Compositions and methods for treatment of liver disorders

Abstract

To provide novel therapies that can be used to modulate cholesterol levels and triglycerides and control other metabolic disorders while minimizing undesired effects.SOLUTION: The foregoing problem is solved by a method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject in need thereof, and including a step of administering to the subject in need thereof at least one TR-β agonist in combination with one or more second pharmaceutical agents.SELECTED DRAWING: Figure 8

Description

[Technical field]

[0001] The present disclosure relates broadly to the field of treatments for fatty liver disease, and more specifically to the field of small molecule drugs for the treatment of non-alcoholic steatohepatitis. [Background technology]

[0002] Thyroid hormones (TH) are synthesized in the thyroid gland in response to thyroid-stimulating hormone (TSH) secreted by the pituitary gland in response to various stimuli (e.g., thyrotropin-releasing hormone (TRH) from the hypothalamus). Thyroid hormones are iodized O-aryltyrosine analogs that are excreted into the circulation primarily as 3,3',5,5'-tetraiodothyronine (T4). T4 is rapidly deiodized in local tissues by thyroxine 5'-deiodinase to 3,3',5'-triiodothyronine (T3), the most potent TH. T3 is metabolized to inactive metabolites via various pathways, including those involving deiodination, glucuronidation, sulfation, and decarboxylation. The majority of circulating T4 and T3 are lost through the liver.

[0003] The biological activity of THs is largely mediated by the thyroid hormone receptor (TR). TRs belong to the nuclear receptor superfamily and, together with their common partner, the retinoid X receptor, form heterodimers that act as ligand-inducible transcription factors. Like other nuclear receptors, TRs have ligand-binding and DNA-binding domains and regulate gene expression by ligand-dependent interactions with DNA response elements (thyroid response elements, TREs). Currently, the literature indicates that TRs are encoded by two separate genes (TRα and TRβ) and that multiple isoforms are produced through alternative splicing (Williams, Mol. Cell. Biol. 20(22):8329-42 (2000); Nagaya et al., Biochem. Biophys. Res. Commun. 226(2):426-30 (1996)). The major isoforms identified to date are TRα-1, TRα-2, TRβ-1 and TRβ-2. TRα-1 is expressed ubiquitously in rats, with highest expression in skeletal muscle and brown fat. TRβ-1 is also expressed ubiquitously, with highest expression in liver, brain, and kidney. TRβ-2 is expressed in specific regions of the anterior pituitary gland and hypothalamus, as well as in the developing brain and inner ear. In rat and mouse liver, TRβ-1 is the predominant isoform (80%). The TR isoforms found in humans and rats are highly homologous to each other in their amino acid sequences, suggesting that each serves specialized functions. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2010 / 108051 [Patent Document 2] WO 87 / 05297, Johnston et al., published September 11, 1987 [Patent Document 3] U.S. Patent No. 7,829,552 [Patent Document 4] U.S. Patent No. 7,514,419 [Patent Document 5] U.S. Patent Application Publication No. 2009 / 002895 [Patent Document 6] U.S. Patent Application Publication No. 2010 / 0081634 [Patent Document 7] U.S. Patent Application Publication No. 2012 / 0046364 [Patent Document 8] International Publication No. 2011 / 038207 [Non-Patent Document]

[0005] [Non-Patent Document 1] Williams, Mol. Cell. Biol. 20(22): 8329 - 42 (2000) [Non-Patent Document 2] Nagaya et al., Biochem. Biophys. Res. Commun. 226(2): 426 - 30 (1996) [Non-Patent Document 3] The Organic Chemistry of Drug Design and Drug Action, Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems", 352 - 401 [Non-Patent Document 4] Design of Prodrugs, edited by H. Bundgaard, Elsevier Science, Amsterdam, 1985 [Non-Patent Document 5] Design of Biopharmaceutical Properties through Prodrugs and Analogs, edited by E. B. Roche, American Pharmaceutical Association, Washington, 1977 [Non-Patent Document 6] Drug Delivery Systems, edited by R. L. Juliano, Oxford Univ. Press, Oxford, 1980

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

[0006] TH affects the growth, metabolism and physiological function of almost all organs. TH reduces serum cholesterol and triglycerides. However, the side effects of TH action include cardiac arrhythmia, bone loss, irritability and anxiety. In view of the above, there is a need for novel therapeutic agents that can be used to modulate cholesterol levels and triglycerides and control other metabolic disorders while minimizing undesirable effects. [Means for solving the problem]

[0007] Some embodiments disclosed herein relate to a method of preventing, treating, or ameliorating one or more fatty liver diseases in a subject in need thereof, comprising administering to said subject in need thereof at least one TR-β agonist compound in combination with a second agent.

[0008] In some embodiments, the TR-β agonist is a compound of formula I

[0009] [ka]

[0010] 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)(CRa 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 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 -C 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 of 5-6 atoms containing 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 can 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

[0011] [ka]

[0012] 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 atoms are heteroatoms 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 zO.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.

[0013] In some embodiments, the TR-β agonist is a compound having the structure of Formula (A):

[0014] [ka]

[0015] [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] or a pharma- ceutically acceptable salt thereof.

[0016] In some embodiments, the TR-β agonist is

[0017] [ka]

[0018] or a pharma- ceutically acceptable salt thereof.

[0019] Some embodiments disclosed herein include a method of preventing, treating, or ameliorating one or more fatty liver disorders in a subject in need thereof, comprising administering to said subject in need thereof a

[0020] [ka]

[0021] or a pharma- ceutically acceptable salt thereof, in combination with a second agent.

[0022] In some embodiments, the second agent can be a peroxisome proliferator-activated receptor (PPAR) modulator, a bile acid receptor modulator, an anti-inflammatory compound, an anti-fibrotic compound, a GLP-1 (glucagon-like peptide-1) agonist, a metabolic modulator, or any combination of the above.

[0023] In some embodiments, the second agent can be a PPAR modulator. In some embodiments, the PPAR modulator is

[0024] [ka]

[0025] Or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, the second agent can be a fibric acid derivative. In some embodiments, the fibric acid derivative can be fenofibrate, gemfibrozil, fenofibric acid, or clofibrate, or a pharma- ceutically acceptable salt thereof.

[0027] In some embodiments, the second agent can be a bile acid receptor modulator, such as a farnesoid X receptor (FXR). In some embodiments, the bile acid receptor modulator is

[0028] [ka]

[0029] Or a pharma- ceutically acceptable salt thereof.

[0030] In some embodiments, the second agent can be an anti-inflammatory compound. In some embodiments, the anti-inflammatory compound can be an inhibitor of apoptosis signal-regulating kinase 1 (ASK1). In some embodiments, the anti-inflammatory compound can be:

[0031] [ka]

[0032] Polyclonal or monoclonal anti-LPS immunoglobulins such as 1MM-124E; Or a pharma- ceutically acceptable salt thereof.

[0033] In some embodiments, the second agent can be an anti-fibrotic compound. In some embodiments, the anti-fibrotic compound is

[0034] [ka]

[0035] Or a pharma- ceutically acceptable salt thereof.

[0036] In some embodiments, the second agent can be a GLP-1 agonist. In some embodiments, the GLP-1 agonist is selected from dulaglutide, exenatide, liraglutide, albiglutide, lixisenatide, semaglutide, and insulin glargine. In some embodiments, the GLP-1 agonist is

[0037] [ka]

[0038] (PF06882961). In some embodiments, the second agent has dual activity at the GLP-1 and glucagon receptors (e.g., a dual acting GLP-1 / glucagon agonist). In some embodiments, the second agent has dual activity at the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) (e.g., a dual acting GLP-1 / GIP agonist).

[0039] In some embodiments, the second agent is a metabolic modulator. In some embodiments, the metabolic modulator is a thyroid hormone receptor agonist, a selective androgen receptor modulator, a mitochondrial membrane transport protein modulator, a selective estrogen receptor modulator, a stearoyl-CoA desaturase 1 (SCD1) inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, an inhibitor of sodium glucose cotransporter 1 and / or 2 (SGLT1, SGLT2, or a dual SGLT1 / SGLT2 inhibitor), recombinant fibroblast growth factor 19 (FGF19) or modified analogs, or recombinant fibroblast growth factor 21 (FGF21) and PEGylated variants. In some embodiments, the metabolic modulator is

[0040] [ka]

[0041] or a pharma- ceutically acceptable salt thereof.

