Compounds and methods for CD73 modulation and indications therefor
Disclosed are compounds of Formula I: or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein R 1 , R 2 , R 3 , A, E, L, and G are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.
1. A compound having the following formulae:
or a pharmaceutically acceptable salt thereof, wherein
R 2 is Cl, Br, CF 3 , or CN; and
G is heteroaryl substituted with 0-3 T 5 and 0-1 T 3 ;
T 3 is —(CH 2 ) 0-3 —C(O)N(R 8 )R 9 , —(CH 2 ) 0-3 —N(R 8 )R 9 , —(CH 2 ) 0-3 —C(O)OR 9 , —(CH 2 ) 0-3 -cycloalkyl, —(CH 2 ) 0-3 -cycloalkenyl, —(CH 2 ) 0-3 -heterocycloalkyl, —(CH 2 ) 0-3 -heterocycloalkenyl, —O-heterocycloalkyl optionally substituted with 4-chloropyridazin-3-one-5-yl, or —(CH 2 ) 0-3 -bridged carbocyclic ring, wherein the —(CH 2 ) 0-3 -cycloalkyl, —(CH 2 ) 0-3 -cycloalkenyl, —(CH 2 ) 0-3 -heterocycloalkyl, —(CH 2 ) 0-3 -heterocycloalkenyl, or —(CH 2 ) 0-3 -bridged carbocyclic are each optionally substituted with 1-3 Z 5 and 0-1 Z 1 , provided that when T 3 is attached to a heteroatom of G, G cannot be attached to an oxygen or nitrogen atom of T 3 ;
each T 5 is independently halogen, hydroxyl, alkyl optionally substituted with 1-3 R b , alkenyl optionally substituted with 1-3 R b , alkynyl optionally substituted with 1-3 R b , CN, cyanoalkyl, alkoxyl optionally substituted with 1-3 R b , or alkoxyalkyl optionally substituted with 1-3 R b , provided that when T 5 is attached to a heteroatom of G, T 5 cannot be halogen, hydroxyl, CN, or alkoxyl optionally substituted with 1-3 RD,
R 8 is H, alkyl optionally substituted with 1-4 Z 4 , alkenyl optionally substituted with 1-4 Z 4 , —C 0 -C 3 alkyl-cycloalkyl optionally substituted with 1-4 Z 3 , —C 0 -C 3 alkyl-phenyl optionally substituted with 1-4 Z 3 , —C 0 -C 3 alkyl-heteroaryl optionally substituted with 1-3 Z 5 , —C 0 -C 3 alkyl-heterocycloalkyl optionally substituted with 1-3 Z 5 , or a bridged carbocylic ring substituted with 0-5 T 1 ;
each R 9 is independently H or alkyl optionally substituted with 1-4 Z 4 ,
each T 1 is independently halogen, hydroxyl, alkyl optionally substituted with 1-3 R b , alkenyl optionally substituted with 1-3 RD, alkynyl optionally substituted with 1-3 RD, CN, cyanoalkyl, alkoxyl optionally substituted with 1-3 R b , or alkoxyalkyl optionally substituted with 1-3 R b ;
R b is halogen, CN, CF 3 , or hydroxyl, provided that not more than 1 R b can be CF 3 ;
each Z 3 is independently alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, or CN;
each Z 4 is independently hydroxyl, halogen, alkoxyl, or CN; and
each Z 5 is independently alkyl, haloalkyl, hydroxyl, hydroxyalkyl, halogen, alkoxyl, alkoxyalkyl, CN, or cyanoalkyl, provided that when Z 5 is attached to a heteroatom, then Z 5 is not halogen, hydroxyl, alkoxyl, or CN.
2. The compound according to claim 1 , wherein R2 is Cl.
3. The compound according to claim 2 , wherein G is pyrazolyl substituted with 0-2 T 5 and 0-1 T 3 .
4. The compound according to claim 3 , wherein T 5 is F, Cl, CH 2 Cl, CH 2 F, CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , CH 2 OH, —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH(CH 2 OH) 2 , —CH 2 CH(OH)CF 3 , CH 2 CF 3 , CN, —CH 2 CN, —OCH 3 , —CH 2 OCH 3 , —CHF 2 , —CH 2 CHF 2 , —CH 2 CH(OH)CH 2 CH 2 Cl, —CH(CH 2 OH)CH 2 Cl, —CH(CH 2 OH)CH 2 I, or —CH 2 C(CH 3 )(CH 2 OH)CH 2 Cl.
5. The compound according to claim 4 , wherein G is
6. The compound according to claim 5 , wherein T 3 is —CH 2 C(O)N(H)cyclopropyl, —CH 2 C(O)N(H)CH 3 , —CH 2 —COOH, oxetanyl, —(CH 2 ) 0-2 cyclopropyl, —(CH 2 ) 0-2 cyclobutyl, —(CH 2 ) 0-2 -tetrahydropyran, —(CH 2 ) 0-2 -tetrahydrofuran, —(CH 2 ) 0-2 azetidinyl, —(CH 2 ) 0-2 pyrolidinyl, or —(CH 2 ) 0-2 morpholinyl.
7. The compound according to claim 6 , wherein T 3 is oxetanyl.
8. A pharmaceutical composition comprising a compound having the structure according to claim 1 and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 8 , further comprising a second pharmaceutical agent.
10. A method for treating a subject with a disease or condition mediated by CD73, said method comprising administering to the subject a compound of claim 1 or a pharmaceutical composition of claim 8 , wherein the disease or condition is a neoplastic disorder, a cancer, an age-related disease, an inflammatory disorder, a cognitive disorder, lung fibrosis, liver fibrosis, Alzheimer's disease, multiple sclerosis, Parkinson's disease or a neurodegenerative disease.
11. The method for treatment of a disease or condition according to claim 10 , wherein the cancer is bladder cancer, colorectal cancer, gastric cancer, gall bladder cancer, glioblastoma multiforme, glioma, leukemia, lymphoma, lung cancer, breast cancer, melanoma, multiple myeloma, ovarian cancer, prostate cancer, pancreatic cancer, thyroid cancer.
12. The method for treatment of a disease or condition according to claim 11 , wherein the lymphoma is adult T-cell lymphoma, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, MALT lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, primary effusion lymphoma, or T-cell lymphoma.
13. The method for treatment of a disease or condition according to claim 11 , wherein the leukemia is adult T-cell leukemia, aggressive NK-cell leukemia, B-cell chronic lymphocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, B-cell prolymphocytic leukemia, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, or mast cell leukemia.
14. The method of claim 10 , wherein the cancer is renal cancer, small-cell lung cancer, non-small cell lung cancer, acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, breast cancer or prostate cancer.
15. The method of claim 10 , further comprising administering one or more additional therapeutic agents.
16. The method of claim 15 , wherein the one or more additional therapeutic agents is one or more of i) an alkylating agent; ii) an antibiotic; iii) an antimetabolite; iv) an immunotherapy agent; v) a hormone or hormone antagonist; vi) a taxane; vii) a retinoid; viii) an alkaloid; ix) an antiangiogenic agent; x) a topoisomerase inhibitor; xi) a kinase inhibitor; xii) a targeted signal transduction inhibitor; xiii) a biological response modifier; xiv) an IDO inhibitor; xv) a chemotherapeutic agent; xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor; xix) an EGFR inhibitor; and xx) an epigenetic modulator.
17. The method according to claim 16 , wherein the one or more additional therapeutic agents is one or more of an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan.
18. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin.
19. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate.
20. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of an immunotherapy agent selected from a PD-1 or PD-L1 inhibitor.
21. The method of claim 20 , wherein the PD-1 or PD-L1 inhibitor is nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, or durvalumab.
22. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a hormone or hormone antagonist selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene.
23. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel.
24. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin.
25. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine.
26. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of an antiangiogenic agent selected from AE-941, ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide.
27. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38, rubitecan, topotecan, and 9-aminocamptothecin.
28. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01, vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and vatalanib.
29. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin.
30. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a biological response modifier selected from imiquimod, interferon-α and interleukin-2.
31. The method of claim 16 , wherein the one or more additional therapeutic agents is one or more of a chemotherapeutic agent selected from 3-amino-2-carboxyaldehyde thiosemicarbazone, altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate, ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, a mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt inhibitor, a Hsp90 inhibitor, a farnesyltransferase inhibitor or an aromatase inhibitor.