Granted Patent B2

US 12,440,502 · App. 18/595,919 · Granted Oct 14, 2025

Inventors: Brian Lian (San Diego, CA); Rochelle Hanley (Ann Arbor, MI); Misha Dinerman (Cincinnati, OH); Mark Erion (Brookline, MA); Serge Boyer (San Diego, CA); Hongjian Jiang (Shanghai, CN)

Assignees: Viking Therapeutics, Inc.; Metabasis Therapeutics, Inc.

A61K31/662

Abstract

Claims (55)

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 —CH 2 —;

T is —O—CH 2 —;

m=0-3;

n=0-2;

each R a is independently selected from hydrogen, optionally substituted —C 1 -C 4 alkyl, halogen, —OH, optionally substituted —O—C 1 -C 4 alkyl, —OCF 3 , optionally substituted —S—C 1 -C 4 alkyl, —NR c 2 , optionally substituted —C 2 -C 4 alkenyl, and optionally substituted —C 2 -C 4 alkynyl;

each R b is hydrogen;

R 1 and R 2 are —CH 3 ;

R 3 is selected from hydrogen, halogen, —CF 3 , —OCF 3 , cyano, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) m aryl, optionally substituted (CR a 2 ) m cycloalkyl, optionally substituted (CR a 2 ) m heterocycloalkyl, —OR d , —SR d , —S(O) 1-2 R e , —S(O) 2 NR f R g , —C(O)NR f R g , —C(O)OR h , —C(O)R e , —N(R b )C(O)R e , —N(R b )C(O)NR f R g , —N(R b )S(O) 2 R e , —N(R b )S(O) 2 NR f R g , and —NR f R g ;

R 4 is H;

each R d is selected from optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, optionally substituted —(CR b 2 ) n heterocycloalkyl, and —C(O)NR f R g ;

each R e is selected from optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR a 2 ) n aryl, optionally substituted —(CR a 2 ) n cycloalkyl, and optionally substituted —(CR a 2 ) n heterocycloalkyl;

R f and R g are each independently selected from hydrogen, optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, and optionally substituted —(CR b 2 ) n heterocycloalkyl, or R f and R g may together form an optionally substituted heterocyclic ring, which may contain a second heterogroup selected from O, NR b , and S, wherein any substituents up to four are selected from optionally substituted —C 1 -C 4 alkyl, —OR b , oxo, cyano, —CF 3 , optionally substituted phenyl, and —C(O)OR h ;

each R h is optionally substituted —C 1 -C 12 alkyl, optionally substituted —C 2 -C 12 alkenyl, optionally substituted —C 2 -C 12 alkynyl, optionally substituted —(CR b 2 ) n aryl, optionally substituted —(CR b 2 ) n cycloalkyl, or optionally substituted —(CR b 2 ) n heterocycloalkyl;

R 5 is —OH;

X is P(O)(OR 11 ) 2 ;

R 11 is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH 2 -heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted alkylaryl, —C(R z ) 2 OC(O)NR z2 , NR z —C(O)—R y ,

—C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , —C(R z ) 2 OC(O)SR y , -alkyl-S—C(O)R y , -alkyl-S—S-alkylhydroxy, and -alkyl-S—S—S-alkylhydroxy; or

two R 11 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 —CHR z OH, CHR z OC(O)R y , CHR z OC(S)R y , CHR z OC(S)OR y , CHR z OC(O)SR y , CHR z OCO 2 R y , OR z , —SR z , —CHR z N 3 , CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z 2 )OH, —CH(C CR z )OH, —R z , —NR z 2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ;

q is an integer 2 or 3;

each R z is selected from R y and —H;

each R y 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 —R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl.

2. The method of claim 1 , wherein R 11 is independently selected from —H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, and —C(R z ) 2 —OC(O)R y .

3. The method of claim 1 , wherein two R 11 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 —CHR z OH, —CHR z OC(O)R y , —CHR z OC(S)R y , —CHR z OC(S)OR y , —CH R z OC(O)SR y , —CHR z OCO 2 R y , —OR z , —SR z , —CHR z N 3 , —CH 2 aryl, —CH(aryl)OH, —CH(CH═CR z 2 )OH, —CH(C CR z )OH, —R z , —NR z 2 , —OCOR y , —OCO 2 R y , —SCOR y , —SCO 2 R y , —NHCOR z , —NHCO 2 R y , —CH 2 NHaryl, —(CH 2 ) q —OR z , and —(CH 2 ) q —SR z ;

q is an integer 2 or 3;

each R z is selected from R y and —H;

each R y 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 —R z , then at least one of V, W, and W′ is not —H, alkyl, aralkyl, or heterocycloalkyl.

4. The method of claim 3 , wherein V is substituted aryl, and W and W′ are hydrogen.

5. The method of claim 1 , wherein the thyroid hormone receptor beta agonist is administered daily for three months, followed by a period of time of one month when the thyroid hormone receptor beta agonist is not administered.

6. The method of claim 1 , wherein the thyroid hormone receptor beta agonist is administered every other day for three months, followed by a period of time of one month when the thyroid hormone receptor beta agonist is not administered.

7. The method of claim 1 , wherein the thyroid hormone receptor beta agonist is administered intermittently for three months, followed by a period of time of one month when the thyroid hormone receptor beta agonist is not administered.

Assignments (4)

Continuity (4)

References Cited (43)