Ectonucleotidase inhibitors and methods of use thereof
The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.
1. A compound of formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
Y is
Het is an optionally substituted purinyl ring or an optionally substituted 5-methyl-pyrimidin-2,4-dione ring;
R 1a is selected from H, halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, amino-C 1-6 alkyl, —O—C(O)—O—C 1-6 alkyl, C 1-6 acyloxy, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl;
R 1b is selected from H, halo, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 2a is selected from halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 acyloxy, —O—C(O)—O—C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl;
R 2b is C 2-6 alkynyl;
R 3 is selected from H and alkyl;
R 4 is selected from H, alkyl, CN, aryl, heteroaryl, —C(O)OR 9 , —C(O)NR 11 R 12 , —S(O) 2 R 10 , —P(O)(OR 11 )(OR 12 ), and —P(O)(OR 11 )(NR 13 R 14 );
R 5 is aralkyl or heteroaralkyl wherein the aralkyl is substituted with one or more substituents selected from halo, haloalkyl, alkyl, alkoxy, carbonyl, aryl amino, amino, cycloalkyl, heterocyclyl, and heteroaryl;
R 6 is selected from —C(O)OR 9 , —C(O)NR 16 R 17 , and —P(O)(OR 11 )(OR 12 );
R 9 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
R 10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and
each R 11 and R 12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or
R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl;
R 13 is, independently for each occurrence, H or alkyl;
R 14 is, independently for each occurrence, alkyl or aralkyl;
each R 15 is independently selected from hydroxy, alkoxy acyloxy and NR 13 R 14 ;
each R 16 and R 17 is independently selected from H, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or
R 16 and R 17 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.
2. The compound of claim 1 , wherein:
a) if R 4 and R 6 are each —C(O)OH and R 5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent, then the heterocyclyl or heteroaryl substituent is selected from unsubstituted or substituted pyrrolidinyl, piperazinonyl, piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl; and
b) if R 4 is —C(O)OH or tetrazolyl, R 6 is —C(O)OH, and R 5 is benzyl substituted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with —C(O)OR 9 where R 9 is H or alkyl.
3. The compound of claim 1 , wherein
R 5 is aralkyl or heteroaralkyl with a para substituent on the aryl or heteroaryl ring selected from heterocyclyl, heteroaryl, and aryl; and
R 2b is substituted or unsubstituted C 2 alkynyl.
4. The compound of claim 1 , wherein Y is R
5. The compound of claim 1 , wherein R 5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent.
6. The compound of claim 1 , wherein R 5 is benzyl substituted on the phenyl ring at the 4-position with
7. The compound of claim 1 , wherein
represents
8. The compound of claim 1 , wherein Y is
9. The compound of claim 8 , wherein each R 15 is hydroxy.
10. The compound of claim 1 , wherein Het is
11. The compound of claim 1 , wherein Het is
wherein
Z is N;
R a is selected from H, halo, hydroxy, alkyl, thiophenyl, —NR 7 R 8 , aralkyl, aryl, and heteroaryl;
R b is selected from halo, alkyl, haloalkyl, hydroxy alkyl, alkylthio, amido, carbonyl, amido, and heteroaryl; and
R 7 is selected from H, hydroxy, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl and
R 8 is H or alkyl; or
R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring.
12. The compound of claim 11 , wherein R a is selected from H, Cl, —NR 7 R 8 , and phenyl.
13. The compound of claim 11 , wherein R b is selected from Cl, —CF 3 , carbonyl, and —CONH 2 .
14. The compound of claim 11 , wherein R 7 is selected from H, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl.
15. The compound of claim 1 , wherein R 1a and R 2a are each hydroxy.
16. The compound of claim 1 , wherein R 1a is hydroxy and R 1b is H.
17. The compound of claim 1 , wherein R 2a is hydroxy or C 1-6 alkyl.
18. The compound of claim 1 , wherein R 2b is substituted or unsubstituted C 2 alkynyl.
19. The compound of claim 1 , wherein R 2a is Me and R 2b is ethynyl.
20. The compound of claim 1 , wherein R 2a is hydroxy and R 2b is ethynyl.
21. The compound of claim 1 , wherein R 2b is propynyl, butynyl,
or unsubstituted or substituted
22. The compound of claim 1 , wherein R 4 is selected from —C(O)OR 9 , —C(O)NR 11 R 12 , —S(O) 2 R 10 , and —P(O)(OR 11 )(OR 12 ).
23. The compound of claim 22 , wherein R 4 is —C(O)OR 9 and R 9 is H or alkyl.
24. The compound of claim 22 , wherein R 4 is —C(O)NR 11 R 12 .
25. The compound of claim 24 , wherein each R 11 and R 12 is independently selected from H and alkyl; or R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.
26. The compound of claim 1 , wherein R 6 is —C(O)OR 9 and R 9 is H or alkyl.
27. The compound of claim 1 , wherein R 6 is —C(O)NR 16 R 17 .
28. The compound of claim 1 , wherein R 4 and R 6 are each —C(O)OH.
29. A compound selected from:
Example #
Compound
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or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
31. The compound of claim 1 , wherein R 2b is unsubstituted C 2 alkynyl.
32. The compound of claim 5 , wherein R 5 is benzyl substituted on the phenyl ring at a para position.
33. The compound of claim 5 , wherein:
the phenyl ring substituent is selected from substituted piperidonyl, piperazinonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl, and, optionally,
the piperidonyl, tetrahydropyrimidonyl, pyridonyl, or pyridyl is substituted with one or more of alkyl, hydroxyalkyl or alkoxyalkyl.
34. The compound of claim 28 , wherein R 5 is benzyl substituted on the phenyl ring.
35. A compound of formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof wherein
Y is
Het is
wherein Z is N; R a is selected from —NR 7 R 8 , aralkyl, aryl, and heteroaryl; R b is selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkylthio, amido, carbonyl, amido, and heteroaryl; R 7 is selected from hydroxy, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl and R 8 is H or alkyl; or R 7 and R 8 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl ring;
R 1a is selected from H, halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxyC 1-6 alkyl, amino-C 1-6 alkyl, —O—C(O)—O—C 1-6 alkyl, C 1-6 acyloxy, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl;
R 1b is selected from H, halo, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
R 2a is selected from halo, hydroxy, cyano, azido, amino, C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 acyloxy, —O—C(O)—O—C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, and C 2-6 alkynyl;
R 2b is C 2-6 alkynyl;
R 3 is selected from H and alkyl;
R 4 is selected from H, alkyl, CN, aryl, heteroaryl, —C(O)OR 9 , —C(O)NR 11 R 12 , —S(O) 2 R 10 , —P(O)(OR 11 )(OR 12 ), and —P(O)(OR 11 )(NR 13 R 14 );
R 5 is aralkyl or heteroaralkyl;
R 6 is selected from —C(O)OR 9 , —C(O)NR 16 R 17 , and —P(O)(OR 11 )(OR 12 );
R 9 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;
R 10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; and
each R 11 and R 12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; or
R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl;
R 13 is, independently for each occurrence, H or alkyl;
R 14 is, independently for each occurrence, alkyl or aralkyl;
each R 15 is independently selected from hydroxy, alkoxy acyloxy and NR 13 R 14 ;
each R 16 and R 17 is independently selected from H, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or
R 16 and R 17 , together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.