[0042] In some embodiments, the second agent can be a fish oil derivative. In some embodiments, the fish oil derivative can be an ω-3 fatty acid alkyl ester or an ω-3 fatty acid triglyceride. In some embodiments, the ω-3 fatty acid alkyl ester can be an ω-3 fatty acid ethyl ester. In some embodiments, the ω-3 fatty acid ethyl ester can be ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate, ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate, ethyl (7Z,10Z,13Z,16Z,19Z)-docosapentaenoate, ethyl hexadecatri ... ethyl linolenate, alpha-linolenic acid ethyl ester, ethyl (6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoate, ethyl eicosatrienoate, ethyl eicosatetraenoate, ethyl heneicosapentaenoate, ethyl icosapentaenoate, ethyl heneicosapentaenoate, ethyl tetracosapentaenoate, or herinic acid ethyl ester.

[0043] In some embodiments, the second agent is a diacylglycerol acyltransferase (DGAT) inhibitor, such as the compounds described in WO 2010 / 108051, which is incorporated by reference in its entirety.

[0044] In some embodiments, the compounds and second agents described herein can be used in a method for preventing, treating, or ameliorating one or more fatty liver diseases in a subject in need thereof. In some embodiments, the fatty liver disease can be steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and any combination of the above.

[0045] In some embodiments described herein, the compound described herein and the second agent can be formulated into a pharmaceutical composition. In some embodiments, the composition can be formulated for oral, intravenous, intraarterial, intestinal, rectal, vaginal, nasal, pulmonary, topical, intradermal, transdermal, buccal, lingual, sublingual, or opthalmic administration, or any combination thereof.

[0046] In some embodiments, the compound described herein and the second agent may be administered sequentially. In some embodiments, the compound described herein and the second agent may be administered simultaneously. In some embodiments, administration of the compound described herein and the second agent may prevent, treat, or ameliorate fibrosis, fibrotic conditions, or fibrotic symptoms in a subject. In some embodiments, administration of the compound described herein and the second agent may reduce the amount of extracellular matrix protein present in one or more tissues of a subject. In some embodiments, administration of the compound described herein and the second agent may reduce the amount of collagen present in one or more tissues of a subject. In some embodiments, administration of the compound described herein and the second agent may reduce the amount of collagen type I, type Ia, or type III present in one or more tissues of a subject.

[0047] Some embodiments disclosed herein relate to pharmaceutical compositions comprising one or more compounds of Formula (I) and one or more second pharmaceutical agents. [Brief description of the drawings]

[0048] [Figure 1] FIG. 1 shows total hepatic hydroxyproline content after 8 weeks of treatment in mice with vehicle, Compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), Compound 2 and obeticholic acid (OCA), Compound 2 and cenicriviroc (CVC), or Compound 2 and elafibranor (ELA). [Diagram 2] Representative images of livers stained with hematoxylin and eosin (HE staining) at the end of the treatment period after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), compound 2 and obeticholic acid (OCA), compound 2 and cenicriviroc (CVC), or compound 2 and elafibranor (ELA) (magnification 20x, scale bar = 100 μm). [Diagram 3] FIG. 1 shows a summary of globular degeneration scores in pre- and post-study biopsies after 8 weeks of treatment with vehicle, Compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), Compound 2 and obeticholic acid (OCA), Compound 2 and cenicriviroc (CVC), or Compound 2 and elafibranor (ELA). [Figure 4] Figure 1 shows the relative liver mass as a percentage of body weight after biopsy after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), compound 2 and obeticholic acid (OCA), compound 2 and cenicriviroc (CVC), or compound 2 and elafibranor (ELA). Total liver collagen 1 and 3 (mg / liver) were determined by morphometry after picrosirius red staining. Data are presented as mean ± SEM (n=12). [Diagram 5] Figure 1 shows total liver cholesterol after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), compound 2 and obeticholic acid (OCA), compound 2 and cenicriviroc (CVC), or compound 2 and elafibranor (ELA). Total liver collagen 1 and 3 (mg / liver) were determined by morphometry after picrosirius red staining. Data are presented as mean ± SEM (n=12). [Figure 6]Figure 1 shows total liver triglycerides after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), compound 2 and obeticholic acid (OCA), compound 2 and cenicriviroc (CVC), or compound 2 and elafibranor (ELA). Total liver collagen 1 and 3 (mg / liver) were determined by morphometry after picrosirius red staining. Data are presented as mean ± SEM (n=12). [Figure 7] FIG. 1 shows a summary of NALFD activity scores in pre- and post-study biopsies after 8 weeks of treatment with vehicle, Compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), Compound 2 and obeticholic acid (OCA), Compound 2 and cenicriviroc (CVC), or Compound 2 and elafibranor (ELA). [Figure 8] FIG. 1 shows the change from baseline in NAFLD Activity Score based on pre- and post-study biopsies after 8 weeks of treatment with vehicle, Compound 2, cenicriviroc (CVC), and Compound 2 and cenicriviroc (CVC). [Figure 9] FIG. 1 shows the mean percentage change (%) in NALFD activity scores from baseline based on pre- and post-study biopsies after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), and compound 2 and obeticholic acid (OCA). [Figure 10] Figure 1 shows a summary of fibrosis stage score results after 8 weeks of treatment with vehicle, Compound 2, obeticholic acid (OCA), cenicriviroc (CVC), elafibranor (ELA), Compound 2 and obeticholic acid (OCA), Compound 2 and cenicriviroc (CVC), or Compound 2 and elafibranor (ELA). Changes in biopsies from pre-study to post-study are shown as lines. Points at each scoring step are shifted slightly to allow visual separation of animals (this is done for visualization purposes and does not reflect differences in scores). [Figure 11]FIG. 1 shows the mean percentage change (%) in fibrosis stage from baseline based on pre- and post-study biopsies after 8 weeks of treatment with vehicle, Compound 2, cenicriviroc (CVC), and Compound 2 and cenicriviroc (CVC). [Figure 12] This figure shows the mean percentage change (%) in fibrosis stage from baseline based on pre- and post-study biopsies after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), and compound 2 and obeticholic acid (OCA). [Figure 13] Shown are the mean percentage changes (%) in Plasm Total Cholesterol levels from baseline based on pre- and post-study biopsies after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 14] Shown are the mean percentage changes (%) in Plasma Total Triglycerides from baseline based on pre- and post-study biopsies after 12 weeks of treatment with vehicle, Compound 2, Tropifexol, and Compound 2 and Tropifexol. [Figure 15] The mean percentage change (%) in Liver Weight from baseline based on pre- and post-study biopsies is shown after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 16] Shown are the mean percentage changes (%) in Liver Total Cholesterol from baseline based on pre- and post-study biopsies after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 17] Shown are the mean percentage changes (%) in Liver Hydroxyproline from baseline based on pre- and post-study biopsies after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 18]Figure 1 shows a summary of fibrosis stage score results after 12 weeks of treatment with vehicle, compound 2, tropifexol, and compound 2 and tropifexol. Lines indicate changes in biopsies from pre-study to post-study. Points at each scoring step are shifted slightly to allow for visual separation of animals (this is done for visualization purposes and does not reflect differences in scores). [Figure 19] The mean percentage change (%) in liver fibrosis based on pre- and post-study biopsies was determined by morphometry after picrosirius red staining after 12 weeks of treatment with vehicle, compound 2, tropifexol, and compound 2 and tropifexol. Liver fibrosis was determined by morphometry after picrosirius red (PSR) staining. [Figure 20] FIG. 1 shows a summary of NAFLD activity scores in pre- and post-study biopsies after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 21] The mean percentage change (%) in steatosis score from baseline based on pre- and post-study biopsies is shown after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 22] FIG. 1 shows the ratio of Liber Steatosis to Vehicle after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Diagram 23] Shown is the mean percentage change in Liber Collagen 1a1 after 12 weeks of treatment with vehicle, Compound 2, Tropifexol, and Compound 2 and Tropifexol. [Figure 24] The mean percentage change in hepatic α-SMA from baseline based on pre- and post-study biopsies is shown after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Diagram 25]Shown are the mean percentage changes in hepatic Galectin (Galectin-3) from baseline based on pre- and post-study biopsies after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Figure 26] FIG. 1 shows plasma total cholesterol after 12 weeks of treatment in mice with vehicle, compound 2, semaglutide, a combination of compound 2 and semaglutide, tropifexor, and a combination of compound 2 and tropifexor. [Figure 27] Figure 2 shows total liver triglyceride content after 12 weeks of treatment in mice with vehicle, compound 2, semaglutide, a combination of compound 2 and semaglutide, tropifexor, and a combination of compound 2 and tropifexor. [Figure 28] Figure 2 shows total liver hydroxyproline content after 12 weeks of treatment in mice with vehicle, compound 2, semaglutide, a combination of compound 2 and semaglutide, tropifexor, and a combination of compound 2 and tropifexor. [Figure 29] Figure 2 shows total liver lipid content after 12 weeks of treatment in mice with vehicle, compound 2, semaglutide, a combination of compound 2 and semaglutide, tropifexor, and a combination of compound 2 and tropifexor. [Diagram 30] The mean percentage change in liver fibrosis based on pre- and post-study biopsies is shown after 12 weeks of treatment with vehicle; Compound 2; semaglutide; the combination of Compound 2 and semaglutide; tropifexol; and the combination of Compound 2 and tropifexol. [Diagram 31] FIG. 1 shows the ratio of hepatic triglycerides to vehicle after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Diagram 32] FIG. 1 shows the change from baseline in NAFLD activity scores after 12 weeks of treatment with vehicle, Compound 2, tropifexol, and Compound 2 and tropifexol. [Diagram 33]FIG. 1 shows the ratio of hepatic steatosis to vehicle after 8 weeks of treatment with vehicle, compound 2, obeticholic acid (OCA), and compound 2 and obeticholic acid (OCA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] Fatty acids consist of an alkyl chain with a terminal carboxyl group. Unsaturated fatty acids are commonly present in humans and contain up to six double bonds per chain. Most fatty acids in humans are C16, C18 or C20 in length. Fatty acids are stored primarily as esters of glycerol. Triglycerides (TGs) are triacylglycerols, i.e., all three hydroxyls are esterified with fatty acids. In addition to TGs, there is glycerol esterified with only one fatty acid (monoacylglycerol) or two fatty acids (diacylgycerol, DAG). The distribution of esterification sites on glycerol is influenced by many factors and may have important biological functions. Fatty acids are also used in the synthesis of other molecules, such as esters of cholesterol that can be broken down by esterases back to the parent molecule, and various phospholipids, which consist of phosphorylated acylated glycerols, including lysophosphatidic acid and phosphatidic acid. Many of these products have biological activity, suggesting that modulation of their levels may produce beneficial or deleterious effects.

