Inhibitors of cyclin-dependent kinases, compositions and uses related thereto
View Patent ↗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 prodrug, tautomeric, pharmaceutically acceptable salt, or stereoisomeric form thereof, having a structure of Formula II:
wherein
B represents M n R 8 ;
Ar represents an aryl or heteroaryl ring;
V represents O, S, or N—CN;
W represents O, S, or NR″;
R′ represents, independently for each occurrence, H, lower alkyl, or a metal counterion;
R″ represents, independently for each occurrence, H or lower alkyl;
R 5 represents H, P(═O)(OR′) 2 , or M n Q;
R 6 represents H, OH, or M n Q, provided that only one of R 5 and R 6 represents H;
R 7 represents H, halogen, hydroxyl, lower alkyl or lower alkoxyl;
R 8 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cyclo-alkyl, heterocyclyl, or amine;
M, independently for each occurrence, represents a substituted or unsubstituted methylene group (including C(═O) and C(═S)), NR″, O, S, S(O), or S(O 2 );
n represents an integer from 1-4 when present in B, from 0-6 when present in R 5 , and from 1-3 when present in R 6 ; and
Q represents a substituted or unsubstituted: tertiary amino substituent, or nitrogen-containing heterocycle.
2. A compound of claim 1 , wherein R 8 represents substituted or unsubstituted morpholino, piperazinyl, or cyclohexyl.
3. A compound of claim 1 , wherein R″ represents H.
4. A compound of claim 1 , wherein R 5 represents M n Q.
5. A compound of claim 4 , wherein the occurrence of M attached to Q represents CH 2 , S(O 2 ), C(═S) or C(═O).
6. A compound of claim 5 , wherein the occurrence of M attached to Q represents CH 2 .
7. A compound of claim 5 , wherein the occurrence of M attached to Q is C(═O).
8. A compound of claim 4 , wherein the occurrence of M attached to Q represents substituted NR″.
9. A compound of claim 4 , wherein Q represents a substituted or unsubstituted nitrogen-containing heterocycle.
10. A compound of claim 4 , wherein Q represents a substituted or unsubstituted tertiary amino group.
11. A compound, or a prodrug, tautomeric, pharmaceutically acceptable salt, or stereoisomeric form thereof, having a structure of Formula II:
wherein
B represents M n R 8 ;
Ar represents an aryl or heteroaryl ring;
V represents O, S, or N—CN;
W represents O, S, or NR″;
R′ represents, independently for each occurrence, H, lower alkyl, or a metal counterion;
R″ represents, independently for each occurrence, H or lower alkyl;
R′″ represents H or optionally substituted lower alkyl;
R 5 represents M n , JK;
R 6 represents H, OH, or M n Q;
R 7 represents H, halogen, hydroxyl, lower alkyl or lower alkoxyl;
R 8 represents substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, cyclo-alkyl, heterocyclyl, or amine;
J represents C(═O), C(═S), or SO 2 ;
K represents OR′, N(R″) 2 , or N(R′)SO 2 R″;
M, independently for each occurrence, represents a substituted or unsubstituted methylene group, NR″, O, S, S(O), or S(O 2 );
n represents an integer from 1-7 when present in B, from 0-6 when present in R 5 , and from 1-3 when present in R 6 ; and
Q represents a substituted or unsubstituted: tertiary amino substituent or nitrogen-containing heterocycle.
12. A compound of claim 11 , wherein R 8 represents substituted or unsubstituted morpholino, piperazinyl, or cyclohexyl.
13. A compound of claim 11 , wherein R″ represents H.
14. A compound of claim 11 , wherein R 6 represents M n Q.
15. A compound of claim 14 , wherein the occurrence of M attached to Q represents CH 2 , S(O 2 ), C(═S), or C(═O).
16. A compound of claim 15 , wherein the occurrence of M attached to Q is C(═O).
17. A compound of claim 15 , wherein the occurrence of M attached to Q represents CH 2 .
18. A compound of claim 14 , wherein the occurrence of M attached to Q represents substituted NR″.
19. A compound of claim 14 , wherein Q represents a substituted or unsubstituted tertiary amino substituent.
20. A compound of claim 14 , wherein Q represents a substituted or unsubstituted nitrogen-containing heterocycle.
21. A compound of any of claims 1 , 7 , 9 and 11 , 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).
22. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any of claims 1 , 7 , 9 and 11 .
23. A method of inhibiting the growth of a cyclin dependent kinase (CDK)-dependent or CDK-inhibitor responsive hyperproliferative disease (tumor), comprising administering to an animal a compound of any one of claims 1 , 7 , 9 and 11 .
24. A method of inhibiting proliferation of a cell, comprising contacting the cell with a compound of any one of claims 1 , 7 , 9 and 11 .
25. A method of treating a viral infection, comprising administering to a mammal a compound of any one of claims 1 , 7 , 9 and 11 , wherein the viral infection is caused by a virus selected from the group consisting of a human immunodeficiency virus (HIV), human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus, and adenovirus.
26. A method for the treatment of alopecia induced by chemotherapy or radiation therapy, comprising administering to a mammal a compound of any one of claims 1 , 7 , 9 , and 11 conjointly with one or more chemotherapeutics or radiation therapy.