THYROID HORMONE RECEPTOR BETA AGONIST COMPOUNDS
Provided herein are compounds, preferably thyroid hormone receptor beta (THR beta) agonist compounds, compositions thereof, and methods of their preparation, and methods of agonizing THR beta and methods for treating disorders mediated by THR beta.
1 . A compound of formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
A is
is 5-membered heterocyclyl or 5- to 6-membered heteroaryl, each of which optionally contains 1-2 additional annular heteroatoms selected from the group consisting of N and O,
wherein each heteroatom of the heterocyclyl or heteroaryl is bound to one R 1 group if needed to complete the valency of the heteroatom, and
wherein each carbon atom of the heterocyclyl or heteroaryl is bound to one R 2 group if needed to complete the valency of the carbon atom, provided that no more than one R 2 group is needed to complete the valency of each carbon atom;
Z 1 , Z 2 , and Z 3 are independently N or CH;
Y is N or C;
each R 1 is independently H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl, wherein each C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group is optionally substituted by 1-5 R 3 groups;
each R 2 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), —O(C 3 -C 6 cycloalkyl), hydroxyl, or oxo,
wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), or —O(C 3 -C 6 cycloalkyl) group is optionally substituted by 1-5 R 3 groups;
or R 1 and R 2 are taken together to form a 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclyl;
or two R 2 groups are taken together to form a 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclyl, C 5 -C 7 cycloalkyl, or C 6 aryl; and
each R 3 is independently halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —NH 2 , —CN, or hydroxyl.
2 . (canceled)
3 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
A is
4 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
A is
5 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
is 5-6 membered heteroaryl optionally containing 1-2 additional annular heteroatoms selected from the group consisting of N and O,
wherein each heteroatom of the heteroaryl is bound to one R 1 group if needed to complete the valency of the heteroatom, and
wherein each carbon atom of the heteroaryl is bound to one R 2 group if needed to complete the valency of the carbon atom, provided that no more than one R 2 group is needed to complete the valency of each carbon atom.
6 . (canceled)
7 . The compound of claim 5 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
is
8 . (canceled)
9 . The compound of claim 5 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
is
10 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
is 5-membered heterocyclyl optionally containing 1-2 additional annular heteroatoms selected from the group consisting of N and O,
wherein each heteroatom of the heterocyclyl is bound to one R 1 group if needed to complete the valency of the heteroatom, and
wherein each carbon atom of the heterocyclyl is bound to one R 2 group if needed to complete the valency of the carbon atom, provided that no more than one R 2 group is needed to complete the valency of each carbon atom.
11 . The compound of claim 10 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
is
12 - 17 . (canceled)
18 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Z 1 , Z 2 , and Z 3 are each CH.
19 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Z 1 is N; and
Z 2 and Z 3 are each CH.
20 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
Z 2 is N; and
Z 1 and Z 3 are each CH.
21 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 1 is independently H, C 1 -C 3 alkyl, or C 3 -C 5 cycloalkyl,
wherein each C 1 -C 3 alkyl or C 3 -C 5 cycloalkyl group is optionally substituted by 1-3 R 3 groups.
22 . The compound of claim 21 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 1 is independently H, cyclopropyl, —CH 3 , —CH(CH 3 ) 2 , t-butyl, —CH 2 CH 3 ,
23 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 2 is independently H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, —O(C 1 -C 3 alkyl), —O(C 3 -C 5 cycloalkyl), hydroxyl, or oxo,
wherein each C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, —O(C 1 -C 3 alkyl), or —O(C 3 -C 5 cycloalkyl) group is optionally substituted by 1-3 R 3 groups.
24 . The compound of claim 23 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 2 is independently H, —CH 3 , —CH 2 CH 3 , —OCH 3 , cyclopropyl, or oxo.
25 - 27 . (canceled)
28 . The compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 3 , where present, is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, —NH 2 , —CN, or hydroxyl.
29 . The compound of claim 28 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each R 3 is independently Cl, F, —CH 3 , —CF 3 , —CHF 2 , —CH 2 OH, —NH 2 , —CN, or hydroxyl.
30 . A compound, wherein the compound is
Example
Structure
2
4
5
6
8
10
11
12
18
20
22
24
25
27
29
30
32
33
36
37
39
41
42
43
45
47
51
53
55
or
57
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
31 . A pharmaceutical composition comprising the compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable excipient.
32 . A method of agonizing thyroid hormone receptor beta (THR beta) comprising contacting either an effective amount of the compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, with the THR beta.
33 . A method of treating non-alcoholic steatohepatitis (NASH) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
34 . (canceled)
35 . A compound of formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
A is
Z 1 , Z 2 , and Z 3 are independently N or CH;
Y is C;
is
R 1 is H, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl,
wherein each C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl group is optionally substituted by 1-5 R 3 groups;
R 2 is H, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), —O(C 3 -C 6 cycloalkyl), or hydroxyl,
wherein each C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), or —O(C 3 -C 6 cycloalkyl) group is optionally substituted by 1-5 R 3 groups;
or R 1 and R 2 are taken together to form a 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclyl; and
each R 3 is independently halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —NH 2 , —CN, or hydroxyl.
36 . A compound of formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
A is
Z 1 , Z 2 , and Z 3 are independently N or CH;
Y is C;
is
each R 2 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), —O(C 3 -C 6 cycloalkyl), or hydroxyl,
wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), or —O(C 3 -C 6 cycloalkyl) group is optionally substituted by 1-5 R 3 groups;
or two R 2 groups are taken together to form a 5- to 6-membered heteroaryl, 5- to 7-membered heterocyclyl, C 5 -C 7 cycloalkyl, or C 6 aryl; and
each R 3 is independently halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —NH 2 , —CN, or hydroxyl.
37 . A compound of formula (I):
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
A is
Z 1 , Z 2 , and Z 3 are independently N or CH;
Y is N;
is
R 1 is C 3 -C 6 cycloalkyl optionally substituted by 1-5 R 3 groups;
R 2 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), —O(C 3 -C 6 cycloalkyl), or hydroxyl,
wherein each C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —O(C 1 -C 6 alkyl), or —O(C 3 -C 6 cycloalkyl) group is optionally substituted by 1-5 R 3 groups;
or R 1 and R 2 are taken together to form a 5- to 6-membered heteroaryl or 5- to 7-membered heterocyclyl; and
each R 3 is independently halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —NH 2 , —CN, or hydroxyl.
38 . A compound, wherein the compound is
TABLE 1
Example
Structure
1
3
7
9
13
14
15
16
17
19
21
23
26
28
31
34
35
38
40
44
46
48
49
50
52
54
56
58
or
59
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
39 . The compound of claim 38 , wherein the compound is
Example
Structure
9
13
14
15
16
17
23
26
28
34
35
40
44
46
48
52
54
56
or
58
or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.