[0050] Fatty acids are taken up from the circulation by the liver. Dietary fatty acids enter the circulation after ingestion and passage through the lymphatic system. Once in the circulation, fatty acids are taken up by tissues and used immediately or in the future as an energy source. If not used immediately, fatty acids are usually converted to TGs. TGs are then hydrolyzed to produce free fatty acids and glycerol. Both are often transported to the liver from cells, such as adipocytes, that store large amounts of TGs. Lipolysis of TGs occurs through the action of lipases. For example, lipoprotein lipase hydrolyzes triacylglycerol from plasma lipoproteins. Another example is hormone-sensitive lipase (HSL), which hydrolyzes TGs stored in adipocytes. HSL is highly sensitive to several hormones, such as insulin, glucagon, epinephrine, and ACTH, which inactivate the enzyme.

[0051] Fatty acids in the liver are also supplied by de novo synthesis from small intermediates derived from the metabolic breakdown of sugars, amino acids and other fatty acids. Thus, excess dietary protein and carbohydrates are easily converted into fatty acids and stored as TG. The key enzyme in fatty acid synthesis is acetyl-CoA carboxylase, which controls the total synthesis of fatty acids by controlling the synthesis of malonyl-CoA from acetyl-CoA. Fatty acid synthase then catalyzes the addition of two carbon units to the activated carboxyl terminus of the growing chain. The result is the fatty acid palmitate. Palmitate is the precursor fatty acid for almost all other fatty acids. Enzymes leading to unsaturated or elongated fatty acids are available.

[0052] Fatty acids are used in mitochondria for energy production primarily by oxidation. The first step involves the conversion of fatty acids to fatty acyl-CoA by acyl-CoA synthetase. Since the oxidative enzymes are located inside the inner mitochondrial membrane, which CoA and its derivatives cannot cross, carnitine is used together with carnitine palmitoyltransferase (CPT) to transfer acyl-CoA to the mitochondria. This step is rate-limiting in fatty acid oxidation. Two carbon units are removed from the carboxy terminus using four enzyme-catalyzed reactions. The product is acyl-CoA, which can then be used in the synthesis of fatty acids (futile cycle), ketone bodies, or enter the TCA cycle where it is converted to CO2 and ATP. Some of the energy generated by fatty acid oxidation is stored as ATP, some is used in the biosynthesis of other molecules, and some is lost in the form of heat. Agents that increase thermogenesis can allow for net energy expenditure.

[0053] Adiposity occurs when there is a net energy intake relative to energy expenditure. Energy is often stored as fat, and more specifically as TGs. Ideally, fat is stored in its natural storage site, the adipocyte. However, when in excess, fat is stored in other tissues, some of which may be adversely affected. Fat accumulation in the liver depends on a number of factors, including fatty acid delivery from the circulation, lipogenesis (i.e., de novo lipid synthesis) in the liver, and free fatty acid oxidation.

[0054] Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological term that encompasses a spectrum of diseases ranging from simple TG accumulation in hepatocytes to hepatic steatosis with inflammation (nonalcoholic steatohepatitis, NASH) to fibrosis and cirrhosis. NAFLD is the most frequent cause of elevated liver enzymes. The prevalence of NAFLD in the population is estimated to be 14-28%. Hepatic insulin resistance is associated with hepatic steatosis.

[0055] Products from TG metabolism, such as DAG and long-chain acyl-CoA (LCACoA), are believed to negatively mediate insulin response through their effects on insulin receptor phosphorylation. Long-chain CoA and DAG increase Ser / Thr phosphorylation of insulin receptor substrates (IRS 1-3), thereby preventing Tyr phosphorylation of these substrates by the insulin receptor. The resulting hepatic insulin resistance contributes to the development of compensatory hyperinsulinemia that further drives fat accumulation via SREBP1. Reduction of TG can reduce the levels of DAG and LCACoA, thus improving response to insulin. Improved response to insulin can also reduce further fat accumulation.

[0056] Oxidative stress results from an imbalance between pro-oxidant and antioxidant species, leading to oxidative damage. Oxidation of fatty acids is an important source of reactive oxygen species (ROS). Some of the consequences of increased ROS are ATP depletion, membrane destruction due to lipid peroxidation, and release of inflammatory cytokines. Increased hepatic triglycerides can lead to increased oxidative stress in hepatocytes and progression of hepatic steatosis to NASH. Human livers with NASH have increased lipid peroxidation and mitochondrial dysfunction. This can lead to cell death, hepatic stellate cell activation, and fibrosis and inflammation. All of these activities can put NAFLD patients at risk for NASH, a more severe form of the disease with a higher risk of cirrhosis and hepatocellular carcinoma. TH is known to increase fatty acid oxidation and mitochondrial enzyme activity, which can lead to increased ROS and liver damage. Prodrugs activated by P450s can also cause increased ROS.

[0057] The present disclosure relates to the use of a TR-β agonist in combination with one or more second agents in a method for reducing fat content in the liver of an animal, the method comprising administering to the animal a therapeutically effective amount of a TR-β agonist compound, a pharma- ceutically acceptable salt thereof, or a prodrug thereof or a pharma- ceutically acceptable salt of said prodrug, and one or more second agents. The present disclosure also relates to a method for preventing, treating, or ameliorating fatty liver disease in an animal, the method comprising administering to the animal a therapeutically effective amount of a TR-β agonist compound, a pharma- ceutically acceptable salt thereof, or a prodrug thereof or a pharma- ceutically acceptable salt of said prodrug, and one or more second agents. The compound of formula I and / or the second agent can be in its active form or a prodrug. The present disclosure also includes the use of pharma- ceutically acceptable salts, including but not limited to acid addition salts and physiological salts, and cocrystals of the compound of formula I and / or the second agent. Further included in the disclosure is the use of prodrugs and / or second agents of the compounds of Formula I in their active forms and pharma- ceutically acceptable salts, including, but not limited to, acid addition salts and physiological salts, and co-crystals thereof.

[0058] 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.

[0059] "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.

[0060] "Subject in need thereof" means a subject identified as in need of therapy or treatment.

[0061] 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.

[0062] The phrase "therapeutically effective amount" refers to an amount of a compound or combination of compounds that ameliorates, reduces or eliminates one or more symptoms of a particular disease or condition, or prevents, alters, or delays the onset of one or more symptoms of a particular disease or condition.

[0063] "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.

[0064] "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.

[0065] "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.

[0066] "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.

[0067] "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.

[0068] The administration of the compounds disclosed herein or their pharmaceutically acceptable salts, or the second agents disclosed herein, can be administered via any of the accepted modes of administration of agents with similar efficacy, 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 preferred embodiments.

[0069] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarterial, and intracranial administration.

[0070] "Subcutaneous administration" means administration just beneath the skin.

[0071] "Intravenous administration" means administration into a vein.

[0072] "Intra-arterial administration" means administration into an artery.

[0073] 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.

[0074] "Drug" means a substance that produces a therapeutic effect when administered to a subject.

[0075] "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.

[0076] "Active pharmaceutical ingredient" means the substance in a pharmaceutical composition that provides a desired effect.

[0077] 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.

[0078] "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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] "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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] The term "acyl" refers to -C(O)R, where R is alkyl, heterocycloalkyl, or aryl.

[0096] 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.

[0097] The term "carboxyl" refers to -C(O)OH.

[0098] The term "oxo" refers to =O in an alkyl or heterocycloalkyl group.

[0099] 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.

[0100] The term "-carboxylamide" refers to -CONR2, where each R is independently hydrogen or alkyl.

[0101] The term "sulphonylamido or sulfonylamido" refers to -S(=O)2NR2, where each R is independently hydrogen or alkyl.

[0102] The term "halogen" or "halo" refers to -F, -Cl, -Br and -I.

[0103] 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.

[0104] The term "sulphonyl" or "sulfonyl" refers to -SO2R, where R is H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0105] The term "sulphonate" or "sulfonate" refers to -SO2OR, where R is -H, alkyl, aryl, aralkyl, or heterocycloalkyl.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] The term "acyloxy" refers to an ester group -OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, aralkyl, or heterocycloalkyl.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] The term "alkoxyaryl-" refers to an aryl group substituted with an alkyloxy group. In "lower alkyloxyaryl-", the alkyl group is lower alkyl.

[0115] The term "aryloxyalkyl-" refers to an alkyl group substituted with an aryloxy group.

[0116] 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.

[0117] The terms "alkoxy-" or "alkyloxy-" refer to an alkyl-O- group.

[0118] 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.

[0119] The term "alkylthio-" refers to an alkyl-S- group.

[0120] 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.

[0121] The term "alkoxycarbonyloxy-" refers to alkyl-OC(O)-O-.

[0122] The term "aryloxycarbonyloxy-" refers to aryl-OC(O)-O-.

[0123] The term "alkylthiocarbonyloxy-" refers to alkyl-SC(O)-O-.

[0124] 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).

[0125] 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-.

[0126] 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-.

[0127] 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.

[0128] 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.

[0129] The term "hydroxyalkyl" refers to an alkyl group substituted with one -OH.

[0130] The term "haloalkyl" refers to an alkyl group substituted with a halo.

[0131] The term "cyano" refers to -C≡N.

[0132] The term "nitro" refers to --NO.

[0133] The term "acylalkyl" refers to alkyl-C(O)-alk-, where "alk" is alkylene.

[0134] 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.

[0135] The term "heteroarylalkyl" refers to an alkylene group substituted with a heteroaryl group.

[0136] 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.

[0137] compound In some embodiments, the compounds for use described herein are compounds according to formula I

[0138] [ka]

[0139] 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 -(CR a2) 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 -C 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 of 5-6 atoms containing 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 can 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

[0140] [ka]

[0141] 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 atoms are heteroatoms 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.

[0142] 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.

[0143] In some embodiments, the compound is

[0144] [ka]

[0145] or a pharma- ceutically acceptable salt thereof.

[0146] In other embodiments, the compound is

[0147] [Table 1A]

[0148] [Table 1B]

[0149] [Table 1C]

[0150] [Table 1D]

[0151] [Table 1E]

[0152] [Table 1F]

[0153] [Table 1G]

[0154]

Table 1H

[0155]

Table 1I

[0156]

Table 1J

[0157]

Table 1K

[0158]

Table 1L

[0159]

Table 1M

[0160]

Table 1N

[0161]

Table 1O

[0162]

Table 1P

[0163]

Table 1Q

[0164] [Table 1R]

[0165] [Table 1S]

[0166] [Table 1T]

[0167] [Table 1U]

[0168] [Table 1V]

[0169] [Table 1W]

[0170] [Table 1X]

[0171] [Table 1Y]

[0172] [Table 1Z]

[0173] or a pharma- ceutically acceptable salt thereof.

[0174] The above compounds can be prepared according to known methods, including the method described in U.S. Patent No. 7,829,552, which is incorporated herein by reference in its entirety. Additional thyroid receptor agonists are described in U.S. Patent No. 7,514,419; U.S. Patent Application Publication No. 2009 / 002895; U.S. Patent Application Publication No. 2010 / 0081634; U.S. Patent Application Publication No. 2012 / 0046364; and International Publication No. 2011 / 038207, all of which are incorporated herein by reference in their entirety.

[0175] In some embodiments, the TR-β agonist is a compound having the structure of Formula (A):

[0176] [ka]

[0177] 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.

[0178] In some embodiments, the TR-β agonist is

[0179] [ka]

[0180] and pharma-ceutically acceptable salts thereof.

[0181] Second drug The TR-β agonist compounds presented herein can be administered in combination with one or more second drugs. In some embodiments, the compounds can be administered in combination with one second drug. In some embodiments, the compounds can be administered in combination with two second drugs. In some embodiments, the compounds can be administered in combination with three or more second drugs.

[0182] In some embodiments, the TR-β agonist compounds presented herein may be co-administered with one or more secondary agents. In other embodiments, the compounds of the present disclosure may be administered sequentially with one or more secondary agents.

[0183] In one aspect, the TR-β agonist compounds presented herein can be administered in combination with peroxisome proliferator-activated receptor (PPAR) modulators. PPAR modulators are pharmaceutical compounds that can be used, for example, to lower triglyceride levels and blood glucose levels in a subject. PPAR modulators can be classified as PPARα modulators, PPARγ modulators, or PPARδ agonists. In some embodiments, the PPAR modulator is

[0184] [ka]

[0185] In some embodiments, the PPAR modulator may be:

[0186] [ka]

[0187] In some embodiments, the PPAR modulator may be:

[0188] [ka]

[0189] In some embodiments, the PPAR modulator may be:

[0190] [ka]

[0191] In some embodiments, the PPAR modulator can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0192] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with fibric acid derivatives. Fibric acid derivatives are a group of lipid-lowering drugs that have the ability to lower the lipid profile of a subject. In some embodiments, the fibric acid derivative may be fenofibrate. In some embodiments, the fibric acid derivative may be gemfibrozil. In some embodiments, the fibric acid derivative may be fenofibric acid. In some embodiments, the fibric acid derivative may be clofibrate. In some embodiments, the fibric acid derivative may be any pharma- ceutically acceptable salt or prodrug of the above.

[0193] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with a bile acid receptor modulator. Bile acid receptors include, but are not limited to, FXR (farnesoid X receptor) and TGR5. In some embodiments, the bile acid receptor modulator is

[0194] [ka]

[0195] In some embodiments, the bile acid receptor modulator can be:

[0196] [ka]

[0197] In some embodiments, the bile acid receptor modulator can be:

[0198] [ka]

[0199] In some embodiments, the bile acid receptor modulator can be:

[0200] [ka]

[0201] (tropifexol). In some embodiments, the bile acid modulator can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0202] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with a bile acid receptor modulator. In some embodiments, the bile acid receptor modulator may be selected from the group consisting of FXR agonists, FXR antagonists, TGR agonists, and FXR / TGR dual agonists. In some embodiments, the bile acid receptor modulator is

[0203] [ka]

[0204] (wherein n is 2 or 3);

[0205] [ka]

[0206] where R is H or F;

[0207] [ka] [ka] [ka] [ka]

[0208] where R is H or benzyl,

[0209] [ka] [ka]

[0210] where R is H or methyl;

[0211] [ka] [ka]

[0212] where R is H or methyl;

[0213] [ka]

[0214] (wherein Y is F or Cl),

[0215] [ka] [ka] [ka] [ka]

[0216] where X is H or OMe;

[0217] [ka] [ka]

[0218] where R is H or ethyl;

[0219] [ka]

[0220] (wherein R is H or OH),

[0221] [ka]

[0222] or a pharma- ceutically acceptable salt of any of the above, the entirety of which is incorporated herein by reference.

