Aromatic compounds for use as protein phosphatase 2a (pp2a) modulators

A compound of formula (II), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof:

• wherein:
• Ar is C6-C10 aryl or C2-C10 heteroaryl, which is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C10 heteroaryl, C6-C10 aryl, C6-C10 aryloxy, halogen, OH, N(Ra)(Rb), CN, NO2, —C(═O)Ra, —C(═O)ORa, and —C(═O)N(Ra)(Ra),
• wherein each C6-C10 aryl, C2-C10 heteroaryl, or C6-C10 aryloxy substituent in Ar is independently optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, —C(═O)ORa, and —C(═O)N(Ra)(Ra), and
• wherein two vicinal substituents of Ar may combine to provide a 5- to 8-membered ring which is fused with the C6-C10 aryl or C2-C10 heteroaryl in Ar;
• L is selected from the group consisting of *—N(RB)S(═O)2—, *—C(═O)N(RB)—, and optionally substituted C2-C10 heteroarylene;
• R5 is selected from the group consisting of
• R6 is selected from the group consisting of optionally substituted C6-C10 aryl and optionally substituted C2-C10 heteroaryl,
• wherein each optional substituent in R6 is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)ORa, —S(═O)2(C6-C10 aryl), and —S(═O)2(C2-C10 heteroaryl);
• R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h, if present, are each independently selected from the group consisting of are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxyl, C1-C4 haloalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C6 heterocyclyl, optionally substituted phenyl, and optionally substituted phenoxy,
• wherein each optional substituent is at least one selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, C(═O)ORa, and C(═O)N(Ra)(Ra),
• wherein two geminal substituents selected from R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h may combine with the carbon atom to which they are bound to form a moiety selected from the group consisting of an optionally substituted C3-C8 cycloalkyl and an optionally substituted C2-C10 heterocyclyl,
• wherein two vicinal substituents selected from R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h may combine with the carbon atoms to which they are bound to form a moiety selected from the group consisting of an optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C10 heterocyclyl, and optionally substituted phenyl;
• wherein two substituents selected from R7a, R7b, R7c, R7d, R7e, R7f, R7g, and R7h, which are separated by two to five carbon atoms, may combine with the carbon atoms to which they are bound to form a moiety selected from the group consisting of optionally substituted C4-C7 cycloalkyl and optionally substituted C4-C8 heterocyclyl;
• R8 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted phenyl, optionally substituted benzyl, —C(═O)ORb, —C(═O)Rb, and —S(═O)2-optionally substituted phenyl,
• wherein each optional substituent in the phenyl, benzyl, or —S(═O)2-phenyl is independently at least one selected from the group consisting of F, Cl, Br, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, hydroxyl, and —NH—C(═O)Ra;
• R9 is is selected from the group consisting of optionally substituted C6-C10 aryl and optionally substituted C2-C10 heteroaryl,
• wherein each optional substituent in R9 is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)ORa, —S(═O)2(C6-C10 aryl), and —S(═O)2(C2-C10 heteroaryl);
• R10 is selected from the group consisting of -(optionally substituted C1-C6 alkylenyl) (optionally substituted C2-C12 heterocycloalkyl) and optionally substituted C1-C6 aminoalkyl,
• wherein each optional substituent in R10 is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)ORa, —S(═O)2(C6-C10 aryl), and —S(═O)2(C2-C10 heteroaryl);
• R11 is H;
• RB is H;
• each occurrence of Ra is independently selected from the group consisting of H, C1-C6 alkyl, benzyl, and C6-C10 aryl;
• and
• each occurrence of Rbis independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl, wherein the C1-C6 alkyl, benzyl, phenyl, or naphthyl in Rb is independently optionally substituted with at least one selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(═O)ORa, and C(═O)N(Ra)(Ra).

A compound of formula (III), or a salt, solvate, enantiomer, diastereoisomer, isotopologue, or tautomer thereof:

• wherein:
• Ar is C6-C10 aryl or C2-C10 heteroaryl, which is optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C10 heteroaryl, C6-C10 aryl, C6-C10 aryloxy, halogen, OH, N(Ra)(Rb), CN, NO2, —C(═O)Ra, —C(═O)ORa, and —C(═O)N(Ra)(Rb),
• wherein each C6-C10 aryl, C2-C10 heteroaryl, or C6-C10 aryloxy substituent in Ar is independently optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, F, Cl, Br, I, OH, CN, NO2, —C(═O)ORa, and —C(═O)N(Ra)(Rb), and
• wherein two vicinal substituents of Ar may combine to provide a 5- to 8-membered ring which is fused with the C6-C10 aryl or C2-C10 heteroaryl in Ar;
• R13 is selected from the group consisting of
• R14a, R14b, R14c, and R14d are each independently selected from the group consisting of C6-C10 aryl and optionally substituted C2-C10 heteroaryl,
• wherein each optional substituent in R14a, R14b, R14c, and R14d is at least one selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, and —C(═O)ORa;
• R15a, R15b, R15c, R15d, R15e, R15f, R15g, R15h, R15i are each independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, —C(═O)ORa;
• R16 is H;
• R17a, R17b, R17d, R17e, R17f, R17g, R17h, R17i, R17j, R17k, and R17l, if present, are each independently selected from the group consisting of H, halogen, and C2-C8 heterocycloalkyl;
• R18a, R18b, R18c, and R18d are each independently selected from the group consisting of H and C1-C6 alkyl;
• R19 is selected from the group consisting of optionally substituted cyclohexyl and —CH2NMe2;
• X is selected from the group consisting of —NR16— and —C(R17k)(R17l)—;
• RC is H;
• each occurrence of Ra is independently selected from the group consisting of H, C1-C6 alkyl, benzyl, and C6-C10 aryl;
• and
• each occurrence of Rb is independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted naphthyl, wherein the C1-C6 alkyl, benzyl, phenyl, or naphthyl in Rb is independently optionally substituted with at least one selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, halogen, OH, CN, NO2, C(═O)ORa, and C(═O)N(Ra)(Ra);
• wherein if R13 is
• then at least one of the following applies:
• (a) at least one selected from the group consisting of R17a, R17b, R17d, R17e, R17f, R17g, R17h, R17i, R17j, R17k, and R17l, if present, is a halogen, wherein the halogen is optionally F;
• (b) R14b is phenyl substituted with at least two fluorine atoms;
• (c) R14b is 4-chlorophenyl and Ar is selected from the group consisting of phenyl optionally substituted with at least two substituents and pyridyl optionally substituted with C1-C6 alkoxy;
• and
• (d) R14b is 4-chlorophenyl and Ar is not selected from the group consisting of 4-trifluoromethoxy and 6-trifluoromethoxy-3-pyridyl;
• wherein if R13 is
• then at least one of the following applies:
• (a) R14c is phenyl and one, three, or four selected from R18a, R18b, R18c, and R18d is CH3;
• and
• (b) R14c is phenyl and Ar is optionally substituted pyridyl;
• wherein if R13 is
• and R19 is CH2NMe2, then the compound of formula (III) is N-(1-(3,4-dichlorophenyl)-2-(dimethylamino)ethyl)-4-(3-(trifluoromethyl)phenoxy)benzenesulfonamide;
• and
• wherein if R13 is
• and R19 is optionally substituted cyclohexyl, then at least one of the following applies:
• (a) Ar is optionally substituted pyridyl;
• and
• (b) Ar is substituted with at least one C1-C6 alkoxy substituent.