Inhibitors of cyclin-dependent kinases, compositions and uses related thereto
The invention pertains to novel cyclin dependent kinase inhibitors (cdks) and specifically, but not exclusively, as inhibitors of cdk/cyclin complexes. As described herein, the inhibitors of this invention are capable of inhibiting the cell-cycle machinery and consequently may be useful in modulating cell-cycle progression, ultimately controlling cell growth and differentiation. Such compounds would be useful for treating subjects having disorders associated with excessive cell proliferation.
1. A compound, or stereoisomeric, prodrug, tautomeric, pharmaceutically acceptable salt, or N-oxide form thereof, of the structure of Formula II:
wherein
Z represents O or NR″;
W represents C(═O), C(═S), SO 2 , or CH 2 ;
R″ represents, independently for each occurrence, H or lower alkyl;
R 5 represents P(═O)(OR′) 2 , M n JK, or M n Q;
R′ represents, independently for each occurrence, H, lower alkyl, or a metal counter ion;
R 6 represents H;
R 7 represents H;
J represents C(═O), C(═S), or SO 2 ;
K represents OR′, NR″, or N(R′)SO 2 R″;
M, independently for each occurrence, represents a substituted or unsubstituted methylene group,
C(═S), C(═O), NR″, O, S, S(O), or S(O 2 );
n represents an integer from 0-6 when present in R 5 ; and
Q represents a substituted or unsubstituted nitrogen-containing heteroaryl ring, secondary amino substituent, tertiary amino substituent, or nitrogen-containing heterocycle.
2. The compound of claim 1 , wherein, in Formula II, Q represents a substituted or unsubstituted: nitrogen-containing heteroaryl ring or secondary amino substituent.
3. The compound of claim 1 , wherein, in Formula II, R 5 represents M n JK, provided that R 5 is not CH 2 COOH.
4. A compound of claim 1 , wherein, in Formula II, R 5 represents M n Q and Q represents a substituted or unsubstituted: nitrogen-containing heteroaryl ring, tertiary amino substituent, or nitrogen-containing heterocycle.
5. A compound of claim 4 , wherein, in Formula II, Q represents a substituted or unsubstituted tertiary amino group.
6. A compound of claim 4 , wherein; in Formula II, Q represents a substituted or unsubstituted nitrogen-containing heterocycle.
7. A compound of claim 1 , wherein, in Formula II, R 5 represents M n Q and Q represents a substituted or unsubstituted secondary amino group.
8. A compound of claim 1 , wherein, in Formula II, R 5 represents M n Q and Q is a substituted or unsubstituted nitrogen-containing heteroaryl ring.
9. A compound of claim 1 , wherein, in Formula II, R″ represents H.
10. A compound of claim 1 , wherein, in Formula II, W represents CH 2 .
11. The compound of claim 1 , wherein, in Formula II, M when attached to Q is CH 2 , S(O 2 ), C(═S), or C(═O).
12. The compound of claim 11 , wherein, in Formula II, M when attached to Q is CH 2 .
13. A compound of claim 1 , wherein substituents include, independently for each occurrence, alkyl, oxo, acyl amino, hydroxyl, carbonyl, sulfonyl, ester, amide, NR″, hydroxy alkyl, alkoxy alkyl, aryl, heterocyclyl, cycloalkyl, or oligo(ethylene glycol).
14. A compound 1 , claim selected from
15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .