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 method of treating a disease or disorder 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, the method comprising administering to a subject a therapeutically effective amount of a CD73 inhibitor, wherein the CD73 inhibitor comprises a compound having the following formula:
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 or heteroaralkyl is optionally substituted with one or more substituents selected from halo, haloalkyl, alkyl, alkoxy, carbonyl, aryl, amino, amido, 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 method of claim 1 , wherein the disease or disorder is cancer 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.
3. The method of claim 2 , wherein the cancer is selected from breast cancer, brain cancer, colon cancer, fibrosarcoma, kidney cancer, lung cancer, melanoma, ovarian cancer, and prostate cancer.
4. The method of claim 2 , wherein the cancer is breast cancer.
5. The method of claim 2 , further comprising conjointly administering one or more additional chemotherapeutic agents.
6. The method of claim 5 , wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, navitoclax (ABT-2631, afatinib dimaleate, axitinib, aminoglutethimide, amsacrine, anastrozole, adenosine 5′-(α,β-methylene)diphosphate (APCP), asparaginase, capivasertib (AZD5363), Bacillus Calmette-Guerin vaccine (bcg), bicalutamide, bleomycin, bortezomib, β-methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, trametinib (GSK1120212), hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, 8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3 (2H)-one (MK-2206), mutamycin, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, 8,8′-(carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)) bis(1,3,5-naphthalenetrisulfonic acid) (NF279), 4,4′,4″4″′-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449), nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, 2-amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7 (8H)-one (PF-04691502), plicamycin, pomalidomide, porfimer, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), procarbazine, quercetin, raltitrexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucaparib, selumetinib, sirolimus, sodium 2,4-dinitrobenzenesulfonate, sorafenib, streptozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA).
7. The method of claim 5 , wherein the one or more additional chemotherapeutic agents are selected from 1-amino-4-phenylamino-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (acid blue 25), 1-amino-4-[4-hydroxyphenyl-amino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[1-naphthylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[4-fluoro-2-carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, 1-amino-4-[2-anthracenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, APCP, β-methylene-ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, quercetin, reactive blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.
8. The method of claim 5 , wherein the additional chemotherapeutic agent is an immuno-oncology agent.
9. The method of claim 1 , wherein provisos a) or b) apply, wherein provisos a) and b) are as follows:
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 5 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.
10. The method 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.
11. The method of claim 1 , wherein Y is
12. The method of claim 1 , wherein R 5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent, 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.
13. The method of claim 1 , wherein R 5 is benzyl substituted on the phenyl ring with
14. The method of claim 1 , wherein
represents
15. The method of claim 1 , wherein Y is
16. The method of claim 15 , wherein each R 15 is hydroxy.
17. The method of claim 1 , wherein Het is selected from
18. The method 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.
19. The method of claim 18 , wherein Het is
20. The method of claim 18 , wherein R a is selected from H, halo, alkyl, thienyl, —NR 7 R 8 , aryl, and heteroaryl.
21. The method of claim 18 , wherein R b is selected from halo, alkyl, hydroxyalkyl, haloalkyl, amido, carbonyl, amido, and heteroaryl.
22. The method of claim 18 , wherein R 7 is selected from H, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl.
23. The method of claim 1 , wherein R 1a and R 2a are each hydroxy.
24. The method of claim 1 , wherein R 1a is hydroxy and Rib is H.
25. The method of claim 4 , wherein R 2a is hydroxy or C 1-6 alkyl.
26. The method of claim 1 , wherein R 2b is substituted or unsubstituted C 2 alkynyl.
27. The method of claim 1 , wherein R 2a is Me and R 2b is ethynyl.
28. The method of claim 1 , wherein R 2a is hydroxy and R 2b is ethynyl.
29. The method of claim 1 , wherein R 2b is propynyl, butynyl,
or unsubstituted or substituted
30. The method 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 ).
31. The method of claim 30 , wherein R 4 is —C(O)OR 9 and R 9 is H or alkyl.
32. The method of claim 30 , wherein R 4 is —C(O)NR 11 R 12 .
33. The method of claim 32 , 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.
34. The method of claim 1 , wherein R 6 is —C(O)OR 9 and R 9 is H or alkyl.
35. The method of claim 1 , wherein R 6 is —C(O)NR 16 R 17 .
36. The method of claim 1 , wherein R 4 and R 6 are each —C(O)OH.
37. The method of claim 18 , wherein R a is selected from H, Cl, —NR 7 R 8 , and phenyl.
38. The method of claim 1 , wherein R 5 is benzyl.
39. The method of claim 1 , wherein the CD73 inhibitor is selected from any one of the following compounds:
Example #
Compound
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or pharmaceutically acceptable salts and/or prodrugs thereof.