[0223] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with an anti-inflammatory compound. In some embodiments, the anti-inflammatory compound is

[0224] [ka]

[0225] In some embodiments, the anti-inflammatory compound can be:

[0226] [ka]

[0227] In some embodiments, the anti-inflammatory compound can be a polyclonal or monoclonal anti-LPS immunoglobulin. In some embodiments, the anti-LPS immunoglobulin can be IMM-124E. In some embodiments, the anti-inflammatory compound can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0228] In some embodiments, the second agent can be an anti-fibrotic compound. In some embodiments, the anti-fibrotic compound is

[0229] [ka]

[0230] In some embodiments, the anti-fibrotic compound can be:

[0231] [ka]

[0232] In some embodiments, the anti-fibrotic compound can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0233] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with a GLP-1 agonist. GLP-1 is a pharmaceutical compound that can be used, for example, to treat type 2 diabetes in a subject. In some embodiments, the GLP-1 agonist can be dulaglutide. In some embodiments, the GLP-1 agonist can be exenatide. In some embodiments, the GLP-1 agonist can be liraglutide. In some embodiments, the GLP-1 agonist can be albiglutide. In some embodiments, the GLP-1 agonist can be lixisenatide. In some embodiments, the GLP-1 agonist can be semaglutide. In some embodiments, the GLP-1 agonist can be insulin glargine. In some embodiments, the GLP-1 agonist can be

[0234] [ka]

[0235] (PF06882961). In some embodiments, the GLP-1 agonist can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0236] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with a GLP-1 metabolic modulator. In some embodiments, the metabolic modulator may be a thyroid hormone receptor agonist. In other embodiments, the metabolic modulator may be a selective androgen receptor modulator. In some embodiments, the metabolic modulator may be a mitochondrial membrane transport protein modulator. In other embodiments, the metabolic modulator may be a selective estrogen receptor modulator. In some embodiments, the metabolic modulator may be a stearoyl-CoA desaturase 1 (SCD1) inhibitor. In some embodiments, the metabolic modulator may be a dipeptidyl peptidase 4 (DPP-4) inhibitor. In some embodiments, the metabolic modulator may be an inhibitor of sodium glucose cotransporter 1 and / or 2 (SGLT1, SGLT2, or a dual SGLT1 / SGLT2 inhibitor). In some embodiments, the metabolic modulator may be recombinant fibroblast growth factor 19 (FGF19) or a modified analog, or recombinant fibroblast growth factor 21 (FGF21) or a PEGylated variant thereof.

[0237] [ka]

[0238] In some embodiments, the metabolic modulator may be:

[0239] [ka]

[0240] In some embodiments, the metabolic modulator may be:

[0241] [ka]

[0242] In some embodiments, the metabolic modulator may be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0243] In some embodiments, the TR-β agonist compounds presented herein may be administered in combination with a fish oil derivative. Fish oil contains ω-3-fatty acids, which are polyunsaturated fatty acids (PUFAs) characterized by a double bond that is three atoms away from the terminal methyl group. They are widely distributed in nature and play an important role in the human diet and human physiology, especially in relation to lipid metabolism. In some embodiments, the fish oil derivative can be an ω-3-fatty acid alkyl ester. For example, the fish oil derivative can be an ω-3-fatty acid methyl ester, ethyl ester, n-propyl ester, or isopropyl ester. In some embodiments, the fish oil derivative can be an ω-3-fatty acid triglyceride. In some embodiments, the fish oil derivative can be ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate. In some embodiments, the fish oil derivative can be ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate. In some embodiments, the fish oil derivative can be ethyl (7Z,10Z,13Z,16Z,19Z)-docosapentaenoate. In some embodiments, the fish oil derivative can be ethyl hexadecatrienoate. In some embodiments, the fish oil derivative can be alpha-linolenic acid ethyl ester. In some embodiments, the fish oil derivative can be ethyl (6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoate. In some embodiments, the fish oil derivative can be ethyl eicosatrienoate. In some embodiments, the fish oil derivative can be ethyl eicosatetraenoate. In some embodiments, the fish oil derivative can be ethyl heneicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl eicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl heneicosapentaenoate. In some embodiments, the fish oil derivative can be ethyl tetracosapentaenoate. In some embodiments, the fish oil derivative can be herring acid ethyl ester.In some embodiments, the fish oil derivative can be a pharma- ceutically acceptable salt or prodrug of any of the above.

[0244] Pharmaceutical Compositions The above TR-β agonist compound and / or the above second agent can be formulated into a pharmaceutical composition 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), the entirety of which is incorporated herein by reference.Thus, some embodiments include a pharmaceutical composition comprising: (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.

[0245] In some embodiments, the TR-β agonist compounds described herein and the second agents described herein may be formulated into a single pharmaceutical composition for use in treating the conditions described herein. In some embodiments, the formulations comprising the TR-β agonist compounds described herein may be administered in combination with one or more second agents described herein or pharmaceutical compositions comprising one or more second agents described herein.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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.

[0250] 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).

[0251] 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.

[0252] 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.

[0253] 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.

[0254] 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.

[0255] The compositions described herein can optionally include other pharmaceutical actives.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] Ophthalmologically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] The actual unit dose of the TR-β agonist compounds described herein and / or the second agents 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 / 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 0.1 mg. In some embodiments, the actual unit dose is 0.5 mg. In some embodiments, the actual unit dose is 1 mg. In some embodiments, the actual unit dose is 1.5 mg. In some embodiments, the actual unit dose is 2 mg. In some embodiments, the actual unit dose is 2.5 mg. In some embodiments, the actual unit dose is 3 mg. In some embodiments, the actual unit dose is 3.5 mg.In some embodiments, the actual unit dose is 4 mg. In some embodiments, the actual unit dose is 4.5 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.

[0268] In some embodiments, the TR-β agonist compound is administered in an amount of about 1-50 mg / m 2 of body surface area. 2In some embodiments, the TR-β agonist compound is administered at a dose ranging from about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 13.75, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 22.5, 1 to 25, 1 to 27.5, 1 to 30, 1.5 to 2, 1.5 to 3, 1.5 to 4, 1.5 to 5, 1.5 to 6, 1.5 to 7, 1.5 to 8, 1.5 to 9, 1.5 to 10, 1.5 to 11, 1.5 to 12, 1.5 to 13, 1.5 to 13.75, 1.5 to 14, 1.5 to 15, 1.5~16, 1.5~17, 1.5~18, 1.5~19, 1.5~20, 1.5~22.5, 1.5~25, 1.5~27.5, 1.5~30, 2.5~2, 2.5~3, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~8, 2.5~9, 2.5~10, 2.5~11, 2.5~12, 2.5~13, 2.5~13.75, 2.5~14, 2.5~15, 2.5~16, 2.5~17, 2.5~18, 2.5~19, 2.5~20, 2.5~22.5, 2.5~25, 2.5~27.5, 2.5~30, 2.5~7.5 , 3~4, 3~5, 3~6, ​​3~7, 3~8, 3~9, 3~10, 3~11, 3~12, 3~13, 3~13.75, 3~14, 3~15, 3~16, 3~17, 3~18, 3~19, 3~20, 3~22.5, 3~25, 3~27.5, 3~30, 3.5~6.5, 3.5~13.75, 3.5~15, 2.5~17.5, 4~5, 4~6, 4~7, 4~8, 4~9, 4~10, 4~11, 4~12, 4~13, 4~13.75, 4~14, 4~15, 4~16, 4~17, 4~18, 4~19, 4~20, 4~22.5, 4~25, 4~2 7.5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27.5, 6-30, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-13.75, 7~14, 7~15, 7~16, 7~17, 7~18, 7~19, 7~20, 7~22.5, 7~25, 7~27.5, 7~30, 7.5~12.5, 7.5~13.5, 7.5~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~13.75, 8~14, 8~ 15, 8~16, 8~17, 8~18, 8~19, 8~20, 8~22.5, 8~25, 8~27.5, 8~30, 9~10, 9~11, 9~12, 9~13, 9~13.75, 9~14, 9~15, 9~16, 9~17, 9~18, 9~19, 9~20, 9~22.5, 9~25 , 9~27.5, 9~30, 10~11, 10~12, 10~13, 10~13.75, 10~14, 10~15, 10~16, 10~17, 10~18, 10~19, 10~20, 10~22.5, 10~25, 10~27.5, 10~30, 11.5~15.5, 12.5~1 4.5, 7.5-22.5, 8.5-32.5, 9.5-15.5, 15.5-24.5, 5-35, 17.5-22.5, 22.5-32.5, 25-35, 25.5-24.5, 27.5-32.5, 2-20, 2.5-22.5, or 9.5-21.5 mg / m2 of body surface area. 2 In some embodiments, the TR-β agonist compound is administered at a dose ranging from about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 1 7.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26 .5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area 2In some embodiments, the TR-β agonist compound is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 10 7.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26 .5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area 2 In some embodiments, the TR-β agonist compound is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50mg / 1m of body surface area 2 It is administered in doses of over 100 mg / kg.

