1-Amino 1H-imidazoquinolines
View Patent ↗1-Amino 1H-imidazoquinoline compounds, 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 the Formula (I-1):
wherein:
R 1 ′ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 ′ is bonded;
R 1 is selected from the group consisting of:
—R 4 ,
—Y—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X—C(R 7 )—N(R 6 )—R 4 ,
—X—S(O) 2 —N(R 6 )—R 4 , and
—X—O—R 4 ;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
heteroaryl,
heterocyclyl,
-alkylene-Z-alkyl,
-alkylene-Z-aryl,
-alkylene-Z-alkenyl, and
alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—C(R 7 )-aryl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—N(R 6 )—S(O) 2 -aryl,
—C(O)—C 1-10 alkyl,
—O—C(R 7 )—C 1-10 alkyl,
—O—C(R 7 )-aryl,
—O—C(R 7 )—N(R 6 )—C 1-10 alkyl,
—O—C(R 7 )—N(R 6 )-aryl;
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl;
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 ′,
each R is independently selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino;
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, 1, or 2;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaxyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclyalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the nitrogen atom to which R 1 is bonded;
R 5 is selected from the group consisting of:
X is C 2-20 alkylene;
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 —N(R 6 )—, and —C(R 7 )—N(R 9 )—; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
Z is selected from the group consisting of —O— and —S(O) 0-2 —;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
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, heteroaryalkylenyl, 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:
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 azylene, heteroarylene, or heterocyclylene and optionally interrupted by one or more —O— groups;
Y′ is selected from the group consisting of:
Z′ is a bond or —O—;
A′ is selected from the group consisting of CH 2 —, —O—, —C(O)—, —S(O) 0-2 —, and —N(R 4 ′)—;
Q is selected from the group consisting of a bond, —C(R 7 )—, —C(R 7 )—C(R 7 )—, —S(O) 2 —, —C(R 7 —N(R 11 )—W—, —S(O) 2 —N(R 11 )—, —C(R 7 )—O—, and —C(R 7 )—N(OR 12 )—;
V is selected from the group consisting of —C(R 7 )—, —O—C(R 7 )—, —N(R 11 )—C(R 7 )—, and —S(O) 2 ;
W is selected from the group consisting of a bond, —C(O)—, and S(O) 2 —;
c and d are independently integers from 1 to 6 with the proviso that c+d is ≦7, and when A′ is —O— or —N(R 4 ′)— then c and d are independently integers from 2 to 4;
each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R 7 is independently selected from the group consisting of ═O and ═S;
each R 8 is independently C 2-7 alkylene;
R 10 is C 3-8 alkylene;
each R 11 is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 alkoxy C 2-10 alkylenyl, and arylC 1-10 alkylenyl; and
R 12 is selected from the group consisting of hydrogen and alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of —R 4 , —Y—R 4 , —X—R 5 , —X—N(R 6 )—Y—R 4 , —X—C(R 7 )—N(R 6 )—R 4 , and —X—O—R 4 ; R 1 ′ is selected from the group consisting of hydrogen and alkyl; and R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl.
3. The compound or salt of claim 1 wherein R 1 is selected from the group consisting of —R 4 , —Y—R 4 , and —X—N(R 6 )—Y—R 4 wherein Y is —C(R 7 )—, —S(O) 2 —, or —C(R 7 )—N(R 9 )—.
4. The compound or salt of claim 3 wherein R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, alkylaminocarbonyl, alkylaminocarbonylaminoalkylenyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl, arylaminocarbonylaminoalkylenyl, heteroarylcarbonylaminoalkylenyl, and heteroarylaminocarbonylaminoalkylenyl.
5. The compound or salt of claim 4 wherein R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and —CH 2 CH 2 CH 2 —NHR 13 , wherein R 13 is selected from the group consisting of methylcarbonyl, isopropylcarbonyl, cyclopentylcarbonyl, tetrahydropyran-4-ylcarbonyl, methanesulfonyl, phenylsulfonyl, benzyl, ethylaminocarbonyl, isopropylaminocarbonyl, morpholine-4-carbonyl, phenylaminocarbonyl, pyridin-3-ylcarbonyl, and pyridin-3-ylaminocarbonyl.
6. The compound or salt of claim 1 wherein R 1 ′ is hydrogen.
7. The compound or salt of claim 1 wherein R 1 and R 1 ′ are each independently alkyl.
8. The compound or salt of claim 1 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
9. The compound or salt of claim 8 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, 2-methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
10. The compound or salt of claim 1 wherein n is 0.
11. The compound or salt of claim 1 wherein n is 0, and R 3 is selected from the group consisting of -Z′-R 4 ′, -Z′-X—R 4 ′, and -Z′-X—Y′—R 4 ′.
