Compositions for treatment of fibrosis and inflammation

Abstract

To provide therapeutic approaches that can treat both fibroses and inflammation.SOLUTION: The foregoing problem is solved by a method of treating fibrosis, a fibrotic condition or a fibrotic symptom in a subject in need thereof, comprising the step for administering one or more agonists of Thyroid Receptor β (TRβ) to the subject in need thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The compositions and methods of the present disclosure relate broadly to the field of treatments for fibrotic diseases and inflammation. [Background technology]

[0002] Fibrosis can affect a wide variety of tissues, including the liver (e.g., nonalcoholic steatohepatitis, glycogen storage disease type IX, cirrhosis), lungs (e.g., chronic interstitial lung disease, pneumoconiosis, silicosis, emphysema, fibrotic lung disease, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia), vasculature (e.g., diffuse interstitial fibrosis; atherosclerosis), heart (e.g., myocardial fibrosis; atrial fibrosis; endomyocardial fibrosis), and pulmonary fibrosis (e.g., pulmonary fibrosis; pulmonary fibrosis; pulmonary fibrosis). Fibrosis is a hallmark of the development of numerous pathologies affecting the lining of the body, including the skin (e.g., keloid lesions, nephrogenic systemic fibrosis, scleroderma), joints and interstitial tissues (e.g., arthrofibrosis, Dupuytren's disease), pancreas (e.g., pancreatitis), mouth (e.g., oral fibroproliferative lesions), intestine (e.g., fibrotic stenosis, e.g., fibrotic stenosis associated with Crohn's disease), and brain (glial scar, leptomeningeal fibrosis associated with bacterial meningitis). Fibrosis can also result from environmental insults or various insults, such as exposure to ionizing radiation (such as during cancer treatment), as a result of cyst rupture in the breast (causing palpable lesions in breast tissue), and also as a result of excess deposition of collagen following wound or tissue insult, such as generally after injury or surgery.

[0003] Some types of fibrosis are associated with an underlying genetic predisposition (e.g., Dupuytren's disease), but most types are associated with prolonged inflammation of the affected tissue (e.g., hepatic fibrosis and pneumoconiosis fibrosis). Symptoms can be as little as pruritus and cosmetic concern (e.g., in the case of keloid lesions of the skin) or as severe as pulmonary failure and death (e.g., in the end-stage manifestations of pulmonary fibrosis and myocardial fibrosis). Although fibrosis is essentially irreversible once definitively diagnosed, treatments exist to slow the progression of various fibrotic conditions or to ameliorate fibrosis or fibrotic conditions. Current antifibrotic treatments include anti-inflammatory compounds such as pirfenidone and the fibroblast growth factor receptor antagonist nintedanib. For cutaneous and subcutaneous fibrosis, examples of current treatments include surgery, phototherapy, and injections of Clostridium histolyticum collagenase. However, because many forms of fibrosis are irreversible and current treatments have limited effectiveness, there remains a need for additional therapeutic approaches to this class of pathologies.

[0004] Inflammation is part of the complex biological response of body tissues to harmful stimuli such as pathogens, damaged cells, or irritants, and is a defense reaction involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cellular injury, remove necrotic cells and tissues damaged by the original insult and inflammatory process, and initiate tissue repair. Inflammation can be classified as acute or chronic. Acute inflammation is the body's initial response to harmful stimuli and is caused by an increased migration of plasma and white blood cells from the blood to the injured tissue. A series of biochemical events unfolds and matures the inflammatory response involving the local vasculature, immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, is characterized by the simultaneous destruction and healing of tissue during the inflammatory process, leading to progressive changes in cell types present at the site of inflammation, such as mononuclear cells. Chronic inflammation can lead to a number of diseases, such as periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer. Thus, inflammation is normally tightly regulated by the body. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO 87 / 05297, Johnston et al., published September 11, 1987 [Patent Document 2] U.S. Patent No. 7,829,552 [Patent Document 3] U.S. Patent No. 5,883,294 [Patent Document 4] U.S. Patent No. 6,194,454 [Patent Document 5] U.S. Patent No. 6,395,784 [Patent Document 6] U.S. Patent No. 6,787,652 [Patent Document 7] U.S. Patent No. 6,831,102 [Patent Document 8] U.S. Patent No. 6,989,402 [Patent Document 9] U.S. Patent No. 7,514,419 [Patent Document 10] U.S. Patent No. 8,835,469 [Patent Document 11] U.S. Patent No. 9,266,861 [Patent Document 12] US Patent Application Publication No. 2008 / 0004251 [Patent Document 13] US Patent Application Publication No. 2009 / 002895 [Patent Document 14] US Patent Application Publication No. 2010 / 0081634 [Patent Document 15] US Patent Application Publication No. 2012 / 0046364 [Patent Document 16] WO 03 / 009841 [Patent Document 17] International Publication No. 2004 / 018421 [Patent Document 18] International Publication No. 2007 / 003419 [Patent Document 19] International Publication No. 2007 / 009913

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Non-licensed literature

[0006] [Non-licensed document 1] Alfonso-Merino, Proc. Nat. Acad. Sci. 113(24):E3451-60 (2016) [Non-licensed document 2] The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems", pages 352~401 [Non-licensed document 3] Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985

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[0007] Inflammation is often associated with fibrosis, fibrotic conditions and fibrotic systems, and therefore there is a need for therapeutic approaches that can treat both fibrosis and inflammation. [Means for solving the problem]

[0008] Disclosed herein are methods for treating fibrosis, fibrotic conditions or conditions, and inflammatory diseases or disorders in a subject in need thereof, comprising administering to the subject one or more thyroid hormone receptor-β (TRβ) agonists.

[0009] In accordance with the methods and compositions described herein, the compound administered is a compound having the structure of Formula I

[0010] [ka]

[0011] or a pharma- ceutically acceptable salt thereof. [In the formula, G is selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(C1-C4 alkyl)-, -CH(C1-C4 alkoxy)-, -C(=CH2)-, -NH-, and -N(C1-C4 alkyl)-; T is -(CR a 2)k -, -CR b =CR b -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2)n-, N(R c )(CR b 2)(CR a 2) n -, N(R b )C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2) C(O)(CR a 2) n , -(CR a 2) n C(O)(CR a 2) - and -C(O)NH(CR b 2)(CR a 2) p - selected from the group consisting of k is an integer from 1 to 4, m is an integer from 0 to 3; n is an integer from 0 to 2, p is an integer from 0 to 1; R a are each independently hydrogen, an optionally substituted -C1 to C4 alkyl, a halogen, -OH, an optionally substituted -O-C1 to C4 alkyl, -OCF3, an optionally substituted -S-C1 to C4 alkyl, or -NR b R c , optionally substituted -C2-C4 alkenyl, and optionally substituted -C2-C4 alkynyl, provided that one R a is bonded to C via an O, S, or N atom, the other R bonded to the same C a is hydrogen or is attached via a carbon atom; R b are each independently selected from the group consisting of hydrogen and optionally substituted -C1-C4 alkyl; R c are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano; R 6 , R 7 , R 8 , and R 9are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano, or R 6 and T together with the carbon to which they are attached form -NR i forming a ring having 5-6 atoms including 0-2 heteroatoms independently selected from -, -O-, and -S-, provided that when there are two heteroatoms in the ring and both heteroatoms are different from nitrogen, both heteroatoms must be separated by at least one carbon atom, and X is attached to the ring by a direct bond to a ring carbon or to a ring carbon or nitrogen, -(CR a 2) provided that the bond is - or -C(O)-, R i is selected from the group consisting of hydrogen, -C(O)C1-C4 alkyl, -C1-C4 alkyl, and -C1-C4-aryl; R 3 and R 4 is hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -C 12 Alkynyl, -SR d , -S(=O)R e , -S(=O)2R e , -S(=O)2NR f R g , -C(O)OR h , -C(O)R e , -N(R b )C(O)NR f R g , -N(R b )S(=O)2R e , -N(R b )S(=O)2NR f R g , and -NR f R gare independently selected from the group consisting of R d Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 is selected from the group consisting of R e Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 hydrogen, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 gTogether, O, NR C and S, wherein the optionally substituted heterocyclic ring may include a second hetero group selected from the group consisting of optionally substituted -C1-C4 alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h and optionally substituted with 0 to 4 substituents selected from the group consisting of R h Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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; R 5 is -OH, optionally substituted -OC1-C6 alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ), and -NHC(O)NH(R h ) selected from the group consisting of X is P(O)YR 11 Y'R 11 and Y and Y′ are —O— and —NR v -, and when Y and Y' are -O-, R bonded to -O- is 11is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y , -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; Y and Y' are -NR v -NR v - R bonded to 11 -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Y is -O- and Y' is -NR v -, R bonded to -O- 11 is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(Rz )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y -alkyl-S-S-alkylhydroxy, -alkyl-S-S-alkylhydroxy, -NR v - R bonded to 11 is H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Alternatively, Y and Y′ are —O— and —NR v - When selected independently, R as a whole 11 and R 11 is -alkyl-SS-alkyl-, forming a cyclic group, or taken together as R 11 and R 11 is based on the following

[0012] [ka]

[0013] where: V, W, and W' are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group containing 5-7 atoms substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 3 atoms away from both Y groups bonded to phosphorus, where 0-1 atom is a heteroatom and the remaining atoms are carbon; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group fused to an aryl group at positions β and γ relative to Y which is attached to phosphorus, where 0-1 atoms are heteroatoms and the remaining atoms are carbon; or V and W together are linked via three further carbon atoms to form an optionally substituted cyclic group containing six carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bonded to one of said carbon atoms that is three atoms away from Y bonded to phosphorus; or Z and W taken together are linked through an additional 3-5 atoms to form a cyclic group (wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon); V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or W and W' taken together are linked through an additional 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms and the remaining atoms are carbon; and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is -CHR z OH, -CHR z O.C.(O)R y ,-CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR z OC(O)SR y , -CHR z OCO2Ry , -OR z , -SR z , -CHR z N3, -CH2-aryl, -CH(aryl)OH, -CH(CH=CR z 2) OH, -CH(C≡CR z )OH, -R z , -NR z 2. -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z , -NHCO2R y , -CH2NH-aryl, -(CH2)q-OR z , and -(CH2)q-SR z is selected from the group consisting of q is an integer of 2 or 3; R z are R y and -H; R y are each selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; R x are each independently selected from the group consisting of -H and alkyl, or taken together as R x and R x forms a cyclic alkyl group, R v are each selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.

[0014] According to the methods and compositions described herein, the compound administered is:

[0015] [ka]

[0016] The composition may include one or more of a compound having a structure selected from the group consisting of:

[0017] In accordance with the methods and compositions described herein, the compound administered may also be a compound having the structure of Formula I.

[0018] [ka]

[0019] It does not include any pharma- ceutically acceptable salts thereof. [In the formula, G is selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(C1-C4 alkyl)-, -CH(C1-C4 alkoxy)-, -C(=CH2)-, -NH-, and -N(C1-C4 alkyl)-; T is -(CR a 2)k -, -CR b =CR b -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2)n-, N(R c )(CR b 2)(CR a 2) n -, N(R b )C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2) C(O)(CR a 2) n , -(CRa 2) n C(O)(CR a 2) - and -C(O)NH(CR b 2)(CR a 2) p - selected from the group consisting of k is an integer from 1 to 4, m is an integer from 0 to 3; n is an integer from 0 to 2, p is an integer from 0 to 1; R a are each independently hydrogen, an optionally substituted -C1 to C4 alkyl, a halogen, -OH, an optionally substituted -O-C1 to C4 alkyl, -OCF3, an optionally substituted -S-C1 to C4 alkyl, or -NR b R c , optionally substituted -C2-C4 alkenyl, and optionally substituted -C2-C4 alkynyl, provided that one R a is bonded to C via an O, S, or N atom, the other R bonded to the same C a is hydrogen or is attached via a carbon atom; R b are each independently selected from the group consisting of hydrogen and optionally substituted -C1-C4 alkyl; R c are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano; R 6 , R 7 , R 8 , and R 9are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano, or R 6 and T together with the carbon to which they are attached form -NR i forming a ring having 5-6 atoms including 0-2 heteroatoms independently selected from -, -O-, and -S-, provided that when there are two heteroatoms in the ring and both heteroatoms are different from nitrogen, both heteroatoms must be separated by at least one carbon atom, and X is attached to the ring by a direct bond to a ring carbon or to a ring carbon or nitrogen, -(CR a 2) provided that the bond is - or -C(O)-, R i is selected from the group consisting of hydrogen, -C(O)C1-C4 alkyl, -C1-C4 alkyl, and -C1-C4-aryl; R 3 and R 4 is hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -C 12 Alkynyl, -SR d , -S(=O)R e , -S(=O)2R e , -S(=O)2NR f R g , -C(O)OR h , -C(O)R e , -N(R b )C(O)NR f R g , -N(R b )S(=O)2R e , -N(R b )S(=O)2NR f R g , and -NR f R gare independently selected from the group consisting of R d Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 is selected from the group consisting of R e Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 hydrogen, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 gTogether, O, NR C and S, wherein the optionally substituted heterocyclic ring may include a second hetero group selected from the group consisting of optionally substituted -C1-C4 alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h and optionally substituted with 0 to 4 substituents selected from the group consisting of R h Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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; R 5 is -OH, optionally substituted -OC1-C6 alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ), and -NHC(O)NH(R h ) selected from the group consisting of X is P(O)YR 11 Y'R 11 and Y and Y′ are —O— and —NR v -, and when Y and Y' are -O-, R bonded to -O- is 11is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y , -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; Y and Y' are -NR v -NR v - R bonded to 11 -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Y is -O- and Y' is -NR v -, R bonded to -O- 11 is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(Rz )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y -alkyl-S-S-alkylhydroxy, -alkyl-S-S-alkylhydroxy, -NR v - R bonded to 11 is H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Alternatively, Y and Y′ are —O— and —NR v - When selected independently, R as a whole 11 and R 11 is -alkyl-SS-alkyl-, forming a cyclic group, or taken together as R 11 and R 11 is based on the following

[0020] [ka]

[0021] where: V, W, and W' are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group containing 5-7 atoms substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 3 atoms away from both Y groups bonded to phosphorus, where 0-1 atom is a heteroatom and the remaining atoms are carbon; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group fused to an aryl group at positions β and γ relative to Y which is attached to phosphorus, where 0-1 atoms are heteroatoms and the remaining atoms are carbon; or V and W together are linked via three further carbon atoms to form an optionally substituted cyclic group containing six carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bonded to one of said carbon atoms that is three atoms away from Y bonded to phosphorus; or Z and W taken together are linked through an additional 3-5 atoms to form a cyclic group (wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon); V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or W and W' taken together are linked through an additional 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms and the remaining atoms are carbon; and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is -CHR z OH, -CHR z O.C.(O)R y ,-CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR z OC(O)SR y , -CHR z OCO2Ry , -OR z , -SR z , -CHR z N3, -CH2-aryl, -CH(aryl)OH, -CH(CH=CR z 2) OH, -CH(C≡CR z )OH, -R z , -NR z 2. -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z , -NHCO2R y , -CH2NH-aryl, -(CH2)q-OR z , and -(CH2)q-SR z is selected from the group consisting of q is an integer of 2 or 3; R z are R y and -H; R y are each selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; R x are each independently selected from the group consisting of -H and alkyl, or taken together as R x and R x forms a cyclic alkyl group, R v are each selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.

[0022] According to the methods and compositions described herein, the compound administered is:

[0023] [ka]

[0024] The present invention does not include compounds having a structure selected from the group consisting of:

[0025] According to the methods and compositions described herein, the compound administered is:

[0026] [ka]

[0027] and pharma- ceutically acceptable salts thereof.

[0028] In accordance with the methods and compositions described herein, the compound administered is a compound having the structure of formula (A):

[0029] [ka]

[0030] or a pharma- ceutically acceptable salt thereof. [In the formula, R 3 ' is H or CH2R a' and R a' is a hydroxyl, an O-linked amino acid, -OP(O)(OH)2 or OC(O)R b' and R b' is lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or -(CH2) n' -heteroaryl, n' is 0 or 1; R 4 ' is H and R 5 ' is CH2COOH, C(O)CO2H, or an ester or amide thereof, or R 4' and R 5' are taken together, -N=C(R c' )-C-(O)-NH-C(O)-, and R c' is H or cyano.

[0031] In accordance with the methods and compositions disclosed herein, the compounds are useful in treating and preventing the development of a number of diseases, including, but not limited to, glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, muscle fibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, liver and gallbladder cirrhosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory tract infections, and the like. Inspiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes mellitus, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection-induced fibrosis In one embodiment, the therapeutic agent may be administered to treat, ameliorate, prevent, or cure one or more fibrotic conditions selected from the group consisting of fibrosis, complications of surgery, fibrotic chronic transplant vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal stenosis, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, psoriasis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components such as collagen that can be affected by intervention in the TRβ pathway, or any combination thereof. Methods and compositions according to the present disclosure may include primary fibrosis or conditions in which the fibrosis, fibrotic condition or symptom is associated with or indicative of another condition.

[0032] In some embodiments of the methods and compositions disclosed herein, the fibrosis, fibrotic condition, or condition is selected from the group consisting of scleroderma, atherosclerosis, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, hepatic fibrosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial lung disease, chronic interstitial lung disease, pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endocardial fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, pulmonary fibrosis, idiopathic interstitial fibrosis, pulmonary ... The conditions may include one or more of myofibrosis, renal fibrosis, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, fibrotic complications of surgery, fibrotic chronic transplant vasculopathy, fibrosis associated with ischemia-reperfusion injury, arthrofibrosis, Dupuytren's disease, fibroproliferative lesions of the oral cavity, fibrotic intestinal strictures, glial scars, leptomeningeal fibrosis, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or any combination thereof.

[0033] In some other embodiments, the fibrosis, fibrotic condition or condition is selected from the group consisting of glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), nonalcoholic steatohepatitis (NASH), liver cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, cirrhosis of the gallbladder, diffuse parenchymal lung disease, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, emphysema, chronic kidney disease, type II diabetes, macular degeneration, pulmonary emphysema, chronic kidney disease, type II diabetes, pulmonary edema ... It may be associated with one or more, or any combination of, degeneration, chronic rejection of transplanted organs, post-vasectomy pain syndrome, rheumatoid arthritis, dermatomyositis-polymyositis, mixed connective tissue disease, Crohn's disease, meningitis, systemic lupus erythematosus, or symptoms or sequelae thereof, or other diseases or conditions that result in excessive deposition of extracellular matrix components such as collagen that can be affected by intervention in the TRβ pathway.

[0034] In some other embodiments, the fibrosis, fibrotic condition or symptom can include symptoms or sequelae of GSD III, GSD IX, non-alcoholic steatohepatitis, hepatic or pancreatic cirrhosis, Dupuytren's disease, scleroderma, idiopathic pulmonary fibrosis, or alcoholic fatty liver disease, or any combination thereof.

[0035] According to the methods and compositions disclosed herein, the compounds may treat, prevent, or ameliorate inflammation. In some embodiments, the inflammation may be chronic inflammation of an organ, tissue, spatial region, or fluid-connected area of ​​the subject's body.

[0036] The disclosed methods and compositions further provide for administration of one or more of the compounds listed above to a subject, the subject suffering from glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), hepatitis, scleroderma, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the gallbladder, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, Acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes mellitus, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, and complications of surgery. The patient has one or more conditions selected from the group consisting of chronic fibrosis, fibrotic chronic transplant vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrotic intestinal stenosis, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components such as collagen that can be affected by intervention in the TRβ pathway, or any combination thereof. The methods and compositions of the present disclosure contemplate said administration wherein the condition is primary fibrosis, secondary fibrosis, or a fibrotic manifestation of the condition.

[0037] In accordance with the methods and compositions of the present disclosure, primary fibrosis is selected from the group consisting of scleroderma, atherosclerosis, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, hepatic fibrosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial lung disease, chronic interstitial lung disease, pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, and macular degeneration. The conditions may include one or more of: fibrosis, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, fibrotic complications of surgery, fibrotic chronic transplant vasculopathy, fibrosis associated with ischemia-reperfusion injury, arthrofibrosis, Dupuytren's disease, fibroproliferative lesions of the oral cavity, fibrotic intestinal stenosis, glial scars, leptomeningeal fibrosis, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or any combination thereof.

[0038] In accordance with the methods and compositions of the present disclosure, secondary fibrosis is characterized by a variety of conditions, including glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), hepatitis, scleroderma, atherosclerosis, asthma, cirrhosis of the gallbladder, diffuse parenchymal lung disease, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, emphysema, chronic kidney disease, type II diabetes mellitus, macular degeneration, chronic rejection of transplanted organs, post-vasectomy pain syndrome, rheumatoid arthritis, dermatomyositis-polymyositis, mixed connective tissue disease, Crohn's disease, meningitis, systemic lupus erythematosus, or symptoms or sequelae thereof, or fibrosis associated with one or more of, or any combination of, other diseases or conditions that result in excessive deposition of extracellular matrix components such as collagen that can be affected by intervention in the TRβ pathway.

[0039] According to the methods and compositions of the present disclosure, primary fibrosis can include symptoms or sequelae of GSD III, GSD IX, pancreatic cirrhosis, Dupuytren's disease, scleroderma, idiopathic pulmonary fibrosis, or alcoholic fatty liver disease, or any combination thereof. In some embodiments described herein, the compounds can be administered to treat fibrosis and inflammation.

[0040] In some embodiments described herein, the compounds may be administered to further treat, alleviate, prevent, or cure one or more inflammatory diseases or disorders. In some embodiments, the inflammatory disease or disorder is acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, Cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis , enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis Ureitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, nonalcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris vularis), pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein inflammation, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, bladder trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, vulvitis, and any combination thereof.

[0041] In some embodiments, the inflammatory disease or disorder can be arthritis, which can include one or more of osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple's disease, Behcet's disease, septic arthritis, gouty arthritis, pseudogout, and Still's disease.

[0042] In some embodiments, the inflammatory disease or disorder can be an autoimmune disease or disorder, which can be acute disseminated encephalomyelitis (ADEM), Addison's disease, allergy or sensitivity, amyotrophic lateral sclerosis, antiphospholipid syndrome (APS), arthritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune pancreatitis, bullous pemphigoid, celiac disease, Chagas' disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's thyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenia, idiopathic thrombocytopenia, idiopathic pulmonary fibrosis ... The conditions may include one or more of: paucity of purpura, inflammatory bowel disease, interstitial cystitis, lupus (including discoid lupus erythematosus, drug-induced lupus erythematosus, lupus nephritis, neonatal lupus erythematosus, subacute cutaneous lupus erythematosus, and systemic lupus erythematosus), morphea, multiple sclerosis (MS), myasthenia gravis, myopathy, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, relapsing disseminated encephalomyelitis (multiphasic disseminated encephalomyelitis), rheumatic fever, schizophrenia, scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis, and vitiligo.

[0043] According to the methods and compositions of the present disclosure, the compounds may be administered to a subject in need thereof to alter the expression level of one or more fibrosis-related genes. In some embodiments, the fibrosis-related genes may be Col1a1, Col3a1, αSMA, LGALS1, or any combination thereof. In some embodiments, the compounds may be administered to a subject in need thereof to further alter the expression level of one or more inflammation-related genes in the subject. In some embodiments, the inflammation-related gene may be ANXA2. In some embodiments, the inflammation-related gene marker may be LGALS3.

[0044] According to the methods and compositions of the present disclosure, the compositions administered may further comprise one or more pharma- ceutically acceptable excipients and may be formulated for oral, intravenous, intra-arterial, intestinal, rectal, intravaginal, nasal, pulmonary, topical, intradermal, transdermal, buccal, lingual, sublingual, or ocular administration, or any combination thereof.

