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US 7,071,216 B2Granted
Substituted benz-azoles and methods of their use as inhibitors of Raf kinase
AssigneeChiron Corporation
InventorsPaul A. Renhowe, Savithri Ramurthy, Payman Amiri, Barry Haskell Levine, Daniel J. Poon, Sharadha Subramanian, Leonard Sung, Wendy Fantl, Teresa Hansen, Christopher McBride, Cynthia M. Shafer
Life of this patent
Estimating the term…
Abstract
New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
Claims66
A compound of the formula (I):
- wherein, X1 and X2 are ═N— or —NR4—, provided that if X1 is —NR4—, then X2 is ═N—, or if X2 is —NR4—, then X1 is ═N—;
- Y is O or S;
- A1 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
- A2 is substituted or unsubstituted heteroaryl;
- R1 is O or H, and R2 is NR5 R6 or hydroxyl;
- or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group;
- wherein, the dashed line represents a single or double bond, provided that
- represents a double bond when R1 is O and
- represents a single bond when R1 is H;
- R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
- R4 is hydrogen, hydroxyl, alkylamino, dialkylamino or alkyl;
- R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl;
- or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
- and
- the pharmaceutically acceptable salts, esters and prodrugs thereof.
12 more elements
A compound of the formula (II):
- wherein and Y is O or S;
- A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
- A2 is substituted or unsubstituted heteroaryl;
- R1 is O and R2 is NR5 R6;
- or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group;
- wherein, the dashed line represents a single or double bond, provided that R1 is O,
- represents a double bond;
- R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
- R4 is hydrogen or loweralkyl;
- R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl;
- or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
- and
- the pharmaceutically acceptable salts, esters, and prodrugs thereof.
10 more elements
A compound of the formula (III):
- wherein X is NR4;
- A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
- A2 is substituted or unsubstituted heteroaryl;
- R1 is O and R2 is NR5 R6;
- or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group;
- wherein, the dashed line represents a single or double bond, provided that when R1 is O,
- represents a double bond;
- R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
- R4 is hydrogen or loweralkyl;
- R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl;
- or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
- and
- the pharmaceutically acceptable salts, esters and prodrugs thereof.
10 more elements
A compound of the formula (IV):
- wherein X is NR4;
- Y is O or S;
- A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
- R1 is O and R2 is NR5 R6;
- or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group;
- wherein, the dashed line represents a single or double bond, provided that when R1 is O,
- represents a double bond;
- R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
- R4 is hydrogen or loweralkyl;
- R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl;
- or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
- and
- the pharmaceutically acceptable salts, esters and prodrugs thereof.
10 more elements
A compound of the formula (V):
- wherein X is NR4;
- A1 is substituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroarylheteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
- R1 is O and R2 is NR5 R6;
- or R1 is taken together with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group;
- wherein, the dashed line represents a single or double bond, provided that when R1is O,
- represents a double bond;
- R3 is hydrogen, halogen, loweralkyl, or loweralkoxy;
- R4 is hydrogen or loweralkyl;
- R5 and R6 are independently selected from hydrogen, and substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl;
- or R5 and R6 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
- and
- the pharmaceutically acceptable salts, esters and prodrugs thereof.
9 more elements
Dependencies are inferred from the claim text.