초록 ▼

The disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formul

The disclosure relates to inhibitors of USP7 inhibitors useful in the treatment of cancers, neurodegenerative diseases, immunological disorders, inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases, having the Formula: where R1, R2, R3, R5, R5′, X1, X2, n, and m are described herein.

대표청구항 ▼

1. A compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:X1 is C;X2 is R1 is —OH;R2 is (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, heterocycloalkyl, —NR10R11, or —OR10, wherein the alkyl is substituted with on

1. A compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:X1 is C;X2 is R1 is —OH;R2 is (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, heterocycloalkyl, —NR10R11, or —OR10, wherein the alkyl is substituted with one or more R8, and wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R8;R3 is independently at each occurrence selected from D, (C1-C6) alkyl;R4 is H, (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 R12;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, halogen, or CN;R6 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, halogen, NO2, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R14;R7 is H, D, (C1-C6) alkyl, halogen, CN, NO2, (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; orR6 and R7 together with the atoms to which they are attached form a (C3-C8)cycloalkyl optionally substituted with one or more R16;each R8 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —(C1-C3)-alkylene-O—(C1-C6) alkyl, —(C0-C4)-alkylene-aryl, —(C0-C4)-alkylene-heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, —(C0-C4)-alkylene-O-aryl, —(C0-C4)-alkylene-O-heteroaryl, —O—(C3-C8)cycloalkyl, —S-heteroaryl, —C(O)R21, —CO(O)R21, —C(O)NR21R22, —S(O)qR21, —S(O)qNR21R22; —NR21S(O)qR22, —(C0-C3)-alkylene-NR21R22, —NR21C(O)R22, —NR21C(O)C(O)R22, —NR21C(O)NR21R22, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, or —OR21, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R9; ortwo R8 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R9; or two R8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R9;each R9 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C14) aryl, heteroaryl, —NH2, —OH, —C(O)R23, —C(O)NR23R24, —NR23C(O)R24, —NR23R24, —S(O)qR23, —S(O)qNR23R24, —NR23S(O)qR24, 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 R26;R10 and R11 are independently H, (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 R18; orR10 and R11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R18;each R12 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —C(O)O(C1-C6) alkyl, —C(O)NR27R28, —S(O)qNR27R28, —NR27R28, —NR27C(O)NR27R28, —NR27C(O)OR28, —NR27S(O)qR28, —NR27C(O)R28, halogen, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, or —SF5, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R13; ortwo R12 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R13; or two R12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R13; or two R12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R13; or two R12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R13;each R13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R29;each R14 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R15;each R15 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(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, CN, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, —OH, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R17;each R17 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R18 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, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R19;each R19 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R21 and R22 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 R25;each R23 and R24 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 R25;each R25 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R26 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NR27C(O)R28, —NR27S(O)qR28, —C(O)R27, —C(O)NR27R28, —NR27R28, —S(O)qR27, —S(O)qNR27R28, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —OH, or CN;each R27 and R28 is independently at each occurrence 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) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;each R29 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;m is 0;n is 1; andq is independently at each occurrence 0, 1, or 2. 2. The compound of claim 1, wherein R4 is (C6-C14) aryl or heteroaryl. 3. The compound of claim 1, wherein R5 is H. 4. The compound of claim 1, wherein R5′ is H. 5. The compound of claim 1, wherein is R6 is H, (C1-C6) alkyl, or (C6-C14) aryl. 6. The compound of claim 1, wherein R7 is H, (C1-C6) alkyl, or (C6-C14) aryl. 7. The compound of claim 1, wherein R6 and R7 together with the atoms to which they are attached form a (C3-C8)cycloalkyl optionally substituted with one or more R16. 