| CPC A61K 31/662 (2013.01) | 7 Claims |
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1. A method of treating X-linked adrenoleukodystrophy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a thyroid hormone receptor beta agonist of Formula I:
 or a pharmaceutically acceptable salt thereof;
wherein:
G is —CH2—;
T is —O—CH2—;
m=0-3;
n=0-2;
each Ra is independently selected from hydrogen, optionally substituted —C1-C4 alkyl, halogen, —OH, optionally substituted —O—C1-C4 alkyl, —OCF3, optionally substituted —S—C1-C4 alkyl, —NRc2, optionally substituted —C2-C4 alkenyl, and optionally substituted —C2-C4 alkynyl;
each Rb is hydrogen;
R1 and R2 are —CH3;
R3 is selected from hydrogen, halogen, —CF3, —OCF3, cyano, optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRa2)maryl, optionally substituted (CRa2)mcycloalkyl, optionally substituted (CRa2)mheterocycloalkyl, —ORd, —SRd, —S(O)1-2Re, —S(O)2NRfRg, —C(O)NRfRg, —C(O)ORh, —C(O)Re, —N(Rb)C(O)Re, —N(Rb)C(O)NRfRg, —N(Rb)S(O)2Re, —N(Rb)S(O)2NRfRg, and —NRfRg;
R4 is H;
each Rd is selected from optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRb2)naryl, optionally substituted —(CRb2)ncycloalkyl, optionally substituted —(CRb2)nheterocycloalkyl, and —C(O)NRfRg;
each Re is selected from optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRa2)naryl, optionally substituted —(CRa2)ncycloalkyl, and optionally substituted —(CRa2)nheterocycloalkyl;
Rf and Rg are each independently selected from hydrogen, optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRb2)naryl, optionally substituted —(CRb2)ncycloalkyl, and optionally substituted —(CRb2)nheterocycloalkyl, or Rf and Rg may together form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from O, NRb, and S, wherein any substituents up to four are selected from optionally substituted —C1-C4 alkyl, —ORb, oxo, cyano, —CF3, optionally substituted phenyl, and —C(O)ORh;
each Rh is optionally substituted —C1-C12 alkyl, optionally substituted —C2-C12 alkenyl, optionally substituted —C2-C12 alkynyl, optionally substituted —(CRb2)naryl, optionally substituted —(CRb2)ncycloalkyl, or optionally substituted —(CRb2)nheterocycloalkyl;
R5 is —OH;
X is P(O)(OR11)2;
R11 is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted alkylaryl, —C(Rz)2OC(O)NRz2, NRz—C(O)—Ry,
—C(Rz)2—OC(O)Ry, —C(Rz)2—O—C(O)ORy, —C(Rz)2OC(O)SRy, -alkyl-S—C(O)Ry, -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; or
two R11 groups come together to form
 wherein:
V, W, and W′ are independently selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl;
or together V and Z are connected via an additional 3-5 atoms to form a cyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, substituted with hydroxy, acyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom that is three atoms from both Y groups attached to the phosphorus; or
together V and Z are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, that is fused to an aryl group at the beta and gamma position to the Y attached to the phosphorus;
together V and W are connected via an additional 3 carbon atoms to form an optionally substituted cyclic group containing 6 carbon atoms and substituted with one substituent selected from hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy, attached to one of said carbon atoms that is three atoms from a Y attached to the phosphorus;
together Z and W are connected via an additional 3-5 atoms to form a cyclic group, wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
together W and W′ are connected via an additional 2-5 atoms to form a cyclic group, wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon, and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
Z is selected from —CHRzOH, CHRzOC(O)Ry, CHRzOC(S)Ry, CHRzOC(S)ORy, CHRzOC(O)SRy, CHRzOCO2Ry, ORz, —SRz, —CHRzN3, CH2aryl, —CH(aryl)OH, —CH(CH═CRz2)OH, —CH(C CRz)OH, —Rz, —NRz2, —OCORy, —OCO2Ry, —SCORy, —SCO2Ry, —NHCORz, —NHCO2Ry, —CH2NHaryl, —(CH2)q—ORz, and —(CH2)q—SRz;
q is an integer 2 or 3;
each Rz is selected from Ry and —H;
each Ry is selected from alkyl, aryl, heterocycloalkyl, and aralkyl;
with the provisos that:
a) V, Z, W, W′ are not all —H; and
b) when Z is —Rz, then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl.
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