Oxime and hydroxylamine substituted thiazolo[4,5-
View Patent ↗Thiazolo[4,5-c]ring compounds, (e.g. thiazolopyridine, thiazoloquinoline, 6,7,8,9-tetrahydrothiazoloquinoline, thiazolonaphthyridine, and 6,7,8,9-tetrahydrothiazolonaphthyridine compounds) having an oxime or hydroxylamine substituent at the 2-position, pharmaceutical compositions containing the compounds, intermediates, and methods of making and methods of use of these compounds as immunomodulators, for modulating cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.
1. A compound of Formula I:
wherein:
Z is selected from the group consisting of:
—O—N═C(R 2-2 )—,
—C(═N—O—R 2-3 )—,
—O—N(R 2-4 )—Y—, and
—C(R 2-6 )(—N(—OR 2-3 )—Y—R 2-5 )—;
X is selected from the group consisting of C 1-4 alkylene and C 3-4 alkenylene; with the proviso that X can also be a bond when Z is —C(═N—O—R 2-3 )— or —C(R 2-6 )(—N(—OR 2-3 )—Y—R 2-5 )—;
R 2-1 , R 2-2 , R 2-3 , R 2-4 , and R 2-5 are independently selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
—S(O) 0-2 —R 2-7 ,
—NH—S(O) 2 —R 2-7 ,
haloalkoxy,
halogen,
cyano,
nitro,
—N 3 ,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
—C(O)—O-alkyl,
—C(O)—N(R 8 ) 2 ,
—N(R 8 )—C(O)—R 2-7 ,
—NH—C(O)—NH—R 2-7 ,
—NH—C(O)—NH 2 ,
—O—(CO)-alkyl, and
—C(O)-alkyl;
with the proviso that R 2-3 is other than alkenyl wherein the carbon atom bonded to —O— is doubly bonded to another carbon atom;
or R 2-1 and R 2-2 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 2-1 and R 2-4 together with the Y group and the nitrogen atom to which they are bonded can join to form a ring selected from the group consisting of:
R 2-6 is selected from the group consisting of hydrogen, C 1-4 alkyl, and phenyl;
R 2-7 is selected from the group consisting of alkyl, aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, alkoxy, dialkylamino, alkylthio, haloalkyl, haloalkoxy, alkyl, and —N 3 ;
Y is selected from the group consisting of:
a bond,
—C(R 6 )—,
—S(O) 2 —,
—S(O) 2 —N(R 8 )—,
—C(O)—O—,
—C(R 6 )—N(R 8 )—, and
R A and R B are each independently selected from the group consisting of:
hydrogen,
alkyl,
alkoxy;
or when taken together, R A and R B form a fused benzene ring wherein the fused benzene ring is unsubstituted or substituted by one or more R″′ groups;
or when taken together, R A and R B form a fused cyclohexene ring, wherein the fused cyclohexene 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 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 6 is ═O;
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, hydroxy-C 1-10 alkylenyl, heteroaryl-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 c and R d are independently selected from the group consisting of hydrogen; 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;
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 )—, —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(R 6 )—O—, and —C(R 6 )—N(OR 9 )—;
W is selected from the group consisting of a bond, —C(O)—, and —S(O) 2 —; and
wherein the one or more R″′ groups are one R 3 group, or one R 3 group and one R group, or one, two, three, or four R groups when on the fused benzene ring; wherein R 3 is selected from the group consisting of:
—Z′—R 4 ,
—Z′—X′—R 4 ,
—Z′—X′—Y′—R 4 , and
X′ is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
—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 )—
—O—N(R 8 )-Q-,
—O—N═C(R 4 )—,
—C(═N—O—R 8 )—,
—CH(—N(—O—R 8 )-Q—R 4 )—,
Z′ is a bond or —O—;
R 5 is selected from the group consisting of:
A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, —CH 2 —, and —N(-Q-R 4 )—;
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 ; 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 Formula II:
wherein:
Z is selected from the group consisting of:
—O—N═C(R 2-2 )—,
—C(═N—O—R 2-3 )—,
—O—N(R 2-4 )—Y—, and
—C(R 2-6 )(—N(—OR 2-3 )—Y—R 2-5 )—;
X is selected from the group consisting of C 1-4 alkylene and C 3-4 alkenylene; with the proviso that X can also be a bond when Z is —C(═N—O—R 2-3 )— or —C(R 2-6 )(—N(—OR 2-3 )—Y—R 2-5 )—;
R 2-1 , R 2-2 , R 2-3 , R 2-4 , and R 2-5 are independently selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
arylalkylenyl,
heteroaryl,
heteroarylalkylenyl,
heterocyclyl,
heterocyclylalkylenyl, and
alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, or heterocyclylalkylenyl, substituted by one or more substituents selected from the group consisting of:
hydroxy,
alkyl,
haloalkyl,
hydroxyalkyl,
alkoxy,
dialkylamino,
—S(O) 0-2 —R 2-7 ,
—NH—S(O) 2 —R 2-7 ,
haloalkoxy,
halogen,
cyano,
nitro,
—N 3 ,
heterocyclyl,
aryloxy,
arylalkyleneoxy,
—C(O)—O-alkyl,
—C(O)—N(R 8 ) 2 ,
—N(R 8 )—C(O)—R 2-7 ,
—NH—C(O)—NH—R 2-7 ,
—NH—C(O)—NH 2 ,
—O—(CO)-alkyl, and
—C(O)-alkyl;
with the proviso that R 2-3 is other than alkenyl wherein the carbon atom bonded to —O— is doubly bonded to another carbon atom;
or R 2-1 and R 2-2 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 2-1 and R 2-4 together with the Y group and the nitrogen atom to which they are bonded can join to form a ring selected from the group consisting of:
R 2-6 is selected from the group consisting of hydrogen, C 1-4 alkyl, and phenyl;
R 2-7 is selected from the group consisting of alkyl, aryl, arylalkylenyl, heteroaryl, and heteroarylalkylenyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, cyano, nitro, alkoxy, dialkylamino, alkylthio, haloalkyl, haloalkoxy, alkyl, and —N 3 ;
Y is selected from the group consisting of a bond, —C(R 6 )—, —S(O) 2 —, —S(O) 2 —N(R 8 )—,
—C(O)—O—, —C(R 6 )—N(R 8 )—, and
;
R is selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio, and
—N(R 9 ) 2 ;
R 3 is selected from the group consisting of:
—Z′—R 4 ,
—Z′—X′—R 4 ,
—Z′—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;
X′ is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene, wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated by arylene, heteroarylene or heterocyclylene and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of —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 )—, —O—N(R 8 )-Q-, —O—N═C(R 4 )—, —C(═N—O—R 8 )—, —CH(—N(—O—R 8 )-Q-R 4 )—,
Z′ is a bond or —O—;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl, wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, 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 ═O;
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, hydroxy-C 1-10 alkylenyl, heteroaryl-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 c and R d are independently selected from the group consisting of hydrogen; 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;
A is selected from the group consisting of —O—, —C(O)—, —S(O) 0-2 —, —CH 2 —, and —N(-Q-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 )—, —S(O) 2 —, —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.
3. The compound or salt of claim 1 wherein R is halogen or hydroxy.
4. The compound or salt of claim 2 wherein n is 0.
5. The compound or salt of claim 2 wherein R 3 is selected from the group consisting of phenyl, pyridin-3-yl, pyridin-4-yl, 5-(hydroxymethyl)pyridin-3-yl, 2-ethoxyphenyl, 3-(morpholine-4-carbonyl)phenyl, and 3-(N,N-dimethylaminocarbonyl)phenyl.
6. The compound or salt of claim 2 wherein m is 0.
7. The compound or salt of claim 1 wherein Z is —O—N═C(R 2-2 )—.
8. The compound or salt of claim 7 wherein R 2-1 and R 2-2 join together to form a ring system selected from the group consisting of
wherein Q is a bond or —C(O)—, and R 4 is alkyl.
9. The compound or salt of claim 7 wherein at least one of R 2-1 or R 2-2 is selected from the group consisting of alkyl, alkenyl, aryl, arylalkylenyl, heteroaryl, heteroarylalkylenyl, heterocyclyl, and heterocyclylalkylenyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, dialkylamino, —S(O) 0-2 —R 2-7 , —NH—S(O) 2 —R 2-7 , haloalkoxy, halogen, cyano, nitro, heterocyclyl, aryloxy, arylalkyleneoxy, —C(O)—O-alkyl, —C(O)—N(R 8 ) 2 , —N(R 8 )—C(O)—R 2-7 , —N(H)—C(O)—NH—R 2-7 , —O—(CO)-alkyl, and —C(O)-alkyl.
10. The compound or salt of claim 9 wherein at least one of R 2-1 or R 2-2 is selected from the group consisting of alkyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl, each of which is unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, halogen, cyano, and —C(O)—O-alkyl.
11. The compound or salt of claim 10 wherein R 2-1 and R 2-2 are independently C 1-10 alkyl.
12. The compound or salt of claim 11 wherein R 2-1 and R 2-2 are each methyl.
13. The compound or salt of claim 7 wherein one of R 2-1 or R 2-2 is hydrogen.
14. The compound or salt of claim 1 wherein Z is —O—N(R 2-4 )—Y—.
15. The compound or salt of claim 14 wherein R 2-4 is hydrogen.
16. The compound or salt of claim 14 wherein Y is selected from the group consisting of —C(O)—, —S(O) 2 —, —S(O) 2 —N(R 8 )—, —C(O)—O—, and —C(O)—N(R 8 )—.
17. The compound or salt of claim 14 wherein R 2-1 is selected from the group consisting of alkyl, aryl, arylalkylenyl, heteroaryl, and heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, and halogen.
18. The compound or salt of claim 1 wherein Z is —C(═N—O—R 2-3 )—.
19. The compound or salt of claim 18 wherein R 2-3 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, and heteroarylalkylenyl.
20. The compound or salt of claim 19 wherein R 2-3 is hydrogen, C 1-4 alkyl, benzyl, or pyridin-2-ylmethyl.
21. The compound or salt of claim 1 wherein Z is —C(R 2-6 )(—N(—OR 2-3 )—Y—R 2-5 )—.
22. The compound or salt of claim 21 wherein R 2-6 is hydrogen.
23. The compound or salt of claim 21 wherein R 2-3 is selected from the group consisting of hydrogen, alkyl, arylalkylenyl, and heteroarylalkylenyl.
24. The compound or salt of claim 23 wherein R 2-3 is hydrogen, C 1-4 alkyl, benzyl, or pyridin-2-ylmethyl.
25. The compound or salt of claim 21 wherein R 2-5 is hydrogen or methyl, and Y is a bond.
26. The compound or salt of claim 18 wherein R 2-1 is selected from the group consisting of hydrogen, alkyl, and aryl.
27. The compound or salt of claim 26 wherein R 2-1 is hydrogen, C 1-4 alkyl, or phenyl.
28. The compound or salt of claim 1 wherein X is C 1-4 alkylene.
29. The compound or salt of claim 28 wherein X is methylene.
30. The compound or salt of claim 18 wherein X is a bond.
31. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
32. A method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or salt of claim 1 to the animal.