8. The compound of claim 1, having Formula (Ia), Formula (Ic), Formula (Ie), or Formula (Ig): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:X1 is C;R1 is —OH;R2 is (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, heterocycloalkyl, —NR10R11, or —OR10, wherein the alkyl is substituted with one or more R8, and wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R8;R3 is independently at each occurrence selected from D, (C1-C6) alkyl;R4 is H, (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 R12;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, halogen, or CN;R7 is H, D, (C1-C6) alkyl, halogen, CN, NO2, (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 R8 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —(C1-C3)-alkylene-O—(C1-C6) alkyl, —(C0-C4)-alkylene-aryl, —(C0-C4)-alkylene-heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, —(C0-C4)-alkylene-O-aryl, —(C0-C4)-alkylene-O-heteroaryl, —O—(C3-C8)cycloalkyl, —S-heteroaryl, —C(O)R21, —CO(O)R21, —C(O)NR21R22, —S(O)qR21, —S(O)qNR21R22; —NR21S(O)qR22, —(C0-C3)-alkylene-NR21R22, —NR21C(O)R22, —NR21C(O)C(O)R22, —NR21C(O)NR21R22, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, or —OR21, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R9; ortwo R8 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R9; or two R8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R9;each R9 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C14) aryl, heteroaryl, —NH2, —OH, —C(O)R23, —C(O)NR23R24, —NR23C(O)R24, —NR23R24, —S(O)qR23, —S(O)qNR23R24, —NR23S(O)qR24, oxo, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R26;R10 and R11 are independently H, (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 R18; orR10 and R11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R18;each R12 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —C(O)O(C1-C6) alkyl, —C(O)NR27R28, —S(O)qNR27R28, —NR27R28, —NR27C(O)NR27R28, —NR27C(O)OR28, —NR27S(O)qR28, —NR27C(O)R28, halogen, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, or —SF5, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R13; ortwo R12 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R13; or two R12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R13; or two R12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R13; or two R12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R13;each R13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R29;each R16 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, —OH, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R17;each R17 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R18 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, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R19;each R19 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R21 and R22 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 R25;each R23 and R24 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 R25;each R25 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R26 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NR27C(O)R28, —NR27S(O)qR28, —C(O)R27, —C(O)NR27R28, —NR27R28, —S(O)qR27, —S(O)qNR27R28, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —OH, or CN;each R27 and R28 is independently at each occurrence 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) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;each R29 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;m is 0;n is 1; andq is independently at each occurrence 0, 1, or 2. 9. The compound of claim 1, having Formula (Ib), Formula (Id), Formula (If), or Formula (Ih): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:X1 is C;R1 is —OH;R2 is (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, heterocycloalkyl, —NR10R11, or —OR10, wherein the alkyl is substituted with one or more R8, and wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R8;R3 is independently at each occurrence selected from D, (C1-C6) alkyl;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, halogen, or CN;R6 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) haloalkyl, halogen, NO2, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R14;R7 is H, D, (C1-C6) alkyl, halogen, CN, NO2, (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; orR6 and R7 together with the atoms to which they are attached form a (C3-C8)cycloalkyl optionally substituted with one or more R16;each R8 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —(C1-C3)-alkylene-O—(C1-C6) alkyl, —(C0-C4)-alkylene-aryl, —(C0-C4)-alkylene-heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, —(C0-C4)-alkylene-O-aryl, —(C0-C4)-alkylene-O-heteroaryl, —O—(C3-C8)cycloalkyl, —S-heteroaryl, —C(O)R21, —CO(O)R21, —C(O)NR21R22, —S(O)qR21, —S(O)qNR21R22, —NR21S(O)qR22, —(C0-C3)-alkylene-NR21R22, —NR21C(O)R22, —NR21C(O)C(O)R22, —NR21C(O)NR21R22, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, or —OR21, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R9; ortwo R8 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R9; or two R8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R9;each R9 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C14) aryl, heteroaryl, —NH2, —OH, —C(O)R23, —C(O)NR23R24, —NR23C(O)R24, —NR23R24; —S(O)qR23, —S(O)qNR23R24, —NR23S(O)qR24; oxo, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R26;R10 and R11 are independently H, (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 R18; orR10 and R11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R18;each R14 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R15;each R15 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(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, CN, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, —OH, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R17;each R17 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R18 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, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R19;each R19 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R21 and R22 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 R25;each R23 and R24 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 R25;each R25 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R26 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NR27C(O)R28, —NR27S(O)qR28, —C(O)R27, —C(O)NR27R28, —NR27R28, —S(O)qR27, —S(O)qNR27R28, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —OH, or CN;each R27 and R28 is independently at each occurrence 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) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;m is 0;n is 1; andq is independently at each occurrence 0, 1, or 2. 