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US 2006/0069097 A1Published application
Pyradazine compounds as gsk-3 inhibitors
AssigneeSmithKline Beecham Corporation
InventorsScott Dickerson, Francis Tavares, Huiqiang Zhou
Life of this patent
Estimating the term…
Abstract
The present invention relates generally to inhibitors of the kinases, such as GSK3, and more particularly to fused pyradazine compounds and methods of their use.
Claims23
A compound of Formula (I):
- or a salt, solvate, or physiologically functional derivative thereof, wherein
- D is N or CH;
- R1 is aryl or heteroaryl, where said aryl or said heteroaryl may be optionally substituted one or more times with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, halogen, C1-C6 haloalkyl, heterocyclyl, heteroaryl, aryl, cyano, azido, nitro, or —NR4R5;
- a is 1 or 2;
- y is 0, 1, or 2;
- R2 is hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl, cyano, azido, nitro, —OR8, —OR6R8, —R6R7, —R6R′, S(O)yR7, —C(O)R7, —C(O)OR7, —C(O)NR4R5, —NR′(C═NR4)NR4R5, —OC(O)NR4R5, —OC(O)OR7, —C(═NR4)NR4R5, —NR4R5, —OC(O)R7, or —NR7C(O)R7;
- R3 is -(Q)p-(Q1)
- where
- Q is O, N(R8) or S(O)y,
- p is 0 or 1,
- y is 0, 1, or 2, and
- Q1 is C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, aryl, aryl substituted with —C(O)N(H)R6NR4R5 or —OC(H)(OH)R6NR4R5, heteroaryl, aralkyl, or —R6NR4R5;
- R4 and R5 are independently hydrogen, C1-C3 alkyl, C3-C7 cycloalkyl, or R4 and R5 together with the nitrogen atom to which they are bound form a heterocyclyl;
- R6 is alkylene, arylene, heteroarylene, cycloalkylene, alkenylene, cycloalkenylene, or alkynylene;
- R7 is hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, —NR4R5, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)yR8, —C(O)R8, —C(O)OR8, —C(O)NR4R5, —S(O)2NR4R5, —NR′(C═NR4)NR4R5, —OC(O)NR4R5, —OC(O)OR8, —C(═NR4)NR4R5, —NR4R5, or —NR7C(O)R7
- R8 is hydrogen, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, —NR4R5, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or —S(O)2R9;
- R9 is C1-C6 alkyl or C1-C6 haloalkyl;
- R′ is C1-C3 alkylene;
- and
- R″ is —OR7, —OC(O)NR4R5, —OC(O)OR7, —OC(O)R7.
17 more elements
A method for the treatment or prophylaxis of a disorder in a mammal, said disorder being characterized by misregulation of GSK-3, comprising administering a compound of Formula (I):
- or a salt, solvate, or physiologically functional derivative thereof, wherein
- D is N or CH;
- R1 is hydrogen, C1-C6 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C1-C3 alkoxy, halogen, hydroxy, cyano, —S(O)yC1-C3 alkyl, —NR4R5, aryl, or heteroaryl, where said aryl or said heteroaryl may be optionally substituted one or more times with C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, oxo, hydroxy, mercapto, carboxy, tetrazolyl, carbamoyl optionally substituted with alkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, halogen, C1-C6 haloalkyl, heterocyclyl, heteroaryl, aryl, cyano, azido, nitro, or —NR4R5;
- a is 1 or 2;
- y is 0, 1, or 2;
- R2 is hydrogen, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl, cyano, azido, nitro, —OR8, —OR6R8, —R6R7, —R6R″, S(O)yR7, —C(O)R7, —C(O)OR7, —C(O)NR4R5, —NR′(C═NR4)NR4R5, —OC(O)NR4R5, —OC(O)OR7, —C(═NR4)NR4R5, —NR4R5, —OC(O)R7, —NR7C(O)R7;
- R3 is -(Q)p-(Q1)
- where
- Q is O, N(R8) or S(O)y, p is 0 or 1, y is 0, 1, or 2 and
- Q1 is C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, aryl, aryl substituted with —C(O)N(H)R6NR4R5 or —OC(H)(OH)R6NR4R5, heteroaryl, aralkyl, or —R6NR4R5;
- R4 and R5 are independently hydrogen, C1-C3 alkyl, C3-C7 cycloalkyl, or R4 and R5, together with the nitrogen atom to which they are bound, form a heterocyclyl;
- R6 is alkylene, arylene, heteroarylene, cycloalkylene, alkenylene, cycloalkenylene, and alkynylene;
- R7 is hydrogen, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, —NR4R5, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)yR8, —C(O)R8, —C(O)OR8, —C(O)NR4R5, —S(O)2NR4R5, —NR′(C═NR4)NR4R5, —OC(O)NR4R5, —OC(O)OR8, —C(═NR4)NR4R5, —NR4R5, ——NR7C(O)R7
- R8 is hydrogen, C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, —NR4R5, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or —S(O)2R9;
- R9 is C1-C6 alkyl or C1-C6 haloalkyl;
- R′ is C1-C3 alkylene;
- and
- R″ is —OR7, —OC(O)NR4R5, —OC(O)OR7, —OC(O)R7.
15 more elements
21-23. (canceled)
Dependencies are inferred from the claim text.