Isoindolin-1-ones as macrophage migration inhibitory factor (mif) inhibitors

A compound of Formula (I):

• or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof,
• wherein:
• X1 is hydrogen, halogen, optionally substituted C1-6 alkyl, —CO2H, —CO2RX1, or —C(═O)NHRX1, wherein RX1 is optionally substituted C1-6 alkyl, optionally substituted C3-6 carbocyclyl, an oxygen protecting group when attached to oxygen, or a nitrogen protecting group when attached to nitrogen;
• X2 is hydrogen, halogen, optionally substituted C1-6 alkyl, —CO2H, —CO2RX2, or —C(═O)NHRX2, wherein RX2 is optionally substituted C1-6 alkyl, optionally substituted C3-6 carbocyclyl, an oxygen protecting group when attached to oxygen, or a nitrogen protecting group when attached to nitrogen;
• X3 is hydrogen, halogen, optionally substituted C1-6 alkyl, —OH, —ORX3, —CO2H, —CO2RX3, or —C(═O)NHRX3, wherein RX3 is optionally substituted C1-6 alkyl, optionally substituted C3-6 carbocyclyl, an oxygen protecting group when attached to oxygen, or a nitrogen protecting group when attached to nitrogen;
• L is a linking group selected from the group consisting of:
• optionally substituted C3-14 carbocyclylene,
• -L1-L2-, wherein L1 is optionally substituted C1-6 alkylene and attached to the N atom, and L2 is optionally substituted C3-14 carbocyclylene and attached to Q, and
• -L3-L4-, wherein L3 is attached to the N atom and is methylene (—CH2—), ethylene (—CH2CH2—), or optionally substituted C3-6 alkylene, and L4 is optionally substituted C6-14 arylene and attached to Q;
• Q is:
• hydrogen,
• —OH (hydroxyl),
• C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl, C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl,
• aryl optionally substituted with one to three groups independently selected from the group consisting of halogen, carboxyl, hydroxyl, —ORQ, —CO2RQ, and —C(═O)NHRQ, wherein RQ is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 carbocyclyl, an oxygen protecting group when attached to oxygen, or a nitrogen protecting group when attached to nitrogen,
• or Q is selected from the group consisting of:
• wherein R1 and R2 are each independently hydrogen, C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl, or C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl;
• each instance of Y is independently, as valency and stability permits, —O—, —S—, —N(RY)—, or —C(RY)2—, wherein m is 2, 3, or 4, and RY is hydrogen or C1-6 alkyl;
• p is 0, 1, 2, 3, or 4;
• X4 is —O— or —(RX)N—,
• wherein RX is selected from the group consisting of:
• hydrogen,
• C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl, C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl,
• —C(═O)RX5, wherein RX5 is optionally substituted C1-6 alkyl,
• -LX1-CO2RX6, wherein LX1 is C1-9 alkylene optionally substituted with substituted or unsubstituted alkyl or substituted or unsubstituted aryl, and RX6 is hydrogen or optionally substituted C1-6 alkyl, and
• -LX2-O—RX7, wherein LX2 is optionally substituted C1-6 alkylene, and RX7 is optionally substituted C1-6 alkyl;
• R3 is:
• hydrogen,
• C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl, C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl,
• —C(═O)R3A wherein R3A is optionally substituted C1-6 alkyl or optionally substituted aryl,
• C1-6 alkyl optionally substituted with a substituted or unsubstituted 5- or 6-membered heterocycle wherein the heterocyclic ring contains from one to four hetero atoms selected from the group consisting of N, S or O,
• C1-6 alkyl optionally substituted with a substituted or unsubstituted heteroaryl,
• aryl optionally substituted with one to three groups selected from the group consisting of halogen, —CO2H, —OH, —OR3B, —C(═O)OR3B, and —C(═O)NHR3B, wherein R3B is optionally substituted C1-6 alkyl,
• or R3 and RX are joined to form an optionally substituted 5-membered heteroaryl ring,
• or R3 is a group of formula:
• wherein each instance of Y is independently, as valency and stability permits, —O—, —S—, —N(RY)—, or —C(RY)2—, wherein m is 2, 3, or 4, and RY is hydrogen or C1-6 alkyl;
• R4 and R5 are each independently selected from the group consisting of:
• hydrogen,
• —CO2H,
• —C(═O)NHR4A, wherein R4A is optionally substituted C1-6 alkyl,
• —OH,
• —OR4A, wherein R4A is optionally substituted C1-6 alkyl,
• -L4-CO2R4A, wherein L4 is C1-9 alkylene optionally substituted with substituted or unsubstituted alkyl or substituted or unsubstituted aryl, and R4A is hydrogen or optionally substituted C1-6 alkyl,
• C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl,
• C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl,
• 5- or 6-membered optionally substituted heterocyclic ring containing one to four atoms of N, S or O, and
• aryl unsubstituted or substituted with 1, 2, or 3 groups selected from the group consisting of halogen, —CO2H, —OH, —OR4A, —C(═O)OR4A, and —C(═O)NHR4A, wherein R4A is optionally substituted C1-6 alkyl;
• R6, R7, R8, and R9 are each independently selected from the group consisting of:
• hydrogen,
• C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl,
• C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl,
• -L6-CO2R6A, wherein L6 is absent or C1-9 alkylene optionally substituted with substituted or unsubstituted alkyl or substituted or unsubstituted aryl, and R6A is hydrogen or optionally substituted C1-6 alkyl,
• -L6-C(═O)NHR6A, wherein L6 is absent or C1-9 alkylene optionally substituted with substituted or unsubstituted alkyl or substituted or unsubstituted aryl, and R6A is hydrogen or optionally substituted C1-6 alkyl,
• 5- or 6-membered optionally substituted heterocyclic ring containing one to four atoms of N, S or O, and
• aryl unsubstituted or substituted with 1, 2, or 3 groups selected from the group consisting of halogen, —CO2H, —OH, —OR6A, —C(═O)OR6A, and —C(═O)NHR6A, wherein R6A is optionally substituted C1-6 alkyl;
• and
• R10 and R11 are each independently selected from the group consisting of:
• hydrogen,
• C3-12 cycloalkyl optionally substituted with substituted or unsubstituted C1-6 alkyl,
• C1-6 alkyl optionally substituted with substituted or unsubstituted C3-12 cycloalkyl,
• —C(═O)R10A, wherein R10A is optionally substituted C1-6 alkyl,
• -L10-CO2R10B, wherein L10 is C1-9 alkylene optionally substituted with substituted or unsubstituted alkyl or substituted or unsubstituted aryl, and R10B is hydrogen or optionally substituted C1-6 alkyl, and
• -L11-O—R10A, wherein L11 is optionally substituted C1-6 alkylene, and R10A is optionally substituted C1-6 alkyl.