Inhibitors of protein methyltransferase dot1l and methods of use thereof

A compound of Formula (I) below or a pharmaceutically acceptable salt or ester thereof:

• wherein,
• Nuc is adenosine-like moiety or an analog or a derivative thereof,
• T is —CH2-L1-L2-L3-, with L3 connected to R9 wherein:
• L1 is N(Y), S, SO, or SO2;
• L2 is CO or absent when L1 is N(Y), or L2 is absent when L1 is S, SO, or SO2, in which Y is H, Rd, SO2Rd, or CORd when L2 is absent, or Y is H or Rd when L2 is CO, Rd being C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and Rd being optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, carboxyl, cyano, C1-C6 alkoxyl, C1-C6 alkylsulfonyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 8-membered heterocycloalkyl, 5 to 6-membered heteroaryl, ORd′, OCORd′, and N(Rd′)2, and with C3-C8 cycloalkyl, C6-C10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C1-C6 alkyl, OC(O)—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, each Rd′ independently being H, C1-C6 alkyl, silyl, C1-C6 alkyl-C3-C8 cycloalkyl, C6-C10 aryl, 5 to 6-membered heteroaryl, aralkyl, or heteroaralkyl;
• L3 is —(CR4R5)n-unsubstituted or substituted C3-C8 cycloalkyl-(CR6R7)m—, with (CR6R7)m connected to R9;
• each of R4, R5, R6 and R7, independently, is H, halo, hydroxyl, carboxyl, cyano, or RS2, RS2 being amino, C1-C6 alkoxyl, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, and each RS2 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
• or two geminal R4 and R5 or two geminal R6 and R7 taken together are ethylene, propylene or butylene;
• m is 0, 1, or 2;
• n is 0, 1, or 2;
• Nuc-T is capable of binding within the SAM binding pocket of human DOT1L which comprises amino acid residues 135-241 of SEQ ID NO:
• 1;
• and
• R9 is a group such that R9 induces a conformational adaptation in human DOT1L, wherein the conformational adaptation is the formation of a hydrophobic pocket domain which comprises amino acid residues 139-312 of SEQ ID NO:
• 1.