US2017088559A1PendingUtilityA1
Alkyloxy substituted thiazoloquinolines and thiazolonaphthyridines
Assignee: 3M INNOVATIVE PROPERTIES COPriority: Feb 9, 2005Filed: Dec 12, 2016Published: Mar 30, 2017
Est. expiryFeb 9, 2025(expired)· nominal 20-yr term from priority
Inventors:Ryan B. PrinceBryon A. MerrillPhilip D. HeppnerTushar A. KshirsagarJoshua R. WurstKarl J. ManskeMichael J. Rice
A61P 37/02A61P 43/00A61P 31/12C07D 513/04A61P 35/00C07D 519/00
55
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Claims
Abstract
Thiazoloquinolines and thiazolonaphthyridines with an alkoxy substituent at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, intermediates, methods of making 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
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I:
wherein:
R A and R B taken together form a fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is substituted by one —O—R 3 group, or substituted by one —O—R 3 group and one R group;
R 3 is selected from the group consisting of:
—Z—Y—R 4 ,
—Z—Y—X—Y—R 4 ,
—Z—Y—X—Y—X—Y—R 4 ,
—Z—R 5 ,
—Z-Het,
—Z-Het′-R 4 , and
—Z-Het′-Y—R 4 ;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
R″ is hydrogen or a non-interfering substituent;
Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with 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 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
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 with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
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, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
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 —O—, —CH 2 —, —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;
with the proviso that Z can also be a bond when:
R 3 is —Z-Het, —Z-Het′-R 4 , or —Z-Het′-Y—R 4 , and Z is attached to an atom other than N in Het or Het′; or
R 3 is —Z—Y—R 4 , —Z—Y—X—Y—R 4 , or —Z—Y—X—Y—X—Y—R 4 , and the Y group bonded to Z is —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—,
wherein V is —C(R 6 )— or —S(O) 2 —, or
or
R 3 is —Z—R 5 , and R 5 is
wherein V is —C(R 6 )— or —S(O) 2 —, or
and
with the further proviso that Y can also be —O— when:
Y is bonded to R 4 , and R 4 is selected from the group consisting of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl can be unsubstituted or substituted by one or more substituents; or
Y is bonded to Z and X, and X is arylene or heteroarylene;
or a pharmaceutically acceptable salt thereof.
2 . The compound or salt of claim 1 wherein R″ is R 2 ; wherein R 2 is selected from the group consisting of —R 4 , —X—R 4 , —X—Y′—R 4 , and —X—R 5 ′; wherein
Y′ is selected from the group consisting of:
—O—,
—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 )—,
and
R 5 ′ is selected from the group consisting of:
3 . A compound of Formula VII:
wherein:
R A and R B taken together form a fused benzene ring or fused pyridine ring wherein the benzene ring or pyridine ring is substituted by one —O—R 3 group, or substituted by one —O—R 3 group and one R group;
R 3 is selected from the group consisting of:
—Z—Y—R 4 ,
—Z—Y—X—Y—R 4 ,
—Z—Y—X—Y—X—Y—R 4 ,
—Z—R 5 ,
—Z-Het,
—Z-Het′-R 4 , and
—Z-Het′-Y—R 4 ;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
G is selected from the group consisting of:
—C(O)—R′,
α-aminoacyl,
α-aminoacyl-α-aminoacyl,
—C(O)—O—R′,
—C(O)—N(R′″)R′,
—C(═NY 1 )—R′,
—CH(OH)—C(O)—OY 1 ,
—CH(OC 1-4 alkyl)Y 0 ,
—CH 2 Y 2 , and
—CH(CH 3 )Y 2 ;
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 may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of 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, —O—C(O)—CH 3 , —C(O)—O—CH 3 , —C(O)—NH 2 , —O—CH 2 —C(O)—NH 2 , —NH 2 , and —S(O) 2 —NH 2 , with the proviso that R′″ can also 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;
Y 1 is selected from the group consisting of hydrogen, C 1-6 alkyl, and benzyl;
Y 0 is selected from the group consisting of C 1-6 alkyl, carboxy-C 1-6 alkylenyl, amino-C 1-4 alkylenyl, mono-N—C 1-6 alkylamino-C 1-4 alkylenyl, and di-N,N—C 1-6 alkylamino-C 1-4 alkylenyl;
