JPWO2021080955A5 - - Google Patents

Claims (38)

Compound 1:

or an enantiomer, a mixture of enantiomers, a tautomer, an isotopologue, or a pharmaceutically acceptable salt thereof, the pharmaceutical composition for treating a hematological malignancy, wherein the compound is It is characterized in that it is used to be administered in combination with a second active agent, the second active agent being an EZH2 inhibitor, an HDAC inhibitor, a BCL2 inhibitor, a BTK inhibitor, an mTOR inhibitor. , PI3K inhibitor, PKCβ inhibitor, SYK inhibitor, JAK2 inhibitor, Aurora kinase inhibitor, BET inhibitor, hypomethylating agent, DOT1L inhibitor, HAT inhibitor, WDR5 inhibitor, DNMT1 inhibitor, LSD- 1 inhibitor, G9A inhibitor, PRMT5 inhibitor, BRD inhibitor, SUV420H1/H2 inhibitor, CARM1 inhibitor, PLK1 inhibitor, NEK2 inhibitor, MEK inhibitor, PHF19 inhibitor, PIM inhibitor, IGF-1R inhibitor A pharmaceutical composition that is one or more of a drug, an XPO1 inhibitor, a BIRC5 inhibitor, or chemotherapy. 2. The pharmaceutical composition of claim 1, wherein the second active agent is an EZH2 inhibitor. The EZH2 inhibitor is tazemetostat, GSK126, CPI-1205, 3-deazaneplanocin A (DZNep), EPZ005687, EI1, UNC1999, or sinefungin, or a stereoisomer, mixture of stereoisomers, tautomer, The pharmaceutical composition according to claim 2, which is an isotopologue or a pharmaceutically acceptable salt. The pharmaceutical composition according to claim 3, wherein the EZH2 inhibitor is tazemetostat, GSK126 or CPI-1205. 5. The pharmaceutical composition according to claim 4, wherein the EZH2 inhibitor is tazemetostat. the second active agent is an HDAC inhibitor, wherein the HDAC inhibitor is panobinostat, romidepsin, vorinostat , or citalinostat , or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutical agent thereof; The pharmaceutical composition according to claim 1 , which is a pharmaceutically acceptable salt. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a BCL2 inhibitor, wherein the BCL2 inhibitor is venetoclax, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. the second active agent is a BTK inhibitor, the BTK inhibitor being ibrutinib, or acalabrutinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof; The pharmaceutical composition according to claim 1 , which is. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is an mTOR inhibitor, and the mTOR inhibitor is everolimus. The second active agent is a PI3K inhibitor, and the PI3K inhibitor is idelalisib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. Item 1. Pharmaceutical composition according to item 1 . the second active agent is a PKCβ inhibitor, the PKCβ inhibitor is enzastaurin, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof; , the pharmaceutical composition according to claim 1 . 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a SYK inhibitor, and the SYK inhibitor is fostamatinib, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. the second active agent is a JAK2 inhibitor, the JAK2 inhibitor is fedratinib, pacritinib, ruxolitinib, baricitinib, gundotinib, lestaurtinib, or momelotinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue thereof; The pharmaceutical composition according to claim 1 , which is a pharmaceutically acceptable salt thereof. The second active agent is an aurora kinase inhibitor, and the aurora kinase inhibitor is alisertib, valasertib, AZD1152-HQPA, danucertib, AT9283, PF-03814735, AMG900, tozasertib, ZM447439, MLN8054, hesperidin, SNS-314, PHA -680632, CYC116, GSK1070916, TAK-901, or CCT137690, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof . The second active agent is a BET inhibitor, the BET inhibitor being birabresib or 4-[2-(cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one. , BMS-986158, RO-6870810, CPI-0610, or molybresib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof . Pharmaceutical compositions as described. the second active agent is a hypomethylating agent, wherein the hypomethylating agent is 5-azacytidine or decitabine, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or a pharmaceutically acceptable The pharmaceutical composition according to claim 1 , which is a salt of. the second active agent is a DOT1L inhibitor, the DOT1L inhibitor being SGC0946 or pinometostat, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof; The