3-(5-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof

A method of treating a disease or disorder that is affected by the modulation of IKZF2 protein levels comprising administering to the patient in need thereof a compound of Formula (I′)

• wherein:
• X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, —CN, —OH, or —NH2;
• Rx is H or D;
• R1 is
• each R2 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —CN, —OH, or —NH2;
• or
• two R2 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R2 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —OH, or —NH2;
• R4 is —OR5 or —NR6R6′;
• R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents independently selected from (C6-C10)aryl and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• R6 and R6′ are each independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R7 and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R12;
• or
• R6 and R6′ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four R8;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R7 is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R8;
• each R8 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —CN, —OH, —NR13R14, —NH2, —O(C3-C7)cycloalkyl, —O-4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, —O(C6-C10)aryl, or —O-5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkoxy is optionally substituted with one to three R10 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three R11;
• or
• two R8 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with two R15;
• or two R8 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R8 together with the same atom to which they are attached form a ═(O);
• each R9 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, —OH, —CN, —NH2, or —NR13R14;
• or
• two R9 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with one or more substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• or two R9 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R10 is independently at each occurrence selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R11 is independently at each occurrence selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, and —NH2;
• each R12 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, or —NH2;
• two R12 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• R13 and R14 are each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• two R15 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• m and m1 are each independently 0, 1 or 2;
• n1 is 0, 1, 2, or 3;
• and
• each s and n is independently 1, 2, or 3, wherein s+n is ≤4;
• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

A method of modulating IKZF2 protein levels comprising administering to the patient in need thereof a compound of Formula (I′)

• wherein:
• X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, —CN, —OH, or —NH2;
• Rx is H or D;
• R1 is
• each R2 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —CN, —OH, or —NH2;
• or
• two R2 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R2 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —OH, or —NH2;
• R4 is —OR5 or —NR6R6′;
• R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents independently selected from (C6-C10)aryl and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• R6 and R6′ are each independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R7 and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R12;
• or
• R6 and R6′ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four R8;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R7 is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R8;
• each R8 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —CN, —OH, —NR13R14, —NH2, —O(C3-C7)cycloalkyl, —O-4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, —O(C6-C10)aryl, or —O-5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkoxy is optionally substituted with one to three R10 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three R11;
• or
• two R8 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with two R15;
• or two R8 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R8 together with the same atom to which they are attached form a ═(O);
• each R9 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, —OH, —CN, —NH2, or —NR13R14;
• or
• two R9 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with one or more substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• or two R9 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R10 is independently at each occurrence selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R11 is independently at each occurrence selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, and —NH2;
• each R12 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, or —NH2;
• two R12 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• R13 and R14 are each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• two R15 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• m and m1 are each independently 0, 1 or 2;
• n1 is 0, 1, 2, or 3;
• and
• each s and n is independently 1, 2, or 3, wherein s+n is ≤4;
• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

A method of reducing the proliferation of a cell the method comprising, contacting the cell with a compound of Formula (I′)

• wherein:
• X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, —CN, —OH, or —NH2;
• Rx is H or D;
• R1 is
• each R2 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —CN, —OH, or —NH2;
• or
• two R2 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R2 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —OH, or —NH2;
• R4 is —OR5 or —NR6R6′;
• R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents independently selected from (C6-C10)aryl and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• R6 and R6′ are each independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R7 and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R12;
• or
• R6 and R6′ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four R8;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R7 is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R9;
• each R8 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —CN, —OH, —NR13R14, —NH2, —O(C3-C7)cycloalkyl, —O-4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, —O(C6-C10)aryl, or —O-5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkoxy is optionally substituted with one to three R10 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three R11;
• or
• two R8 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with two R15;
• or two R8 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R8 together with the same atom to which they are attached form a ═(O);
• each R9 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, —OH, —CN, —NH2, or —NR13R14;
• or
• two R9 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with one or more substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• or two R9 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R10 is independently at each occurrence selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R11 is independently at each occurrence selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, and —NH2;
• each R12 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, or —NH2;
• two R12 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• R13 and R14 are each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from 0, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• two R15 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• m and m1 are each independently 0, 1 or 2;
• n1 is 0, 1, 2, or 3;
• and
• each s and n is independently 1, 2, or 3, wherein s+n is ≤4;
• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

A method of treating cancer comprising administering to the patient in need thereof a compound of Formula (I′)

