Covalent small molecule DCN1 inhibitors and therapeutic methods using the same

A compound having a structural formula (I)

• wherein;
• Q is C═O, C═S or SO2;
• Ar1 is a five or six-membered aromatic or heteroaromatic ring or a bicyclic aromatic or heteroaromatic ring having 8-12 atoms, including up to four heteroatoms chosen from N, O and S, in a chemically stable arrangement, optionally substituted with up to four R2 substituents;
• T is halogen, SS—C1-6 lower alkyl, pentafluorophenoxy, tetrafluorophenoxy:
• X is selected from a bond, CR7R8, CR7R8NR12, CR7R8NR12CO, CR7R8NR12CONR12, CR7R8NR12SO2, CR7R8O, CR7R8S(O)x CONR12;
• Y is selected from C1-6 alkylidyl, C3-6 cycloalkylidyl, C4-7 heterocloalkylidyl, arylene, heteroarylene, aryl(m)ethylene, heteroaryl(m)ethylene, fused C5-8 bicycloalkylidyl or C5-9 spirocycloalkylidyl;
• or Y and R9 are taken together with the nitrogen atom to which they are attached to form a heterocyclic or heteroaryl ring of four to seven members, optionally including any chemically stable combination of one to three groups selected from O, C═O, N, NR5 and S;
• Z is
• R1 is selected from the group consisting of H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 cycloalkylmethylene, NHMe, N(Me)2, NHEt, NH-cyclopropyl, OMe, OEt, O-cyclopropyl;
• R2 are independently selected from the group consisting of halo, CN, N3, CF3, NO2, H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, C4-7 heterocycloalkyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl, OR5, NR3R4, COOR5, CONR3R4;
• R3 and R4, independently, are selected from the group consisting of hydrogen, C1-6 alkyl, allyl, C3-6 cycloalkyl, C4-7 heterocyclyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-6 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, or are taken together with the nitrogen atom to which they are attached to form a ring of four to seven members, optionally including any chemically stable combination of one to three O, C═O, NR5 and S;
• R5 is selected from the group consisting of hydrogen, CF3, CHF2, C1-6 alkyl, allyl, propargyl, C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C4-7 heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-7 heterocycloalkyl, C1-6 alkaryl, C1-6 alkyl-heteroaryl, C1-6 acyl, C3-6 cycloalkylcarbonyl, C4-7 heterocycloalkylcarbonyl, aroyl, heteroaroyl, each optionally substituted with up to three substituents independently selected from halo, hydroxy, oxo, thio, thiono, amino, cyano, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylamino, C1-6 dialkylamino, C4-7 heterocycloalkyl, aryl, and heteroaryl;
• R6 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C4-6 cycloalkenyl, C4-7 heterocycloalkyl, C2-6 alkynyl, C1-6 alkyl-C3-6 cycloalkyl, C1-6 alkyl-C4-6 cycloalkenyl, C1-6 alkyl-C4-7 heterocycloalkyl, aryl, C1-6 alkylaryl, heteroaryl, C1-6 alkyl-heteroaryl, C5-10 bicycloalkyl and C1-6 alkyl-C5-10 bicycloalkyl;
• R7 and R8 may be independently H, C1-6 alkyl, substituted C1-6 alkyl, C2-6 alkenyl, substituted C2-6 alkenyl, C2-6 alkynyl, substituted C2-6 alkynyl, or taken together with the C atom to which they are attached, form a carbonyl group, a thionyl group, an oxime, a hydrazone, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl or C4-7 heterocycloalkyl:
• R9 is selected from the group consisting of H, C1-6 alkyl, substituted C1-6 alkyl, C3-6 alkenyl, substituted C3-6 alkenyl, C3-6 alkynyl, substituted C3-6 alkynyl, C3-6 cycloalkyl, substituted C3-6 cycloalkyl, C4-6 cycloalkenyl substituted C4-6 cycloalkenyl, phenyl, substituted phenyl, monocyclic heteroaryl, substituted monocyclic heteroaryl or C4-7 heterocycloalkyl:
• R10 is H, F, Cl, CF3, CHF2, (CH2)nNR3R4, CH2SO2R12, CH2OCOR12, CN or R12;
• R11e is H, R12, (CH2)nR2, CF2(CH2)xR2, COR5, CO2R5 or CONR3R4;
• R11z is H, F, Cl, CF3, CHF2, CF2R12 or R12;
• or R11e and R11z may be taken together with the sp2 carbon atom to which both are bonded to form an alicyclic ring of 4 to 7 members where one of the ring atoms may be NR12, O, or S(O)x, optionally substituted with halogen, oxo, OH, OR5, NR3R4;
• or R11e and R11z taken together may be R11eR11zC═, forming an allenyl group;
• or R10 and R11e may be taken together with the sp2 C atoms to which they are attached to form a partially saturated carbocyclic or heterocyclic ring of 5-7 atoms, with up to two of the ring atoms being O, S(O)x, NR12, and said ring may be substituted with hydroxy, oxo, C1-6 alkoxy,
• R11t is C1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, C4-7 heterocycloalkyl, CH2NR3R4;
• R12 is H or C1-6 alkyl, either straight chain or branched;
• n is 1, 2 or 3;
• x is 0, 1, or 2;
• or a pharmaceutically acceptable salt, hydrate, or solvate thereof.