Pyrrolotriazinones and imidazotriazinones as ubiquitin-specific protease 7 inhibitors

A method of treating a disease or disorder associated with modulation of USP7 comprising, administering to a patient in need thereof an effective amount of a compound of formula (Ib):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X1 is C;
• R2 is (C1-C8) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R8;
• R4 is H or (C1-C6) alkyl;
• R6 is H;
• R7 is H, halogen, —NR17C(O)R18 or —NR17C(O)NR18R19;
• each R8 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —(C0-C4)-alkylene-aryl, —(C0-C4)-alkylene-heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, —C(O)R12, —S(O)qR12, —(C0-C3)-alkylene-NR12R13, or —OR12, wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R9;
• each R9 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, halogen, CN, —S(O)qR14, —S(O)qNR14R15, —C(O)NR14R15, —NR14C(O)R15, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R10;
• or
• two R9 together with the atoms to which they are attached form a (C6-C14) aryl ring optionally substituted with one or more R10;
• or
• two R9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R10;
• or
• two R9 together with the atoms to which they are attached form a (C5-C8) cycloalkyl ring optionally substituted with one or more R10;
• or
• two R9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R10;
• each R10 is independently at each occurrence (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, —OH, or CN;
• or
• two R10 together with the atoms to which they are attached form a (C6-C14) aryl ring optionally substituted with one or more R11;
• or
• two R10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R11;
• or
• two R10 together with the atoms to which they are attached form a (C5-C8) cycloalkyl ring optionally substituted with one or more R11;
• or
• two R10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —NH2, or CN;
• each R12 and R13 is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R16;
• each R14 and R15 is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R16;
• or
• R14 and R15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R16, when R9 is —C(O)NR14R15;
• each R16 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, or CN;
• R17 is independently H or (C1-C6) alkyl;
• R18 is independently (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R20;
• R19 is independently H or (C1-C6) alkyl;
• each R20 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, CN, (C6-C14) aryl, —O(C6-C14) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R21;
• or
• two R20 together with the atoms to which they are attached form a (C6-C14) aryl ring optionally substituted with one or more R21;
• or
• two R20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R21;
• or
• two R20 together with the atoms to which they are attached form a (C5-C8) cycloalkyl ring optionally substituted with one or more R21;
• or
• two R20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R21;
• each R21 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, or CN;
• and
• q is independently at each occurrence 0, 1, or 2.

A compound of Formula (I):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• X1 is C, S, or S(O);
• X2 is CR7 or N;
• R1 is H, D, —OH, —SH, —NH2, —NH(C1-C4) alkyl, —N((C1-C4) alkyl)2, or F;
• R2 is (C1-C8) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, heterocycloalkyl, —NR25R26, or —OR25, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R8;
• each R3 is independently at each occurrence selected from D, (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R21;
• or
• two R3 together when on adjacent carbons form a (C3-C8) cycloalkyl optionally substituted with one or more R21;
• or two R3 together form a (C3-C8) spirocycloalkyl optionally substituted with one or more R21;
• or two R3 together form a spiroheterocycloalkyl optionally substituted with one or more R21;
• or two R3 together when on adjacent carbons form an aryl ring optionally substituted with one or more R21;
• or two R3 together when on adjacent carbons form an heteroaryl ring optionally substituted with one or more R21;
• R4 is H, (C1-C6) alkyl, CD3, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R22;
• R5 and R5′ are independently H, D, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —CH2OH, —CH2NH2, or halogen;
• R6 is H, D, or (C1-C6) alkyl;
• R7 is H, D, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, halogen, —NR17C(O)R18, CN, —P(O)((C1-C6)alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —NR17C(O)NR18R19, or —C(O)NR17R18, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with one or more R21;
• each R8 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —(C1-C3)-alkylene-O(C1-C6) alkyl, —(C0-C4)-alkylene-aryl, —(C0-C4)-alkylene-heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, —(C0-C4)-alkylene-O-aryl, 7 of 11 —(C0-C4)-alkylene-O-heteroaryl, —O—(C3-C8)cycloalkyl, —S-heteroaryl, halogen, —CN, —C(O)R12, —CO(O)R12, —C(O)NR12R13, —S(O)qR12, —S(O)qNR12R13, —NR12S(O)qR13, —(C0-C3)-alkylene-NR12R13, —NR12C(O)R13, —NR12C(O)C(O)R13, —NR12C(O)NR12R13, —P(O)((C1-C6)alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, or —OR12, wherein alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R9;
• each R9 is independently at each occurrence D, (C1-C6) alkyl, (C1-C6) alkoxy, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C14) aryl, heteroaryl, halogen, —OH, —CN, —C(O)R14, —C(O)NR14R15, —NR14C(O)R15, —NR14R15, —S(O)qR14, —S(O)qNR14R15, —NR14S(O)qR15, oxo, —P(O)((C1-C6)alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —O-aryl, CN, or —O-heteroaryl, wherein alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R10;
• or
• two R9 together with the atoms to which they are attached form a (C6-C14) aryl ring optionally substituted with one or more R10;
• or two R9 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R10;
• or two R9 together with the atoms to which they are attached form a (C5-C8) cycloalkyl ring optionally substituted with one or more R10;
• or two R9 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R10;
• each R10 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NR23C(O)R24, —NR23S(O)qR24, —C(O)R23, —C(O)NR23R24, —NR23R24, —S(O)qR23, —S(O)qNR23R24, —P(O)((C1-C6)alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —OH, or CN;
• or
• two R10 together with the atoms to which they are attached form a (C6-C14) aryl ring optionally substituted with one or more R11;
• or two R10 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R11;
• or two R10 together with the atoms to which they are attached form a (C5-C8) cycloalkyl ring optionally substituted with one or more R11;
• or two R10 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R11;
• each R11 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, —NH2, or CN;
• each R12 and R13 is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R16;
• each R14 and R15 is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R16;
• or
• R14 and R15 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R16, when R9 is —C(O)NR14R15;
• each R16 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, or CN;
• R17 is independently H or (C1-C6) alkyl;
• R18 is independently (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R20;
• R18 is independently H or (C1-C6) alkyl;
• each R20 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, CN, (C6-C14) aryl, —O(C6-C14) aryl, or heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more R21;
• or
• two R20 together with the atoms to which they are attached form a (C6-C14) aryl ring optionally substituted with one or more R21;
• or two R20 together with the atoms to which they are attached form a heteroaryl ring optionally substituted with one or more R21;
• or two R20 together with the atoms to which they are attached form a (C5-C8) cycloalkyl ring optionally substituted with one or more R21;
• or two R20 together with the atoms to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R21;
• each R21 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —OH, or CN;
• each R22 is independently at each occurrence D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C3-C8) cycloalkyl, (C6-C14) aryl, heteroaryl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —S(O)q(C1-C6) alkyl, —C(O)O(C1-C6) alkyl, —C(O)NR23R24, —S(O)qNR23R24, —NR23R24, —NR23C(O)NR23R24, —NR23C(O)OR24, —NR23S(O)qR23, —NR23C(O)R24, halogen, —P(O)((C1-C6)alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5 or —OH, wherein alkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl are optionally substituted with one or more substituents independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, —OH, CN, —NH2, —NH(C1-C4) alkyl, —N((C1-C4) alkyl)2, (C6-C14) aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, wherein the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl are optionally substituted one or more substituents independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl —OH, CN, —NH2, —NH(C1-C4) alkyl, or —N((C1-C4) alkyl)2;
• each R23 and R24 is independently at each occurrence H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl;
• each R25 and R26 is independently H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, halogen, (C1-C6) haloalkoxy, (C1-C6) hydroxyalkyl, —OH, CN, —NH2, —NH(C1-C4) alkyl, or —N((C1-C4) alkyl)2;
• m is 0, 1, 2, 3, or 4;
• n is 0, 1, 2, or 3;
• and
• q is independently at each occurrence 0, 1, or 2.