pharmaceutical composition according to claim 1 , which is 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a HAT inhibitor, and the HAT inhibitor is C646, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a WDR5 inhibitor, and the WDR5 inhibitor is OICR-9429, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. . The second active agent is a DNMT1 inhibitor, and the DNMT1 inhibitor is GSK3484862, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. Item 1. Pharmaceutical composition according to item 1 . The second active agent is an LSD-1 inhibitor, wherein the LSD-1 inhibitor is 4-(2-(4-aminopiperidin-1-yl)-5-(3-fluoro-4-methoxyphenyl)- 1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)-2-fluorobenzonitrile or seclidemstat, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof , the pharmaceutical composition according to claim 1 . 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a G9A inhibitor, wherein the G9A inhibitor is UNC0631, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof. The second active agent is a PRMT5 inhibitor, and the PRMT5 inhibitor is GSK3326595, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. Item 1. Pharmaceutical composition according to item 1 . the second active agent is a BRD inhibitor, the BRD inhibitor being LP99 or JQ1 , or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof; , the pharmaceutical composition according to claim 1 . 2. The second active agent is an SUV420H1/H2 inhibitor, wherein the SUV420H1/H2 inhibitor is A-196, or a tautomer, isotopologue, or pharmaceutically acceptable salt thereof . Pharmaceutical composition . The second active agent is a CARM1 inhibitor, and the CARM1 inhibitor is EZM2302, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or pharmaceutically acceptable salt thereof. Item 1 is a pharmaceutical composition . The second active agent is a PLK1 inhibitor, and the PLK1 inhibitor is BI2536, volasertib, CYC140, onvansertib, GSK461364, or TAK960, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue, or The pharmaceutical composition according to claim 1 , which is a pharmaceutically acceptable salt. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a NEK2 inhibitor, and the NEK2 inhibitor is JH-295 or rac-CCT250863. the second active agent is a MEK inhibitor, wherein the MEK inhibitor is trametinib, trametinib dimethyl sulfoxide, cobimetinib, binimetinib, or selumetinib, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue thereof, or a pharmaceutically acceptable salt, the pharmaceutical composition according to claim 1 . the second active agent is a PIM inhibitor, the PIM inhibitor is LGH-447, AZD1208, SGI-1776, or TP-3654, or a stereoisomer, mixture of stereoisomers, tautomer, isotopologue thereof; The pharmaceutical composition according to claim 1 , which is a pharmaceutically acceptable salt thereof. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is an IGF-1R inhibitor, and the IGF-1R inhibitor is lincitinib. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is an XPO1 inhibitor, and the XPO1 inhibitor is selinexor. 2. The pharmaceutical composition of claim 1 , wherein the second active agent is a BIRC5 inhibitor, and the BIRC5 inhibitor is YM155. the second active agent is chemotherapy, the chemotherapy is bendamustine, doxorubicin, etoposide, methotrexate, cytarabine, vincristine, ifosfamide, melphalan, oxaliplatin, or dexamethasone, or a stereoisomer or mixture of stereoisomers thereof; The pharmaceutical composition according to claim 1 , which is a tautomer, isotopolog, prodrug, or pharmaceutically acceptable salt. 35. A pharmaceutical composition according to any one of claims 1 to 34 , wherein the compound is the hydrochloride salt of Compound 1. Hematologic malignancies include acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), and Hodgkin's lymphoma. (HL), T-cell lymphoma (TCL), Burkitt's lymphoma (BL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone lymphoma (MZL), or myelodysplastic syndrome (MDS) 36. The pharmaceutical composition according to any one of claims 1 to 35 . 37. The pharmaceutical composition of claim 36 , wherein the hematological malignancy is recurrent or refractory. 37. The pharmaceutical composition according to claim 36 , wherein a hematological malignancy is newly diagnosed.