10. The compound of claim 1, having Formula (Ii): or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:R2 is (C1-C6) alkyl, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, heterocycloalkyl, —NR10R11, or —OR10, wherein the alkyl is substituted with one or more R8, and wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R8;R4 is (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 R12;each R8 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —(C1-C3)-alkylene-O—(C1-C6) alkyl, —(C0-C4)-alkylene-aryl, —(C0-C4)-alkylene-heteroaryl, —(C3-C10) cycloalkyl, heterocycloalkyl, —(C0-C4)-alkylene-O-aryl, —(C0-C4)-alkylene-O-heteroaryl, —O—(C3-C8)cycloalkyl, —S-heteroaryl, —C(O)R21, —CO(O)R21, —C(O)NR21R22, —S(O)qR21, — S(O)qNR21R22, —NR21S(O)qR22, —(C0-C3)-alkylene-NR21R22, —NR21C(O)R22, —NR21C(O)C(O)R22, —NR21C(O)NR21R22, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, or —OR21, wherein the alkyl, alkylene, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R9; ortwo R8 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R9; or two R8 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an aryl ring optionally substituted with one or more R9; or two R8 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R9;each R9 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, (C3-C8) cycloalkyl, heterocycloalkyl, (C6-C14) aryl, heteroaryl, —NH2, —OH, —C(O)R23, —C(O)NR23R24, —NR23C(O)R24, —NR23R24, —S(O)qR23, —S(O)qNR23R24, —NR23S(O)qR24, oxo, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —O-aryl, CN, or —O-heteroaryl, wherein the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R26;R10 and R11 are independently H, (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 R18; orR10 and R11 together with the nitrogen to which they are attached form a heterocycloalkyl ring optionally substituted with one or more R18;each R12 is independently D, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, CN, —OH, —NH2, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —C(O)O(C1-C6) alkyl, —C(O)NR27R28, —S(O)qNR27R28, —NR27R28, —NR27C(O)NR27R28, —NR27C(O)OR28, —NR27S(O)qR28, —NR27C(O)R28, halogen, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, or —SF5, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R13; ortwo R12 together when on adjacent atoms form a (C3-C8) cycloalkyl optionally substituted with one or more R13; or two R12 together when on adjacent atoms form a heterocycloalkyl ring optionally substituted with one or more R13; or two R12 together when on adjacent atoms form an aryl ring optionally substituted with one or more R13; or two R12 together when on adjacent atoms form an heteroaryl ring optionally substituted with one or more R13;each R13 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl, —O—(C3-C8)cycloalkyl, —OH, or CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R29;each R18 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, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, (C6-C14) aryl, heteroaryl, (C5-C8) cycloalkyl, or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R19;each R19 is independently (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R21 and R22 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 R25;each R23 and R24 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 R25;each R25 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN;each R26 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —NR27C(O)R28, —NR27S(O)qR28, —C(O)R27, —C(O)NR27R28, —NR27R28, —S(O)qR27, —S(O)qNR27R28, —P(O)((C1-C6) alkyl)2, —P(O)(aryl)2, —SiMe3, —SF5, —OH, or CN;each R27 and R28 is independently at each occurrence 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) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, —NH2, (C1-C6) alkylamino, or di(C1-C6) alkylamino;each R29 is independently at each occurrence (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, halogen, —C(O)(C1-C6) alkyl, —S(O)q(C1-C6) alkyl, —NH2, (C1-C6) alkylamino, di(C1-C6) alkylamino, —OH, or CN; andq is independently at each occurrence 0, 1, or 2. 11. The compound of claim 1 selected from: 3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)thieno[2,3-d]pyrimidin-4(3H)-one;3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one;3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5,6,7-tetrahydro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one;3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-propylthieno[2,3-d]pyrimidin-4(3H)-one;3-((4-hydroxy-1-(3-phenylpentanoyl)piperidin-4-yl)methyl)thieno[2,3-d]pyrimidin-4(3H)-one;3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one;6-ethyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)thieno[2,3-d]pyrimidin-4(3H)-one;3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one;7-(4-fluorophenyl)-3-((4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methyl)thieno[3,2-d]pyrimidin-4(3H)-one;3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one;(E)-4-(dimethylamino)-N-(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)but-2-enamide; or(E)-4-(dimethylamino)-N-(4-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-oxobutyl)but-2-enamide. 12. A pharmaceutical composition comprising, a compound of claim 1, and a pharmaceutically acceptable carrier.