Substituted xanthines and methods of use thereof

A compound of Formula I(a):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1-4 R5;
• R2 is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylalkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, —S—, —S—C1-C6 alkyl, —S(O)—, —S(O)2—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylalkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, —S—, —S—C1-C6 alkyl, —S(O)—, —S(O)2—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R6;
• R3 is C2-C6 hydroxyalkyl or C1-C6 heteroalkyl;
• R4 is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1-4 R8;
• R5, R6, and R8 are each independently C1-C6 alkyl, C1-C6 heteroalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, cyano, nitro, amido, C1-C6 alkylamido, C2-C12 dialkylamido, —S—, —S(O)2—, —C(O)O—, —C(O)—, —C(O)O—C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, heterocycloalkyl, or heteroaryl, each of C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, amido, C1-C6 alkylamido, C2-C12 dialkylamido, —S—, —S(O)2—, —C(O)O—, —C(O)—, —C(O)O—C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R9;
• and
• each R9 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, heterocycloalkyl, C6-C10 aryl, heteroaryl, C4-C10 cycloalkylalkyl, heterocycloalkyl-C1-C6 alkyl, C7-C16 arylalkyl, heteroaryl-C1-C6 alkyl, halo, hydroxyl, C1-C6 alkoxy, C6-C10 aryloxy, C7-C16 arylalkoxy, C2-C8 alkoxyalkoxyl, amino, C1-C6 alkylamino, C2-C12 dialkylamino, C1-C6 alkyl-amino-C1-C6 alkyl, C1-C6 alkyl-amino-C2-C12 dialkyl, —S—, —S—C1-C6 alkyl, —S(O)2—C1-C6 alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C6-C10 aryl, —NHC(O)—C6-C10 aryl, —C(O)NH—C6-C10 aryl, —C(O)OH, —C(O)O—C1-C6 alkyl, —C(O)—C1-C6 alkyl acyl, nitro, or cyano.

A compound of Formula II:

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is phenyl, thiazolyl, pyrimidinyl, or oxazolyl;
• R2 is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, halo, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylalkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, —S—, —S—C1-C6 alkyl, —S(O)—, —S(O)2—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, C3-C7 cycloalkyloxy, C6-C10 aryl, C6-C10 aryloxy, C7-C16 arylalkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, —S—, —S—C1-C6 alkyl, —S(O)—, —S(O)2—, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R6;
• R3 is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkyl, or C1-C6 alkoxy, each of which is optionally substituted with 1-4 R7;
• R4 is C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl or C2-C6 alkynyl, each of which is optionally substituted with 1-4 R8;
• R6, R7, and R8 are each independently C1-C6 alkyl, C1-C6 heteroalkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, cyano, nitro, amido, C1-C6 alkylamido, C2-C12 dialkylamido, —S—, —S(O)2—, —C(O)O—, —C(O)—, —C(O)O—C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, heterocycloalkyl, or heteroaryl, wherein each of C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 alkoxy, amino, C1-C6 alkylamino, C2-C12 dialkylamino, amido, C1-C6 alkylamido, C2-C12 dialkylamido, —S—, —S(O)2—, —C(O)O—, —C(O)—, —C(O)O—C1-C6 alkyl, C3-C7 cycloalkyl, C6-C10 aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R9;
• each R9 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, heterocycloalkyl, C6-C10 aryl, heteroaryl, C4-C10 cycloalkylalkyl, heterocycloalkyl-C1-C6 alkyl, C7-C16 arylalkyl, heteroaryl-C1-C6 alkyl, halo, hydroxyl, C1-C6 alkoxy, C6-C10 aryloxy, C7-C16 arylalkoxy, C2-C8 alkoxyalkoxyl, amino, C1-C6 alkylamino, C2-C12 dialkylamino, C1-C6 alkyl-amino-C1-C6 alkyl, C1-C6 alkyl-amino-C2-C12 dialkyl, —S—, —S—C1-C6 alkyl, —S(O)2—C1-C6 alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C6-C10 aryl, —NHC(O)—C6-C10 aryl, —C(O)NH—C6-C10 aryl, —C(O)OH, —C(O)O—C1-C6 alkyl, —C(O)—C1-C6 alkyl acyl, nitro, or cyano;
• each Ra is C1-C6 alkyl, C1-C6 haloalkyl, halo;
• n is 1 or 2;
• and
• m is 1, 2, or 3.

A compound of Formula III:

• or a pharmaceutically acceptable salt thereof, wherein:
• R2 is C1-C6 alkoxy or C6-C10 aryloxy substituted with 1-3 R6;
• R3 is C1-C6 heteroalkyl or C2-C6 hydroxyalkyl;
• R4 is C1-C6 alkyl;
• R6 is independently C1-C6 alkyl, halo, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 alkoxy;
• each Ra is C1-C6 alkyl, C1-C6 haloalkyl, halo;
• n is 1 or 2;
• and
• m is 1, 2, or 3.