Indazole compounds, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation

A pharmaceutical composition comprising:

• (a) an amount of a cell-cycle control agent effective to inhibit a protein kinase, said cell-cycle control agent being a compound represented by Formula I:
• wherein R1 is hydrogen or a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug o)r metabolite thereof;
• and a pharmaceutically acceptable carrier.

A method of treating a disease or disorder mediated by inhibition of a kinase complex, comprising administering to a subject in need of such treatment an effective amount of a cell-cycle control agent selected from the group consisting of a compound represented by Formula I:

• wherein R1 is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug, or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof.

A pharmaceutical composition comprising:

• (a) a therapeutically effective amount of a compound represented by Formula I:
• wherein R1 is hydrogen or a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof;
• and
• (b) a pharmaceutically acceptable carrier, diluent, vehicle or excipient therefor.

A method of treating a mammalian disease condition mediated by kinase activity, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound represented by Formula I:

• wherein R1 is hydrogen or a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof.

A method of modulating or inhibiting the activity of a protein kinase receptor, comprising contacting the receptor with an effective amount of a compound represented by the Formula I:

• wherein R1 is hydrogen or a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof.

A pharmaceutical composition, comprising an effective amount for inhibiting a kinase complex of a cell-cycle control agent, represented by Formula I:

• wherein R1 is hydrogen or a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof.

A method of treating a disease state or disorder associated with uncontrolled cellular proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula I:

• wherein R1 is hydrogen or a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R2 is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, or
• wherein R4 is H or lower allyl, and X is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula I;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula I, or a pharmaceutically acceptable salt of a prodrug or metabolite thereof.

A compound represented by Formula II

• wherein R′1 is a substituted or unsubstituted aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms or
• wherein each R4 is individually H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R′2 is a substituted or unsubstituted amino, nitro, alkenyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,
• wherein the R4 groups are independently H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula II;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula II, or a pharmaceutically acceptable salt of the prodrug or metabolite thereof.

A method of treating a disease state or disorder associated with uncontrolled cellular proliferation comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula II:

• wherein R′1 is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms or
• wherein each R4 is individually H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• and
• R′2 is a substituted or unsubstituted amino, nitro, alkenyl, alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, a heterocycle
• containing 5-10 ring atoms and 1-3 nitrogen heteroatoms,
• wherein the R4 groups are independently H or lower alkyl, and X is a substituted or unsubstituted alkyl, aryl, a heteroaryl containing 5-10 ring atoms and 1-3 nitrogen heteroatoms, carbocycle, or a heterocycle containing 5-10 ring atoms and 1-3 nitrogen heteroatoms;
• or
• a pharmaceutically acceptable salt of a compound of the Formula II;
• or a prodrug or pharmaceutically active metabolite of a compound of the Formula II, or a pharmaceutically acceptable salt of the prodrug or metabolite thereof.