SUBSTITUTED 3-AMINO-5-PHENYLBENZAMIDE COMPOUNDS AS COVALENT INHIBITORS OF ENHANCER ZESTE HOMOLOG 2 (EZH2) AND PROTEOLYSIS-TARGETING CHIMERIC DERIVATIVES THEREOF (PROTACS) THAT INDUCE DEGRADATION OF EZH2
Disclosed are covalent inhibitors of enhancer zeste homolog 2 (EZH2) which may be utilized as EZH2 targeting agents. The disclosed compounds may be characterized as substituted 3-amino-5-phenylbenzamide compounds. The disclosed compounds may be utilized as covalent inhibitors of EZH2 and further may be derivatized to form proteolysis-targeting chimeric molecules (PROTACs) that target EZH2 for degradation. The disclosed compounds and PROTACs may be used in pharmaceutical compositions and methods for treating cell proliferative disorders associated with EZH2 activity, such as cancer.
1 - 15 . (canceled)
16 . A compound of a Formula I or a salt, hydrate, or solvate thereof.
wherein
R 1 is and electrophile or R 1 is hydrogen, alkyl, or —CH 2 —X, wherein X is selected from hydrogen, alkyl, amino, piperazinyl, morpholinyl, piperidinyl, and maleimidyl, and X optionally is substituted with a substituent selected from alkyl, alkoxy, —C(O)—H, —C(O)—(CH 2 ) m —CH 3 where m is 0-20, —(CH 2 CH 2 O) n —H or —(CH 2 CH 2 O) n —CH 3 where m is 0-20, —C(O)—(CH 2 CH 2 O) n —H or —C(O)—(CH 2 CH 2 O) n —CH 3 where n is 0-20, —C(O)—CH 2 OCH 3 , —C(O)—CH 2 —CH(CH 2 CH 2 CH 3 ) 2 , —C(O)—CH═CH-phenyl, —C(O)—CH 3 , —C(O)—CH 2 Cl, —C(O)—CH═C(CH 3 ) 2 , —C(O)—CH═CH 2 , —C(O)-ethynyl, —C(O)-adamantyl, —S(O)(O)—H, —S(O)(O)—CH 3 , —S(O)(O)-phenyl, —C(O)—CH 2 —CH 3 , —CH 2 —S(O)(O)—H, —CH 2 —CH 2 —S(O)(O)—H, —CH 2 —CH 2 —S(O)(O)—CH 3 , —CH 2 —CH 2 —S(O)(O)-phenyl, —CH═CH—S(O)(O)—H, —CH═CH—S(O)(O)—CH 3 , and —CH═CH—S(O)(O)-phenyl;
R 2 is selected from hydrogen, alkyl, piperidinyl (e.g., piperidin-4-yl) and oxane (e.g., oxan-4-yl), wherein R 3 optionally is substituted with a substituent selected from alkyl, alkoxy, —C(O)—H, —C(O)—(CH 2 ) m —CH 3 where m is 0-20, —(CH 2 CH 2 O) n —H or —(CH 2 CH 2 O) n —CH 3 where m is 0-20, —C(O)—(CH 2 CH 2 O) n —H or —C(O)—(CH 2 CH 2 O) n —CH 3 where n is 0-20, —C(O)—CH 2 OCH 3 , —C(O)—CH 2 —CH(CH 2 CH 2 CH 3 ) 2 , —C(O)—CH═CH-phenyl, —C(O)—CH 3 , —C(O)—CH 2 Cl, —C(O)—CH═C(CH 3 ) 2 , —C(O)—CH═CH 2 , —C(O)-ethynyl, —C(O)-adamantyl, —S(O)(O)—H, —S(O)(O)—CH 3 , —S(O)(O)-phenyl, —C(O)—CH 2 —CH 3 , —CH 2 —S(O)(O)—H, —CH 2 —CH 2 —S(O)(O)—H, —CH 2 —CH 2 —S(O)(O)—CH 3 , —CH 2 —CH 2 —S(O)(O)-phenyl, —CH═CH—S(O)(O)—H, —CH═CH—S(O)(O)—CH 3 , and —CH═CH—S(O)(O)-phenyl;
R 3 is hydrogen or alkyl;
R 4 is hydrogen or alkyl;
R 5 is hydrogen or alkyl; and
R 6 is hydrogen or alkyl.
17 . The compound of claim 16 , wherein R 1 is optionally substituted methyl-piperazinyl or methyl-morpholinyl.
18 . The compound of claim 16 , wherein R 2 is optionally substituted piperidinyl or oxane.
19 . A pharmaceutical composition comprising the molecule of claim 16 and a suitable pharmaceutical carrier, excipient, or diluent.
20 . A method of treating cancer, the method comprising administering the composition of claim 19 to a subject having the cancer.
21 . The method of claim 20 , wherein the cancer is associated with EZH2 activity.
22 . The method of claim 20 , wherein the cancer is selected from prostate cancer and lymphoma.
23 . The compound of claim 16 , wherein R 3 is alkyl.
24 . The compound of claim 16 , wherein R 4 is alkyl.
25 . The compound of claim 16 , wherein R 5 is alkyl.
26 . The compound of claim 16 , wherein R 6 is alkyl.
27 . The compound of claim 16 , wherein R 1 is —CH 2 —X, and X is optionally substituted piperidinyl, amino, or maleimidyl.
28 . The compound of claim 16 , wherein the compound is: