Macrocyclics pyrimidines as aurora kinase inhibitors
View Patent ↗Macrocyclic derivative compounds that inhibit protein kinase enzymes are disclosed along with pharmaceutical compositions comprising these compounds and methods for synthesizing the same. Such compounds have utility in the treatment of proliferative diseases resulting from unregulated and/or disturbed kinase activity such as cancers, psoriasis, viral and bacterial infections, inflammatory and autoimmune diseases.
1. A compound of the Formula I :
wherein:
X is F;
is aryl;
is cyclopentane, optionally substituted by carboxamide and dihydroxyethyl;
- - - represents the presence or absence of a double bond;
L 1 is O;
L 2 is CH 2 ;
L 2′ , and L 3 each independently, is CHOH;
n is 1;
p and q, each independently, is 0 or 1; or a pharmaceutically acceptable salt, tautomer, enantiomer or racemic mix thereof.
2. The compound of claim 1 wherein X is F and
is phenyl, which is unsubstituted or substituted by CN, OH, F or 4-methyl-piperazine.
3. A pharmaceutical composition comprising a compound of Formula I according to claim 1 , and a physiologically acceptable carrier, diluent, or excipient.
4. A kit comprising separate packets, the first having a therapeutically effective amount of a pharmaceutical composition according to claim 3 , and the second having a therapeutically effective amount of a pharmaceutical composition comprising a further pharmaceutically active ingredient.
5. The compound of claim 1 selected from the group consisting of:
(16Z)-4-fluoro-14,19-dioxa-2,6,8,26-tetraazatetracyclo[18.2.2.1˜3,7˜0.1˜9,13˜]hexacosa-3(26),4,6,9(25),10,12,16-heptaene; and
(16E)-4-fluoro-14,19-dioxa-2,6,8,26-tetraazatetracyclo[18.2.2.1˜3,7˜0.1˜9,13˜]hexacosa-3(26),4,6,9(25),10,12,16-heptaene:
or a pharmaceutically acceptable salt, tautomer, enantiomer or racemic mix thereof.