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US 8,133,895 B2Granted
Fused pyrazine compounds useful for the treatment of degenerative and inflammatory diseases
AssigneeJanssen Pharmaceutica NV
InventorsMartin James Inglis Andrews, Mark Stuart Chambers, Wolfgang Schmidt, Grégory Louis Joseph Bar
Life of this patent
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Abstract
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.
Claims13
A compound according to formula I:
- wherein
- Z is N;
- R1 is H or C1-C6 alkyl;
- R2 is H, C1-C6 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkyl-C1-C6 alkyl;
- R8 is cycloalkyl;
- and
- R9 is aryl or heteroaryl;
- wherein each of said R1, R2, R8 and R9 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, carboxy, hydroxyl, carbamoyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
6 more elements
A compound according to formula I
- wherein
- Z is N;
- R1 is H or C1-C6 alkyl;
- R2 is H, C1-C6 alkyl, C3-C7 cycloalkyl, or C3-C6 cycloalkyl-C1-C6 alkyl;
- R8 is substituted cycloalkyl;
- and the substitution is -L-R8d;
- and wherein
- L is a single bond, alkylene, heteroalkylene, —O—, —N(R8e)—, —CO—, —CO2—, —SO—, —SO2—, —CON(R8e)—, —SO2N(R8e)—, —N(R8e)CO—, —N(R8e)SO2—, —N(R8e)CON(R8e)—, or —N(R8e)SO2N(R8e)—;
- and
- R8d is C1-C6 alkyl, C3-C7 cycloalkyl, aryl, 3-7-membered heterocycloalkyl, heteroaryl, amino, aralkyl, C1-C6 heteroarylalkyl or C1-C6 aminoalkyl;
- and
- R8e is H, C1-C6 alkyl or C3-C7 cycloalkyl;
- wherein each of said R8d or R8e that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, carboxy, hydroxyl, carbamoyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl;
- R9 is aryl or heteroaryl;
- wherein each of said R1, R2, R8 and R9 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, carboxy, hydroxyl, carbamoyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
13 more elements
A compound according to formula I:
- wherein
- Z is N;
- R1 is H or C1-C6 alkyl;
- R2 is H, C1-C6 alkyl, C3-C7 cycloalkyl or C3-C7 cycloalkyl-C1-C6 alkyl;
- R8 is cycloalkyl;
- and
- R9 is
- wherein A1 is N or CR9a;
- A2 is N or CR9a;
- and A3 is S, O, or NR9a;
- and each R9a is independently H or C1-C4 alkyl;
- and R9b is CONH2, CONHMe, or CN;
- or
- wherein A1 is N or CR9a;
- A2 is S, O, or NR9a;
- and A3 is N or CR9a;
- and each R9a is independently H or C1-C4 alkyl;
- and R9b is CONH2, CONHMe, or CN;
- wherein each of said R1, R2, R8 and R9a that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, carboxy, hydroxyl, carbamoyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
17 more elements
A compound according to formula I:
- wherein
- Z is N;
- R1 is H or C1-C6 alkyl;
- R2 is H, C1-C6 alkyl, C3-C7 cycloalkyl and C3-C7 cycloalkyl-C1-C6 alkyl;
- R8 is cycloalkyl;
- and
- R9 is
- wherein each of said R1, R2, R8 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, carboxy, hydroxyl, carbamoyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
6 more elements
A compound according for formula I:
- wherein
- Z is N;
- R1 is H or C1-C6 alkyl;
- R2 is H, C1-C6 alkyl, C3-C7 cycloalkyl, or C3-C7 cycloalkyl-C1-C6 alkyl;
- R8 is cycloalkyl;
- and
- R9 is
- each of said R1, R2, and R8 that is not H is independently optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, carboxy, hydroxyl, carbamoyl, C1-C6 hydroxyalkyl, C1-C6 haloalkyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
6 more elements
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 R8a is independently C1-C6 alkyl, carbamoyl, carboxy, C1-C6 hydroxyalkyl, alkoxy, or amino;
- wherein each said R8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, hydroxyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
3 more elements
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 R8a is independently C1-C6 alkyl, carbamoyl, carboxy, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or amino;
- wherein each said R8a is optionally substituted by at least one of fluoro, chloro, bromo, W being C1-C6 alkyl, hydroxyl, C1-C6 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 C1-C6 alkyl;
- or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
3 more elements
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.
6 more elements
Dependencies are inferred from the claim text.