Novel bicyclic heterocyclic compounds, process for their preparation and compositions containing them
The present invention provides, among other things, new bicyclo heterocyclic compounds, compositions comprising these heterocyclic compounds, methods of making the heterocyclic compounds, and methods of using these heterocyclic compounds for treating a variety of conditions and disease states associated with, for example, cellular proliferation, inflammation, glycosidase expression, or the low expression of Perlecan.
1 . A compound having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
wherein when Y 1 is >NR 5 , NR 5 R 1 is a 5-, 6-, or 7-membered heterocyclic ring, which optionally comprises one or two additional heteroatoms selected from >O, >S or >N—, in which NR 5 R 1 is optionally substituted with one, two, or three substituents selected independently from an alkyl, an alkoxy, or a haloalkyl, any of which having up to 10 carbon atoms, or hydroxyl, halogen, or cyano;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 2 is a substituted or an unsubstituted alkyl, haloalkyl, aryl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 5 is a substituted or an unsubstituted alkyl having up to 12 carbon atoms, or hydrogen;
any of R 1 , R 2 , R 3 , R 4 , and R 5 is optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , —CO 2 R 6 , —COR 8 , —CONR 6 R 7 , —SO 2 R 8 and —SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
2 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 5 is a substituted or an unsubstituted alkyl having up to 12 carbon atoms, or hydrogen;
R 9 , in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, SO 2 R 8 , SO 2 NR 6 R 7 , CO 2 R 6 , COR 8 , or CONR 6 R 7 , any of which having up to 10 carbon atoms; or 2) halogen;
m is an integer from 0 to 3, inclusive;
any of R 1 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , —CO 2 R 6 , —COR 8 , —CONR 6 R 7 , —SO 2 R 8 and —SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
3 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 9 and R 10 , in each occurrence, are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen or cyano;
m and n are selected independently from an integer from 0 to 3, inclusive;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen;
R 8 is an alkyl or aryl having up to 10 carbon atoms;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms; and
any of R 3 and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, or a cycloalkyl, any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl.
4 . A compound according to Claim 3 , wherein the compound is:
(3-Chloro-4-methoxy-phenyl)-[5-(3,4-dimethoxy-phenyl)-1-methyl-3-
propyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(3-Chloro-4-methoxy-phenyl)-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(3-Fluoro-4-methoxy-phenyl)-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(3-Fluoro-4-methoxy-phenyl)-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo
[4,3-d]pyrimidin-7-yl]-amine;
(4-Fluoro-phenyl)-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(3,4-Dimethoxy-phenyl)-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
2-Chloro-4-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino)-phenol hydrochloride;
(3-Chloro-4-methoxy-phenyl)-(1-methyl-5-phenyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
(3-Chloro-4-methoxy-phenyl)-(1-methyl-5-phenyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine;
(3-Fluoro-4-methoxy-phenyl)-(1-methyl-5-phenyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
2-Chloro-4-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-ylamino]-phenol hydrochloride;
3-[7-(3-Chloro-4-methoxy-phenylamino)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-5-yl]-4-ethoxy-
benzenesulfonamide hydrochloride;
4-Ethoxy-3-[7-(3-fluoro-4-methoxy-phenylamino)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-5-yl]-benzenesulfonamide hydrochloride;
(3-Chloro-4-methoxy-phenyl)-[5-(2-ethoxy-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
[5-(2-Ethoxy-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7-
yl]-(3-fluoro-4-methoxy-phenyl)-amine hydrochloride;
(3-Fluoro-4-methoxy-phenyl)-[5-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(3-Chloro-4-methoxy-phenyl)-[5-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
2-Chloro-4-[5-(4-fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-
d]pyrimidin-7-ylamino]-phenol hydrochloride;
(4-Chloro-3-methoxy-phenyl)-(1-methyl-5-phenyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
(4-Chloro-3-methoxy-phenyl)-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(3-Chloro-4-methoxy-phenyl)-(1,3-dimethyl-5-phenyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl)-amine hydrochloride;
(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(3-fluoro-4-
methoxy-phenyl)-amine hydrochloride;
(4-Chloro-3-methoxy-phenyl)-(1,3-dimethyl-5-phenyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl)-amine hydrochloride;
2-Fluoro-4-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-ylamino]-phenol hydrochloride;
Benzo[1,3]dioxol-5-yl-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(3-fluoro-
phenyl)-amine hydrochloride;
[5-(4-Fluoro-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-
7-yl]-(3-trifluoromethyl-phenyl)-amine hydrochloride;
[5-(4-Fluoro-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-
7-yl]-(4-trifluoromethoxy-phenyl)-amine hydrochloride;
(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(4-
trifluoromethoxy-phenyl)-amine hydrochloride;
[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-(4-
rifluoromethyl-phenyl)-amine hydrochloride;
(6-Chloro-pyridin-3-yl)-[5-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl]-amine hydrochloride;
N-{5-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-2-hydroxy-phenyl}-acetamide hydrochloride;
[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl]-(4-
methanesulfonyl-phenyl)-amine;
(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(2-methyl-
benzooxazol-5-yl)-amine hydrochloride;
N-[4-(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)-
phenyl]-methanesulfonamide hydrochloride;
4-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-N,N-dimethyl-benzenesulfonamide hydrochloride;
4-(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-ylamino)-
benzenesulfonamide hydrochloride;
3-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-benzamide hydrochloride;
3-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-N-methyl-benzamide hydrochloride;
4-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-benzenesulfonamide hydrochloride;
4-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-N-methyl-benzenesulfonamide hydrochloride;
4-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-benzamide hydrochloride;
4-[5-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino]-N-methyl-benzamide hydrochloride; or
any combination thereof.
5 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 1 is a substituted or an unsubstituted aryl, or a substituted or an unsubstituted heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 9 , in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, SO 2 R 8 , SO 2 NR 6 R 7 , NR 6 R 7 , CO 2 R 6 , COR 8 , or CONR 6 R 7 , any of which having up to 10 carbon atoms; or 2) halogen;
m is an integer from 0 to 3, inclusive;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms; and
any of R 1 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, or a haloalkoxy, any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl.
6 . A compound according to claim 5 , wherein R 1 is an indole, a benzimidazole, a benzoxazole, a benzo[1,3]dioxole, or a pyridine.
7 . A compound according to claim 5 , where the compound is:
(1H-Benzoimidazol-5-yl)-(1,3-dimethyl-5-phenyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl)-amine hydrochloride;
(1,3-Dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(2-methyl-1H-
benzoimidazol-5-yl)-amine hydrochloride;
Benzo[1,3]dioxol-5-yl-[5-(4-fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl]-amine hydrochloride; or
any combination thereof.
8 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 9 and R 10 , in each occurrence, are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen or cyano;
m and n are selected independently from an integer from 0 to 3, inclusive;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen;
R 8 is an alkyl or aryl having up to 10 carbon atoms;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms; and
any of R 3 and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, or a cycloalkyl, any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl.
9 . A compound according to Claim 8 , where the compound is:
4-[5-(3,4-Dimethoxy-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl]-2-methyl-phenol;
2-Methyl-4-(1-methyl-5-phenyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-
7-yl)-phenol;
4-[5-(3-hydroxy,4-methoxy-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl]-2-methyl-phenol;
2-Chloro-4-[5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl]-phenol;
7-(4-Methoxy-3-methyl-phenyl)-1-methyl-5-phenyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidine;
5-(4-fluoro-phenyl)-1,3-dimethyl-7-phenyl-1H-pyrazolo[4,3-d]pyrimidine;
5-(4-Fluoro-phenyl)-1-methyl-3-propyl-7-p-tolyl-1H-pyrazolo[4,3-
d]pyrimidine;
7-(3-Fluoro-4-methoxy-phenyl)-1-methyl-5-phenyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidine;
5-(4-Fluoro-phenyl)-1-methyl-7-phenyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidine;
5-(4-Fluoro-phenyl)-1-methyl-7-(4-methylsulfanyl-phenyl)-3-propyl-1H-
pyrazolo[4,3-d]pyrimidine;
7-(3-Fluoro-4-methoxy-phenyl)-5-(4-fluoro-phenyl)-1-methyl-3-propyl-
1H-pyrazolo[4,3-d]pyrimidine;
5-(4-Fluoro-phenyl)-7-(4-methoxy-3-methyl-phenyl)-1-methyl-3-propyl-
1H-pyrazolo[4,3-d]pyrimidine;
5-(4-Fluoro-phenyl)-7-(4-methanesulfonyl-phenyl)-1-methyl-3-propyl-
1H-pyrazolo[4,3-d]pyrimidine;
7-(3-Methanesulfonyl-phenyl)-1,3-dimethyl-5-phenyl-1H-
pyrazolo[4,3-d]pyrimidine;
5-(4-Fluoro-phenyl)-7-(3-methanesulfonyl-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-d]Pyrimidine;
5-(4-Fluoro-phenyl)-1,3-dimethyl-7-(4-trifluoromethoxy-phenyl)-1H-
pyrazolo[4,3-d]pyrimidine; or
any combination thereof.
10 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 1 is a substituted or an unsubstituted heteroaryl, or a substituted or an unsubstituted heterocyclyl, comprising at least one heteroatom or heterogroup selected from —O—, >N—, —S—, >NR 6 , >CO, or >SO 2 , any of which having up to 10 carbon atoms;
R 9 , in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, SO 2 R 8 , SO 2 NR 6 R 7 , NR 6 R 7 , CO 2 R 6 , COR 8 , or CONR 6 R 7 , any of which having up to 10 carbon atoms; or 2) halogen;
m is an integer from 0 to 3, inclusive;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
any of R 1 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
11 . A compound according to claim 10 , wherein R 1 is an indole, a benzo[1,3]dioxole, or a piperidine.
12 . A compound according to Claim 10 , wherein the compound is:
1-[5-(3,4-Dimethoxy-phenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidin-7-yl]-piperidin-4-ol;
5-(4-Fluoro-phenyl)-7-indol-1-yl-1-methyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidine;
7-(5-Chloro-indol-1-yl)-5-(4-fluoro-phenyl)-1-methyl-3-propyl-1H-
pyrazolo[4,3-d]pyrimidine;
7-Indol-1-yl-1,3-dimethyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidine;
7-Benzo[1,3]dioxol-5-yl-1,3-dimethyl-5-phenyl-1H-pyrazolo[4,3-
d]pyrimidine; or
any combination thereof.
13 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
R 1 is a substituted or an unsubstituted aryl or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 9 , in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, SO 2 R 8 , SO 2 NR 6 R 7 , NR 6 R 7 , CO 2 R 6 , COR 8 , or CONR 6 R 7 , any of which having up to 10 carbon atoms; or 2) halogen;
m is an integer from 0 to 3, inclusive;
R 3 and R 4 are selected independently from a substituted or an unsubstituted allyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
any of R 1 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 8 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
14 . A compound according to claim 13 , wherein the compound is:
7-(4-Fluoro-phenoxy)-1-methyl-5-phenyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidine;
5-(4-Fluoro-phenyl)-1-methyl-7-phenylethynyl-3-propyl-1H-pyrazolo[4,3-
d]pyrimidine; or
any combination thereof.
15 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 2 is a substituted or an unsubstituted haloalkyl or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 10 , in each occurrence, is selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, NR 6 R 7 , OCH 2 O, CO 2 R 6 , COR 6 , CONR 6 R 7 , SO 2 R 6 , SO 2 NR 6 R 7 , NHSO 2 R 6 , or NHCOR 6 , any of which having up to 10 carbon atoms; or 2) halogen or cyano;
n is an integer from 0 to 3, inclusive;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms; and
any of R 2 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, or a cycloalkyl, any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl.
16 . A compound according to claim 15 , wherein R 2 is a thiophene or CF 3 .
17 . A compound according to claim 15 , wherein the compound is:
(3-Chloro-4-methoxy-phenyl)-(1-methyl-3-propyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
(3-Fluoro-4-methoxy-phenyl)-(1-methyl-3-propyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
(1,3-Dimethyl-5-thiophen-2-yl-1H-pyrazolo[4,3-d]pyrimidin-7-yl)-(3-
fluoro-4-methoxy-phenyl)-amine hydrochloride;
(4-Chloro-3-methoxy-phenyl)-(1,3-dimethyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
(3-Chloro-4-methoxy-phenyl)-(1,3-dimethyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
2-Chloro-4-(1,3-dimethyl-5-thiophen-2-yl-1H-pyrazolo[4,3-d]pyrimidin-7-
ylamino)-phenol hydrochloride;
(3-Fluoro-4-methoxy-phenyl)-(1-methyl-3-propyl-5-trifluoromethyl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
(4-Chloro-3-methoxy-phenyl)-(1-methyl-3-propyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride; or
any combination thereof.
18 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 1 and R 2 are independently a substituted or an unsubstituted heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms; and
any of R 1 , R 2 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen or hydroxyl;
R 6 and R 7 , in each occurrence, are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
19 . A compound according to claim 18 , wherein the compound is:
Benzo[1,3]dioxol-5-yl-(1-methyl-3-propyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride;
Benzo[1,3]dioxol-5-yl-(1,3-dimethyl-5-thiophen-2-yl-1H-pyrazolo[4,3-d]
pyrimidin-7-yl)-amine hydrochloride;
Benzo[1,3]dioxol-5-yl-(1-methyl-3-propyl-5-thiophen-2-yl-1H-
pyrazolo[4,3-d]pyrimidin-7-yl)-amine hydrochloride; or
any combination thereof.
20 . A compound according to claim 1 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 3 is CH 3 ; and
R 4 is CH 2 CH 2 CH 3 , CH 2 CH 3 , or CH 3 .
21 . A method of treating a condition or disease state mediated by a high expression of TNF-alpha in a human or an animal, comprising administering an effective amount of at least one compound according to claim 1 to the human or the animal, sufficient to reduce TNF-alpha levels.
22 . A method of treating a condition or disease state mediated by an increased proliferation of smooth muscle cells in a human or an animal, comprising administering an effective amount of at least one compound according to claim 1 to the human or the animal, sufficient to reduce smooth muscle cell proliferation.
23 . A method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia in a human or an animal, comprising administering an effective amount of at least one compound according to claim 1 .
24 . A composition comprising a pharmaceutically acceptable carrier and at least one compound having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
wherein when Y 1 is >NR 5 , NR 5 R 1 is a 5-, 6-, or 7-membered heterocyclic ring, which optionally comprises one or two additional heteroatoms selected from >O, >S or >N—, in which NR 5 R 1 is optionally substituted with one, two, or three substituents selected independently from an alkyl, an alkoxy, or a haloalkyl, any of which having up to 10 carbon atoms, or hydroxyl, halogen, or cyano;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 2 is a substituted or an unsubstituted alkyl, haloalkyl, aryl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 5 is a substituted or an unsubstituted alkyl having up to 12 carbon atoms, or hydrogen;
any of R 1 , R 2 , R 3 , R 4 , and R 5 is optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , —CO 2 R 6 , —COR 8 , —CONR 6 R 7 , —SO 2 R 8 and —SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms;
or a pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof.
25 . The composition as claimed in claim 24 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative;
optionally, a pharmaceutically acceptable excipient;
optionally, a pharmaceutically acceptable diluent; and
optionally, a pharmaceutically acceptable solvate.
26 . The composition as claimed in claim 24 , further comprising an agent selected from an immunosuppressive agent, an anti-inflammatory agent, an antirheumatic agent, an antidyspilidemic agent, or any combination thereof.
27 . The composition as claimed in claim 24 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
28 . A compound having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 2 is a substituted or an unsubstituted alkyl, haloalkyl, aryl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 is a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 4 is a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms, or hydrogen;
R 5 is a substituted or an unsubstituted alkyl having up to 12 carbon atoms, or hydrogen;
any of R 1 , R 2 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
29 . A compound according to claim 28 , wherein
R 2 is a substituted or an unsubstituted haloalkyl, aryl, or thiophenyl, any of which having up to 12 carbon atoms;
R 3 is an alkyl having up to 6 carbon atoms or a phenyl;
R 4 is an alkyl having up to 6 carbon atoms, phenyl, or hydrogen;
any of R 1 or R 2 is optionally substituted with at least one group selected independently from an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
30 . A compound according to claim 28 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 3 and R 4 are selected independently from hydrogen, methyl, ethyl, propyl, or phenyl;
R 9 and R 10 , in each occurrence, are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , or SO 2 NR 6 R 7 , any of which having up to 10 carbon atoms; or 2) halogen or cyano;
m and n are selected independently from an integer from 0 to 3, inclusive;
R 6 and R 7 are selected independently from H or methyl; and
R 8 is methyl.
