Quinazolinones and azaquinazolinones as ubiquitin-specific protease 7 inhibitors

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• X1 is C;
• Y1 is N or CH;
• Y2 is N or CR5;
• Y3 is N or CR6;
• Y4 is N or CR7;
• R1 is —OH;
• R2 is (C1-C6) alkyl, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, or NR10R11, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R8;
• each R3 is independently at each occurrence selected from D, (C1-C6) alkyl, (C6-C14) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C3-C8) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R20;
• or
• two R3 together when on adjacent carbons form a (C3-C8) cycloalkyl optionally substituted with one to three R20;
• or
• two R3 together when attached to the same carbon atom form a (C3-C8) spirocycloalkyl optionally substituted with one to three R20;
• or
• two R3 together when attached to the same carbon atom form a 3- to 7-membered spiroheterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R20;
• or
• two R3 together when on adjacent carbons form a (C6-C14) aryl ring optionally substituted with one to three R20;
• or two R3 together when on adjacent carbons form a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one to three R20;
• R4 and R4′ are independently H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, or CN;
• R5 is H, (C1-C6) alkyl, (C1-C6) haloalkyl, halogen, NO2, or CN, wherein the alkyl is optionally substituted with one to three R12;
• R6 is H, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, NO2, —NH2, —NHC(O)(C1-C6) alkyl, (C6-C14) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C8) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R13;
• R7 is H, (C1-C6) alkyl, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C6) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —N((C1-C6) alkyl)-(C6-C14) aryl, —NH—(C6-C14) aryl, —N((C1-C6) alkyl)-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NH-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R14;
• each R8 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —(C1-C3)-alkylene-O—(C1-C6) alkyl, —(C0-C4)-alkylene-(C6) aryl-(C0-C4)-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C3-C10) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C0-C4)-alkylene-O—(C6) aryl, —(C0-C4)-alkylene-O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C5-C6) cycloalkyl, —S-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —C(O)R21, —CO(O)R21, —C(O)NR21R22, —(C0-C3)-alkylene-NR21R22, —NR21C(O)R22, —NR21C(O)C(O)R22, —NR21C(O)NR21R22, or —OR21, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R9;
• or two R8 together when on adjacent atoms form a (C5-C6) cycloalkyl optionally substituted with one to three R9;
• or two R8 together when on adjacent atoms form a 5- to 6-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R9;
• or two R8 together when on adjacent atoms form a (C6) aryl ring optionally substituted with one to three R9;
• or two R8 together when on adjacent atoms form a 5- or 6-membered heteroaryl ring comprising 1 to 3 heteroatoms selected from O, N, and S optionally substituted with one to three R9;
• each R9 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —(C0-C3)-alkylene-(C6) aryl, —(C0-C3)-alkylene-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —NH2, —OH, —C(O)R23, —C(O)NR23R24, —NR23C(O)R24, —NR23R24, -oxo, —O—(C6) aryl, CN, or —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R19;
• R10 and R11 are independently H, or (C1-C6) alkyl optionally substituted with one to three R17;
• or R10 and R11 together with the nitrogen to which they are attached form a 3- to 7-membered heterocycloalkyl ring comprising 1 to 3 heteroatoms selected from O, N, and S, optionally substituted with one to three R17;
• each R12 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —C(O)(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;
• each R13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, —C(O)(C1-C6) alkyl, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C6) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C5-C6) cycloalkyl, —C(O)O(C1-C6) alkyl, —C(O)NR26R27, —NR26R27, —NR26C(O)NR26R27, —NR26C(O)OR27, —NR26C(O)R27, halogen, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R15;
• each R14 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, —C(O)(C1-C6) alkyl, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C6) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C5-C6) cycloalkyl, —C(O)O(C1-C6) alkyl, —C(O)NR26R27, —NR26R27, —NR26C(O)NR26R27, —NR26C(O)OR27, —NR26C(O)R27, halogen, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R16;
• each R15 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;
• each R16 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C6) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —O-5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C5-C6) cycloalkyl, —OH, or CN, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three R28;
• each R17 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, (C1-C6) hydroxyalkyl, —OH, CN, —C(O)(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, wherein the alkyl is optionally substituted with one to three R18;
• each R18 is independently (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;
• each R19 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NR26C(O)R27, —C(O)R26, —C(O)NR26R27, —NR26R27, —OH, or CN;
• each R20 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —NH2, or CN;
• each R21 and R22 is independently H, (C1-C6) alkyl, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, or 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three R25;
• each R23 and R24 is independently H, (C1-C6) alkyl, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three R25;
• each R25 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, or CN;
• each R26 and R27 is independently at each occurrence H, or (C1-C6) alkyl;
• each R28 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;
• m is 0, 1, 2, 3, or 4;
• n is 0, 1, 2 or 3;
• and
• provided that the compound is further characterized by any one or more of the following:
• i. at least one of Y1, Y2, Y3, or Y4 is N;
• ii. at least one of R6 or R7 is an optionally substituted (C6-C14) aryl;
• iii. R5 is (C1-C6) alkyl or (C1-C6) haloalkyl, wherein the alkyl of R5 is substituted with an R12 that is (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —C(O)(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;
• iv. R6 is (C1-C6) alkyl, (C1-C6) haloalkyl, —NHC(O)(C1-C6) alkyl, (C6-C14) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C8) cycloalkyl, or 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein
• the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R6 is substituted with an R13 that is (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;
• or
• the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R6 is substituted with an R13 that is (C1-C6) alkyl, or that is 3- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the heterocycloalkyl is substituted with one to three R15;
• or
• V. R7 is (C1-C6) alkyl, (C6) aryl, 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, (C5-C6) cycloalkyl, 5- to 6-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from O, N, and S, —O—(C6) aryl, —O-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, —N((C1-C6) alkyl)-(C6-C14) aryl, —NH—(C6-C14) aryl, —N((C1-C6) alkyl)-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, or —NH-5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from O, N, and S, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl of R7 is substituted with an R14 that is (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, —C(O)(C1-C6) alkyl, (C1-C6) alkylamino, or di(C1-C6) alkylamino.