Agents and methods for the treatment of proliferative diseases
The present invention provides selective kinase inhibitors of formula (I)
1. A compound of Formula I
where:
A and B are independently O or S;
X and Y are both hydrogen or, taken together, form a bond;
R 1 is hydrogen or C 1 -C 4 alkyl;
R 2 is optionally up to two substituents independently selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, aryloxy, benzyloxy, C 1 -C 6 alkylthio and arylthio;
R 3 is a substituent optionally selected from the group consisting of aryl heteroaryl, —CH 2 —NH— (1-deoxy-β-D-glucose), and —(CH 2 ) m —Z;
R 4 is hydrogen, C 1 -C 4 alkyl, —(CH 2 ) m —Z, or 2-deoxy-α-D-ribofuranos-1-yl;
R 5 is optionally up to two substituents independently selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, aryloxy, benzyloxy, C 1 -C 6 alkylthio and arylthio;
R 6 is optionally up to three substituents selected from C 1 -C 4 alkyl;
R 7 is a substituent optionally selected from (C 1 -C 6 alkoxy)carbonyl or —(CH 2 ) m —Z;
Z is halo, hydroxy, (C 1 -C 6 alkyl) 3 SiO—, (diphenyl) (C 1 -C 6 alkyl)SiO, carboxy, (C 1 -C 4 alkoxy)carbonyl, or NR 8 R 9 ;
R 8 is hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl;
R 9 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, C 1 -C 6 alkanoyl, substituted C 1 -C 6 alkanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, an amino acid residue, a protected amino acid residue, β-(pyridinyl)alaninyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl; or
R 8 and R 9 taken together with the nitrogen to which they are attached form a saturated heterocycle optionally substituted with one or two hydroxy, amino, or C 1 -C 6 alkyl groups;
Q 1 is O, S(O) n or —(CH 2 ) 1-3 —;
Q 2 is a carbon-carbon single bond, a carbon-carbon double bond, —NR 10 —, or —NR 10 —CHR 11 —;
Q 3 is —(CH 2 ) 1-3 —;
R 10 is hydrogen, (C 1 -C 6 alkyl)sulfonyl, arylsulfonyl, hetroarylsulfonyl, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, (C 1 -C 5 alkyl)carbonyl, substituted (C 1 -C 5 alkyl)carbonyl, an amino acid residue, a protected amino acid residue, β-(pyridinyl)alaninyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl;
R 11 is hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl; or R 10 and R 11 taken together with the atoms to which they are attached form a 5- or 6-membered saturated heterocycle;
m is 0, 1, 2, 3, 4, or 5;
n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 where X and Y, taken together, form a bond.
3. A compound of claim 1 or 2 where Q 2 is a carbon-carbon single bond.
4. A compound of claim 1 or 2 where Q 2 is —NR 10 —.
5. A compound of claim 4 where R 10 is hydrogen.
6. A compound of claim 1 or 2 where Q 2 is —NR 10 —CHR 11 —.
7. A compound of claim 6 where R 10 is hydrogen.
8. A pharmaceutical formulation comprising a compound of Formula I
where:
A and B are independently O or S;
X and Y are both hydrogen or, taken together, form a bond;
R 1 is hydrogen or C 1 -C 4 alkyl;
R 2 is optionally up to two substituents independently selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, aryloxy, benzyloxy, C 1 -C 6 alkylthio and arylthio;
R 3 is a substituent optionally selected from the group consisting of aryl, heteroaryl, —CH 2 —NH— (1-deoxy-β-D-glucose), and —(CH 2 ) m —Z;
R 4 is hydrogen, C 1 -C 4 alkyl, —(CH 2 ) m —Z, or 2-deoxy-α-D-ribofuranos-1-yl;
R 5 is optionally up to two substituents independently selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, C 1 -C 6 alkoxy, aryloxy, benzyloxy, C 1 -C 6 alkylthio and arylthio;
R 6 is optionally up to three substituents selected from C 1 -C 4 alkyl;
R 7 is a substituent optionally selected from (C 1 -C 6 alkoxy)carbonyl or —(CH 2 ) m —Z;
Z is halo, hydroxy, (C 1 -C 6 alkyl) 3 SiO—, (diphenyl) (C 1 -C 6 alkyl)SiO, carboxy, (C 1 -C 4 alkoxy)carbonyl, or NR 8 R 9 ;
R 8 is hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl;
R 9 is hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, C 1 -C 6 alkanoyl, substituted C 1 -C 6 alkanoyl, tert-butoxycarbonyl, benzyloxycarbonyl, an amino acid residue, a protected amino acid residue, β-(pyridinyl)alaninyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl; or
R 8 and R 9 taken together with the nitrogen to which they are attached form a saturated heterocycle optionally substituted with one or two hydroxy, amino, or C 1 -C 6 alkyl groups;
Q 1 is O, S(O) n or —(CH 2 ) 1-3 —;
Q 2 is a carbon-carbon single bond, a carbon-carbon double bond, —NR 10 — or —NR 10 —CHR 11 —;
Q 3 is —(CH 2 ) 1-3 —;
R 10 is hydrogen, (C 1 -C 6 alkyl)sulfonyl, arylsulfonyl, hetroarylsulfonyl, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl, (C 1 -C 5 alkyl)carbonyl, substituted (C 1 -C 5 alkyl)carbonyl, an amino acid residue, a protected amino acid residue, β-(pyridinyl)alaninyl, aryl, heteroaryl, arylcarbonyl, or heteroarylcarbonyl;
R 11 is hydrogen, C 1 -C 6 alkyl, or substituted C 1 -C 6 alkyl, C 1 -C 6 alkenyl, substituted C 1 -C 6 alkenyl; or R 10 and R 11 taken together with the atoms to which they are attached form a 5- or 6-membered saturated heterocycle;
m is 0, 1, 2, 3, 4, or 5;
n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.