisting of —CH(R 13 )-alkylene- and —CH(R 13 )-alkenylene-, wherein the alkylene and alkenylene are optionally interrupted by one or more —O— groups;

Y is selected from the group consisting of:

—S(O) 0-2 —,

—S(O) 2 —N(R 8 )—,

—C(R 6 )—,

—C(R 6 )—O—,

—O—C(R 6 )—,

—O—C(O)—O—,

—N(R 8 )-Q-,

—C(R 6 )—N(R 8 )—,

—O—C(R 6 )—N(R 8 )—,

—C(R 6 )—N(OR 9 )—,

Y′ is selected from the group consisting of:

a bond,

—C(O)—,

—C(S)—,

—S(O) 2 —,

—S(O) 2 —N(R 8 )—,

—C(O)—O—,

—C(O)—N(R 8 )—,

—C(S)—N(R 8 )—,

—C(O)—N(R 8 )—S(O) 2 —,

—C(O)—N(R 8 )—C(O)—,

—C(S)—N(R 8 )—C(O)—,

—C(O)—C(O)—,

—C(O)—C(O)—O—, and

—C(═NH)—N(R 8 )—;

Z is a bond or —O—;

R c and R d are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, aryl, haloalkyl, alkoxy, alkylthio, and —N(R 9 ) 2 ; or R c and R d can join to form a fused aryl ring or fused 5-10 membered heteroaryl ring containing one to four heteroatoms;

R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo;

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 selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy-C 1-10 alkylenyl, and aryl-C 1-10 alkylenyl;

R 9 is selected from the group consisting of hydrogen and alkyl;

R 10 is C 3-8 alkylene;

R 11 is C 1-6 alkylene or C 2-6 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;

R 12 is selected from the group consisting of a bond, C 1-5 alkylene, and C 2-5 alkenylene, wherein the alkylene or alkenylene is optionally interrupted by one heteroatom;

R 13 is selected from the group consisting of hydrogen and alkyl which may be optionally interrupted by one or more —O— groups;

A is selected from the group consisting of —CH 2 —, —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;

A′ is selected from the group consisting of —O—, —S(O) 0-2 —, —N(-Q-R 4 )—, and —CH 2 —;

Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;

V is selected from the group consisting of —C(R 6 )—, —O—C(R 6 )—, —N(R 8 )—C(R 6 )—, and —S(O) 2 —;

W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and

a and b are independently integers from 1 to 6 with the proviso that a+b is ≦7;

or a pharmaceutically acceptable salt thereof.

2. A compound of the Formula IIIa:

wherein:

X is C 1-10 alkylene or C 2-10 alkenylene;

R is selected from the group consisting of:

halogen,

hydroxy,

alkyl,

alkenyl,

haloalkyl,

alkoxy,

alkylthio, and

—N(R 9 ) 2 ;

R 1 is selected from the group consisting of:

—R 4 ,

—X′—R 4 ,

—X′—Y—R 4 ,

X′—Y—X′—Y—R 4 ,

—X′—R 5 ,

—X″—O—NR 1a —Y′—R 1b , and

—X″—O—N═C(R 1 ′)(R 1 ″);

R 2 , R″, R 1a , R 1b , R 1 ′, and R 1 ″ are independently selected from the group consisting of:

hydrogen,

alkyl,

alkenyl,

aryl,

arylalkylenyl,

heteroaryl,

heteroarylalkylenyl,

heterocyclyl,

heterocyclylalkylenyl, and

alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:

hydroxy,

alkyl,

haloalkyl,

hydroxyalkyl,

alkoxy,

amino,

dialkylamino,

—S(O) 0-2 -alkyl,

—S(O) 0-2 -aryl,

—NH—S(O) 2 -alkyl,

—NH—S(O) 2 -aryl,

aryl,

haloalkoxy,

halogen,

cyano,

nitro,

aryl,

heteroaryl,

heterocyclyl,

aryloxy,

arylalkyleneoxy,

—C(O)—O-alkyl,

—C(O)—N(R 8 ) 2 ,

—N(R 8 )—C(O)-alkyl,

—O—(CO)-alkyl, and

—C(O)-alkyl;

or R 2 and R″ and/or R 1 ′ and R 1 ″ can join together to form a ring system selected from the group consisting of:

wherein the total number of atoms in the ring is 4 to 9, and

wherein the total number of atoms in the ring is 4 to 9;

or R 1a and R 1b together with the nitrogen atom and Y′ to which they are bonded can join to form a ring selected from the group consisting of:

R 3 is selected from the group consisting of:

—Z—R 4 ,

—Z—X′—R 4 ,

—Z—X′—Y—R 4 ,

—Z—X′—Y—X′—Y—R 4 , and

—Z—X′—R 5 ;

n is an integer from 0 to 4;

m is 0 or 1; with the proviso that when m is 1, then n is 0 or 1;