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 of said compound, wherein:
R is an unsubstituted aryl or aryl substituted with one or more moieties which moieties 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 , —OCF 3 and heterocyclyl;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1–6 R 9 groups which groups can be the same or different with each R 9 being independently selected, aryl substituted with 1–3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups,
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heteroaryl and heteroarylalkyl,
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, 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 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 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 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —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 ;
m is 0 to 4, and
n is 1 to 4,
with the following provisos: (i) that when R is an unsubstituted phenyl, then R 2 is not alkyl, —C(O 2 )R 6 , aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R 2 is halogen only.
2. The compound of claim 1 , wherein R is an unsubstituted aryl or aryl substituted with one or moieties which moieties can be the same or different with each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , —S(O 2 )NR 5 R 6 , —SO 3 H, CH 2 OR 5 , —S(O 2 )R 6 , —C(O)NR 5 R 6 , —CF 3 , —OCF 3 and heterocyclyl;
R 2 is halogen, CF 3 , CN, lower alkyl and cycloalkyl;
R 3 is H, unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more moieties selected from the group consisting of halogen, CN, —OR 5 , CF 3 , —OCF 3 , lower alkyl and cycloalkyl, heterocyclyl, heteroaryl substituted with one or more moieties selected from the group consisting of halogen, CN, —OR 5 , CF 3 , —OCF 3 , alkyl and cycloalkyl,
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 an unsubstituted phenyl.
4. The compound of claim 2 , wherein R is phenyl substituted with one or more moieties selected from the group consisting of F, Cl, Br, CN, —SO 3 H, —S(O 2 )NR 5 R 6 , —S(O 2 )CH 3 , —NR 5 R 10 , —OH, hydroxymethyl, CF 3 and morpholinyl.
5. The compound of claim 2 , wherein R 2 is F, Cl, Br, CF 3 , lower alkyl and cycloalkyl.
6. The compound of claim 2 , wherein R 3 is H, lower alkyl, unsubstituted aryl, aryl substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of F, Cl, Br, CF 3 , lower alkyl, methoxy, and CN, or
7. The compound of claim 6 , wherein said lower alkyl is methyl, ethyl, isopropyl or tert-butyl.
8. The compound of claim 2 , wherein R 4 is H.
9. The compound of claim 2 , wherein R 5 is H.
10. The compound of claim 2 , wherein m is 0.
11. The compound of claim 2 , wherein R is 4-(methylsulfonyl)phenyl.
12. The compound of claim 2 , wherein R 2 is Cl, Br, isopropyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl.
13. The compound of claim 6 , wherein R 3 is unsubstituted phenyl, or phenyl substituted with —S(O 2 )NR 5 R 6 .
14. The compound of claim 6 , wherein R 3 is tert-butyl or isopropyl.
15. The compound of claim 6 , wherein R 3 is 2-fluorophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2-methylphenyl, 2-methoxyphenyl,
16. The compound of claim 6 , wherein R 3 is 3-(trifluoromethyl)phenyl.
17. The compound of claim 15 , wherein R 3 is:
18. The compound of claim 17 , wherein R 8 is (CH 2 ) n OH or (CH 2 ) n OCH 3 , where n is 1 or 2.
19. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
20. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
21. A compound of claim 1 , in isolated and purified form.