• wherein:
• X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, —CN, —OH, or —NH2;
• Rx is H or D;
• R1 is
• each R2 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —CN, —OH, or —NH2;
• or
• two R2 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R2 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —OH, or —NH2;
• R4 is —OR5 or —NR6R6′;
• R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents independently selected from (C6-C10)aryl and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• R6 and R6′ are each independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R7 and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R12;
• or
• R6 and R6′ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four R8;
• or
• R2 and R6′ together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R7 is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R8;
• each R8 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —CN, —OH, —NR13R14, —NH2, —O(C3-C7)cycloalkyl, —O-4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, —O(C6-C10)aryl, or —O-5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkoxy is optionally substituted with one to three R10 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three R11;
• or
• two R8 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with two R15;
• or two R8 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R8 together with the same atom to which they are attached form a ═(O);
• each R9 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, —OH, —CN, —NH2, or —NR13R14;
• or
• two R9 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with one or more substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• or two R9 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R10 is independently at each occurrence selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R11 is independently at each occurrence selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, and —NH2;
• each R12 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, or —NH2;
• two R12 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• R13 and R14 are each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• two R15 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• m and m1 are each independently 0, 1 or 2;
• n1 is 0, 1, 2, or 3;
• and
• each s and n is independently 1, 2, or 3, wherein s+n is ≤4;
• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

A method for reducing IKZF2 protein levels in a subject comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′)

• wherein:
• X1 and X2 are each independently H, (C1-C4)alkyl, (C1-C6)alkoxy, (C1-C4)haloalkyl, (C1-C6)haloalkoxy, (C3-C7)cycloalkyl, halogen, —CN, —OH, or —NH2;
• Rx is H or D;
• R1 is
• each R2 is independently at each occurrence (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —CN, —OH, or —NH2;
• or
• two R2 together with the carbon atoms to which they are attached form a (C3-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R2 together when on adjacent carbon atoms form a phenyl or a 5- or 6-membered heteroaryl ring consisting of 1-3 heteroatoms selected from O, N, and S;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R3 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, halogen, —OH, or —NH2;
• R4 is —OR5 or —NR6R6′;
• R5 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three substituents independently selected from (C6-C10)aryl and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• R6 and R6′ are each independently H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)hydroxyalkyl, (C3-C7)cycloalkyl, 5- or 6-membered heterocycloalkyl consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkyl is optionally substituted with one to three R7 and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R12;
• or
• R6 and R6′ together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four R8;
• or
• R2 and R6 together with the carbon and nitrogen atoms to which they are attached form a 4- to 6-membered heterocycloalkyl ring optionally consisting of 1-2 additional heteroatoms selected from O, N, and S, and optionally substituted with one to four substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• each R7 is (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to four R8;
• each R8 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, —CN, —OH, —NR13R14, —NH2, —O(C3-C7)cycloalkyl, —O-4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, —O(C6-C10)aryl, or —O-5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S, wherein the alkoxy is optionally substituted with one to three R10 and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one to three R11;
• or
• two R8 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with two R15;
• or two R8 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• or two R8 together with the same atom to which they are attached form a ═(O);
• each R9 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, (C3-C6)cycloalkyl, —OH, —CN, —NH2, or —NR13R14;
• or
• two R9 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 5- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S optionally substituted with one or more substituents each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, halogen, —OH, —CN, and —NH2;
• or two R9 when on adjacent atoms together with the atoms to which they are attached form a (C6-C10)aryl, or 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R10 is independently at each occurrence selected from (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• each R11 is independently at each occurrence selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, and —NH2;
• each R12 is independently at each occurrence (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, halogen, —OH, —CN, or —NH2;
• two R12 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• R13 and R14 are each independently selected from (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C7)cycloalkyl, 4- to 7-membered heterocycloalkyl ring consisting of 1-3 heteroatoms selected from O, N, and S, (C6-C10)aryl, and 5- or 6-membered heteroaryl consisting of 1-3 heteroatoms selected from O, N, and S;
• two R15 together with the atoms to which they are attached form a (C4-C7)cycloalkyl or a 4- to 7-membered heterocycloalkyl ring consisting of 1-2 heteroatoms selected from O, N, and S;
• m and m1 are each independently 0, 1 or 2;
• n1 is 0, 1, 2, or 3;
• and
• each s and n is independently 1, 2, or 3, wherein s+n is ≤4;
• or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.