Modulators of THR-β and methods of use thereof

A compound of Formula I′:

• TL-La-CE-HD (I′)
• or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
• i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId:
• wherein:
• each of Q1, Q2, Q3, Q4, Q5, Q6, and Q8, is independently nitrogen or —CRb—, wherein each Rb is independently hydrogen, halogen, or lower alkyl;
• R1 is hydrogen, an optionally substituted alkyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted C-carboxy or O-carboxy group, —CN, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ring structure;
• R2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, or —CN;
• R3 is hydrogen or lower alkyl;
• R4 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted non-aromatic carbocyclic group, an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted heteroaryl group, an optionally substituted (carbocyclic)alkyl group, an optionally substituted aralkyl group, an optionally substituted (heterocycloalkyl)alkyl group, an optionally substituted (heteroaryl)alkyl group, an optionally substituted amino group, an optionally substituted sulfamoyl group, an optionally substituted carbamoyl group, or an optionally substituted carbamoyl alkyl group, where the nitrogen of the carbamoyl or carbamoyl alkyl group is optionally a heteroatom in a ring structure;
• and
• R5 is hydroxy, NH2, alkylamino, alkanoylamino, or alkylsulfonylamino;
• or R4 and R5 taken together along with the carbon atoms to which they are attached form a five- or six-membered optionally substituted non-aromatic carbocyclic group, optionally substituted aryl group, optionally substituted heterocyclic group, or optionally substituted heteroaryl group;
• or R4 and R5 taken together along with the carbon atoms to which they are attached form a seven to eleven membered, optionally substituted spirocyclic ring or a seven to eleven membered, optionally substituted spiro-heterocyclic ring;
• Alk is hydrogen or an optionally substituted alkyl;
• and
• R11 is an aryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl;
• or a heteroaryl group optionally substituted with one to five substituents independently selected from lower alkyl, alkoxy, haloalkoxy, halogen, and cycloalkyl;
• or a bicyclic ring system;
• or a bicyclic heterocyclic ring system;
• ii) CE is a moiety of Formula IV
• wherein:
• each of R6 and R7 is independently selected from halogen or lower alkyl;
• R8 is selected from hydrogen or lower alkyl;
• or R6 is selected from halogen and lower alkyl, and R7 and R8 taken together, along with the carbon atoms to which they are attached, form a 4-, 5- or 6-membered non-aromatic carbocyclic ring;
• Q7 is —CRc—, wherein Rc is hydrogen;
• (TL) denotes the point where the moiety of Formula IV connects to TL-La-;
• and
• (HD) denotes the point where the moiety of Formula IV connects to —HD;
• iii) HD is a moiety of Formula V:
• wherein:
• R9 is —(C(Rd)2)n−N(Rd)2;
• wherein
• each Rd is independently hydrogen or optionally substituted lower alkyl;
• and
• each n is 0;
• and
• La is —(C(Ra)2)z—;
• oxygen;
• or sulfur;
• wherein each Ra is a hydrogen;
• and z is 1.