Dimers of Covalent NFKB Inhibitors

A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:

• wherein
• X is O, S, or NR4;
• L is C1-18alkylene or C2-18alkenylene optionally interrupted with one or more of (i) non-adjacent heteroatom(s) selected from O, S, and NR4, (ii) C(O)NR4, (iii) C6-10 aryl, (iv) 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, (v) 3-12 membered cycloalkyl ring, and (vi) 3-7 membered heterocycloalkyl ring having 1-3 ring heteroatoms selected from O, S, and N, and said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R4;
• each R1 is independently selected from the group consisting of C1-6 alkyl, halo, CN, N(R4)2, OR4, NO2, CO2R4, (C═O)R4, CON(R4)2, NR4(C═O)R5, C6-10 aryl, and 5-10 membered heteroaryl having 1-4 heteroatoms selected from N, O, and S, and said alkyl can be optionally substituted with 1 to 3 R3;
• each R2 is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, OR4, COR4, CO2R4, CON(R4)2, N(R4)2, and SR4, or a pair of two R2 together with the carbon atom to which they are attached form a saturated or unsaturated 4-8 membered cycloalkyl or heterocycloalkyl ring, wherein the heterocycloalkyl ring has 1 or 2 ring heteroatoms selected from O, S, and N, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl ring, and heterocycloalkyl ring are optionally substituted with 1 to 3 R3, with the proviso that at least one R2 or one pair of two R2 together forming a ring comprise an α,β-unsaturated moiety;
• each R3 is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, N(R4)2, OR4, NO2, oxo, ═S, ═NR4, CO2R4, (C═O)R4, CON(R4)2, C6-10 aryl, and 5-10 membered heteroaryl having 1-4 ring heteroatoms selected from N, O, and S, and wherein said alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 3 R4;
• each R4 is independently selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said alkyl, alkenyl, and alkynyl are optionally substituted with one or more substituents selected from the group consisting of halo, CN, NH2, OH, and C1-6 alkoxy;
• and
• n is 0-4.