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 having formula (IE):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
Y is
Het is selected from the group consisting of
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 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 selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and —C(O)OR 9 ;
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, 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 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
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
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 selected from H, aralkyl and heteroaralkyl; and/or
each aralkyl and heteroaralkyl at R 5 is unsubstituted or substituted with one or more substituents selected from halo, alkyl, alkoxy, carbonyl, amino, amido, cycloalkyl, heterocyclyl, and heteroaryl; and/or
the substituents on the aralkyl and heteroaralkyl at R 5 are selected from halo, haloalkyl, alkoxy, amino, carbonyl, aryl, heterocyclyl, and heteroaryl; and/or
R 5 is benzyl substituted on the phenyl ring (e.g., at a para position) with a heterocyclyl or heteroaryl substituent, e.g., 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; and/or
R 5 is benzyl substituted on the phenyl ring with
4. The compound of claim 1 , wherein
5. The compound of claim 1 , wherein Het is
wherein
Z is CH or 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, hydroxyalkyl, alkylthio, amido, carbonyl, amido, and heteroaryl;
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.
6. The compound of claim 5 , wherein R a is selected from H, halo, alkyl, thienyl, —NR 7 R 8 , aryl, and heteroaryl.
7. The compound of claim 5 , wherein R b is selected from halo, alkyl, hydroxyalkyl, haloalkyl, amido, carbonyl, amido, and heteroaryl.
8. The compound of claim 5 , wherein R 7 is selected from H, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl.
9. The compound of claim 1 , wherein
R 1a is H or hydroxy; and/or
R 1a and R 2a are each hydroxy; and/or
R 2a is hydroxy or C 1-6 alkyl; and/or
R 2b is C 2-6 alkynyl; and/or
R 2a is Me and R 2b is ethynyl; and/or
R 2a is hydroxy and R 2b is ethynyl.
10. The compound of claim 1 , wherein R 2b is propynyl, butynyl,
or unsubstituted or substituted
11. 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 ); and/or
R 4 is —C(O)OR 9 and R 9 is H or alkyl; and/or
R 4 is —C(O)NR 11 R 12 ; and/or
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; and/or
R 4 is —S(O) 2 R 10 and R 10 is alkyl or aryl.
12. The compound of claim 1 , wherein:
R 6 is —C(O)OR 9 and R 9 is H or alkyl; and/or
R 6 is —C(O)NR 16 R 17 ; and/or
R 4 and R 6 are each —C(O)OH.
13. The compound of claim 1 selected from:
Example #
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or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is
15. The compound of claim 1 , wherein the compound is
16. The compound of claim 1 , wherein the compound is
17. The compound of claim 1 , wherein the compound is
18. A pharmaceutical composition, comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
19. A method of inhibiting CD73 in a cell comprising contacting the cell with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
20. A method of treating a disease or disorder mediated by CD73 activity, comprising administering to a subject a therapeutically effective amount of a CD73 inhibitor, wherein the CD73 inhibitor comprises a compound as defined in claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is selected from cancer, cerebral and cardiac ischemic diseases, fibrosis, immune and inflammatory disorders, inflammatory gut motility disorder, neurological, neurodegenerative and CNS disorders and diseases, depression, Parkinson's disease, and sleep disorders, and the cancer is selected from bladder cancer, bone cancer, brain cancer, breast cancer, cardiac cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, head & neck cancer, Kaposi's sarcoma, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, myeloma, ovarian cancer, pancreatic cancer, penile cancer, prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma.