Heterocyclic compounds and uses thereof
Provided herein are heterocyclic compounds of Formula (I), pharmaceutical compositions containing such a compound and their therapeutic uses, methods for their preparation, intermediate compounds, pharmaceutical compositions containing such a compound, and their therapeutic uses.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X, when present, is halo.
2. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutical acceptable excipient or carrier.
4. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutical acceptable excipient or carrier.
5. A pharmaceutical composition comprising a compound of claim 1 and another therapeutic agent.
6. A pharmaceutical composition comprising a compound of claim 2 and another therapeutic agent.
7. The pharmaceutical composition according to claim 5 , wherein the another therapeutic agent is i) 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; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) 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; iv) an antibody therapy agent selected from alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; v) a hormone or hormone antagonist selected from the group consisting of anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) 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 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and vatalanib; xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), 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 and an aromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor, xix) an EGFR inhibitor, or xx) an epigenetic modulator.
8. The pharmaceutical composition according to claim 6 , wherein the another therapeutic agent is i) 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; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) 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; iv) an antibody therapy agent selected from alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan; v) a hormone or hormone antagonist selected from the group consisting of anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) 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 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib selumetinib and vatalanib; xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), 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 and an aromatase inhibitor (anastrozole letrozole exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor, xix) an EGFR inhibitor, or xx) an epigenetic modulator.
9. The pharmaceutical composition according to claim 7 , wherein the another therapeutic agent is an epigenetic modulator selected from the group consisting of:
(a) a DNA methyltransferase;
(b) a histone or protein methyltransferase;
(c) a histone demethylase;
(d) a histone deacetylase inhibitor;
(e) histone acetyltransferase; and
(f) other chromatin remodelers.
10. The pharmaceutical composition according to claim 8 , wherein the another therapeutic agent is an epigenetic modulator selected from the group consisting of:
(a) a DNA methyltransferase;
(b) a histone or protein methyltransferase;
(c) a histone demethylase;
(d) a histone deacetylase inhibitor;
(e) histone acetyltransferase; and
(f) other chromatin remodelers.
11. The pharmaceutical composition according to claim 7 , wherein the epigenetic modulator is a histone deacetylase inhibitor selected from the group consisting of: vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, givinostat, and quisinostat.
12. The pharmaceutical composition according to claim 8 , wherein the epigenetic modulator is a histone deacetylase inhibitor selected from the group consisting of: vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, givinostat, and quisinostat.
13. A method for treating a subject with a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of claim 2 , wherein the disease or condition is an autoimmune condition, an inflammatory condition or a combination thereof.
14. A method for treating a subject with a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of claim 2 , wherein the disease or condition is selected from the group consisting of an autoimmune condition, inflammatory condition, lung cancer, breast cancer, colon cancer, midline carcinomas, acral lentiginous melanoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, bone cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, colorectal cancer, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, gastric cancer, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant peripheral nerve sheath tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, medullary carcinoma of the breast, medulloblastoma, melanoma, merkel cell cancer, mesothelioma, multiple myeloma, neuroblastoma, neurofibroma, nodular melanoma, osteosarcoma, ovarian cancer, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, prostate cancer, pancreatic cancer, -skin cancer, T-cell lymphoma, and uveal melanoma.
15. The method of claim 14 , wherein the autoimmune condition or inflammatory condition is selected from the group consisting of ulcerative colitis, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, and osteoarthritis.
16. The method of claim 13 , wherein the disease or condition is an autoimmune condition or inflammatory condition selected from the group consisting of ulcerative colitis, chronic obstructive pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, and osteoarthritis.
17. The method of claim 16 , wherein the autoimmune condition or inflammatory condition is selected from the group consisting of rheumatoid arthritis, osteoarthritis, ulcerative colitis, and atherosclerosis.
18. A method for treating a subject with a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , wherein the disease or condition is non-small cell lung cancer, small cell lung cancer, ovarian cancer, melanoma, midline carcinomas, breast cancer, lymphomas, neuroblastoma, castration resistant prostate cancer, myelofibrosis, myelodysplastic syndromes, or acute myeloid leukemia.
19. A method for treating a subject with a disease or condition mediated by a bromodomain, said method comprising administering to the subject in need thereof an effective amount of a compound of claim 2 , wherein the disease or condition is acute myeloid leukemia.
20. The method of claim 18 , further comprising administering quizartinib to said subject.
21. The method of claim 19 , further comprising administering quizartinib to said subject.