HETEROARYL COMPOUNDS USEFUL AS INHIBITORS OF SUMO ACTIVATING ENZYME

摘要

Disclosed are chemical entities which are compounds of formula (I):;;or pharmaceutically acceptable salts thereof; wherein Y, Ra, Ra′, Rb, Rc, X1, X2, X3, Rd, Z1, and Z2 have the values described herein and stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry. Chemical entities according to the disclosure can be useful as inhibitors of Sumo Activating Enzyme (SAE). Further provided are pharmaceutical compositions comprising a compound of the disclosure and methods of using the compositions in the treatment of proliferative, inflammatory, cardiovascular, and neurodegenerative diseases or disorders.

主权项

1. A chemical entity which is a compound or pharmaceutically acceptable salt of formula (I):WHEREIN:
stereochemical configurations depicted at asterisked positions indicate absolute stereochemistry; Y is —O—, —CH2—, or —N(H)—; Ra is hydrogen, fluoro, —NH2, or hydroxyl; Ra′ is hydrogen or fluoro, provided that when Ra is —NH2 or hydroxyl, Ra′ is hydrogen; Rb is hydrogen or, together with the oxygen to which it is attached, forms a prodrug; Rc is hydrogen or C1-4 alkyl; Rd is hydrogen, halogen, —CF3, or C1-4 alkyl; X1 is C(H), C(F), or N; X2 is S or O; X3 is C(Rx3) or N; Rx3 is hydrogen, methyl, or halogen; Z1 is hydrogen, halogen, cyano, Rz3, —S—Rz3, —S(O)—Rz3, or —S(O)2—Rz3; Rz3 is an optionally substituted phenyl, an optionally substituted 5- to 7-membered cycloaliphatic, an optionally substituted 5- to 7-membered heterocyclyl, or an optionally substituted C1-4 aliphatic; wherein Z1 is not hydrogen, halogen, methyl, or cyano if Z2 is hydrogen or methyl; and
(a) Z2 is a ring system having an optionally substituted 5- to 7-membered heterocyclyl with 1-2 heteroatoms or an optionally substituted 5- to 7-membered cycloaliphatic fused to
(i) an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered aryl or heteroaryl to form a bicyclic group; or(ii) an optionally substituted 9-membered heteroaryl or an optionally substituted 10-membered aryl or heteroaryl to form a tricyclic group; OR
(b) Z2 is L-Re wherein L is -L1-, —V1-L2-, or -L1-V1-L2-; L1 is a C1-3 alkylene chain wherein 1 or 2 saturated carbon atoms are optionally substituted by (Rf)(Rf′) and in which there are optionally one or two degrees of unsaturation;
each Rf is independently hydrogen; hydroxyl; —N(Rh)(Rh′); C1-4 aliphatic optionally substituted with hydroxyl, —OCH3, or cyclopropyl; —O—C1-4 aliphatic optionally substituted with hydroxyl, —OCH3, or cyclopropyl; or, together with Rf′ and the carbon atom to which they are attached, form C═CH2, or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C1-4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle;each Rf′ is independently hydrogen; C1-4 aliphatic optionally substituted with hydroxyl, —OCH3, or cyclopropyl; —O—C1-4 aliphatic optionally substituted with hydroxyl, —OCH3, or cyclopropyl; or, together with Rf and the carbon atom to which they are attached, form C═CH2, or a 3- to 6-membered carbocycle or 4- to 6-membered heterocycle comprising a heteroatom chosen from N (which may be protonated or C1-4 alkylated), O, or S, the heteroatom optionally located immediately adjacent to the quaternary carbon of the heterocycle; wherein if Rf is hydroxyl, Rf′ is not —O—C1-4 aliphatic optionally substituted with hydroxyl, —OCH3, or cyclopropyl;Rh and Rh′ are each independently hydrogen or C1-4 alkyl;V1 is —S—, —O—, —S(O)—, —S(O)2—, —C(O)— or —N(Rg)—;L2 is a C0-2 alkylene chain wherein one saturated carbon atom is optionally substituted by (Rf)(Rf′); R is hydrogen or C1-4 alkyl; and
either (i) Re is hydrogen, hydroxyl, halogen, —CF3, or an optionally substituted C1-4 aliphatic,with the proviso that Re is not hydrogen if Rf and Rf′ are present and form a ring;OR (ii) Re is a ring chosen from optionally substituted 6-membered aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl, which is optionally fused to a second optionally substituted 6-membered aryl, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 3- to 7-membered cycloaliphatic, or optionally substituted 4- to 7-membered heterocyclyl; OR
(c) Z2 is hydrogen.