31 . A compound according to claim 30 , wherein the compound is:
(3-Chloro-4-methoxy-phenyl)-(1,6-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-
4-yl)-amine hydrochloride;
(3-Fluoro-4-methoxy phenyl)-[6-(4-fluoro-phenyl)-1-phenyl-1H-pyrazolo
[3,4-d]-pyrimidin-4yl]amine hydrochloride;
(4-Chloro-3-trifluoromethyl-phenyl)-[6-(4-fluoro-phenyl)-1-phenyl-1H-
pyrazolo[3,4-d]pyrimidin-4-yl]-amine hydrochloride;
(3-Fluoro-phenyl)-[6-(4-fluoro-phenyl)-1-phenyl-1H-pyrazolo[3,4-
d]pyrimidin-4-yl]-amine hydrochloride;
[6-(4-Fluoro-phenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-
trifluoromethoxy-phenyl)-amine hydrochloride; or
any combination thereof.
32 . A compound according to claim 28 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
33 . A method of treating a condition or disease state mediated by a high expression of TNF-alpha in a human or an animal, comprising administering an effective amount of at least one compound according to claim 28 to the human or the animal, sufficient to reduce TNF-alpha levels.
34 . A method of treating a condition or disease state mediated by an increased proliferation of smooth muscle cells in a human or an animal, comprising administering an effective amount of at least one compound according to claim 28 to the human or the animal, sufficient to reduce smooth muscle cell proliferation.
35 . A method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia in a human or an animal, comprising administering an effective amount of at least one compound according to claim 28 .
36 . A composition comprising a pharmaceutically acceptable carrier and at least one compound having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 2 is a substituted or an unsubstituted alkyl, haloalkyl, aryl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 is a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 4 is a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms, or hydrogen;
R 5 is a substituted or an unsubstituted alkyl having up to 12 carbon atoms, or hydrogen;
any of R 1 , R 2 , R 3 , and R 4 can be optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms;
or a pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof.
37 . The composition as claimed in claim 36 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative;
optionally, a pharmaceutically acceptable excipient;
optionally, a pharmaceutically acceptable diluent; and
optionally, a pharmaceutically acceptable solvate.
38 . The composition as claimed in claim 36 , further comprising an agent selected from an immunosuppressive agent, an anti-inflammatory agent, an antirheumatic agent, an antidyspilidemic agent, or any combination thereof.
39 . The composition as claimed in claim 36 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.
40 . A compound having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 2 is a substituted or an unsubstituted alkyl, haloalkyl, aryl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 5 is an alkyl having up to 12 carbon atoms or hydrogen;
any of R 1 , R 2 , R 3 , and R 4 is optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms.
41 . A compound according to claim 40 , having the formula:
4-Benzo[1,3]dioxol-5-yl-6-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-c]pyridine;
(6-Chloro-pyridin-3-yl)-[6-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-c]pyridin-4-yl]-amine hydrochloride;
6-(4-Fluoro-phenyl)-4-(3-methanesulfonyl-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-c]pyridine;
6-(4-Fluoro-phenyl)-4-(4-methanesulfonyl-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-c]pyridine;
6-(4-Fluoro-phenyl)-1,3-dimethyl-4-(4-trifluoromethoxy-phenyl)-1H-
pyrazolo[4,3-c]pyridine;
any combination thereof.
42 . A compound according to claim 40 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 3 and R 4 are selected independently from methyl, ethyl, propyl, or phenyl;
R 9 and R 10 , in each occurrence, are selected independently from: 1) an alkyl, an alkoxy, a haloalkyl, a haloalkoxy, NR 6 R 7 , CO 2 R 8 , COR 8 , CONR 6 R 7 , SO 2 R 8 , or SO 2 NR 6 R 7 , any of which having up to 10 carbon atoms; or 2) halogen or cyano;
m and n are selected independently from an integer from 0 to 3, inclusive;
R 6 and R 7 are selected independently from H or methyl; and
R 8 is methyl.
43 . A compound according to claim 42 , wherein the compound is:
(3-Chloro-4-methoxy-phenyl)-[6-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-c] pyridin-4-yl]-amine hydrochloride;
(3-Fluoro-4-methoxy-phenyl)-[6-(4-fluoro-phenyl)-1,3-dimethyl-1H-
pyrazolo[4,3-c]pyridin-4-yl]-amine hydrochloride;
(4-Chloro-3-trifluoromethyl-phenyl)-[6-(4-fluoro-phenyl)-1,3-dimethyl-
1H-pyrazolo[4,3-c]pyridin-4-yl]-amine hydrochloride;
[6-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-4-yl]-(3-
trifluoromethyl-phenyl)-amine hydrochloride;
[6-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-4-yl]-(4-
methanesulfonyl-phenyl)-amine;
(1,3-dimethyl-6-(4-fluoro phenyl)-1H-pyrazolo[4,3-c]pyridin-4-yl)-(4-
trifluoromethoxy-phenyl)-amine hydrochloride;
4-[6-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-4-
ylamino]-N-methyl-benzenesulfonamide hydrochloride;
N-{4-[6-(4-Fluoro-phenyl)-1,3-dimethyl-1H-pyrazolo[4,3-c]pyridin-4-
ylamino]-phenyl}-methanesulfonamide hydrochloride; or
any combination thereof.
44 . A compound according to claim 40 , having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
R 3 and R 4 are CH 2 CH 2 CH 3 , CH 2 CH 3 , or CH 3 .
45 . A method of treating a condition or disease state mediated by a high expression of TNF-alpha in a human or an animal, comprising administering an effective amount of at least one compound according to claim 40 to the human or the animal, sufficient to reduce TNF-alpha levels.
46 . A method of treating a condition or disease state mediated by an increased proliferation of smooth muscle cells in a human or an animal, comprising administering an effective amount of at least one compound according to claim 40 to the human or the animal, sufficient to reduce smooth muscle cell proliferation.
47 . A method of treating atherosclerosis, arthritis, restenosis, diabetic nephropathy, or dyslipidemia in a human or an animal, comprising administering an effective amount of at least one compound according to claim 40 .
48 . A composition comprising a pharmaceutically acceptable carrier and at least one compound having the formula:
or a salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof, wherein:
Y 1 is >NR 5 , —C≡C—, >O, or a direct a bond between the 6-membered ring and R 1 ;
R 1 is a substituted or an unsubstituted aryl, heterocyclyl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl or heterocyclyl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, >NR 6 , >SO 2 , or >CO;
R 1 is a substituted or an unsubstituted alkyl, haloalkyl, aryl, or heteroaryl, any of which having up to 12 carbon atoms; wherein any heteroaryl comprises at least one heteroatom or heterogroup selected from >O, >N—, >S, or >NR 6 ;
R 3 and R 4 are selected independently from a substituted or an unsubstituted alkyl or a substituted or an unsubstituted aryl, any of which having up to 12 carbon atoms;
R 5 is an alkyl having up to 12 carbon atoms or hydrogen;
any of R 1 , R 2 , R 3 , and R 4 is optionally substituted with at least one group selected independently from: 1) an alkyl, an alkoxy, an alkylthio, a haloalkyl, a haloalkoxy, a cycloalkyl, NR 6 R 7 , CO 2 R 6 , COR 8 , CONR 6 R 7 , SO 2 R 8 , SO 2 NR 6 R 7 , NHSO 2 R 8 , or NHCOR 8 , any of which having up to 10 carbon atoms; or 2) halogen, hydroxyl, or cyano;
R 6 and R 7 are selected independently from an alkyl or an aryl having up to 10 carbon atoms, or hydrogen; and
R 8 is an alkyl or aryl having up to 10 carbon atoms;
or a pharmaceutically acceptable salt, a prodrug, a diastereomeric mixture, an enantiomer, a tautomer, a racemic mixture, or any combination thereof.
49 . The composition as claimed in claim 48 , further comprising:
optionally, a pharmaceutically acceptable auxiliary;
optionally, a pharmaceutically acceptable preservative;
optionally, a pharmaceutically acceptable excipient;
optionally, a pharmaceutically acceptable diluent; and
optionally, a pharmaceutically acceptable solvate.
50 . The composition as claimed in claim 48 , further comprising an agent selected from an immunosuppressive agent, an anti-inflammatory agent, an antirheumatic agent, an antidyspilidemic agent, or any combination thereof.
51 . The composition as claimed in claim 48 , wherein the composition is in the form of a tablet, a capsule, a cachet, a powder, a granule, a solution, a suspension, an emulsion, a bolus, a lozenge, a suppository, a pessary, a tampon, a cream, a gel, a paste, a foam, a spray, an aerosol, a microcapsule, a liposome, a transdermal patch, a pastille, a paste, or a mouthwash.