[0045] According to the methods and compositions of the present disclosure, the subject to which the compositions listed above are administered may exhibit abnormal or excessive deposition of collagen type 1, type 1a, or type III. In some embodiments of the methods and compositions of the present disclosure, administration of the composition may prevent, ameliorate, or cure the fibrosis, fibrotic condition, or fibrotic symptom, and may further reduce the amount of extracellular matrix protein present in one or more tissues of the subject. In some embodiments, the reduction in the amount of extracellular matrix protein present in one or more tissues of the subject may include a reduction in the amount of collagen present in one or more tissues of the subject, and may further include a reduction in the amount of collagen type I, type Ia, or type III present in one or more tissues of the subject. [Brief description of the drawings]

[0046] [Figure 1]FIG. 1 shows total liver hydroxyproline content (μg / liver) in mice after 8 weeks of treatment with vehicle, low dose Compound 2 (see Example 1, Compound 2 (low)), high dose Compound 2 (see Example 1, Compound 2 (high)), Compound 1, or Elagibranor (control). Compound 2-treated animals show lower total liver hydroxyproline levels than control- or mock-treated animals. [Diagram 2] Representative images of livers stained with picrosirius red (red stain to visualize collagen type I and III deposition) at the end of the treatment period after 8 weeks of treatment with vehicle, low dose compound 2 (see Example 1), high dose compound 2 (see Example 1), compound 1, or elafibranor (control) (10x magnification, scale bar=200 μm). [Diagram 3] Representative images of livers stained with anti-collagen type I (col1a1) (Southern Biotech, Cat. 131001) at the end of the treatment period after 8 weeks of treatment with vehicle, low dose Compound 2 (see Example 1), high dose Compound 2 (see Example 1), Compound 1, or elafibranor (control) (magnification 20x, scale bar=100 μm). [Figure 4] Figure 1 shows total liver Col1A1 content (mg) after biopsy following 8 weeks of treatment with vehicle, low dose Compound 2 (see Example 1), high dose Compound 2 (see Example 1), Compound 1, or elafibranor (control). Compound 2-treated animals show lower total liver Col1A1 content than control- or mock-treated animals. [Diagram 5]Figure 1 shows liver Picro-Sirius Red (PSR) staining after biopsy as determined by histological quantitative assessment after 8 weeks of treatment with vehicle, low dose Compound 2 (see Example 1), high dose Compound 2 (see Example 1), Compound 1, or elafibranor (control). Total liver collagen 1 and 3 (mg / liver) were determined by morphometry after Picro-Sirius Red staining. Liver sections from Compound 1-treated animals showed less PSR staining than liver sections from mock-treated animals, and liver sections from Compound 2-treated animals showed less PSR staining than liver sections from control-treated or mock-treated animals. Data are presented as mean ± SEM (n=11-12). [Figure 6] Figure 1 shows the reduction (%) of total liver triglycerides, cholesterol, and total lipids and NAS in Compound 2-treated animals versus vehicle-treated controls after 8 weeks of Compound 2 administration in a diet-induced mouse model of NASH (see Example 6). [Figure 7] Figure 6 shows the reduction (%) of liver fibrosis in compound 2 treated animals vs. vehicle treated controls after 8 weeks of compound 2 administration in diet-induced mouse model of NASH (see Example 6).Liver fibrosis is assessed in terms of fibrosis score, Type I Collagen level present in liver samples after treatment, and Hydroxyproline level. [Figure 8] Figure 6 shows the reduction (%) of profibrotic gene expression in Compound 2-treated animals versus vehicle-treated controls after 8 weeks of Compound 2 administration in a diet-induced mouse model of NASH (see Example 6). Profibrotic gene expression is assessed in terms of expression levels of Col1a1, Col3a1, ANXA2 (αSMA), and LGALS1 (galectin-1) in liver samples after treatment. [Figure 9]FIG. 1 shows % reduction of Galectin-3 in Compound 2 and Compound 1 treated animals versus vehicle treated controls after 8 weeks of administration of Compound 2 or Compound 1 in a diet-induced mouse model of NASH. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] The present disclosure provides compounds and methods for treating fibrosis, fibrotic conditions, or fibrotic symptoms by administering a thyroid hormone receptor-β (TRβ) agonist. In some embodiments, conditions that result in such fibrosis, fibrotic conditions, or fibrotic symptoms include, but are not limited to, glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), nonalcoholic steatohepatitis (NASH), liver cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, muscle fibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, liver and gallbladder cirrhosis, splenic fibrosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial fibrosis, and pulmonary fibrosis. Interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keratitis TRβ pathway, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components such as collagen, which may be affected by intervention in the TRβ pathway.Such pathologies may involve inflammation and / or injury, and may also involve responses mediated by TGF-β-dependent pathways that can be modulated by thyroid hormone (see, e.g., Alfonso-Merino et al., Proc. Nat. Acad. Sci. 113(24):E3451-60 (2016), which is incorporated herein for its disclosure of the ability of thyroid hormone to modulate TGF-β signaling and associated fibrosis in mice). Because TGF-β-dependent pathways are involved in stimulating fibroblast differentiation and collagen production, and thyroid hormones such as T3 and T4 can affect these pathways via TRβ receptors, the present disclosure provides compositions and methods for preventing, ameliorating, or reducing collagen deposition in one or more tissues of a subject by administering a TRβ agonist compound.

[0048] The disclosure also provides compounds and methods for treating fibrosis, fibrotic conditions or symptoms, and inflammatory diseases or disorders by administering a thyroid hormone receptor-β (TRβ) agonist.In some embodiments, such inflammatory diseases or disorders include acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, sepsis, and the like. Riac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, fetal Endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, cardiac valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease , keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, nonalcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris vularis), pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein inflammation, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, bladder trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, vulvitis, and any combination thereof.In some embodiments, the arthritis can be osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple's disease, Behcet's disease, septic arthritis, gouty arthritis, pseudogout, Still's disease, and any combination thereof. In some embodiments, the autoimmune disease or disorder is acute disseminated encephalomyelitis (ADEM), Addison's disease, allergy or sensitivity, amyotrophic lateral sclerosis, antiphospholipid syndrome (APS), arthritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune pancreatitis, bullous pemphigoid, celiac disease, Chagas' disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's thyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, idiopathic pulmonary fibrosis ... The condition may be plaque disease, inflammatory bowel disease, interstitial cystitis, lupus (including discoid lupus erythematosus, drug-induced lupus erythematosus, lupus nephritis, neonatal lupus erythematosus, subacute cutaneous lupus erythematosus, and systemic lupus erythematosus), morphea, multiple sclerosis (MS), myasthenia gravis, myopathy, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, relapsing disseminated encephalomyelitis (multiphasic disseminated encephalomyelitis), rheumatic fever, schizophrenia, scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis, vitiligo, and any combination thereof.

[0049] The present disclosure also provides compounds and methods for altering the expression level of one or more fibrosis-related genes in a subject in need thereof, comprising administering to the subject one or more thyroid receptor beta (TRβ) agonists. In some embodiments, the fibrosis-related genes can be Col1a1, Col3a1, ACTA2, ENPP2, LGALS1, or any combination thereof. The present disclosure also provides compounds and methods for altering the expression level of one or more fibrosis-related genes in a subject and further altering the level of one or more inflammation-related genes. In some embodiments, the inflammation-related gene can be ANXA2. In some embodiments, the inflammation-related gene marker can be LGALS3.

[0050] definition The term "mammal" is used in its ordinary biological sense, and thus specifically includes humans and non-human mammals such as dogs, cats, horses, donkeys, mules, cows, domestic buffalo, camels, llamas, alpacas, bison, yaks, goats, sheep, pigs, elk, deer, domestic antelope, as well as non-human primates and many other species.

[0051] "Subject," as used herein, means a human or a non-human mammal, including, but not limited to, a dog, cat, horse, donkey, mule, cow, domestic buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer, domestic antelope, or non-human primate, selected for treatment or therapy.

[0052] "Subject suspected of suffering from" means a subject exhibiting one or more clinical indicators of a disease or condition. In some embodiments, the disease or condition is one or more fibrosis, fibrotic condition, or fibrotic symptoms. In some embodiments, the disease or condition is scleroderma. In some embodiments, the disease or condition is non-alcoholic steatohepatitis. In some embodiments, the disease or condition is cirrhosis. In some embodiments, the disease or condition is non-alcoholic fatty liver disease. In some embodiments, the disease or condition is idiopathic pulmonary fibrosis. In some embodiments, the disease or condition is atherosclerosis. In some embodiments, the disease or condition is hepatitis, nonalcoholic fatty liver disease, asthma, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, scleroderma, pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis; interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration. , keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, complications of surgery, fibrotic chronic transplant vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal stenosis, Crohn's disease, glial scars, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components.

[0053] As used herein, "fibrosis" refers to the abnormal deposition of extracellular matrix proteins. Such proteins include, but are not limited to, collagen, elastin, fibronectin, laminin, keratin, keratin sulfate, fibrin, perlecan, agrin, or agrecan. As used herein, "collagen" refers to any one of the collagen subtypes, including, but not limited to, types I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, or XVIII. Exemplary collagen types and subtypes include types I, Ia, II, III, IV, and V, among others. As used herein, fibrosis may occur alone or as a symptom or sequela of another pathology. As used herein, fibrosis may result from a genetic condition, a genetic predisposition, an environmental insult, injury, injury healing, an autoimmune condition, or chronic inflammation, a chronic inflammatory condition, or another condition that leads to abnormal or excessive deposition of extracellular matrix components. Fibrosis as referred to herein may be assessed by assaying or determining the presence or level of one or more biomarkers. Biomarkers for the presence of fibrosis include, but are not limited to, expression of the Col1a1, Col3a1, ACTA2, ENPP2, and / or LGALS1 genes, or any combination or product thereof. Diagnosis or assessment of fibrosis may further be performed by determining the presence or level of type I collagen and / or hydroxyproline, or any combination or product thereof. Diagnosis or assessment of fibrosis may also be performed by histological, histochemical, or immunohistochemical analysis of one or more samples from the subject.

[0054] "Glycogen storage disease" means any one or more of a group of disorders characterized by impairment in the synthesis, transport, or utilization of glycogen, generally due to a deficiency in a necessary enzymatic activity. Glycogen storage diseases are generally classified according to their symptoms and type according to etiology. Known types of GSD include type 0 GSD (aglycogenesis, glycogen synthase deficiency); type 1 GSD (von Gierke's disease, glucose-6-phosphatase translocase / transporter deficiency, GSD I); type 2 GSD (Pompe's disease, α-1-4-glucosidase deficiency, GSD II); type 3 GSD (Cori's disease, Forbes' disease, limit dextrinosis, debranching enzyme; amylo-1-6-glucosidase deficiency due to loss of glucosidase and / or transferase activity, GSD III); type 4 GSD (Anderson's disease, glycogen phosphorylase deficiency, branching enzyme deficiency, amylopectinosis, glycogen branching enzyme deficiency; amylo-1,4→1,6 transglucosidase deficiency, GSD IV); type 5 GSD (McArdle's disease, glycogen phosphorylase (muscle type) deficiency, GSD GSD type 6 (Haas's disease; glycogen phosphorylase E (liver type) deficiency, GSD VI); GSD type 7 (Tarui's disease; phosphofructokinase deficiency, GSD VII); GSD types 8 and 9 (GSD with phosphorylase activation system deficiency; phosphorylase kinase (liver or muscle isoform) deficiency, GSD VIII and GSD IX); GSD type 10 (cyclic AMP-dependent kinase deficiency, GSD X); GSD type 11 (Fanconi-Bickel syndrome; glucose transporter type 2 (GLUT2) deficiency, GSD XI); and GSD type 12 (aldolase A deficiency, GSD XII). Subtypes of glycogen storage diseases are also known, in particular GSD 1a, which is caused by mutations in the glucose-6-phosphatase gene (G6PC) and leads to excessive accumulation of glycogen and lipids in liver tissue, hepatomegaly, hepatic adenoma, and hepatocellular carcinoma, among other symptoms. Symptoms of glycogen storage diseases can include elevated or decreased blood glucose, insulin insensitivity, myopathy, and hepatic symptoms such as steatosis, hyperlipidemia, hypercholesterolemia, cardiac hypertrophy, hepatomegaly, fibrosis, cirrhosis, hepatocellular adenoma, and hepatocellular carcinoma.Symptoms can also include insulin insensitivity, elevated or reduced blood glucose, renal dysfunction, and / or fibrosis.

[0055] As used herein, "inflammatory disease" refers to a disease or disorder characterized by inflammation. Exemplary inflammatory diseases include acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease, cellulitis, uterine fibroids, and thyroiditis. Cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, small intestine Enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, cardiac valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis , keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, nonalcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris vularis), pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal vein inflammation, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, bladder trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis.Inflammation as referred to herein may be assessed by assaying or determining the presence or level of one or more biomarkers. Biomarkers for the presence of inflammation include, but are not limited to, expression of the TNF, CARD15, IL4R, IL23R, CTLA4, ANXA1, ANXA2, LGALS3, and / or PTPN22 genes, or any combination or product thereof.

[0056] The term "atherosclerosis" refers to a condition characterized by irregularly distributed lipid deposits in the intima of large and medium-sized arteries, which lead to fibrosis and calcification. Atherosclerosis increases the risk of angina, stroke, heart attack, or other cardiac or cardiovascular conditions.

[0057] "Subject in need thereof" means a subject identified as in need of therapy or treatment.

[0058] A therapeutic effect relieves to some extent one or more of the symptoms of a disease or disorder, including curing the disease or disorder. "Cure" means that the symptoms of an active disease are eliminated. However, even after a cure is achieved, certain long-term or permanent effects of the disease (such as extensive tissue damage) may exist.

[0059] "Treat", "treatment", or "treating" as used herein refers to administering a pharmaceutical composition for prophylaxis and / or therapy. The term "prophylactic treatment" refers to treating a patient who does not already suffer from the disease or disorder in question, but who is susceptible to or otherwise at risk for a particular disease or disorder, whereby the treatment reduces the likelihood that the patient will develop the disease or disorder. The term "therapeutic treatment" refers to administering a treatment to a patient who already suffers from a disease or disorder.

[0060] "Preventing" or "prevention" refers to delaying or forestalling the onset, occurrence or progression of a condition or disease for a period of time, including weeks, months, or years.

[0061] "Amelioration" refers to a decrease in the severity of at least one indicator of a condition or disease. In certain embodiments, amelioration includes a delay or slowing in the progression of one or more indicators of a condition or disease. The severity of an indicator may be determined by subjective or objective measures known to those skilled in the art.

[0062] "Modulation" refers to a perturbation of function or activity. In certain embodiments, modulation refers to an increase in gene expression. In certain embodiments, modulation refers to a decrease in gene expression. In certain embodiments, modulation refers to an increase or decrease in the total serum level of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the free serum level of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the total serum level of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in the free serum level of a specific non-protein factor. In certain embodiments, modulation refers to an increase or decrease in the total bioavailability of a specific protein. In certain embodiments, modulation refers to an increase or decrease in the total bioavailability of a specific non-protein factor.

[0063] "Administering" means providing an agent or composition to a subject, and includes, but is not limited to, administration by a medical professional and self-administration.

[0064] Administration of the compounds disclosed herein or their pharma- ceutically acceptable salts can be via any of the accepted modes of administration of agents with similar utility, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, pulmonary, intravaginal, rectal, or intraocular administration. Oral and parenteral administration are the norm in treating the indications that are the subject of the preferred embodiments.

[0065] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarterial, and intracranial administration.

[0066] "Subcutaneous administration" means administration just beneath the skin.

[0067] "Intravenous administration" means administration into a vein.

[0068] "Intra-arterial administration" means administration into an artery.

[0069] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof. Agents include, but are not limited to, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0070] "Drug" means a substance that produces a therapeutic effect when administered to a subject.

[0071] "Pharmaceutical composition" refers to a mixture of substances, including a pharmaceutical agent, suitable for administration to an individual. For example, a pharmaceutical composition can include a modified oligonucleotide and a sterile aqueous solution.

[0072] "Active pharmaceutical ingredient" means the substance in a pharmaceutical composition that provides a desired effect.

[0073] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the associated compound and are not biologically or otherwise undesirable. In many cases, the compounds herein are capable of forming acid and / or base salts due to the presence of phenolic and / or phosphonate groups or groups similar thereto. Those skilled in the art will recognize that the protonation state of any or all of these compounds may vary depending on the pH and ionicity of the surrounding solution, and thus, the present disclosure contemplates multiple charge states of each compound. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.; particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987, which is incorporated herein by reference in its entirety.

[0074] "Solvate" refers to a compound formed by the interaction of a solvent with EPI, a metabolite, or a salt thereof. Suitable solvates are pharma- ceutically acceptable solvates, including hydrates.

[0075] The term "prodrug" as used herein refers to any compound that, upon administration to a biological system, produces a biologically active compound as a result of spontaneous, enzyme-catalyzed, and / or metabolic chemical reactions, or a combination of each. Standard prodrugs are formed using groups such as HO-, HS-, HOOC-, RN- that are attached to functionalities associated with the drug and are cleaved in vivo. Standard prodrugs include, but are not limited to, carboxylic acid esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and hydroxyl, thiol, and amine esters where the attached group is acyl, alkoxycarbonyl, aminocarbonyl, phosphate, or sulfate. The groups shown are exemplary and not all inclusive, and one of ordinary skill in the art can prepare other known variations of prodrugs. Such prodrugs of the compounds of the present disclosure are within the scope of the present invention. Prodrugs must undergo some form of chemical transformation to produce the biologically active compound, or a compound that is a precursor of the biologically active compound. In some cases, prodrugs are usually less biologically active than the drug itself and serve to improve drug efficacy or safety, such as by improved oral bioavailability and / or pharmacodynamic half-life. Prodrug forms of the compound can be utilized to, for example, improve bioavailability, improve subject acceptability, such as by masking or reducing unpleasant properties such as bitter taste or gastrointestinal irritation, alter solubility for intravenous use, provide extended or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems", pages 352-401; Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, edited by EB Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, edited by RL Juliano, Oxford Univ. Press, Oxford, 1980.

[0076] Reading from left to right for a T group with more than one atom, the left atom of the T group is R 1 and R 2 The atom to the right of the T group is bonded to a carbon, phosphorus, or other atom in X or E. For example, when T is -O-CH- or -N(H)C(O)-, -phenyl-O-CH-X and -phenyl-N(H)C(O)-X are meant.

[0077] The term "alkyl" refers to a straight or branched or cyclic chain hydrocarbon group having a carbon-carbon single bond. Representative examples include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl, all of which may be substituted. An alkyl group is any of C1 to C6. 20 It is.

[0078] The term "aryl" refers to an aromatic group having 5 to 14 ring atoms and at least one ring having a conjugated pi electron system, and includes carbocyclic aryl, heterocyclic aryl, and biaryl groups, all of which may be optionally substituted.

[0079] Carbocyclic aryl groups are groups having 6 to 14 ring atoms in which the ring atoms of the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.

[0080] Heterocyclic aryl or heteroaryl groups are groups having 5 to 14 ring atoms, with 1 to 4 heteroatoms being aromatic ring atoms and the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, nitrogen, and selenium. Suitable heteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, imidazolyl, and the like, all of which may be substituted.

[0081] The term "biaryl" refers to aryl groups having from 5 to 14 atoms and containing more than one aromatic ring, including both fused ring systems and aryl groups substituted with other aryl groups. Such groups may be optionally substituted. Suitable biaryl groups include naphthyl and biphenyl.

[0082] The term "optionally substituted" or "substituted" means any of the following radicals: lower alkyl, lower aryl, lower aralkyl, lower cyclic alkyl, lower heterocycloalkyl, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy, aralkoxy, lower heteroaryl, lower heteroaryloxy, lower heteroarylalkyl, lower heteroaralkoxy, azido, amino, halo, lower alkylthio, oxo, lower acylalkyl, lower carboxyester, carboxyl, -carboxamido, nitro, lower acyloxy, lower aminoalkyl, lower alkylamino. Includes groups substituted by 1, 2, 3, 4, 5, or 6 substituents independently selected from aryl, lower alkylaryl, lower alkylaminoalkyl, lower alkoxyaryl, lower arylamino, lower aralkylamino, sulfonyl, lower carboxamidoalkylaryl, lower carboxamidoaryl, lower hydroxyalkyl, lower haloalkyl, lower alkylaminoalkylcarboxy-, lower aminocarboxamidoalkyl-, cyano, lower alkoxyalkyl, lower perhaloalkyl, and lower arylalkyloxyalkyl.

[0083] "Substituted aryl" and "substituted heteroaryl" refer to aryl and heteroaryl groups that are substituted with one to three substituents selected from the group consisting of lower alkyl, lower alkoxy, lower perhaloalkyl, halo, hydroxy, and amino.

[0084] The term "-aralkyl" refers to an alkylene group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, which may be substituted. "Heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

[0085] The term "alkylaryl-" refers to an aryl group substituted with an alkyl group. "Lower alkylaryl-" refers to a group in which the alkyl is lower alkyl.

[0086] The term "lower" as referred to herein in connection with an organic group or compound, respectively, refers to six or fewer carbon atoms. Such groups can be straight-chain, branched, or cyclic groups.

[0087] The term "higher" as referred to herein in connection with an organic group or compound, respectively, refers to seven or more carbon atoms. Such groups can be straight-chain, branched, or cyclic groups.

[0088] The term "cyclic alkyl" or "cycloalkyl" refers to cyclic alkyl groups having from 3 to 10 carbon atoms, and in one embodiment from 3 to 6 carbon atoms. Suitable cyclic groups include norbornyl and cyclopropyl. Such groups may be substituted.

[0089] The term "heterocyclic", "heterocyclic alkyl" or "heterocycloalkyl" refers to a cyclic group having 3 to 10 atoms, in one embodiment 3 to 6 atoms, and containing at least one heteroatom, in another embodiment 1 to 3 heteroatoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen. Heterocyclic groups can be attached through a nitrogen or a carbon atom of the ring. Heterocyclic alkyl groups include unsaturated cyclic, fused cyclic, and spirocyclic groups. Suitable heterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl, and pyridyl.

[0090] The terms "arylamino" (a) and "aralkylamino" (b) each refer to the group -NRR', where (a) R is aryl and R' is hydrogen, alkyl, aralkyl, heterocycloalkyl, or aryl, and (b) R is aralkyl and R' is hydrogen, aralkyl, aryl, alkyl, or heterocycloalkyl, respectively.

[0091] The term "acyl" refers to -C(O)R, where R is alkyl, heterocycloalkyl, or aryl.

[0092] The term "carboxy ester" refers to -C(O)OR, where R is alkyl, aryl, aralkyl, cyclic alkyl, or heterocycloalkyl, all of which may be optionally substituted.

[0093] The term "carboxyl" refers to -C(O)OH.

[0094] The term "oxo" refers to =O in an alkyl or heterocycloalkyl group.

[0095] The term "amino" refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, aryl, aralkyl, and heterocycloalkyl, all of which except H are optionally substituted, and R and R' can form a cyclic ring system.

[0096] The term "-carboxylamide" refers to -CONR2, where each R is independently hydrogen or alkyl.

[0097] The term "sulphonylamido or sulfonylamido" refers to -S(=O)2NR2, where each R is independently hydrogen or alkyl.

[0098] The term "halogen" or "halo" refers to -F, -Cl, -Br and -I.

[0099] The term “alkylaminoalkylcarboxy” refers to the group alkyl-NR-alk-C(O)—O—, where “alk” is an alkylene group and R is H or lower alkyl.

[0100] The term "sulphonyl" or "sulfonyl" refers to -SO2R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0101] The term "sulphonate" or "sulfonate" refers to -SO2OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0102] The term "alkenyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon double bond, including straight-chain, branched-chain and cyclic groups. Alkenyl groups may be substituted. Suitable alkenyl groups include allyl. "1-alkenyl" refers to an alkenyl group in which a double bond exists between the first and second carbon atoms. When a 1-alkenyl group is a W substituent that is bonded to another group, for example to a cyclic phosphonate, it is bonded at the first carbon.

[0103] The term "alkynyl" refers to an unsaturated group having 2 to 12 atoms and containing at least one carbon-carbon triple bond, including straight-chain, branched-chain and cyclic groups. Alkynyl groups may be substituted. Suitable alkynyl groups include ethynyl. "1-alkynyl" refers to an alkynyl group in which a triple bond exists between the first and second carbon atoms. When a 1-alkynyl group is a W substituent that is bonded to another group, for example to a cyclic phosphonate, it is bonded at the first carbon.

[0104] The term "alkylene" refers to a divalent linear, branched, or cyclic saturated aliphatic group. In one embodiment, an alkylene group contains 10 or fewer atoms. In another embodiment, an alkylene group contains 6 or fewer atoms. In another embodiment, an alkylene group contains 4 or fewer atoms. An alkylene group can be a linear, branched, or cyclic alkylene group.

[0105] The term "acyloxy" refers to an ester group -OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

[0106] The term "aminoalkyl-" refers to the group NR2-alk-, where "alk" is an alkylene group and R is selected from -H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0107] The term "alkylaminoalkyl-" refers to the group alkyl-NR-alk-, where each "alk" is an independently selected alkylene and R is H or a lower alkyl. "Lower alkylaminoalkyl-" refers to groups in which the alkyl and alkylene groups are lower alkyl and alkylene, respectively.

[0108] The term "arylaminoalkyl-" refers to the group aryl-NR-alk-, where "alk" is an alkylene group and R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl. In "lower arylaminoalkyl-", the alkylene group is lower alkylene.

[0109] The term "alkylaminoaryl-" refers to the group alkyl-NR-aryl-, where "aryl" is a divalent group and R is -H, alkyl, aralkyl, or heterocycloalkyl. In "lower alkylaminoaryl-", the alkyl group is lower alkyl.

[0110] The term "alkoxyaryl-" refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group is lower alkyl.

[0111] The term "aryloxyalkyl-" refers to an alkyl group substituted with an aryloxy group.

[0112] The term "aralkyloxyalkyl-" refers to the group aryl-alk-O-alk-, where "alk" is an alkylene group. "Lower aralkyloxyalkyl-" refers to groups in which the alkylene group is lower alkylene.

[0113] The terms "alkoxy-" or "alkyloxy-" refer to an alkyl-O- group.

[0114] The term "alkoxyalkyl-" or "alkyloxyalkyl-" refers to the group alkyl-O-alk-, where "alk" is an alkylene group. In "lower alkoxyalkyl-", any alkyl and alkylene are lower alkyl and alkylene, respectively.

[0115] The term "alkylthio-" refers to an alkyl-S- group.

[0116] The term "alkylthioalkyl-" refers to the group alkyl-5-alk-, where "alk" is an alkylene group. In "lower alkylthioalkyl-", any alkyl and alkylene are lower alkyl and alkylene, respectively.

[0117] The term "alkoxycarbonyloxy-" refers to alkyl-OC(O)-O-.

[0118] The term "aryloxycarbonyloxy-" refers to aryl-OC(O)-O-.

[0119] The term "alkylthiocarbonyloxy-" refers to alkyl-SC(O)-O-.

[0120] The term "amide" refers to NR2-C(O)-, RC(O)-NR 1 -, NR2-S(=O)2- and RS(=O)2-NR 1 - refers to an NR group adjacent to an acyl or sulfonyl group such as in 1 includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl).

[0121] The term "carboxamide" refers to NR-C(O)- and RC(O)-NR 1 - (where R and R 1includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl. This term does not include urea, -NR-C(O)-NR-.