[0269] In some embodiments, the TR-β agonist compound dose is about 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.5 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 20 mg, 0.5 mg to 10 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 20 mg, 1 mg to 10 mg, 2.5 mg to 50 mg, 2.5 mg to 20 mg, 2.5 mg to 10 mg, or about 2.5 mg to 5 mg. In some embodiments, the TR-β agonist compound dose is about 5 mg to 300 mg, 5 mg to 200 mg, 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, or about 40 mg to 60 mg. In some embodiments, the TR-β agonist compound administered is about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the TR-β agonist compound administered is about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5 mg to 40 mg, 5 mg to 42 mg, 5 mg to 44 mg, 5 mg to 46 mg, 5 mg to 48 mg, 5 mg to 50 mg, 5 mg to 52 mg, 5 mg to 56 mg, 5 mg to 58 mg, 5 mg to 59 mg, 5 mg to 60 mg, 5 mg to 61 mg, 5 mg to 62 mg, 5 mg to 63 mg, 5 mg to 64 mg, 5 mg to 65 mg, 5 mg to 66 mg, 5 mg to 67 mg, 5 mg to 68 mg, 5 mg to 70 mg, 5 mg to 72 mg, 5 mg to 74 mg, 5 mg to 75 mg, 5 mg to 76 mg, 5 mg to 78 mg, 5 mg to 79 mg, 5 mg to 80 mg, 5 mg to 82 mg, 5 mg to 84 mg, 5 mg to 85 mg, 5 mg to 86 mg, 5 mg to 87 mg, 5 mg to 88 mg, 5 mg to 89 mg, 5 mg to 90 mg, 5 mg to 91 mg, 5 mg to 92 mg, mg, 5mg~52mg, 5mg~54mg, 5mg~56mg, 5mg~58mg, 5mg~60mg, 7mg~7.7mg, 7mg~9mg, 7mg~10mg, 7mg~12mg, 7mg~14mg, 7mg~15mg, 7mg~16mg, 7mg~18mg, 7mg ~20mg, 7mg~22mg, 7mg~24mg, 7mg~26mg, 7mg~28mg, 7mg~30mg, 7mg~32mg, 7mg~34mg, 7mg~36mg, 7mg~38mg, 7mg~40mg, 7mg~42mg, 7mg~44mg, 7mg~46mg,7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg, 30mg~32mg, 30mg~34mg, 30mg~36mg, 30mg~38mg, 30mg~40mg, 30mg~42mg, 30mg~44mg, 30mg~46mg, 30mg~48mg, 30m g~50mg, 30mg~52mg, 30mg~54mg, 30mg~56mg, 30mg~58mg, 30mg~60mg, 33mg~34mg, 33mg~36mg, 33mg~38mg, 33mg~40mg, 33mg~4 2mg, 33mg~44mg, 33mg~46mg, 33mg~48mg, 33mg~50mg, 33mg~52mg, 33mg~54mg, 33mg~56mg, 33mg~58mg, 33mg~60mg, 36mg~38mg , 36mg~40mg, 36mg~42mg, 36mg~44mg, 36mg~46mg, 36mg~48mg, 36mg~50mg, 36mg~52mg, 36mg~54mg, 36mg~56mg, 36mg~58mg, 36 mg~60mg, 40mg~42mg, 40mg~44mg, 40mg~46mg, 40mg~48mg, 40mg~50mg, 40mg~52mg, 40mg~54mg, 40mg~56mg, 40mg~58mg, 40mg~ 60mg, 43mg~46mg, 43mg~48mg, 43mg~50mg, 43mg~52mg, 43mg~54mg, 43mg~56mg, 43mg~58mg, 42mg~60mg, 45mg~48mg, 45mg~50m g, 45mg to 52mg, 45mg to 54mg, 45mg to 56mg, 45mg to 58mg, 45mg to 60mg, 48mg to 50mg, 48mg to 52mg, 48mg to 54mg, 48mg to 56mg, 48mg to 58mg, 48mg to 60mg, 50mg to 52mg, 50mg to 54mg, 50mg to 56mg, 50mg to 58mg, 50mg to 60mg, 52mg to 54mg, 52mg to 56mg, 52mg to 58mg, or 52mg to 60mg. In some embodiments, the TR-β agonist compound dose is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg,In some embodiments, the TR-β agonist compound dose is less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the TR-β agonist compound dose is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0270] In some embodiments, the second agent is about 1-50 mg / m2 of body surface area. 2In some embodiments, the second agent is administered at a dose in the range of about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 13.75, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 22.5, 1 to 25, 1 to 27.5, 1 to 30, 1.5 to 2, 1.5 to 3, 1.5 to 4, 1.5 to 5, 1.5 to 6, 1.5 to 7, 1.5 to 8, 1.5 to 9, 1.5 to 10, 1.5 to 11, 1.5 to 12, 1.5 to 13, 1.5 to 13.75, 1.5 to 14, 1.5 to 15, 1.5 ~16, 1.5~17, 1.5~18, 1.5~19, 1.5~20, 1.5~22.5, 1.5~25, 1.5~27.5, 1.5~30, 2.5~2, 2.5~3, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~8, 2.5~9, 2.5~10, 2.5~11, 2.5~12, 2.5~13, 2.5~13.75, 2.5~14, 2.5~15, 2.5~16, 2.5~17, 2.5~18, 2.5~19, 2.5~20, 2.5~22.5, 2.5~25, 2.5~27.5, 2.5~30, 2.5~7.5, 3~4 , 3~5, 3~6, ​​3~7, 3~8, 3~9, 3~10, 3~11, 3~12, 3~13, 3~13.75, 3~14, 3~15, 3~16, 3~17, 3~18, 3~19, 3~20, 3~22.5, 3~25, 3~27.5, 3~30, 3.5~6.5, 3.5~13.75, 3.5~15, 2.5~17.5, 4~5, 4~6, 4~7, 4~8, 4~9, 4~10, 4~11, 4~12, 4~13, 4~13.75, 4~14, 4~15, 4~16, 4~17, 4~18, 4~19, 4~20, 4~22.5, 4~25, 4~27. 5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27.5, 6-30, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-13.75, 7~14, 7~15, 7~16, 7~17, 7~18, 7~19, 7~20, 7~22.5, 7~25, 7~27.5, 7~30, 7.5~12.5, 7.5~13.5, 7.5~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~13.75, 8~14, 8~ 15, 8~16, 8~17, 8~18, 8~19, 8~20, 8~22.5, 8~25, 8~27.5, 8~30, 9~10, 9~11, 9~12, 9~13, 9~13.75, 9~14, 9~15, 9~16, 9~17, 9~18, 9~19, 9~20, 9~22.5, 9~25 , 9~27.5, 9~30, 10~11, 10~12, 10~13, 10~13.75, 10~14, 10~15, 10~16, 10~17, 10~18, 10~19, 10~20, 10~22.5, 10~25, 10~27.5, 10~30, 11.5~15.5, 12.5~1 4.5, 7.5-22.5, 8.5-32.5, 9.5-15.5, 15.5-24.5, 5-35, 17.5-22.5, 22.5-32.5, 25-35, 25.5-24.5, 27.5-32.5, 2-20, 2.5-22.5, or 9.5-21.5 mg / m2 of body surface area. 2 In some embodiments, the second agent is administered at a dose in the range of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5 , 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area 2In some embodiments, the second agent is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5 , 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / 1m of body surface area 2 In some embodiments, the second agent is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5 , 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29 .5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50mg / 1m of body surface area 2 It is administered in doses of over 100 mg / kg.

