Pyrazolopyrimidines as cyclin dependent kinase inhibitors
View Patent ↗In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
1. A compound represented by the structural formula:
or a pharmaceutically acceptable salt thereof,
wherein:
R is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —C(R 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, aryl, heteroaryl, CF 3 , alkynylalkyl, cycloalkyl, —C(O)OR 4 , alkyl substituted with 1–6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —CH 2 OR 5 , —C(O)R 5 , —SO 3 H, —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , —CF 3 , and —OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)OR 4 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyolyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R 7 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —CH 2 OR 4 , —C(O)OR 6 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 6 , —(CH 2 ) n OR 4 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
m is 0 to 4; and
n is 1 to 4.
2. The compound of claim 1 , wherein R is selected from the group consisting of 2-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridyl-N-oxide, 3-pyridyl-N-oxide, 1,3-thiazol-2-yl, pyrimidin-5-yl, pyrazin-3-yl and pyridazin-3-yl wherein each of said pyridyl, thiazolyl, pyrimidinyl, pyrazinyl and pyridazinyl moieties can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, arylCF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 6 , —S(O 2 )NR 5 R 6 , and —N(R 5 )S(O 2 )R 7 ;
R 2 is halogen, CF 3 , CN, lower alkyl, cycloalkyl, —OR 6 , —C(O)OR 4 , —(CH 2 ) n OR 6 , aryl or heteroaryl;
R 3 is H, halogen, lower alkyl, aryl, heteroaryl, —C(O)OR 4 , cycloalkyl, —NR 5 R 6 , cycloalkylalkyl,
wherein said alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl for R 3 are unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF 3 , OCF 3 , lower alkyl, CN and OR 5 ;
R 4 is H or lower alkyl;
R 5 is H or lower alkyl;
m is 0 to 2; and
n is 1 or 2.
3. The compound of claim 2 , wherein R is selected from the group consisting of 2-pyridyl, 4-pyridyl, 3-pyridyl, 4-pyridyl-N-oxide, 3-pyridyl-N-oxide, 1,3-thiazol-2-yl and pyrimidin-5-yl.
4. The compound of claim 2 , wherein R 2 is F, Cl, Br, CF 3 , CN, lower alkyl, cycloalkyl or —(CH 2 ) n OR 6 .
5. The compound of claim 2 , wherein R 3 is H, lower alkyl, cycloalkyl, —C(O)OR 4 , aryl, heteroaryl, cycloalkylalkyl,
wherein said lower alkyl, aryl, cycloalkyl, heteroaryl, and the heterocyclyl moieties shown above for R 3 are unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CF 3 , lower alkyl, —OCH 3 , —CH 2 OH, —CH 2 CH 2 OH, and CN.
6. The compound of claim 2 , wherein R 4 is H.
7. The compound of claim 2 , wherein R 5 is H.
8. The compound of claim 2 , wherein m is 0.
9. The compound of claim 2 , wherein n is 1.
10. The compound of claim 2 , wherein R is 2-pyridyl.
11. The compound of claim 2 , wherein R is 3-pyridyl.
12. The compound of claim 2 , wherein R is 4-pyridyl.
13. The compound 2, wherein R is the N-oxide of 4-pyridyl.
14. The compound of claim 4 , wherein said R 2 is Br.
15. The compound of claim 4 , wherein said R 2 is Cl.
16. The compound of claim 4 , wherein R 2 is isopropyl or ethyl.
17. The compound of claim 4 , wherein R 2 is —CH 2 OH or —CH 2 OCH 3 .
18. The compound of claim 4 , wherein R 2 is cyclopropyl.
19. The compound of claim 4 , wherein R 2 is CN.
20. The compound of claim 2 , wherein R 3 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, —NR 5 R 6 ,
21. The compound of claim 20 , wherein R 3 is isopropyl.
22. The compound of claim 21 , wherein R 3 is
23. The compound of claim 20 , wherein R 3 is unsubstituted phenyl or phenyl substituted with one or more moieties selected from the group consisting of F, Br, Cl, OMe, CH 3 and CF 3 .
24. The compound of claim 20 , wherein R 3 is cyclohexylmethyl.
25. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or solvate thereof.
26. A compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof.
27. A compound of claim 1 , in isolated and purified form.