[0122] The term "sulphonamido" refers to NR2-S(=O)2- and RS(=O)2-NR 1 - (where R and R 1 includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl. This term does not include sulfonylureas, -NR-S(=O)2-NR-.

[0123] The terms “carboxamidoalkylaryl” and “carboxamidoaryl” refer to aryl-alk-NR 1 -C(O) and ar-NR 1 -C(O)-alk-, where "ar" is aryl, "alk" is alkylene, and R 1 and R includes H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0124] The terms “sulfonamidoalkylaryl” and “sulfonamidoaryl” refer to aryl-alk-NR 1 -S(=O)2- and ar-NR 1 -S(=O)2- (where "ar" is aryl, "alk" is alkylene, and R 1 and R includes -H, alkyl, aryl, aralkyl, and heterocycloalkyl.

[0125] The term "hydroxyalkyl" refers to an alkyl group substituted with one -OH.

[0126] The term "haloalkyl" refers to an alkyl group substituted with a halo.

[0127] The term "cyano" refers to -C≡N.

[0128] The term "nitro" refers to --NO.

[0129] The term "acylalkyl" refers to alkyl-C(O)-alk-, where "alk" is alkylene.

[0130] The term “aminocarboxamidoalkyl-” refers to the group NR—C(O)—N(R)-alk-, where R is an alkyl group or H and “alk” is an alkylene group. “Lower aminocarboxamidoalkyl-” refers to the group where “alk” is lower alkylene.

[0131] The term "heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

[0132] The term "perhalo" refers to an aliphatic or aryl group in which every C-H bond is replaced with a C-halo bond. Suitable perhaloalkyl groups include -CF3 and -CFCl2.

[0133] compound In some embodiments, the TRβ agonist for the uses described herein is a compound according to formula I

[0134] [ka]

[0135] and pharma- ceutically acceptable salts thereof. [In the formula, G is selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(C1-C4 alkyl)-, -CH(C1-C4 alkoxy)-, -C(=CH2)-, -NH-, and -N(C1-C4 alkyl)-; T is -(CR a 2)k -, -CR b =CR b -(CRa 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2)n-, N(R c )(CR b 2)(CR a 2) n -, N(R b )C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CR a 2) m C(O)-, -(CR a 2) C(O)(CR a 2) n , -(CR a 2) n C(O)(CR a 2) - and -C(O)NH(CR b 2)(CR a 2) p - selected from the group consisting of k is an integer from 1 to 4, m is an integer from 0 to 3; n is an integer from 0 to 2, p is an integer from 0 to 1; R a are each independently hydrogen, an optionally substituted -C1 to C4 alkyl, a halogen, -OH, an optionally substituted -O-C1 to C4 alkyl, -OCF3, an optionally substituted -S-C1 to C4 alkyl, or -NR b R c , optionally substituted -C2-C4 alkenyl, and optionally substituted -C2-C4 alkynyl, provided that one R ais bonded to C via an O, S, or N atom, the other R bonded to the same C a is hydrogen or is attached via a carbon atom; R b are each independently selected from the group consisting of hydrogen and optionally substituted -C1-C4 alkyl; R c are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl, and -C(O)H; R 1 and R 2 are each independently selected from the group consisting of halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano; R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano, or R 6 and T together with the carbon to which they are attached form -NR i forming a ring having 5-6 atoms including 0-2 heteroatoms independently selected from -, -O-, and -S-, provided that when there are two heteroatoms in the ring and both heteroatoms are different from nitrogen, both heteroatoms must be separated by at least one carbon atom, and X is attached to the ring by a direct bond to a ring carbon or to a ring carbon or nitrogen, -(CR a 2) provided that the bond is - or -C(O)-, R iis selected from the group consisting of hydrogen, -C(O)C1-C4 alkyl, -C1-C4 alkyl, and -C1-C4-aryl; R 3 and R 4 is hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -C 12 Alkynyl, -SR d , -S(=O)R e , -S(=O)2R e , -S(=O)2NR f R g , -C(O)OR h , -C(O)R e , -N(R b )C(O)NR f R g , -N(R b )S(=O)2R e , -N(R b )S(=O)2NR f R g , and -NR f R g are independently selected from the group consisting of R d Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 is selected from the group consisting of R e Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12Alkenyl, optionally substituted -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 hydrogen, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 Together, O, NR C and S, wherein the optionally substituted heterocyclic ring may include a second hetero group selected from the group consisting of optionally substituted -C1-C4 alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h and optionally substituted with 0 to 4 substituents selected from the group consisting of R h Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -C 12 Alkynyl, optionally substituted -(CR b 2) n Aryl, optionally substituted -(CR b 2) nCycloalkyl and optionally substituted -(CR b 2) n heterocycloalkyl; R 5 is -OH, optionally substituted -OC1-C6 alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ), and -NHC(O)NH(R h ) selected from the group consisting of X is P(O)YR 11 Y'R 11 and Y and Y′ are —O— and —NR v -, and when Y and Y' are -O-, R bonded to -O- is 11 is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y , -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; Y and Y' are -NR v -NR v - R bonded to 11 -H, -[C(R z )2]q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Y is -O- and Y' is -NR v -, R bonded to -O- 11 is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y -alkyl-S-S-alkylhydroxy, -alkyl-S-S-alkylhydroxy, -NR v - R bonded to 11 is H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Alternatively, Y and Y′ are —O— and —NR v - When selected independently, R as a whole 11 and R 11is -alkyl-SS-alkyl-, forming a cyclic group, or taken together as R 11 and R 11 is based on the following

[0136] [ka]

[0137] where: V, W, and W' are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group containing 5-7 atoms substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 3 atoms away from both Y groups bonded to phosphorus, where 0-1 atom is a heteroatom and the remaining atoms are carbon; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group fused to an aryl group at positions β and γ relative to Y which is attached to phosphorus, where 0-1 atoms are heteroatoms and the remaining atoms are carbon; or V and W together are linked via three further carbon atoms to form an optionally substituted cyclic group containing six carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bonded to one of said carbon atoms that is three atoms away from Y bonded to phosphorus; or Z and W taken together are linked through an additional 3-5 atoms to form a cyclic group (wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon); V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or W and W' taken together are linked through an additional 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms and the remaining atoms are carbon; and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is -CHR z OH, -CHR z O.C.(O)R y ,-CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR z OC(O)SR y , -CHR z OCO2R y , -OR z , -SR z , -CHR z N3, -CH2-aryl, -CH(aryl)OH, -CH(CH=CR z 2) OH, -CH(C≡CR z )OH, -R z , -NR z 2. -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z , -NHCO2R y , -CH2NH-aryl, -(CH2)q-OR z , and -(CH2)q-SR z is selected from the group consisting of q is an integer of 2 or 3; R z are R y and -H; R y are each selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; R x are each independently selected from the group consisting of -H and alkyl, or taken together as R x and R x forms a cyclic alkyl group, R v are each selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.

[0138] In some embodiments, the compound of formula I is provided with the following: a) G is -O-, T is -CH2-, and R 1 and R 2 are bromo and R 3 isopropyl, R 4 is hydrogen and R 5 is -OH, X is not P(O)(OH)2 or P(O)(OCH2CH3)2, b) V, Z, W, and W' are not all -H; c) Z is -R z at least one of V, W, and W' is not -H, alkyl, aralkyl, or heterocycloalkyl; d) G is -O- and T is -(CH2) 1~4 - and R 1 and R 2 are independently halogen, alkyl, and cycloalkyl; R 3 is alkyl, and R 4 is hydrogen and R 5 is -OH, X is not -P(O)(OH)2 or -P(O)(O-lower alkyl)2; e) G is -O- and R 5 But -NHC(O)R e , -NHS(=O) 1~2 R e , -NHC(S)NH(R b ), or -NHC(O)NH(R h ) and T is -(CH2) m -, -CH=CH-, -O(CH2) 1~2- or -NH(CH2) 1~2 -, X is not -P(O)(OH)2 or -P(O)(OH)NH2.

[0139] In some embodiments, the compound is

[0140] [ka]

[0141] or a pharma- ceutically acceptable salt thereof.

[0142] In other embodiments, the compound is

[0143] [Table 1A]

[0144] [Table 1B]

[0145] [Table 1C]

[0146] [Table 1D]

[0147] [Table 1E]

[0148] [Table 1F]

[0149] [Table 1G]

[0150]

Table 1H

[0151]

Table 1I

[0152]

Table 1J

[0153]

Table 1K

[0154]

Table 1L

[0155]

Table 1M

[0156]

Table 1N

[0157]

Table 1O

[0158]

Table 1P

[0159]

Table 1Q

[0160] [Table 1R]

[0161] [Table 1S]

[0162] [Table 1T]

[0163] [Table 1U]

[0164] [Table 1V]

[0165] [Table 1W]

[0166] [Table 1X]

[0167] [Table 1Y]

[0168] [Table 1Z]

[0169] or a pharma- ceutically acceptable salt thereof.

[0170] The above compounds can be prepared according to known methods, including those described in US Pat. No. 7,829,552, which is incorporated herein by reference in its entirety.

[0171] In some embodiments, the TRβ agonist for the uses described herein is a compound according to formula I

[0172] [ka]

[0173] and its pharma- ceutically acceptable salts. [In the formula, G is selected from the group consisting of -O-, -S-, -S(=O)-, -S(=O)2-, -Se-, -CH2-, -CF2-, -CHF-, -C(O)-, -CH(OH)-, -CH(C1-C4 alkyl)-, -CH(C1-C4 alkoxy)-, -C(=CH2)-, -NH-, and -N(C1-C4 alkyl)-; T is -(CR a 2)k -, -CR b =CR b -(CR a 2) n -, -(CR a 2) n -CR b =CR b -, -(CR a 2)-CR b =CR b -(CR a 2)-, -O(CR b 2)(CR a 2) n -, -S(CR b 2)(CR a 2)n-, N(R c )(CR b 2)(CR a 2) n -, N(R b )C(O)(CR a 2) n , -C(O)(CR a 2) m -, -(CRa 2) m C(O)-, -(CR a 2) C(O)(CR a 2) n , -(CR a 2) n C(O)(CR a 2) - and -C(O)NH(CR b 2)(CR a 2) p - selected from the group consisting of k is an integer from 1 to 4, m is an integer from 0 to 3; n is an integer from 0 to 2, p is an integer from 0 to 1; R a are each independently hydrogen, an optionally substituted -C1 to C4 alkyl, a halogen, -OH, an optionally substituted -O-C1 to C4 alkyl, -OCF3, an optionally substituted -S-C1 to C4 alkyl, or -NR b R c , optionally substituted -C2-C4 alkenyl, and optionally substituted -C2-C4 alkynyl, provided that one R a is bonded to C via an O, S, or N atom, the other R bonded to the same C a is hydrogen or is attached via a carbon atom; R b are each independently selected from the group consisting of hydrogen and optionally substituted -C1-C4 alkyl; R c are each independently selected from the group consisting of hydrogen, optionally substituted -C1-C4 alkyl, optionally substituted -C(O)-C1-C4 alkyl, and -C(O)H; R 1 and R 2are each independently selected from the group consisting of halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano; R 6 , R 7 , R 8 , and R 9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted -C1-C4 alkyl, optionally substituted -S-C1-C3 alkyl, optionally substituted -C2-C4 alkenyl, optionally substituted -C2-C4 alkynyl, -CF3, -OCF3, optionally substituted -O-C1-C3 alkyl, and cyano, or R 6 and T together with the carbon to which they are attached form -NR i forming a ring having 5-6 atoms including 0-2 heteroatoms independently selected from -, -O-, and -S-, provided that when there are two heteroatoms in the ring and both heteroatoms are different from nitrogen, both heteroatoms must be separated by at least one carbon atom, and X is attached to the ring by a direct bond to a ring carbon or to a ring carbon or nitrogen, -(CR a 2) provided that the bond is - or -C(O)-, R i is selected from the group consisting of hydrogen, -C(O)C1-C4 alkyl, -C1-C4 alkyl, and -C1-C4-aryl; R 3 and R 4 is hydrogen, halogen, -CF3, -OCF3, cyano, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -C 12 Alkynyl, -SR d , -S(=O)R e , -S(=O)2R e , -S(=O)2NR f Rg , -C(O)OR h , -C(O)R e , -N(R b )C(O)NR f R g , -N(R b )S(=O)2R e , -N(R b )S(=O)2NR f R g , and -NR f R g are independently selected from the group consisting of R d Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 is selected from the group consisting of R e Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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 hydrogen, optionally substituted -C1 to -C 12 Alkyl, optionally substituted -C2-C 12Alkenyl, optionally substituted -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 Together, O, NR C and S, wherein the optionally substituted heterocyclic ring may include a second hetero group selected from the group consisting of optionally substituted -C1-C4 alkyl, -OR b , oxo, cyano, -CF3, optionally substituted phenyl, and -C(O)OR h and optionally substituted with 0 to 4 substituents selected from the group consisting of R h Each of -C1 to -C 12 Alkyl, optionally substituted -C2-C 12 Alkenyl, optionally substituted -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; R 5 is -OH, optionally substituted -OC1-C6 alkyl, OC(O)R e , -OC(O)OR h , -F, -NHC(O)R e , -NHS(=O)R e , -NHS(=O)2R e , -NHC(=S)NH(R h ), and -NHC(O)NH(R h ) selected from the group consisting of X is P(O)YR 11 Y'R 11 and Y and Y′ are —O— and —NR v -, and when Y and Y' are -O-, R bonded to -O- is 11 is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y , -alkyl-SS-alkylhydroxy, and -alkyl-SSS-alkylhydroxy; Y and Y' are -NR v -NR v - R bonded to 11 -H, -[C(R z )2] q -COOR y , -C(R x )2COOR Y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Y is -O- and Y' is -NR v -, R bonded to -O- 11is -H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl (wherein the cyclic moiety comprises a carbonate or thiocarbonate), optionally substituted -alkylaryl, -C(R z )2OC(O)NR z 2, -NR z -C(O)-R y , -C(R z )2-OC(O)R y , -C(R z )2-OC(O)OR y , -C(R z )2OC(O)SR y , -alkyl-SC(O)R y -alkyl-S-S-alkylhydroxy, -alkyl-S-S-alkylhydroxy, -NR v - R bonded to 11 is H, -[C(R z )2] q -COOR y , -C(R x )2COOR y , -[C(R z )2] q -C(O)SR y , and -cycloalkylene-COOR y are independently selected from the group consisting of Alternatively, Y and Y′ are —O— and —NR v - When selected independently, R as a whole 11 and R 11 is -alkyl-SS-alkyl-, forming a cyclic group, or taken together as R 11 and R 11 is based on the following