[0271] In some embodiments, the dose of the second agent is about 5 mg to 300 mg, 5 mg to 200 mg, 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, or about 40 mg to 60 mg. In some embodiments, the dose of the second agent administered is about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the dose of the second agent administered is between about 5 mg and 7.5 mg, 5 mg and 9 mg, 5 mg and 10 mg, 5 mg and 12 mg, 5 mg and 14 mg, 5 mg and 15 mg, 5 mg and 16 mg, 5 mg and 18 mg, 5 mg and 20 mg, 5 mg and 22 mg, 5 mg and 24 mg, 5 mg and 26 mg, 5 mg and 28 mg, 5 mg and 30 mg, 5 mg and 32 mg, 5 mg and 34 mg, 5 mg and 36 mg, mg, 5mg~38mg, 5mg~40mg, 5mg~42mg, 5mg~44mg, 5mg~46mg, 5mg~48mg, 5mg~50mg, 5mg~52mg, 5mg~54mg, 5mg~5 6mg, 5mg~58mg, 5mg~60mg, 7mg~7.7mg, 7mg~9mg, 7mg~10mg, 7mg~12mg, 7mg~14mg, 7mg~15mg, 7mg~16mg, 7mg~ 18mg, 7mg~20mg, 7mg~22mg, 7mg~24mg, 7mg~26mg, 7mg~28mg, 7mg~30mg, 7mg~32mg, 7mg~34mg, 7mg~36mg, 7mg ~38mg, 7mg~40mg, 7mg~42mg, 7mg~44mg, 7mg~46mg, 7mg~48mg, 7mg~50mg, 7mg~52mg, 7mg~54mg, 7mg~56mg, 7m g~58mg, 7mg~60mg, 9mg~10mg, 9mg~12mg, 9mg~14mg, 9mg~15mg, 9mg~16mg, 9mg~18mg, 9mg~20mg, 9mg~22mg, 9 mg~24mg, 9mg~26mg, 9mg~28mg, 9mg~30mg, 9mg~32mg, 9mg~34mg, 9mg~36mg, 9mg~38mg, 9mg~40mg, 9mg~42mg,9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~16mg、10mg~18mg、10mg~20mg、10mg~22mg、10mg~24mg、10mg~26mg、10mg~28mg、10mg~30mg、10mg~32mg、10mg~34mg、10mg~36mg、10mg~38mg、10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg, 33mg~50mg, 33mg~52mg, 33mg~54mg, 33mg~56mg, 33mg~58mg, 33mg~60mg, 36mg ~38mg, 36mg~40mg, 36mg~42mg, 36mg~44mg, 36mg~46mg, 36mg~48mg, 36mg~50mg, 36mg~52m g, 36mg~54mg, 36mg~56mg, 36mg~58mg, 36mg~60mg, 40mg~42mg, 40mg~44mg, 40mg~46mg, 40 mg~48mg, 40mg~50mg, 40mg~52mg, 40mg~54mg, 40mg~56mg, 40mg~58mg, 40mg~60mg, 43mg~46 mg, 43mg to 48mg, 43mg to 50mg, 43mg to 52mg, 43mg to 54mg, 43mg to 56mg, 43mg to 58mg, 42mg to 60mg, 45mg to 48mg, 45mg to 50mg, 45mg to 52mg, 45mg to 54mg, 45mg to 56mg, 45mg to 58mg, 45mg to 60mg, 48mg to 50mg, 48mg to 52mg, 48mg to 54mg, 48mg to 56mg, 48mg to 58mg, 48mg to 60mg, 50mg to 52mg, 50mg to 54mg, 50mg to 56mg, 50mg to 58mg, 50mg to 60mg, 52mg to 54mg, 52mg to 56mg, 52mg to 58mg, or 52mg to 60mg. In some embodiments, the dose of the second agent is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or greater than about 200 mg. In some embodiments, the dose of the second agent is less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dose of the second agent is less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg,About 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0272] In some embodiments, the mass ratio of the TR-β agonist compound to the second drug is about 10:1 to about 1:10. In some embodiments, the mass ratio of the TR-β agonist compound to the second drug is about 7:1 to about 1:7. In some embodiments, the mass ratio of the TR-β agonist compound to the second drug is about 5:1 to about 1:5. In some embodiments, the mass ratio of the TR-β agonist compound to the second drug is about 3:1 to about 1:3. In some embodiments, the mass ratio of the TR-β agonist compound to the second drug is about 2:1 to about 1:2. In some embodiments, the mass ratio of the TR-β agonist compound to the second drug is about 10:1 to about 1:1, about 7:1 to about 1:1, about 5:1 to about 1:1, about 3:1 to about 1:1, or about 2:1 to about 1:1. In some embodiments, the mass ratio of the TR-β agonist compound to the second agent is about 1:1 to about 1:2, about 1:1 to about 1:3, about 1:1 to about 1:5, about 1:1 to about 1:7, or about 1:1 to about 1:10. In some embodiments, the mass ratio of the TR-β agonist compound to the second agent is about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, or any range between two of these values.

[0273] In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is

[0274] [ka]

[0275] In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is fenofibrate, gemfibrozil, fenofibric acid, or clofibrate. In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is

[0276] [ka]

[0277] (tropifexor). In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is

[0278] [ka]

[0279] or IMM-124E. In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is dulaglutide, exenatide, liraglutide, albiglutide, lixisenatide, semaglutide, or insulin glargine. In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is

[0280] [ka]

[0281] In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is

[0282] [ka]

[0283] In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is

[0284] [ka]

[0285] In some embodiments, the TR-β agonist compound is Compound 2 and the second agent is ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate, ethyl (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate, ethyl (7Z,10Z,13Z,16Z,19Z)-docosapentaenoate, ethyl heparin, ethyl hexadecatrienoate, alpha-linolenic acid ethyl ester, ethyl (6Z,9Z,12Z,15Z)-6,9,12,15-octadecatetraenoate, ethyl eicosatrienoate, ethyl eicosatetraenoate, ethyl heneicosapentaenoate, ethyl icosapentaenoate, ethyl heneicosapentaenoate, ethyl tetracosapentaenoate, or herinic acid ethyl ester.

[0286] The TR-β agonist compounds described herein and / or the second agents described herein may also be incorporated into formulations for delivery outside the systemic circulation. Such formulations may include enteric capsules, tablets, softgels, spray-dried powders, polymeric matrices, hydrogels, enteric solids, crystalline solids, amorphous solids, glassy solids, coated microparticles, liquids, nebulized liquids, aerosols, or microcapsules.

[0287] 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.

[0288] 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.

[0289] In some embodiments, the TR-β agonist compounds presented herein may be co-administered with one or more secondary agents. In other embodiments, the compounds of the present disclosure may be administered sequentially with one or more secondary agents.

[0290] In some embodiments, the TR-β agonist compound may be administered prior to administration of the second agent. In some embodiments, the TR-β agonist compound may be administered about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 24 hours prior to administration of the second agent described herein. In some embodiments, the TR-β agonist compound may be administered after administration of the second agent. In some embodiments, the TR-β agonist compound may be administered about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 24 hours after administration of the second agent described herein.

[0291] Treatment Some embodiments of the disclosed methods and compositions are directed to a method for preventing, treating, or ameliorating one or more fatty liver diseases in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula I as described herein in combination with one or more second agents. In some embodiments, the fatty liver disease can be steatosis. In other embodiments, the fatty liver disease can be non-alcoholic fatty liver disease. In some embodiments, the fatty liver disease can be non-alcoholic steatohepatitis (NASH). In some embodiments, the subject can have two or more of the fatty liver diseases listed above.

[0292] Some embodiments of the disclosed methods and compositions 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 of formula I as described herein in combination with one or more second agents as 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 disclosed compositions and methods 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 as described herein.

[0293] In some embodiments, the compounds and compositions comprising the compounds of formula I described herein and / or one or more second agents 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), 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, pulmonary fibrosis, idiopathic pulmonary fibrosis, diffuse parenchymal lung disease, idiopathic interstitial fibrosis, diffuse ... 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.

[0294] 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.

[0295] According to the methods and compositions of the present disclosure, thyroid receptor agonists, particularly those disclosed herein, including compounds 1-4, may be administered to a subject in combination with one or more second agents described herein 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 in which fibrosis is a sequelae may further include chronic inflammation. According to the methods and compositions disclosed herein, the fibrotic condition or condition in which fibrosis is a sequelae 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 in which fibrosis is a sequelae 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 of the methods and compositions disclosed herein, the fibrotic condition or condition having a sequelae of fibrosis can include one or more conditions that are prevented, ameliorated, or cured by administering one or more of compounds 1-4 in combination with one or more second agents described herein.In some embodiments, the one or more TRβ agonists, or the one or more of Compounds 1-4, and the one or more second agents may be co-administered with one or more excipients. In some embodiments, the one or more TRβ agonists, or the one or more of Compounds 1-4, and the one or more second agents may be administered before, during, or after surgery, phototherapy, or ultrasound therapy.

[0296] 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 of the methods and compositions disclosed herein, the collagen deposition may be prevented, ameliorated, or cured by administering one or more of Compounds 1-4 in combination with one or more second agents. In some embodiments, the one or more TRβ agonists, or the one or more of Compounds 1-4, and the one or more second agents may be co-administered with one or more excipients. In some embodiments, the one or more TRβ agonists, or the one or more of Compounds 1-4, and the one or more second agents may be administered before, during, or after surgery, phototherapy, or ultrasound therapy.

[0297] In some embodiments, administering any of Compounds 1-4, Compound 2, or any of the compounds or compositions disclosed herein in combination with one or more second agents described herein reduces expression of Colal, Col3al, α-SMA, and / or Galectin 1 genes, or any combination or product thereof, in a subject to which the combination is administered. In some embodiments, administering any of Compounds 1-4, Compound 2, or any of the compounds or compositions disclosed herein in combination with one or more second agents reduces the degree of fibrosis, observable by histology, histochemistry, immunohistochemistry, etc., in a subject to which the combination 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 Compounds 1-4, Compound 2, or any of the compounds or compositions disclosed herein in combination with one or more second agents 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.

[0298] The methods described herein are further illustrated by the following examples. EXAMPLES

[0299] Pretreatment liver biopsy samples were collected before acclimation, and DIO-NASH mice were acclimated for 3 weeks. Mice were randomly assigned to one of seven treatment groups, with 12 mice per group. The assigned doses were: Compound 2 (10 mg / kg); Obeticholic acid (OCA) (30 mg / kg); Cenicriviroc (CVC) (30 mg / kg); Elafibranor (ELA) (30 mg / kg); Compound 2 (10 mg / kg) and Obeticholic acid (30 mg / kg); Compound 2 (10 mg / kg) and Cenicriviroc (30 mg / kg); Compound 2 (10 mg / kg) and Elafibranor (30 mg / kg). One group was a mock group treated with vehicle only as a control. The dosage forms of the combinations disclosed herein were orally administered once per day. Absolute and relative body weights of mice were recorded daily. After 8 weeks, animals were sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol were measured, terminal necropsies of each liver were performed, relative liver mass was determined as a percentage of body weight, whole liver biochemistry was assayed including total liver triglycerides and total liver cholesterol, and histological assessments of total liver hydroxyproline, NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, and galactin-3 levels were performed. Tissue samples were saved for characterization using RNAseq. RNAseq was used to determine the expression levels of genes that showed differential expression and / or genes known to be associated with fibrosis in Compound 2 + second drug treated animals versus vehicle treated animals.

[0300] Total liver hydroxyproline content is shown in Figure 1. Because 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.

[0301] Final liver biopsy samples were also subjected to histochemical and immunohistochemical staining. Representative images of livers stained with hematoxylin and eosin (HE staining) at the end of the treatment period after 8 weeks of treatment with vehicle, compound 2, obeticholic acid, cenicriviroc, elafibranor, compound 2 and obeticholic acid, compound 2 and cenicriviroc, or compound 2 and elafibranor are shown in Figure 2. The globular degeneration score was determined by HE staining of pretreatment and final liver biopsy samples (Figure 3). The fibrosis score was also calculated based on the observation of the final liver biopsy samples.

[0302] As shown in Figure 4, relative liver mass was reduced in Compound 2 + OCA and Compound 2 + CVC treated animals compared to vehicle treated animals. Total liver cholesterol content (Figure 5) and total liver triglyceride content (Figure 6) were also reduced in Compound 2 + OCA and Compound 2 + CVC treated animals compared to vehicle treated animals.

[0303] Significant improvements in NAFLD activity scores were observed in Compound 2 + OCA and Compound 2 + CVC treated animals compared to vehicle treated animals or compared to treatment with either Compound 2, CVC, or OCA alone (Figures 7-9). Moreover, improvements in fibrosis scores were observed in Compound 2 + OCA and Compound 2 + CVC treated animals compared to vehicle treated animals or compared to treatment with either Compound 2, CVC, or OCA alone (Figures 10-12). No significant toxicity was observed. Figures 7-9 show that treatment with the combination of Compound 2 and CVC and the combination of Compound 2 and OCA have a synergistic effect on improving NAFLD activity scores compared to treatment with either Compound 2, CVC, or OCA alone. Similarly, Figures 10-12 show that treatment with the combination of Compound 2 and CVC and the combination of Compound 2 and OCA have a synergistic effect on improving fibrosis scores compared to treatment with either Compound 2, CVC, or OCA alone.

[0304] Synergy analysis verified that the combination of Compound 2 and CVC exhibited synergistic effects. The combination of Compound 2 and CVC significantly reduced NAFLD activity scores from baseline compared to the single agents alone (p=0.0745) using a general linear model ( FIG. 8 ). Similarly, analysis of the change from baseline in fibrosis scores showed synergy with a p-value of 0.1967 using a general linear model.

[0305] Similarly, synergy analysis verified that the combination of Compound 2 and OCA exhibited synergistic effects. The ratio of hepatic steatosis to vehicle was analyzed for Compound 2 and OCA alone and in combination (FIG. 33). Analysis of log-transformed data showed synergy with a p-value of <0.0001. EXAMPLES

[0306] 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 by reference herein 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 to each subject appropriate for the formulation daily or, where appropriate, in combination with one or more second agents described herein for 6-10 weeks. Unilateral forelimb biopsies were 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 a combination of a compound disclosed herein and a second agent 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. EXAMPLES

[0307] 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 to each subject animal appropriate for its formulation daily or in combination with one or more second agents, as appropriate, 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 and a second agent described herein, 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. EXAMPLES

[0308] 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 comprising any one of compounds 1-4, or any other compound disclosed herein, to each subject appropriate for the formulation daily or, where appropriate, in combination with one or more second agents described herein for 6-10 weeks. 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 a compound disclosed herein and a second agent exhibit 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. EXAMPLES

[0309] 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 comprising any one of compounds 1-4, or any other compound disclosed herein, to each subject appropriate for the formulation daily or, where appropriate, in combination with one or more second agents described herein for 6-10 weeks. 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 combinations disclosed herein, particularly those treated with compound 2 and a second agent, 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. EXAMPLES

[0310] After induction of the GAN diet (GAN = Gubra Amylin NASH diet, an AMLN diet in which Primex is replaced by palm oil), DIO-NASH mice were randomly assigned to one of six treatment groups with 13-15 mice per group. The assigned doses were vehicle (PO, BID) [n=15]; Compound 2 (10 mg / kg PO, QD) [n=13]; semaglutide (30 nmol / kg SC, QD) [n=15]; Compound 2 (10 mg / kg PO, QD) and semaglutide (30 mg / kg SC, QD) [n=15]; tropifexol (0.3 mg / kg PO, QD) [n=14]; and Compound 2 (10 mg / kg PO, QD) and tropifexol (30 mg / kg PO, QD) [n=15]. Mice undergo a 14-day titration period for a total treatment period of 12 weeks. Baseline steatosis score, fibrosis stage, and Col1a1 levels are determined 1 week prior to treatment. Mouse weights were recorded daily. After 12 weeks of dosing, animals were sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol were measured, terminal necropsies of each liver were performed, relative liver mass was determined as a percentage of body weight, total liver biochemistry was assayed including total liver triglycerides and total liver cholesterol, and histological assessments of total liver hydroxyproline, NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, α-SMA, and galactin-3 levels were performed. