Fused pyrazine compounds useful for the treatment of degenerative and inflammatory diseases
Novel fused pyrazine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, inflammation, rheumatoid arthritis and others.
1. A compound according to formula I:
wherein
Z is N;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl;
R 8 is cycloalkyl; and
R 9 is aryl or heteroaryl;
wherein each of said R 1 , R 2 , R 8 and R 9 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
2. The compound according to claim 1 , wherein R 8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; and said R 8 is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl.
3. A compound according to claim 1 , wherein R 8 is cyclopropyl, cyclohexyl, cyclobutyl, cyclopentyl, or cycloheptyl; and said R 8 is optionally substituted by at least one of W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl.
4. A compound according to claim 1 , wherein the compound is according to formula IIa, IIb, IIc, IId, or IIe:
wherein
Z is N,
the subscript n is selected from 0, 1, 2, 3, or 4; and
each R 8a is independently C 1 -C 6 alkyl, carbamoyl, carboxy, hydroxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or amino; and each said R 8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, cyano, W′ being amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said W′ is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
5. A compound according to claim 1 , wherein R 9 is phenyl, and said R 9 being phenyl is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .
7. A compound according to formula I
wherein
Z is N;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 6 cycloalkyl-C 1 -C 6 alkyl;
R 8 is substituted cycloalkyl; and the substitution is -L-R 8d ; and wherein
L is a single bond, alkylene, heteroalkylene, —O—, —N(R 8e )—, —CO—, —CO 2 —, —SO—, —SO 2 —, —CON(R 8e )—, —SO 2 N(R 8e )—, —N(R 8e )CO—, —N(R 8e )SO 2 —, —N(R 8e )CON(R 8e )—, or —N(R 8e )SO 2 N(R 8e )—; and
R 8d is C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, aryl, 3-7-membered heterocycloalkyl, heteroaryl, amino, aralkyl, C 1 -C 6 heteroarylalkyl or C 1 -C 6 aminoalkyl; and
R 8e is H, C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl;
wherein each of said R 8d or R 8e that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, and amino, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;
R 9 is aryl or heteroaryl;
wherein each of said R 1 , R 2 , R 8 and R 9 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
8. A compound according to formula I:
wherein
Z is N;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl;
R 8 is cycloalkyl; and
R 9 is
wherein A 1 is N or CR 9a ; A 2 is N or CR 9a ; and A 3 is S, O, or NR 9a ; and each R 9a is independently H or C 1 -C 4 alkyl; and R 9b is CONH 2 , CONHMe, or CN; or
wherein A 1 is N or CR 9a ; A 2 is S, O, or NR 9a ; and A 3 is N or CR 9a ; and each R 9a is independently H or C 1 -C 4 alkyl; and R 9b is CONH 2 , CONHMe, or CN;
wherein each of said R 1 , R 2 , R 8 and R 9a that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
9. A compound according to formula I:
wherein
Z is N;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl;
R 8 is cycloalkyl; and
R 9 is
wherein each of said R 1 , R 2 , R 8 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
10. A compound according for formula I:
wherein
Z is N;
R 1 is H or C 1 -C 6 alkyl;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, or C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl;
R 8 is cycloalkyl; and
R 9 is
each of said R 1 , R 2 , and R 8 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, carboxy, hydroxyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said amino is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
11. A compound according to formula IVa, IVb, IVc, IVd, or IVe:
wherein
the subscript n is 0, 1, 2, 3 or 4;
Z is N;
each R 8a is independently C 1 -C 6 alkyl, carbamoyl, carboxy, C 1 -C 6 hydroxyalkyl, alkoxy, or amino;
wherein each said R 8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 haloalkyl, alkoxy, cyano, W′ being amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said W′ is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
12. A compound according to formula VIa, VIb, VIc, VId, or VIe:
wherein
Z is N;
the subscript n is 0, 1, 2, 3 or 4;
each R 8a is independently C 1 -C 6 alkyl, carbamoyl, carboxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or amino;
wherein each said R 8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C 1 -C 6 alkyl, hydroxyl, C 1 -C 6 haloalkyl, cyano, W′ being amino, aryl, 3-7-membered heterocycloalkyl, aralkyl, and heteroaryl, wherein said W is optionally substituted by at least one of fluoro, chloro, and bromo, and wherein said W′ is optionally substituted by C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
13. A compound that is:
4-(8-(cyclobutylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)furan-2-carboxamide;
5-(8-(cyclobutylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)isoindolin-1-one;
5-(8-(cyclohexylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)isoindolin-1-one;
5-(8-(cyclopentylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)isoindolin-1-one;
5-(8-(cyclopropylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)isoindolin-1-one;
5-(8-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl)isoindolin-1-one;
tert-butyl 4-(5-(1-oxoisoindolin-5-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)cyclohexylcarbamate;
or a pharmaceutically acceptable salt; stereoisomer, or tautomer thereof.