[0174] [ka]

[0175] where: V, W, and W' are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aralkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl, and optionally substituted 1-alkynyl; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group containing 5-7 atoms substituted with hydroxy, acyloxy, alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy bonded to a carbon atom that is 3 atoms away from both Y groups bonded to phosphorus, where 0-1 atom is a heteroatom and the remaining atoms are carbon; or V and Z taken together are linked through a further 3-5 atoms to form a cyclic group fused to an aryl group at positions β and γ relative to Y which is attached to phosphorus, where 0-1 atoms are heteroatoms and the remaining atoms are carbon; or V and W together are linked via three further carbon atoms to form an optionally substituted cyclic group containing six carbon atoms and substituted with one substituent selected from the group consisting of hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy bonded to one of said carbon atoms that is three atoms away from Y bonded to phosphorus; or Z and W taken together are linked through an additional 3-5 atoms to form a cyclic group (wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon); V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or W and W' taken together are linked through an additional 2-5 atoms to form a cyclic group, where 0-2 atoms are heteroatoms and the remaining atoms are carbon; and V must be aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Z is -CHR z OH, -CHR z O.C.(O)Ry ,-CHR z OC(S)R y , -CHR z OC(S)OR y , -CHR z OC(O)SR y , -CHR z OCO2R y , -OR z , -SR z , -CHR z N3, -CH2-aryl, -CH(aryl)OH, -CH(CH=CR z 2) OH, -CH(C≡CR z )OH, -R z , -NR z 2. -OCOR y , -OCO2R y , -SCOR y , -SCO2R y , -NHCOR z , -NHCO2R y , -CH2NH-aryl, -(CH2)q-OR z , and -(CH2)q-SR z is selected from the group consisting of q is an integer of 2 or 3; R z are R y and -H; R y are each selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; R x are each independently selected from the group consisting of -H and alkyl, or taken together as R x and R x forms a cyclic alkyl group, R v are each selected from the group consisting of -H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.

[0176] In some embodiments, the TRβ agonist is not a compound having the following structure or a pharma- ceutically acceptable salt thereof.

[0177] [ka]

[0178] In some embodiments, the TRβ agonist for the uses described herein is

[0179] [ka]

[0180] and pharma- ceutically acceptable salts thereof.

[0181] In some embodiments, the TRβ agonist can be a compound having the structure of formula (A) or a pharma- ceutically acceptable salt thereof.

[0182] [ka]

[0183] [In the formula, R 3 ' is H or CH2R a' and R a' is a hydroxyl, an O-linked amino acid, -OP(O)(OH)2 or OC(O)R b' and R b' is lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or -(CH2) n' -heteroaryl, n' is 0 or 1; R 4 ' is H and R 5 ' is CH2COOH, C(O)CO2H, or an ester or amide thereof, or R 4' and R 5' are taken together, -N=C(R c' )-C-(O)-NH-C(O)-, and R c' is H or cyano.

[0184] For additional TRβ agonists, see U.S. Patent No. 5,883,294; U.S. Patent No. 6,194,454; U.S. Patent No. 6,395,784; U.S. Patent No. 6,787,652; U.S. Patent No. 6,831,102; U.S. Patent No. 6,989,402; U.S. Patent No. 7,514,419; U.S. Patent No. 8,835,469; U.S. Patent No. 9,266,861; U.S. Patent Application Publication No. 2008 / 0004251; U.S. Patent Application Publication No. 2009 / 002895; U.S. Patent Application Publication No. 2009 / 003063; U.S. Patent Application Publication No. 2009 / 003064; U.S. Patent Application Publication No. 2009 / 003065; U.S. Patent Application Publication No. 2009 / 003066; U.S. Patent Application Publication No. 2009 / 003067; U.S. Patent Application Publication No. 2009 / 003068; U.S. Patent Application Publication No. 2009 / 003067 ... No. 10 / 0081634; U.S. Patent Application Publication No. 2012 / 0046364; WO 03 / 009841; WO 2004 / 018421; WO 2007 / 003419; WO 2007 / 009913; WO 2007 / 132475; WO 2008 / 062649; WO 2010 / 122980; and WO 2011 / 038207, each of which is incorporated by reference herein in its entirety.

[0185] Pharmaceutical Compositions The above useful compounds can be formulated into pharmaceutical compositions for use in treating the conditions described herein.Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins (2005), which is incorporated herein by reference in its entirety.Thus, some embodiments include pharmaceutical compositions that include: (a) a safe and therapeutically effective amount of a compound described herein or its pharmaceutically acceptable salt; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0186] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, diluents, emulsifiers, binders, buffers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, or any other compounds known to those skilled in the art to be useful in preparing pharmaceutical formulations. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients can also be incorporated into the composition. In addition, various adjuvants commonly used in the art may be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various ingredients in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press.

[0187] Some examples of substances which can serve as pharma- ceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers such as Tweens; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0188] The choice of a pharma- ceutically acceptable carrier to be used in conjunction with the subject compounds is determined by the way the compound is to be administered.

[0189] The compositions described herein are preferably provided in unit dosage forms. As used herein, a "unit dosage form" is a composition that contains an amount of a compound that is suitable for administration to a subject in a single dose, according to good medical practice. The preparation of a single or unit dosage form, however, does not imply that the dosage form is administered once per day or once per course of treatment. A unit dosage form may include a single daily dose, or a fractional dose in which several unit dosage forms are administered over the course of a day to complete a daily dose. In accordance with the present disclosure, unit dosage forms may be given more or less frequently than once per day, and may be administered more than once in a course of treatment. Such dosage forms may be administered in any manner that does not impair their formulation, including orally, parenterally, and may be administered over a period of time (e.g., from about 30 minutes to about 2-6 hours) as an infusion. Although single doses are specifically contemplated, compositions administered according to the methods described herein may also be administered as a continuous infusion or via an implantable infusion pump.

[0190] The methods as described herein can utilize any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular or other parenteral routes of administration. The skilled artisan will recognize that oral and nasal compositions include compositions administered by inhalation and made using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surface active agents, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the activity of the compound can be included. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes ed., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004).

[0191] A variety of oral dosage forms may be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow inducers, and melting agents, and may be compressed, tablet powder, enteric coated, sugar coated, film coated, or multiple compressed. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents.

[0192] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharma- ceutically compatible adjuvants as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmellose; lubricants such as magnesium stearate, stearic acid, microcrystalline cellulose, carboxymethylcellulose and talc. Tablets can also contain solubilizers or emulsifiers such as poloxamer, cremophor / Kolliphor® / Lutrol®, methylcellulose, hydroxypropylmethylcellulose, or others known in the art. Glidants such as silicon dioxide can be used to improve the flow characteristics of the powder mixture. Colorants such as FD&C dyes can be added for appearance. Sweeteners and flavorings, such as aspartame, saccharin, menthol, peppermint and fruit flavors, are useful adjuvants for chewable tablets.Capsules typically contain one or more solid diluents as disclosed above.The selection of carrier components depends on secondary considerations such as taste, cost and storage stability, and can be easily made by those skilled in the art.

[0193] Oral (PO) compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components such as sweeteners, flavorings and colorings disclosed above.

[0194] These compositions can also be coated by conventional methods, typically using pH or time dependent coatings, so that the compound of interest is released in the vicinity of the desired local application or at various times in the gastrointestinal tract to extend the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coating, wax and shellac.

[0195] The compositions described herein can optionally include other pharmaceutical actives.

[0196] Other compositions that are useful for achieving systemic delivery of the target compound include sublingual, buccal and nasal dosage forms.These compositions typically comprise soluble filler material, such as sucrose, sorbitol and mannitol; and binder, such as one or more of acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.They can also comprise the glidant, lubricant, sweetener, colorant, antioxidant and flavoring agent disclosed above.

[0197] The liquid composition that is formulated for topical ophthalmic use is formulated so that it can be administered locally to the eye. Comfort can be maximized as much as possible, but sometimes formulation considerations (e.g., drug stability) may require less than optimal comfort. In cases where comfort cannot be maximized, the liquid should be formulated so that the liquid is tolerable to patients for topical ophthalmic use. In addition, ophthalmically acceptable liquids can either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0198] For ophthalmic use, solutions or medicaments are often prepared using physiological saline solution as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0199] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0200] Tonicity adjusters can be added where necessary or convenient, including, but not limited to, salts, especially sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjuster.

[0201] Various buffers and means for adjusting pH can be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is between 4 and 9. Thus, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases can be used to adjust the pH of these formulations when necessary.

[0202] Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0203] Another vehicle component that can be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents can be used as appropriate or in conjunction therewith.

[0204] For topical use, including transdermal administration, creams, ointments, gels, solutions or suspensions, etc., containing the compounds disclosed herein are used. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0205] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J. Pharm. Sci. Tech. 2011, 65 287-332, both of which are incorporated herein by reference in their entireties. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0206] Compositions for intravenous administration can be provided to the caregiver in one or more solid forms that are reconstituted with an appropriate diluent, such as sterile water, saline, or dextrose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution that is ready to be administered parenterally. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administering a combination of a compound described herein and another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents prior to administration, or the two agents can be administered separately.

[0207] The actual unit dose of the active compounds described herein will depend on the particular compound and the condition being treated. In some embodiments, the dose can be from about 0.01 mg / kg body weight to about 120 mg or more / kg body weight, from about 0.05 mg or less / kg body weight to about 70 mg / kg body weight, from about 0.1 mg / kg body weight to about 50 mg / kg body weight, from about 1.0 mg / kg body weight to about 10 mg / kg body weight, from about 5.0 mg / kg body weight to about 10 mg / kg body weight, or from about 10.0 mg / kg body weight to about 20.0 mg / kg body weight. In some embodiments, the dosage can be less than 100 mg / kg body weight, 90 mg / kg body weight, 80 mg / kg body weight, 70 mg / kg body weight, 60 mg / kg body weight, 50 mg / kg body weight, 40 mg / kg body weight, 30 mg / kg body weight, 25 mg / kg body weight, 20 mg / kg body weight, 10 mg / kg body weight, 7.5 mg / kg body weight, 6 mg / kg body weight, 5 mg / kg body weight, 4 mg / kg body weight, 3 mg / kg body weight, 2.5 mg / kg body weight, 1 mg / kg body weight, 0.5 mg / kg body weight, 0.1 mg / kg body weight, 0.05 mg / kg body weight, or 0.005 mg / kg body weight. In some embodiments, the actual unit dosage is 0.05, 0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0, or 25.0 mg / kg body weight. Therefore, when administered to a 70 kg human, the dose range is about 0.1 mg to 70 mg, about 1 mg to about 50 mg, about 0.5 mg to about 10 mg, about 1 mg to about 10 mg, about 2.5 mg to about 30 mg, about 35 mg or less to about 700 mg or more, about 7 mg to about 600 mg, about 10 mg to about 500 mg, about 20 mg to about 300 mg, or about 200 mg to about 2000 mg. In some embodiments, the actual unit dose is 5 mg. In some embodiments, the actual unit dose is 10 mg. In some embodiments, the actual unit dose is 25 mg. In some embodiments, the actual unit dose is 250 mg or less. In some embodiments, the actual unit dose is 100 mg or less. In some embodiments, the actual unit dose is 70 mg or less.

[0208] The compounds may also be incorporated into formulations for delivery outside the systemic circulation, which may include enteric coated capsules, tablets, softgels, spray dried powders, polymer matrices, hydrogels, enteric coated solids, crystalline solids, amorphous solids, glassy solids, coated microparticles, liquids, nebulized liquids, aerosols, or microcapsules.

[0209] Method of administration The composition may be administered through any suitable route of administration, such as injection, such as subcutaneous, intramuscular, intraperitoneal, intravenous, or intra-arterial injection; topical administration, such as cream, lotion, or patch; oral administration, such as pill, dissolved liquid, oral suspension, buccal film, or mouthwash; nasal administration, such as nasal aerosol, powder, or spray; or ocular administration, such as eye drops. In some embodiments, the composition may be administered once, twice, three times, or four times per day. In other embodiments, the composition may be administered once, twice, or three times per week. In other embodiments, the composition is administered every other day, every third day, or every third day. In other embodiments, the composition is administered every other week, every two weeks, or every third week. In other embodiments, the composition is administered once or twice per month.

[0210] In some embodiments, the initial loading dose is administered more than the subsequent doses (maintenance doses). The dosage form or mode of administration of the maintenance dose may be different from that used for the loading dose. In any of the embodiments disclosed herein, the maintenance dose may include administration of the unit dosage form at any administration schedule contemplated herein, including but not limited to once a month or multiple times a month, once every two weeks or multiple times a week, once a week or multiple times a week, once a day or multiple times a day. It is contemplated within the present disclosure that a drug holiday may be incorporated into the administration period of the maintenance dose. Such a drug holiday may occur immediately after administration of the loading dose or at any time during the administration period of the maintenance dose. In some embodiments, the loading dose is 300 mg or less; 250 mg or less, 200 mg or less, 150 mg or less, or 100 mg or less. In some embodiments, the maintenance dose is 300 mg or less, 200 mg or less, 100 mg or less, 50 mg or less, 25 mg or less, 10 mg or less, 5 mg or less, or 1 mg or less.

[0211] Treatment Some embodiments of the methods and compositions of the present disclosure relate to a method of reducing or preventing deposition of an extracellular matrix protein, comprising administering to a subject in need thereof an effective amount of a compound described herein. In some embodiments, the deposition of an extracellular matrix protein can comprise abnormal or excessive deposition of the protein. In some embodiments, the extracellular matrix protein can comprise one or more of collagen, keratin, elastin, or fibrin. In some embodiments, the extracellular matrix protein can comprise collagen. In some embodiments, the extracellular matrix protein can comprise type I collagen. In some embodiments, the extracellular matrix protein can comprise type Ia collagen. In some embodiments, the extracellular matrix protein can comprise type III collagen. Some embodiments of the compositions and methods of the present disclosure relate to a method of treating fibrosis or a symptom or sequelae thereof, comprising administering to a subject in need thereof an effective amount of a compound described herein.

[0212] In some embodiments, the compounds and compositions comprising the compounds described herein can be used to treat a variety of conditions resulting from fibrosis or inflammation, particularly conditions associated with abnormal collagen deposition. Examples of conditions include glycogen storage disease type III (GSD III), glycogen storage disease type VI (GSD VI), glycogen storage disease type IX (GSD IX), non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, muscle fibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, liver and gallbladder cirrhosis, splenic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, and diffuse interstitial fibrosis. Fibrosis, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, surgical complications, fibrotic chronic transplant vasculopathy and / or chronic rejection of transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal strictures, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, or symptoms or sequelae thereof, or other diseases or conditions resulting in excessive deposition of extracellular matrix components such as collagen.

[0213] In some embodiments, the disclosed methods include methods of treating, ameliorating, or preventing a fibrotic condition. In some embodiments, the fibrotic condition may be associated with another condition. In some embodiments, the fibrotic condition or primary condition may further include chronic inflammation of an organ, tissue, spatial region, or fluid-connected area of ​​the subject's body. In some embodiments, the inflammation may include activation of one or more TGF-β-dependent signaling pathways. In some embodiments, the TGF-β-dependent signaling pathways may include one or more elements responsive to T3 or T4. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of one or more of collagen, keratin, or elastin. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type I collagen. In some embodiments, the fibrotic condition may include abnormal or excessive deposition of type Ia collagen. In some embodiments, the fibrotic condition can involve abnormal or excessive deposition of type III collagen.In some embodiments, the fibrotic condition is Glycogen Storage Disease Type III (GSD III), Glycogen Storage Disease Type VI (GSD VI), Glycogen Storage Disease Type IX (GSD IX), nonalcoholic steatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma, myocardial fibrosis, organ graft fibrosis, myofibrosis, pancreatic fibrosis, bone marrow fibrosis, liver fibrosis, cirrhosis of the liver and gallbladder, splenic fibrosis, scleroderma, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse interstitial fibrosis, interstitial pneumonitis, desquamative interstitial pneumonia, respiratory bronchiolitis, interstitial lung disease, chronic interstitial lung disease, acute interstitial pneumonitis, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, idiopathic organizing pneumonia, lymphocytic interstitial pneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis, myocardial fibrosis, atrial fibrosis , endomyocardial fibrosis, renal fibrosis, chronic kidney disease, type II diabetes, macular degeneration, keloid lesions, hypertrophic scars, nephrogenic systemic fibrosis, injection fibrosis, complications of surgery, fibrotic chronic transplant vasculopathy and / or chronic rejection in transplanted organs, fibrosis associated with ischemia-reperfusion injury, post-vasectomy pain syndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixed connective tissue disease, fibroproliferative lesions of the oral cavity, fibrosing intestinal strictures, Crohn's disease, glial scar, leptomeningeal fibrosis, meningitis, systemic lupus erythematosus, fibrosis due to radiation exposure, fibrosis due to ruptured breast cysts, myelofibrosis, retroperitoneal fibrosis, and progressive massive fibrosis. In some embodiments, the fibrotic condition can include one or more of GSD III, GSD IX, non-alcoholic steatohepatitis, cirrhosis of the liver and / or pancreas, scleroderma, idiopathic pulmonary fibrosis, psoriasis, non-alcoholic fatty liver disease, Dupuytren's disease, and / or any combination thereof.

[0214] According to the methods and compositions of the present disclosure, thyroid receptor agonists, such as those disclosed herein, may be administered to a subject to treat, ameliorate, prevent, or cure a fibrotic condition or a condition in which fibrosis is a symptom or sequelae. According to the methods and compositions disclosed herein, the fibrotic condition or condition with sequelae of fibrosis may further include chronic inflammation. According to the methods and compositions disclosed herein, the fibrotic condition or condition with sequelae of fibrosis may further include activation of one or more TGF-β-dependent signaling pathways. According to the methods and compositions disclosed herein, the fibrotic condition or condition with sequelae of fibrosis may further include activation and / or suppression of one or more thyroid receptor β (TRβ)-dependent signaling pathways. According to the methods and compositions disclosed herein, the fibrotic or fibrotic condition may further include the involvement of a signaling pathway responsive to triiodothyronine (T3), thyroxine (T4), any combination thereof, or a mimetic thereof. According to the methods and compositions disclosed herein, the fibrotic or fibrotic condition may further include the involvement of a receptor responsive to T3, T4, any combination thereof, or a mimetic thereof. In some embodiments according to the methods and compositions disclosed herein, the fibrotic or fibrotic condition may include the involvement of TRβ. In some embodiments according to the methods and compositions disclosed herein, the fibrotic or fibrotic condition may include one or more conditions that are prevented, ameliorated, or cured by administration of one or more TRβ agonists. In some embodiments, the one or more TRβ agonists may be co-administered with one or more active drug compounds and / or one or more excipients. In some embodiments, the one or more TRβ agonists may be administered before, during, or after surgery, phototherapy, or ultrasound therapy.In some embodiments, the one or more TRβ agonists may be co-administered with one or more of pirfenidone, nintedanib, and / or a fibroblast growth factor receptor antagonist, and / or a collagenase, such as Clostridium histolyticum collagenase.

[0215] In some embodiments, the compositions and methods described herein provide compositions and methods for the treatment, amelioration, prevention, or cure of collagen deposition. In some embodiments, the collagen deposition includes abnormal or excessive deposition of collagen. In some embodiments, the collagen deposition can include abnormal or excessive deposition of type I collagen. In some embodiments, the collagen deposition can include abnormal or excessive deposition of type Ia collagen. In some embodiments, the collagen deposition can include abnormal or excessive deposition of type III collagen. According to the methods and compositions disclosed herein, the collagen deposition can further include the involvement of a receptor responsive to T3, T4, any combination thereof, or a mimic thereof. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition can include the involvement of TRβ. In some embodiments according to the methods and compositions disclosed herein, the collagen deposition can be prevented, ameliorated, or cured by administration of one or more TRβ agonists. In some embodiments, the one or more TRβ agonists may be co-administered with one or more active drug compounds and / or one or more excipients. In some embodiments, the one or more TRβ agonists may be administered before, during, or after surgery, phototherapy, or ultrasound therapy. In some embodiments, the one or more TRβ agonists may be co-administered with one or more of pirfenidone, nintedanib, and / or a fibroblast growth factor receptor antagonist, and / or a collagenase, such as Clostridium histolyticum collagenase.

[0216] In some embodiments, administering any of the compounds or compositions disclosed herein reduces the expression of Col1a1, Col3a1, ACTA2, ENPP2, and / or LGALS1 genes, or any combination or product thereof, in a subject to which the compound or composition is administered. In some embodiments, administering any of the compounds or compositions disclosed herein reduces the degree of fibrosis, observable by histology, histochemistry, immunohistochemistry, etc., in a subject to which the compound or composition is administered, and / or reduces the amount, accumulation, or distribution of type 1 collagen and / or hydroxyproline, or any combination thereof. In some embodiments, administering any of the compounds or compositions disclosed herein reduces total serum lipids, total serum cholesterol, total serum triglycerides, total liver lipids, total liver cholesterol, total liver triglycerides, or any combination thereof.

[0217] In some embodiments, inflammation may be treated, prevented, or ameliorated by administration of any of the compounds or compositions disclosed herein, hi some embodiments, inflammation may be chronic inflammation of an organ, tissue, spatial region, or fluid-connected area of ​​the subject's body.

[0218] In some embodiments, the disclosed methods include methods of treating, ameliorating, or preventing fibrotic conditions or symptoms, and inflammatory diseases or disorders, including acne, acid reflux / heartburn, age-related macular degeneration (AMD), allergies, allergic rhinitis, Alzheimer's disease, amyotrophic lateral sclerosis, anemia, appendicitis, arteritis, arthritis, asthma, atherosclerosis, autoimmune disorders, balanitis, blepharitis, bronchiolitis, bronchitis, bullous pemphigoid, burns, bursitis, cancer, cardiac arrest, carditis, celiac disease. , cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis, colitis, congestive heart failure, conjunctivitis, cyclophosphamide-induced cystitis, cystic fibrosis, cystitis, cold, dacryoadenitis, dementia, dermatitis, dermatomyositis, diabetes, diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic ulcer, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometrium inflammation, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, connective tissue inflammation, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis, hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection, inflammatory bowel disease, inflammatory cardiac hypertrophy, inflammatory neuropathy, insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, Keratitis, keratoconjunctivitis, laryngitis, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), migraine, multiple sclerosis, myelitis, myocarditis, myositis, nephritis, nonalcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vulgaris vularis), pericarditis, peritonitis, pharyngitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, portal phlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, rhinitis, salpingitis, sarcoidosis, sialadenitis, sinusitis, spastic colon, stenosis, stomatitis, stroke, surgical complications, synovitis, tendinitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, graft rejection, bladder trigonitis, tuberculosis, tumor, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0219] In some embodiments, the inflammatory disease or disorder can be arthritis, which can include one or more of osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Reiter's syndrome, psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple's disease, Behcet's disease, septic arthritis, gouty arthritis, pseudogout, and Still's disease.

[0220] In some embodiments, the inflammatory disease or disorder can be an autoimmune disease or disorder, which can be acute disseminated encephalomyelitis (ADEM), Addison's disease, allergy or sensitivity, amyotrophic lateral sclerosis, antiphospholipid syndrome (APS), arthritis, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune pancreatitis, bullous pemphigoid, celiac disease, Chagas' disease, chronic obstructive pulmonary disease (COPD), diabetes mellitus type 1 (IDDM), endometriosis, fibromyalgia, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's thyroiditis, hidradenitis suppurativa, idiopathic thrombocytopenia, idiopathic thrombocytopenia, idiopathic pulmonary fibrosis ... The conditions may include one or more of: paucity of purpura, inflammatory bowel disease, interstitial cystitis, lupus (including discoid lupus erythematosus, drug-induced lupus erythematosus, lupus nephritis, neonatal lupus erythematosus, subacute cutaneous lupus erythematosus, and systemic lupus erythematosus), morphea, multiple sclerosis (MS), myasthenia gravis, myopathy, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, relapsing disseminated encephalomyelitis (multiphasic disseminated encephalomyelitis), rheumatic fever, schizophrenia, scleroderma, Sjogren's syndrome, tenosynovitis, vasculitis, and vitiligo. The methods described herein are further illustrated by the following examples.

[0221] Example 1 Pretreatment liver biopsy samples were collected prior to acclimation and DIO-NASH mice were acclimated for 3 weeks. Mice were randomly assigned to one of five treatment groups, with 12 mice per group. The assigned doses were Compound 2 (low): 3 mg / kg; Compound 2 (high): 10 mg / kg; Compound 1: 10 mg / kg; and Elafibranor (30 mg / kg). One group was a mock group treated with vehicle only as a control. The dosage forms were administered orally once per day. After 8 weeks, animals were sacrificed and liver samples were collected. Liver samples were assayed for total liver hydroxyproline and subjected to immunohistochemical observation for fibrosis stage and extent of ColaI (type Ia collagen) staining. As shown in Figure 1, Compound 2-treated animals show lower total liver hydroxyproline levels than control-treated or mock-treated animals. Since hydroxyproline is an important component of collagen and collagen is the most important source of hydroxyproline in animal tissues, the level of hydroxyproline is a reliable surrogate measure of the presence of collagen in a sample.

[0222] Final liver biopsy samples were also subjected to histochemical and immunohistochemical staining. After 8 weeks of treatment with vehicle, low dose compound 2, high dose compound 2, compound 1, or elafibranor, representative images of livers stained with picrosirius red (red staining to visualize collagen type I and III deposition) at the end of the treatment period are shown in Figure 2. Total liver collagen (mg / liver) 1 and 3 were determined by morphometry following picrosirius red staining, as shown in Figure 5. Liver sections from compound 1-treated animals showed lower PSR staining than liver sections from mock-treated animals, and liver sections from compound 2-treated animals showed lower PSR staining than liver sections from control-treated or mock-treated animals. Representative images of livers stained with anti-collagen type I (col1a1) (Southern Biotech, Cat. 131001) at the end of the treatment period after 8 weeks of treatment with vehicle, low dose Compound 2, high dose Compound 2, Compound 1, or elafibranor are shown in Figure 3. The extent of Col1A1 content was calculated as total liver Col1A1 staining in the final liver biopsy samples. As shown in Figure 4, Compound 2-treated animals show lower total liver Col1A1 content than control-treated or mock-treated animals.

[0223] Fibrosis scores were also calculated based on the observation of the final liver biopsy sample. Furthermore, the percentage of animals treated with Compound 1 or Compound 2 that showed a reduction in fibrosis scores after treatment was higher than that of mock-treated animals. Compound 2-treated animals did not show an increase in fibrosis scores after treatment.

[0224] Example 2 Pulmonary fibrosis is induced in healthy male Dunkin-Hartley guinea pigs by intratracheal administration of bleomycin. Control subjects are induced by intratracheal administration of saline. After promenal fibrosis is established in the bleomycin-treated animals, a test article comprising any one of compounds 1-4, or any other compound disclosed herein, is administered daily or for 6-10 weeks as appropriate to each subject appropriate for that formulation. Unilateral lung biopsies are taken prior to the first administration of the test article and again after sacrifice following the last administration of the test article. Biopsies are analyzed as described in Example I, with the addition of immunohistochemical staining for collagen type III. Both lungs from animals treated with the compounds disclosed herein, particularly those treated with compound 2, show reduced hydroxyproline levels, reduced collagen III staining, and reduced fibrosis scores compared to levels shown prior to administration of the test article. Mock-treated animals show little or no reduction in fibrosis, hydroxyproline content, or collagen III content.

[0225] Example 2 Palmar fascial fibrosis is induced in nude mice by introducing fibroblasts from fascicles of Dupuytren's disease patients as described in Stish, L. et al., BMC Musculoskelet. Disord., 16: 138-148 (2015), which is incorporated herein by reference for its description of the establishment of an animal model system for the study of palmar fascial fibrosis. A test article comprising any one of compounds 1-4, or any other compound disclosed herein, is administered daily or as appropriate for 6-10 weeks to each subject appropriate for the formulation. Unilateral forelimb biopsies are taken prior to the first administration of test article and again after sacrifice following the last administration of test article. Biopsies are analyzed as described in Example I with the addition of immunohistochemical staining for collagen type III. Palmar fascia from animals treated with compounds disclosed herein, particularly those treated with compound 2, show reduced hydroxyproline levels, reduced collagen III staining, and reduced fibrosis scores compared to levels shown prior to administration of the test article. Mock-treated animals show little or no reduction in fibrosis, hydroxyproline content, or type III collagen content.

[0226] Example 3 Hypertrophic skin lesions are induced in Sprague-Dawley rats by subcutaneous injection of capsaicin as described in Wallengren, J. et al., Skin Pharm. Appl. Skin Physiol. 15(3):154-165 (2002), which is incorporated by reference herein for its description of induction of hypertrophic skin lesions in rats, or in C57BL or other suitable strain mice by subcutaneous administration of CCl4 and / or bleomycin as described in Alonso-Merino et al., Proc. Nat. Acad. Sci. 113(24):E3451-60 (2016), which is incorporated by reference herein for its disclosure of induction of fibrotic skin lesions in mice. After hypertrophic skin lesions are established in the capsaicin, CCl4 and / or bleomycin treated animals, a test article comprising any one of compounds 1-4, or any other compound disclosed herein, is administered daily or as appropriate to each subject animal for 6-10 weeks. Skin biopsies from the injection site are taken prior to the first administration of the test article and again after sacrifice following the last administration of the test article. The biopsies are analyzed as described in Example I with the addition of immunohistochemical staining for collagen III. Injection site skin samples from animals treated with the compounds disclosed herein, particularly those treated with compound 2, show reduced hydroxyproline levels, reduced collagen III staining, and reduced fibrosis scores compared to levels exhibited prior to administration of the test article. Mock treated animals show little or no reduction in fibrosis, hydroxyproline content, or collagen III content.

[0227] Example 4 Treatment of glucose-6-phosphatase-α deficient mice (Agl- / -, see, e.g., Liu, KM, et al., Mol. Genet. Metabol. 111(4):467-76 (2014)) exhibiting GSD-3-like liver symptoms, including hypercholesterolemia and hyperlipidemia, involves administering a test article, including any one of Compounds 1-4, or any other compound disclosed herein, daily to each subject as appropriate for the formulation, or for 6-10 weeks, as appropriate. Liver biopsies were taken prior to the first administration of the test article, and again after sacrifice following the last administration of the test article. Biopsies were analyzed as described in Example I. Liver samples from animals treated with the compounds disclosed herein, particularly those treated with Compound 2, show reduced hydroxyproline levels, reduced collagen I staining, and reduced fibrosis scores compared to levels exhibited prior to administration of the test article. Mock-treated animals show little or no reduction in fibrosis, hydroxyproline content, or type I collagen content.

[0228] Example 5 Treatment of phosphorylase kinase deficient mice (PhKc- / -, see e.g. Varsanyi, M., et al., Biochem. Genet., 18(3-4): 247-61 (1980)) exhibiting GSD-8 / 9-like liver pathology, including hypercholesterolemia and hyperlipidemia, involves administering a test article, including any one of Compounds 1-4, or any other compound disclosed herein, daily to each subject for 6-10 weeks, or as appropriate for that formulation. Liver biopsies were taken prior to the first administration of the test article and again after sacrifice following the last administration of the test article. Biopsies were analyzed as described in Example I. Liver samples from animals treated with the compounds disclosed herein, particularly those treated with Compound 2, exhibit reduced hydroxyproline levels, reduced collagen type I staining, and reduced fibrosis scores compared to levels exhibited prior to administration of the test article. Mock-treated animals show little or no reduction in fibrosis, hydroxyproline content, or type I collagen content.

[0229] Example 6 Compound 2 was evaluated in a diet-induced NASH mouse model (see, e.g., Hansen, H. et al., Drug Discovery Today 22(17):1701-1718 (2017), incorporated herein by reference for disclosure of diet-induced, genetic, chemical, and other NASH mouse models). Diet-driven NASH in this model results in steatohepatitis / fibrosis without relying on chemical / toxin effects. Animals were biopsied prior to the study, and only animals with NASH and fibrosis were selected for the study. Selected animals were acclimated and randomized, with experimental groups of 11-12 animals per cohort receiving oral administration of Compound 2 according to the following schedule: daily dosing for 8 weeks; or daily dosing for 0-1 week followed by weekly dosing for 2-8 weeks. At week 8, animals were sacrificed and tissues were analyzed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol were measured, and a terminal necropsy was performed on each liver to assay total liver biochemistry including total liver triglycerides and total liver cholesterol, and histological assessment of NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, and galactin-3 levels. Tissue samples were saved for characterization using RNAseq. RNAseq was used to determine expression levels of genes showing differential expression and / or known to be associated with fibrosis in Compound 2-treated versus vehicle-treated animals. Additionally, expression levels of genes known to be associated with inflammation, such as ANXA2, were determined in Compound 2-treated versus vehicle-treated animals. Significant reductions in liver triglycerides and cholesterol were observed in the treatment groups compared to untreated controls. As shown in Figure 6, total lipid content in liver was reduced by about 80%, plasma lipid was similarly reduced, and NAS score was significantly improved. No significant toxicity was observed. As shown in Figure 9, administration of Compound 2 and Compound 2 reduced total liver galectin-3 compared to vehicle.

[0230] As shown in FIG. 7, there was also a significant reduction in fibrosis, collagen type 1 deposition, and hydroxyproline (50.2%, 60.2%, and 46.3%, respectively) compared to pretreatment samples. After treatment, the expression of the profibrotic genes Col1a1, Col3a1, ACTA2 (αSMA), and LGALS1 (galectin 1) was reduced by 36.3%, 27.1%, 37%, and 64.7%, respectively (FIG. 8), confirming the results observed by histology. In addition, the expression of the proinflammatory gene ANXA2 was reduced by 40.3%. Thus, 8 weeks of Compound 2 administration significantly improved and also demonstrated improvement in histological, biochemical, and genetic markers associated with steatosis, fibrosis, nonalcoholic steatohepatitis, and inflammation in the diet-induced NASH model. The results are summarized in Table 1 below. Additionally, the results of the expression of genetic markers after 8 weeks of Compound 1 administration are listed in Table 2.

[0231] [Table 2]

[0232] [Table 3]

[0233] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art can convert from plural to singular and / or from singular to plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly set forth herein for clarity.

[0234] In general, it is understood by those skilled in the art that the terms used herein, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "including, but not limited to," etc.). It is further understood by those skilled in the art that if a particular number of introduced claim recitations is intended, such intention will be clearly set forth in the claim, and that in the absence of such a setting, no such intention exists. For example, as an aid to understanding, the following appended claims include the use of the introductory phrases "at least one" and "one or more" to introduce the claim recitations. However, the use of such phrases should not be construed as indicating that the introduction of a claim recitation with the indefinite article "a" or "an" limits any particular claim that includes such introduced claim recitation to embodiments that include only one such recitation, even when the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"). The same applies to the use of definite articles used to introduce claim recitations. Moreover, even when a specific number of introduced claim recitations is explicitly recited, those skilled in the art will recognize that such recitation should be construed to mean at least the recited number (e.g., the recitation "two recitations" without other modifiers simply means at least two recitations, or more than two recitations).Furthermore, when a term similar to "at least one of A, B, and C, etc." is used, such a structure is generally intended in the sense that one of ordinary skill in the art would understand the term (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B and C together, etc.). When a term similar to "at least one of A, B, or C, etc." is used, such a structure is generally intended in the sense that one of ordinary skill in the art would understand the term (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B and C together, etc.). It will further be appreciated by those skilled in the art that virtually any disjunctive word and / or phrase, whether in the specification, claims, or drawings, presenting two or more alternative terms, should be understood to contemplate the possibility of including one of the terms, either the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A" or "B" or "A and B."

[0235] Additionally, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also described thereby with respect to any individual members of the Markush group or subgroups of members thereof.

[0236] As will be understood by those skilled in the art, for all purposes, including in terms of providing a written description, all ranges disclosed herein encompass all possible subranges and combinations of subranges. Any range described is fully described and can be readily recognized as being capable of breaking down the same range into at least equal divisions, thirds, fourths, fifths, tenths, etc. As a non-limiting example, each of the ranges discussed herein can be readily broken down into a lower third, a middle third, and an upper third, etc. As will also be understood by those skilled in the art, all language such as "up to," "at least," "greater than," "less than," etc., refers to a range that includes the recited number and can then be broken down into the subranges discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1-5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0237] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those of skill in the art. The various aspects and embodiments disclosed herein are intended to be illustrative and not limiting, with the true scope and spirit being indicated by the following claims.

Claims

[Claim 1] 1. A method of treating fibrosis, a fibrotic condition or a fibrotic symptom in a subject in need thereof, comprising administering to the subject in need thereof one or more thyroid receptor beta (TRβ) agonists.

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