Y 2 is selected from the group consisting of mono-N—C 1-6 alkylamino, di-N,N—C 1-6 alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and 4-C 1-4 alkylpiperazin-1-yl;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 , —X—Y′—R 4 , and
—X—R 5 ′;
Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with 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 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
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 with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
—O—,
—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 )—,
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 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, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
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 —O—, —CH 2 —, —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;
with the proviso that Z can also be a bond when:
R 3 is —Z-Het, —Z-Het′-R 4 , or —Z-Het′-Y—R 4 , and Z is attached to an atom other than N in Het or Het′; or
R 3 is —Z—Y—R 4 , —Z—Y—X—Y—R 4 , or —Z—Y—X—Y—X—Y—R 4 , and the Y group bonded to Z is —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—,
wherein V is —C(R 6 )— or —S(O) 2 —, or
or
R 3 is —Z—R 5 , and R 5 is
wherein V is —C(R 6 )— or —S(O) 2 —, or
and
with the further proviso that Y can also be —O— when:
Y is bonded to R 4 , and R 4 is selected from the group consisting of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl can be unsubstituted or substituted by one or more substituents; or
Y is bonded to Z and X, and X is arylene or heteroarylene;
or a pharmaceutically acceptable salt thereof.
4 . The compound or salt of claim 1 or claim 3 wherein R A and R B taken together form a fused benzene ring wherein the benzene ring is substituted by one —O—R 3 group, or substituted by one —O—R 3 group and one R group.
5 . A compound of Formula II:
wherein:
R 3 is selected from the group consisting of:
—Z—Y—R 4 ,
—Z—Y—X—Y—R 4 ,
—Z—Y—X—Y—X—Y—R 4 ,
—Z—R 5 ,
—Z-Het,
—Z-Het′-R 4 , and
—Z-Het′-Y—R 4 ;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
n is 0 or 1;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 , —X—Y′—R 4 , and
—X—R 5 ′;
Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with 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 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q-R 4 )—,
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
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 with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
—O—,
—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 )—,
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 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, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
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 —O—, —CH 2 —, —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;
with the proviso that Z can also be a bond when:
R 3 is —Z-Het, —Z-Het′-R 4 , or —Z-Het′-Y—R 4 , and Z is attached to an atom other than N in Het or Het′; or
R 3 is —Z—Y—R 4 , —Z—Y—X—Y—R 4 , or —Z—Y—X—Y—X—Y—R 4 , and the Y group bonded to Z is —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—,
wherein V is —C(R 6 )— or —S(O) 2 —, or
or
R 3 is —Z—R 5 , and R 5 is
wherein V is —C(R 6 )— or —S(O) 2 —, or
and
with the further proviso that Y can also be —O— when:
Y is bonded to R 4 , and R 4 is selected from the group consisting of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl can be unsubstituted or substituted by one or more substituents; or
Y is bonded to Z and X, and X is arylene or heteroarylene;
or a pharmaceutically acceptable salt thereof.
6 . The compound or salt of claim 5 wherein n is 0.
7 . The compound or salt of any one of claims 2 , 3 , 5 , and 6 or claim 4 as dependent on claim 3 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
8 . The compound or salt of claim 7 wherein R 2 is selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, ethoxymethyl, methoxymethyl, and 2-methoxyethyl.
9 . The compound or salt of any one of claims 1 through 8 wherein R 3 is —Z—Y—R 4 or —Z—Y—X—Y—R 4 .
10 . The compound or salt of claim 9 wherein Y is —N(R 8 )-Q-,
or —C(O)—; wherein
Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, —C(R 6 )—N(R 8 )—, and —S(O) 2 —N(R 8 )—;
R 6 is selected from the group consisting of ═O or ═S;
R 7 is C 2-3 alkylene;
R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl;
R 10 is C 3-6 alkylene; and
R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl;
wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, halogen, and aryl;
wherein aryl, heteroaryl, and arylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, dialkylamino, and alkoxy;
and wherein heterocyclyl is unsubstituted or substituted by one or more alkyl substituents.
11 . The compound or salt of claim 9 wherein Y is —N(R 8 )-Q- or
wherein
Q is selected from the group consisting of a bond, —C(O)—, —C(O)—O—, —S(O) 2 —, and —C(R 6 )—N(R 8 )—;
R 6 is selected from the group consisting of ═O or ═S;
R 7 is C 2-3 alkylene;
R 8 is selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 alkoxyC 1-4 alkylenyl; and
R 4 is selected from the group consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl;
wherein alkyl is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, and aryl;
wherein aryl and arylalkylenyl are unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, dialkylamino, and alkoxy; and
wherein heterocyclyl is unsubstituted or substituted by one or more alkyl substituents.
12 . The compound or salt of any one of claims 1 through 11 wherein Y is —N(R 8 )-Q-.
13 . The compound or salt of any one of claims 10 through 12 wherein Q is —C(O)—.
14 . The compound or salt of any one of claims 10 through 12 wherein Q is —S(O) 2 —.
15 . The compound or salt of any one of claims 10 through 12 wherein Q is —C(R 6 )—N(R 8 )—.
16 . The compound or salt of any one of claims 13 through 15 wherein R 4 is C 1-4 alkyl and R 8 is hydrogen.
17 . The compound or salt of any one of claims 13 through 15 wherein R 4 is phenyl that is unsubstituted or substituted by methoxy and R 8 is hydrogen.
18 . The compound or salt of claim 12 wherein Q is a bond, R 4 is heterocyclyl that is unsubstituted or substituted by one or more alkyl groups, and R 8 is C 1-4 alkyl.
19 . The compound or salt of claim 9 wherein:
R 3 is —Z—Y—R 4 , wherein Y is —O— and R 4 is phenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, halogen, cyano, alkoxy, nitro, and haloalkyl; or
R 3 is —Z—Y—X—Y—R 4 , wherein Y is —O—, X is phenylene, and Y c —R 4 is selected from the group consisting of —C(O)-alkyl, —C(O)—O-alkyl, —S-alkyl, —NH—C(O)-alkyl, —C(O)—NH 2 , and —S(O) 2 —NH 2 .
20 . The compound or salt of any one of claims 1 through 8 wherein R 3 is —Z—R 5 .
21 . The compound or salt of any one of claims 1 through 8 or claim 20 wherein R 5 is selected from the group consisting of:
wherein A is —O—, —CH 2 —, or —S(O) 2 —; R 7 is C 2-4 alkylene; R 8 is hydrogen or C 1-4 alkyl; and a and b are each independently 1, 2, or 3.
22 . The compound or salt of any one of claims 1 through 8 or claim 20 wherein R 5 is
wherein R 7 is C 2-4 alkylene.
23 . The compound or salt of any one of claims 1 through 8 wherein R 3 is —Z-Het or —Z-Het′-R 4 .
24 . The compound or salt of any one of claims 1 through 8 or claim 23 wherein Het and Het′ are, respectively, selected from the group consisting of the monovalent and divalent forms of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which is unsubstituted or substituted by one or more substituents.
25 . The compound or salt of claim 24 wherein Het and Het′ are, respectively, selected from the group consisting of the monovalent and divalent forms of pyrrolidinyl, piperidinyl, and morpholinyl, each of which is unsubstituted or substituted by one or more substituents.
26 . The compound or salt of any one of claims 1 through 8 or any one of claims 23 through 25 wherein Het is substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, hydroxyalkyleneoxyalkylenyl, and dialkylamino.
27 . The compound or salt of any one of claims 23 through 25 wherein R 4 is heterocyclyl.
28 . The compound or salt of any one of claims 1 through 8 wherein R 3 is —Z-Het′-Y—R 4 .
29 . The compound or salt claim 28 , wherein Het′ is selected from the group consisting of the divalent form of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl.
30 . The compound or salt of claim 28 or claim 29 wherein —Y—R 4 is selected from the group consisting of —C(O)-alkyl, —C(O)—O—H, —C(O)—O-alkyl, —C(O)—NH 2 , —C(O)—NH-alkyl, and —NH—C(O)-alkyl.
31 . The compound or salt of any one of claims 1 through 30 wherein Z is alkylene optionally interrupted with one or more —O— groups.
32 . The compound or salt of claim 31 wherein Z is selected from the group consisting of C 1-6 alkylene and —CH 2 CH 2 —O—CH 2 CH 2 —.
33 . The compound or salt of any one of claims 1 through 10 wherein Z is a bond.
34 . The compound or salt of any one of claims 1 through 33 wherein —O—R 3 is at the 7-position.
35 . A compound of the Formula X:
wherein:
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
n is 0 or 1;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 , —X—Y′—R 4 , and
—X—R 5 ′;
Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with one or more —O— groups;
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 with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
—O—,
—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 )—,
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, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
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 —O—, —CH 2 —, —C(O)—, —S(O) 0-2 —, and —N(R 4 )—;
Q is selected from the group consisting of a bond, —C(R 6 )—, —C(R 6 )—C(R 6 )—, —S(O) 2 —, —C(R 6 )—N(R 8 )—W—, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
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.
36 . The compound or salt of claim 35 wherein n is 0 and R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
37 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of any one of claims 1 through 36 and a pharmaceutically acceptable carrier.
38 . A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of any one claims 1 through 36 or the pharmaceutical composition of claim 37 to the animal.
39 . A method of treating a viral disease in an animal in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1 through 36 or the pharmaceutical composition of claim 37 to the animal.
40 . A method of treating a neoplastic disease in an animal in need thereof comprising administering a therapeutically effective amount of a compound or salt of any one of claims 1 through 36 or the pharmaceutical composition of claim 37 to the animal.
41 . A compound of the Formula XII:
wherein:
R 3 is selected from the group consisting of:
—Z—Y—R 4 ,
—Z—Y—X—Y—R 4 ,
—Z—Y—X—Y—X—Y—R 4 ,
—Z—R 5 ,
—Z-Het,
—Z-Het′-R 4 , and
—Z-Het′-Y—R 4 ;
R is selected from the group consisting of alkyl, alkoxy, hydroxy, halogen, and trifluoromethyl;
n is 0 or 1;
R 2 is selected from the group consisting of:
—R 4 ,
—X—R 4 , —X—Y′—R 4 , and
—X—R 5 ′;
Z is selected from the group consisting of alkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, and alkynylene can be optionally interrupted with 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 )—,
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R)-Q-R 4 )—,
Het is heterocyclyl which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo;
Het′ is heterocyclylene which can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;
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 with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
—O—,
—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 )—,
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 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, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, and heteroarylalkylenyl;
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 —O—, —CH 2 —, —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;
with the proviso that Z can also be a bond when:
R 3 is —Z-Het, —Z-Het′-R 4 , or —Z-Het′-Y—R 4 , and Z is attached to an atom other than N in Het or Het′; or
R 3 is —Z—Y—R 4 , —Z—Y—X—Y—R 4 , or —Z—Y—X—Y—X—Y—R 4 , and the Y group bonded to Z is —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—, —C(R 6 )—O—, —C(R 6 )—N(R 8 )—,
wherein V is —C(R 6 )— or —S(O) 2 —, or
or
R 3 is —Z—R 5 , and R 5 is
wherein V is —C(R 6 )— or —S(O) 2 —,
or
and
with the further proviso that Y can also be —O— when:
Y is bonded to R 4 , and R 4 is selected from the group consisting of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl can be unsubstituted or substituted by one or more substituents; or
Y is bonded to Z and X, and X is arylene or heteroarylene;
or a pharmaceutically acceptable salt thereof.Join the waitlist — get patent alerts
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