Prodrugs of Thyroid Hormone Analogs, Methods of Making and Methods of Using Thereof

A compound of Formula I:

• stereoisomers thereof, pharmaceutically acceptable salts thereof, deuterium substitutes thereof, isomers thereof, prodrugs thereof, and metabolites thereof,
• wherein:
• G is selected from the group consisting of —O—, and —C(X9X8)—;
• T is selected from the group consisting of —(CRd)m—, and —O—(CRd)m—;
• m is an integer from 0-3;
• X is selected from the group consisting of:
• each of Ra and Rb is independently selected from the group consisting of CH3, CD3, Cl, Br, I and CF3;
• wherein Rc is selected from the group consisting of hydrogen, halogen, —CF3, —OCF3, cyano, optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted-C2-C12 alkynyl, optionally substituted —C0-6alkyl-aryl, optionally substituted —C0-6 alkyl-cycloalkyl, optionally substituted —C0-6 alkyl-heterocycloalkyl, and optionally substituted —C3-8 cycloalkyl;
• wherein Rc is optionally substituted with one to ten halogen, H or D;
• each of Rd is independently selected from the group consisting of hydrogen, halogen, and C1-6 alkyl;
• wherein each of R1 and R2 is independently selected from the group consisting of H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, C6-10 aryl, heteroaryl, C1-6 alkyl-C6-10 aryl, and C1-6 alkyl-heteroaryl, or R1 and R2 are combined with the atoms to which they are attached to form a C3-10 cycloalkyl or a heterocyclyl;
• wherein R3 is selected from the group consisting of H, C1-30 alkyl, C5-10 cycloalkyl, C1-30 haloalkyl, C6-10 aryl, and C6-10 aryl-C1-8 alkyl, wherein R3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH2, NO2, OH, CN, —C1-6 alkyl, C1-6 haloalkyl, and O—C1-6 alkyl;
• wherein R4 is selected from the group consisting of C6-10 aryl, C1-6 alkyl-C6-10 aryl, and 5-10 membered heteroaryl, wherein R4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH2, NO2, OH, CN, —C1-6 alkyl, C1-6 haloalkyl, and O—C1-6 alkyl;
• wherein R5 is selected from the group consisting of H, —COR6, —COOR6, CH2OC(O)OR7, —CONHR6, —CONR7R10, —CONR6R7, —CH2OCOR6, —CH2OCONHR6, and
• wherein each of R6 is independently C1-30 alkyl, C1-30 alkenyl, and C1-30 alkynyl, wherein C1-30 alkyl, C1-30 alkenyl, and C1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, —O—C1-30 alkyl, —S—C1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the —O—C1-30 alkyl, —S—C1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-3 alkyl;
• wherein R7 is selected from the group consisting of H, —C1-30 alkyl, —C2-30 alkenyl, —C2-30 alkynyl, —C(O)C1-30 alkyl, —C(O)C2-30 alkenyl, —C(O)C2-30 alkynyl, —C(O)OC1-30 alkyl, —C(O)OC2-30 alkenyl, —C(O)OC2-30 alkynyl, —C(O)NRCC1-30 alkyl, —C(O) NRCC2-30 alkenyl, and —C(O) NRCC2-30 alkynyl, wherein each of the —C1-30 alkyl, —C2-30 alkenyl, —C2-30 alkynyl, —C(O)C1-30 alkyl, —C(O)C2-30 alkenyl, —C(O)C2-30 alkynyl, —C(O)OC1-30 alkyl, —C(O)OC2-30 alkenyl, —C(O)OC2-30 alkynyl, —C(O)NRCC1-30 alkyl, —C(O) NRCC2-30 alkenyl, and —C(O) NRCC2-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, —O—C1-30 alkyl, —S—C1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the —O—C1-30 alkyl, —S—C1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-3 alkyl;
• or R6 and R7 are combined with atoms to which they are attached to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH2, NO2, OH, CN, —C1-6 alkyl, C1-6 haloalkyl, and O—C1-6 alkyl;
• wherein each of R8 and R9 is independently selected from the group consisting of H, OH, C1-6 alkyl, halo, —O—C1-3 alkyl, —S—C1-3 alkyl, —C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the C1-6 alkyl, —O—C1-3 alkyl, —S—C1-3 alkyl, —C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from the group consisting of OH, halo, —O—C1-3 alkyl, —S—C1-3 alkyl, —C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;
• or wherein R8 and R9 are combined with the atoms to which they are attached to form a 3-10 membered heterocyclyl, which is optionally substituted with one to four R6, wherein each R6 is independently H, halo, C1-6 alkyl, C1-6 haloalkyl, or alkoxy;
• wherein R10 is selected from the group consisting of H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2), C3-10cycloalkyl, —(CH2), aryl, and —(CH2), heteroaryl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —(CH2), C3-10cycloalkyl, —(CH2)n aryl, and —(CH2)n heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, —O—C1-3 alkyl, —S—C1-3 alkyl, —C3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;
• wherein X8 and X9 is independently H, D or halo;
• wherein n=0, 1, 2, or 3;
• wherein each 5-10 membered heteroaryl mentioned above has one to four heteroatoms, and each is independently N, O, or S;
• and
• wherein each 3-10 membered heterocyclyl mentioned above has one to four heteroatoms, and each is independently N, O, or S,
• provided that the compound of formula I is not isopropyl (((4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)(phenoxy)phosphoryl)-L-alaninate.