Thyromimetics
Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X 1 , X 2 , Q, R 1 , R 2 and n are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.
1. A compound having the structure of Formula (I):
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
X 1 is lower alkyl, lower haloalkyl, or halo;
X 2 is lower alkyl, lower haloalkyl, or halo;
R 1 is —NR 1a R 1b or —OR 1c ;
R 1a and R 1b are each, independently, H, lower alkyl, lower alkenyl, lower alkynyl, —OR a , —NR a R b , carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form heterocycle;
R 1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;
Q is a bond;
A is aryl or heteroaryl;
each R 2 is, independently, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocyclealkyl, heterocyclealkyl, —OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —S(O) 2 R a , or —S(O) 2 OR a ;
n is 1-5; and
R a and R b are each, independently, H, lower alkyl, or lower haloalkyl;
wherein R 1a , R 1b , R 1c , R 2 , R a , and R b are each, independently, optionally substituted with one or more halo, cyano, —OR′, —NR′R″, —S(O) 2 R′ or —S(O) 2 OR′, wherein R′ and R″ are each, independently, H, lower alkyl, or lower haloalkyl.
2. The compound of claim 1 having the structure of Formula (III):
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
X 1 is lower alkyl, lower haloalkyl, or halo;
X 2 is lower alkyl, lower haloalkyl, or halo;
R 1 is NR 1a R 1b or —OR 1c ;
R 1a and R 1b are each, independently, H, lower alkyl, lower alkenyl, lower alkynyl, —OR a , —NR a R b , carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form heterocycle;
R 1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;
A is aryl or heteroaryl;
each R 2 is, independently, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocyclealkyl, heterocyclealkyl, —OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —S(O) 2 R a , or —S(O) 2 OR a ;
n is 1-5; and
R a and R b are each, independently, H, lower alkyl, or lower haloalkyl;
wherein R 1a , R 1b , R 1c , R 2 , R a , and R b are each, independently, optionally substituted with one or more halo, cyano, —OR′, —NR′R″, —S(O) 2 R′ or —S(O) 2 OR′, wherein R′ and R″ are each, independently, H, lower alkyl, or lower haloalkyl.
3. The compound of claim 1 having the structure of Formula (IV):
or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
X 1 is lower alkyl, lower haloalkyl, or halo;
X 2 is lower alkyl, lower haloalkyl, or halo;
R 1 is —NR 1a R 1b or —OR 1c ;
R 1a and R 1b are each, independently, H, lower alkyl, lower alkenyl, lower alkynyl, —OR a , —NR a R b , carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, or R 1a and R 1b taken together with the nitrogen atom to which they are attached form heterocycle;
R 1C is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;
R 2a is halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocyclealkyl, heterocyclealkyl, —OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —S(O) 2 R a , or —S(O) 2 OR a ;
each R 2b is, independently, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocyclealkyl, heterocyclealkyl, —OR a , —NR a R b , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)R b , —S(O) 2 R a , or —S(O) 2 OR a ;
m is 0-4; and
R a and R b are each, independently, H, lower alkyl, or lower haloalkyl;
wherein R 1a , R 1b , R 1c , R 2a , R 2b , R a , and R b are each, independently, optionally substituted with one or more halo, cyano, —OR′, —NR′R″, —S(O) 2 R′ or —S(O) 2 OR′, wherein R′ and R″ are each, independently, H, lower alkyl, or lower haloalkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1a is lower alkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1a is methyl.
6. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1b is H.
7. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1c is H or lower alkyl.
8. The compound of claim 7 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1c is methyl.
9. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 is methyl.
10. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 is Cl or Br.
11. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 is —CF 3 .
12. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 is methyl.
13. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 is Cl or Br.
14. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 is —CF 3 .
15. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is lower alkyl.
16. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is lower alkyl substituted with —OR′, wherein R′ is H or lower alkyl.
17. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is lower haloalkyl.
18. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is —OR a .
19. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is —C(O)R a .
20. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is —NR a C(O)R b .
21. The compound of claim 20 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R a is H and R b is lower alkyl.
22. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is —C(O)OR a .
23. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is —S(O) 2 R a .
24. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is halo.
25. The compound of claim 24 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is F.
26. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 2 is cyano.
27. The compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, having the structure of any one of the following compounds:
Compound
Number
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
28. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient.
29. A method of treating a subject having NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver disease/alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, genetic lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage diseases, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Najjar Syndrome, lysosomal acid lipase deficiency, liver disease in cystic fibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
30. A method of treating a subject having Alport syndrome, diabetic nephropathy, FSGS, fibrosis associated with IgA nephropathy, chronic kidney diseases (CKD), post AKI, HIV associated CKD, chemotherapy induced CKD, CKD associated with nephrotoxic agents, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD), the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
31. A method of treating a subject having IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases like rheumatoid arthritis, scleroderma or Sjogren's syndrome, asthma-related pulmonary fibrosis, COPD, asbestos or silica induced PF, silicosis, respiratory bronchiolitis, Idiopathic interstitial pneumonias (IIP), Idiopathic nonspecific interstitial pneumonia, Respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, Rare IIPs: Idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, unclassifiable idiopathic interstitial pneumonias, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis—pneumoconiosis, bronchiectasis, byssinosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension (PAH), or Cystic fibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
32. A method of treating a subject having scleroderma/systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda , restrictive dermopathy, Dupuytren's contracture, dermal fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemicals or physical agents, GvHD induced fibrosis, Scleredema adultorum , Lipodermatosclerosis, or Progeroid disorders (progeria, acrogeria, Werner's syndrome), the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
33. A method of treating a subject having atrial fibrosis, endomyocardial fibrosis, cardiac fibrosis, atherosclerosis , restenosis, or arthrofibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
34. A method of treating a subject having mediastinal fibrosis, myelofibrosis, post-polycythermia vera myelofibrosis, or post essential thrombocythemia, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
35. A method of treating a subject having Crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, GI fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
36. A method of treating a subject having endometrial fibrosis, uterine fibroids, or Peyronie's disease, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
37. A method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular diseases, or vitreal retinopathy, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.
38. A method of treating a subject having scarring associated with trauma, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or composition thereof.