Modulators of THR-β and methods of use thereof
Disclosed herein are compounds of Formula I: TL-L a -CE-HD (I) or a pharmaceutically acceptable salt, prodrug, amide or ester thereof, where i) TL is a moiety of Formula IIa, IIb, IIIa, IIIb, IIIc, or IIId; ii) CE is a moiety of Formula IV; iii) HD is a moiety of Formula V or VI; where the substituents are as defined herein. Disclosed are also pharmaceutical compositions comprising the above compounds, and methods of treating disease by administering or contact a patient with one or more of the above compounds.
1. 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 IIIb:
wherein:
Q 4 is —CH— and Q 5 is nitrogen;
R 4 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
Alk is hydrogen or an optionally substituted alkyl;
ii) CE is a moiety of Formula IV
wherein:
each of R 6 and R 7 is independently selected from halogen, —CN, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkenyl, or cyclopropyl;
R 8 is selected from hydrogen, optionally substituted lower alkyl, optionally substituted lower alkoxy, cyano, or halogen;
optionally R 7 and R 8 taken together, along with the carbon atoms to which they are attached, form a 4-, 5- or 6-membered non-aromatic carbocyclic, heterocycloalkyl, aryl, or heteroaryl ring;
Q 7 is nitrogen or —CR c —, wherein R c is hydrogen, halogen, or lower alkyl;
(TL) denotes the point where the moiety of Formula IV connects to TL-L a -; and
(HD) denotes the point where the moiety of Formula IV connects to —HD;
iii) HD is a moiety of Formula V:
wherein:
R 9 is —(C(R d ) 2 ) n —N(R a ) 2 ; wherein
each R d is independently hydrogen or optionally substituted lower alkyl; and
each n is independently selected from 0 or 1;
L a is independently a bond; —(C(R a ) 2 ) z —; oxygen; sulfur; or —NR a —; wherein:
each R a is independently a hydrogen or lower alkyl; and
z is 0, 1, 2, 3, 4 or 5.
2. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl; C 2 -C 10 alkenyl; a non-aromatic C 3 -C 12 carbocyclic ring; a C 6 -C 10 aryl group; a 3- to 6-membered heterocycloalkyl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; a (carbocyclic)alkyl group; an aralkyl group; or a (heterocycloalkyl)alkyl group; and R 4 is optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy, or two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.
3. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl, C 2 -C 10 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyridazin-3(2H)-one, phenyl, naphthyl, pyridinyl, cinnolinyl, isoquinolinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, benzo[b]thiophenyl, a (cyclobutyl)alkyl group, a (cyclopentyl)alkyl group, a benzyl group, a (tetrahydrofuranyl)alkyl group, or a (tetrahydropyranyl)alkyl group; and R 4 is optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy, or two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.
4. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 6 -C 10 aryl group or a five- to ten-membered heteroaryl ring containing one to four ring heteroatoms independently selected from oxygen, sulfur, or nitrogen; and R 4 is optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy, or two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.
5. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is benzene optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy, or two R g together with the atoms to which they are attached form a ring, or two R g together with the atoms to which they are attached form an aromatic or non-aromatic 3- to 6-membered ring, optionally containing one or two ring heteroatoms independently selected from oxygen, sulfur, or nitrogen.
6. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein L a is oxygen or —CH 2 —.
7. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 7 is —CH—.
8. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein
each of R 6 and R 7 is independently halogen or C 1 -C 5 alkyl optionally substituted with one to five substituents independently selected from hydroxy, halogen, and C 1 -C 6 alkoxy; and R 8 is hydrogen; or
R 6 is halogen or C 1 -C 5 alkyl optionally substituted with one to five substituents independently selected from hydroxy, halogen, and C 1 -C 6 alkoxy; and R 7 and R 8 taken together, along with the carbon atoms to which they are attached, form a 4-, 5- or 6-membered carbocyclic ring.
9. The compound of claim 1 , or a stereoisomer or a tautomer thereof, orapharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl or anon-aromatic C 3 -C 12 carbocyclic ring; and R 4 is optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy.
10. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is C 1 -C 6 alkyl optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy.
11. The compound of claim 1 , or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 is a non-aromatic C 3 -C 12 carbocyclic ring optionally substituted with one to five R g independently selected from the group consisting of hydroxy, halogen, CN, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, and C 6 -C 10 aralkoxy.
12. The compound of claim 1 selected from the group consisting of:
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 selected from the group consisting of:
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 selected from the group consisting of:
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 selected from the group consisting of:
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 selected from the group consisting of:
or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising the compound of claim 1 , or the stereoisomer or the tautomer thereof, or the pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.