12. The compound or salt of claim 11 wherein R 3 is selected from the group consisting of 2-(pyridin-3-yl)ethyl, pyridinyl, (hydroxymethyl)pyridinyl, phenyl, (hydroxymethyl)phenyl, ethoxyphenyl, (morpholine-4-carbonyl)phenyl, 3-(methanesulfonylamino)phenyl, 2-(methanesulfonylamino)ethoxy, 3-(methanesulfonylamino)propoxy, and benzyloxy.
13. The compound or salt of claim 1 wherein m is 0 and n is 1.
14. The compound or salt of claim 13 wherein R is halogen or hydroxy.
15. The compound or salt of claim 1 wherein m and n are each 0.
16. A compound of the Formula (I-2):
wherein:
R B is selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, and trifluoromethyl;
n is an integer from 0 to 4;
R 1 ′ is selected from the group consisting of hydrogen and alkyl;
R 1 is selected from the group consisting of:
—R 4 ,
—Y—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X—C(R 7 )—N(R 6 )—R 4 , and
—X—O—R 4 ;
or R 1 ′ and R 1 together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
R 2 is selected from the group consisting of:
-hydrogen,
-alkyl,
-alkenyl,
-aryl,
-heteroaryl,
-heterocyclyl,
-alkylene-Z-alkyl,
-alkylene-Z-aryl,
-alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
-halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
-aryl,
-heteroaryl,
-heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the nitrogen atom to which R 1 is bonded;
R 5 is selected from the group consisting of:
each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R 7 is independently selected from the group consisting of ═O and ═S;
R 8 is C 2-7 alkylene;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
X is C 2-20 alkylene;
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 —N(R 6 )—, and —C(R 7 )—N(R 9 )—; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
Z is selected from the group consisting of —O— and —S(O) 0-2 —; and
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
or a pharmaceutically acceptable salt thereof.
17. The compound or salt according to claim 16 wherein R 1 is selected from the group consisting of —R 4 , —Y—R 4 , and —X—N(R 6 )—Y—R 4 wherein Y is —C(R 7 )—, —S(O) 2 —, or —C(R 7 )—N(R 9 )—.
18. The compound or salt according to claim 17 wherein R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylaminocarbonyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, and arylaminocarbonylaminoalkylenyl.
19. The compound or salt according to claim 18 wherein R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, cinnamyl, furan-2-ylmethyl, and —CH 2 CH 2 CH 2 —NHR 13 , wherein R 13 is selected from the group consisting of methanesulfonyl, phenylsulfonyl, benzyl, and phenylaminocarbonyl.
20. The compound or salt according to claim 16 wherein R 1 ′ is hydrogen.
21. The compound or salt of claim 16 wherein R 1 and R 1 ′ are each independently alkyl.
22. The compound or salt of claim 16 wherein R 1 and R 1 ′ join to form the group:
23. The compound or salt according to claim 16 wherein R 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.
24. The compound or salt according to claim 23 wherein R 2 is selected from the group consisting of hydrogen, butyl, 2-methoxyethyl, and ethoxymethyl.
25. The compound or salt according to claim 16 wherein n is 0.
26. The compound or salt according to claim 16 wherein n is 1, and R B is halogen or hydroxy.
27. A compound of the Formula (I-3):
wherein:
R B is selected from alkyl, alkoxy, halogen, hydroxy, and trifluoromethyl;
n is an integer from 0 to 4;
R 1 ′ is selected from hydrogen and alkyl;
R 1 is selected from:
—R 4 ,
—Y—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X—CR 7 —N(R 6 )—R 4 , and
—X—O—R 4 ;
or R 1 ′ and R 1 together with the nitrogen atom to which they are bonded can join to form a group selected from:
R 2A is selected from:
-hydrogen,
-alkyl,
-alkenyl,
-aryl,
-heteroaryl,
-alkylene-Z-alkyl,
-alkylene-Z-aryl,
-alkylene-Z-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected from:
—OH,
-halogen,
—N(R 6 ) 2 ,
—CR 7 —N(R 6 ) 2 ,
—SO 2 —N(R 2 ) 2 ,
—N(R 6 )—CR 7 —C 1-10 alkyl,
—N(R 6 )—SO 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
-aryl,
-heteroaryl,
-heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl;
R 4 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the nitrogen atom to which R 1 is bonded;
R 5 is selected from:
R 6 is selected from hydrogen, alkyl, and arylalkylenyl;
R 7 is selected from ═O and ═S;
R 8 is C 2-7 alkylene;
R 9 is selected from hydrogen, alkyl, and arylalkylenyl, or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
A is selected from —CHR 6 —, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
X is C 2-20 alkylene;
Y is selected from —CR 7 —, —SO 2 —, —SO 2 —N(R 6 )—, and —CR 7 —N(R 9 )—;
Z is selected from —O— and —S(O) 0-2 —;
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
and pharmaceutically acceptable salts thereof.
28. The compound or salt according to claim 27 wherein R 1 is selected from —R 4 , —Y—R 4 , and —X—N(R 6 )—Y—R 4 wherein Y is —CR 7 —, —SO 2 —, or —CR 7 —N(R 9 )—.
29. The compound or salt according to claim 28 wherein R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylaminocarbonyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, and arylaminocarbonylaminoalkylenyl.
30. The compound or salt according to claim 29 wherein R 1 is selected from hydrogen, isopropyl, butyl, cyclohexyl, benzyl, cinnamyl, and —CH 2 CH 2 CH 2 —NHR 13 , wherein R 13 is selected from methanesulfonyl, phenylsulfonyl, benzyl, and phenylaminocarbonyl.
31. The compound or salt according to claim 27 wherein R 1 ′ is hydrogen.
32. The compound or salt according to claim 27 wherein R 2A is selected from hydrogen, alkyl, and alkoxyalkylenyl.
33. The compound or salt according to claim 32 wherein R 2A is selected from hydrogen, butyl, methoxyethyl, and ethoxymethyl.
34. The compound or salt according to claim 27 wherein n is 0.
35. A compound of the Formula (II-1):
wherein:
each R A is independently selected from the group consisting of:
halogen,
hydroxy,
alkyl,
alkenyl,
haloalkyl,
alkoxy,
alkylthio,
—NH 2 ,
—NH(alkyl), and
—N(alkyl) 2 ;
n is an integer from 0 to 4;
R 1 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 ′ is bonded;
R 1 is selected from the group consisting of:
—R 4 ,
—Y—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X—C(R 7 )—N(R 6 )—R 4 ,
—X—S(O) 2 —N(R 6 )—R 4 , and
—X—O—R 4 ;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
heteroaryl,
heterocyclyl,
-alkylene-Z-alkyl,
-alkylene-Z-aryl,
-alkylene-Z-alkenyl, and
alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—C(R 7 )-aryl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—N(R 6 )—S(O) 2 -aryl,
—C(O)—C 1-10 alkyl,
—O—C(R 7 )—C 1-10 alkyl,
—O—C(R 7 )-aryl,
—O—C(R 7 )—N(R 6 )—C 1-10 alkyl,
—O—C(R 7 )—N(R 6 )-aryl;
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaxyl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkykmino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the nitrogen atom to which R 1 is bonded;
R 5 is selected from the group consisting of:
each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R 7 is independently selected from the group consisting of ═O and ═S;
R 8 is C 2-7 alkylene;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
X is C 2-20 alkylene;
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 —N(R 6 )—, and —C(R 7 )—N(R 9 )—; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
Z is selected from the group consisting of —O— and —S(O) 0-2 —; and
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 — then a and b are independently integers from 2 to 4;
or a pharmaceutically acceptable salt thereof.
36. The compound or salt of claim 35 wherein R 1 is selected from the group consisting of —R 4 , —Y—R 4 , —X—R 5 , —X—N(R 6 )—Y—R 4 , —X—C(R 7 )—N(R 6 )—R 4 , and —X—O—R 4 ; R 1 ′ is selected from the group consisting of hydrogen and alkyl; and R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl.
37. The compound or salt according to claim 36 wherein R 1 is selected from the group consisting of —R 4 , —Y—R 4 , and —X—N(R 6 )—Y—R 4 wherein Y is —C(R 7 )—, —S(O) 2 —, or —C(R 7 )—N(R 9 )—.
38. The compound or salt according to claim 37 wherein R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylaminocarbonyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, and arylaminocarbonylaminoalkylenyl.
39. The compound or salt according to claim 38 wherein R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, cinnamyl, furan-2-ylmethyl, and —CH 2 CH 2 CH 2 —NHR 13 , wherein R 13 is selected from the group consisting of methanesulfonyl, phenylsulfonyl, benzyl, and phenylaminocarbonyl.
40. The compound or salt according to claim 37 wherein R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylaminocarbonyl, alkylaminocarbonylaminoalkylenyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl, and arylaminocarbonylaminoalkylenyl.
41. The compound or salt according to claim 40 wherein R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and —CH 2 CH 2 CH 2 —NHR 13 , wherein R 13 is selected from the group consisting of methanesulfonyl, phenylsulfonyl, benzyl, isopropylaminocarbonyl, morpholine-4-carbonyl, and phenylaminocarbonyl.
42. The compound or salt of claim 37 wherein R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkylenyl, arylalkenylenyl, heteroarylalkylenyl, heteroarylalkenylenyl, aminoalkylenyl, alkoxyalkylenyl, acyl, alkylsulfonylaminoalkylenyl, arylsulfonylaminoalkylenyl, alkylcarbonylaminoalkylenyl, alkylaminocarbonyl, alkylaminocarbonylaminoalkylenyl, arylaminocarbonyl, (arylalkylenyl)aminoalkylenyl, heterocyclylcarbonylaminoalkylenyl, arylaminocarbonylaminoalkylenyl, heteroarylcarbonylaminoalkylenyl, and heteroarylaminocarbonylaminoalkylenyl.
43. The compound or salt of claim 42 wherein R 1 is selected from the group consisting of hydrogen, methyl, isopropyl, butyl, 2-methylpropyl, 1-ethylpropyl, 3-methylbutyl, cyclohexyl, benzyl, 3-phenylpropyl, cinnamyl, furan-2-ylmethyl, and —CH 2 CH 2 CH 2 —NHR 13 , wherein R 13 is selected from the group consisting of methylcarbonyl, isopropylcarbonyl, cyclopentylcarbonyl, tetrahydropyran-4-ylcarbonyl, methanesulfonyl, phenylsulfonyl, benzyl, ethylaminocarbonyl, isopropylaminocarbonyl, morpholine-4-carbonyl, phenylaminocarbonyl, pyridin-3-ylcarbonyl, and pyridin-3-ylaminocarbonyl.
44. The compound or salt according to claim 36 wherein R 1 ′ is hydrogen.
45. The compound or salt of claim 36 wherein R 1 and R 1 ′ are each independently alkyl.
46. The compound or salt according to claim 36 wherein R 2 is selected from the group consisting of hydrogen, alkyl, and alkoxyalkylenyl.
47. The compound or salt according to claim 46 wherein R 2 is selected from the group consisting of hydrogen, butyl, 2-methoxyethyl, and ethoxymethyl.
48. The compound or salt according to claim 46 wherein R 2 is selected from the group consisting of hydrogen, methyl, propyl, butyl, 2-methoxyethyl, and ethoxymethyl.
49. The compound or salt of claim 35 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl.
50. The compound or salt of claim 49 wherein R 2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, n-butyl, methoxymethyl, 2-methoxyethyl, ethoxymethyl, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl.
51. The compound or salt according to claim 36 wherein n is 0.
52. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
53. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 16 and a pharmaceutically acceptable carrier.
54. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 27 and a pharmaceutically acceptable carrier.
55. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 35 and a pharmaceutically acceptable carrier.
56. A compound of the Formula (X):
wherein:
each R B is independently selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, and trifluoromethyl;
n is an integer from 0 to 4;
R 1 ′ is hydrogen or alkyl;
R 1a is selected from the group consisting of:
R 4a ,
—Y—R 4a ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4a ,
—X—C(R 7 )—N(R 6 )—R 4a , and
—X—O—R 4a ;
or R 1 ′ and R 1a together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
R 2a is selected from the group consisting of:
-hydrogen,
-alkyl,
-alkenyl,
-aryl,
-alkylene-Z″-alkyl,
-alkylene-Z″-aryl,
-alkylene-Z″-alkenyl, and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
-halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
-aryl,
-heterocyclyl, and
—C(O)-aryl;
R 4a is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4a is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the nitrogen atom to which R 1 is bonded;
R 5 is selected from the group consisting of
each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R 7 is independently selected from the group consisting of ═O and ═S;
R 8 is C 2-7 alkylene;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
X is C 2-20 alkylene;
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 —N(R 6 )—, and —C(R 7 )—N(R 9 )—; wherein R 9 is selected from the group consisting of hydrogen, alkyl and arylalkylenyl, or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
Z″ is selected from the group consisting of —O— and —S(O) 2 —; and
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
or a pharmaceutically acceptable salt thereof.
57. A compound of the Formula XLII:
wherein:
R is selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino;
1 is 0, 1, or 2;
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
heteroaryl,
heterocyclyl,
-alkylene-Z-alkyl,
-alkylene-Z-aryl,
-alkylene-Z-alkenyl, and
alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—C(R 7 )-aryl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—N(R 6 )—S(O) 2 -aryl,
—C(O)—C 1-10 alkyl,
—O—C(R 7 )—C 1-10 alkyl,
—O—C(R 7 )-aryl,
—O—C(R 7 )—N(R 6 )—C 1-10 alkyl,
—O—C(R 7 )—N(R 6 )-aryl;
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl;
each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
R 7 is selected from the group consisting of ═O and ═S; and
Z is selected from the group consisting of —O— and —S(O) 0-2 —;
or a pharmaceutically acceptable salt thereof.
58. The compound or salt of claim 57 wherein R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl.
59. A compound of the Formula XLIII:
wherein:
R is selected from the group consisting of alkyl, alkenyl, alkoxy, halogen, fluoroalkyl, hydroxy, amino, alkylamino, and dialkylamino;
1 is 0, 1, or 2;
R 1 ′ is selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl wherein the alkylenyl group contains at least two carbon atoms between the hydroxy or alkoxy substituent and the nitrogen atom to which R 1 ′ is bonded;
R 1 is selected from the group consisting of:
—R 4 ,
—Y—R 4 ,
—X—R 5 ,
—X—N(R 6 )—Y—R 4 ,
—X—C(R 7 )—N(R 6 )—R 4 ,
—X—O—C(R 7 )—N(R 6 )—R 4 ,
—X—S(O) 2 —N(R 6 )—R 4 , and
—X—O—R 4 ;
or R 1 ′ and R 1 together with the nitrogen atom to which they are bonded can join to form a group selected from the group consisting of:
R 2 is selected from the group consisting of:
hydrogen,
alkyl,
alkenyl,
aryl,
heteroaryl,
heterocyclyl,
-alkylene-Z-alkyl,
-alkylene-Z-aryl,
-alkylene-Z-alkenyl, and
alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—C(R 7 )-aryl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—N(R 6 )—S(O) 2 -aryl,
—C(O)—C 1-10 alkyl,
—O—C(R 7 )—C 1-10 alkyl,
—O—C(R 7 )-aryl,
—O—C(R 7 )—N(R 6 )—C 1-10 alkyl,
—O—C(R 7 )—N(R 6 )-aryl;
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl;
R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkylenyl, amino, alkylamino, (arylalkylenyl)amino, dialkylamino, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo, with the proviso that when R 4 is a substituted alkyl group and the substituent contains a hetero atom which bonds directly to the alkyl group then the alkyl group contains at least two carbons between the substituent and the nitrogen atom to which R 1 is bonded;
R 5 is selected from the group consisting of
each R 6 is independently selected from the group consisting of hydrogen, alkyl, and arylalkylenyl;
each R 7 is independently selected from the group consisting of ═O and ═S;
R 8 is C 2-7 alkylene;
A is selected from the group consisting of —CH(R 6 )—, —O—, —N(R 6 )—, —N(Y—R 4 )—, and —N(X—N(R 6 )—Y—R 4 )—;
X is C 2-20 alkylene;
Y is selected from the group consisting of —C(R 7 )—, —C(R 7 )—O—, —S(O) 2 —, —S(O) 2 —N(R 6 )—, and —C(R 7 )—N(R 9 )—; wherein R 9 is selected from the group consisting of hydrogen, alkyl, and arylalkylenyl; or R 9 and R 4 together with the nitrogen atom to which R 9 is bonded can join to form the group
Z is selected from the group consisting of —O— and —S(O) 0-2 —; and
a and b are independently integers from 1 to 4 with the proviso that when A is —O—, —N(R 6 )—, —N(Y—R 4 )—, or —N(X—N(R 6 )—Y—R 4 )— then a and b are independently integers from 2 to 4;
or a pharmaceutically acceptable salt thereof.
60. The compound or salt of claim 59 wherein R 1 is selected from the group consisting of —R 4 , —Y—R 4 , —X—R 5 , —X—N(R 6 )—Y—R 4 , —X—C(R 7 )—N(R 6 )—R 4 , and —X—O—R 4 ; R 1 ′ is selected from the group consisting of hydrogen and alkyl; and R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, -alkylene-Z-alkyl, -alkylene-Z-aryl, -alkylene-Z-alkenyl, and alkyl or alkenyl substituted by one or more substituents selected from the group consisting of:
—OH,
halogen,
—N(R 6 ) 2 ,
—C(R 7 )—N(R 6 ) 2 ,
—S(O) 2 —N(R 6 ) 2 ,
—N(R 6 )—C(R 7 )—C 1-10 alkyl,
—N(R 6 )—S(O) 2 —C 1-10 alkyl,
—C(O)—C 1-10 alkyl,
—C(O)—O—C 1-10 alkyl,
—N 3 ,
aryl,
heteroaryl,
heterocyclyl,
—C(O)-aryl, and
—C(O)-heteroaryl.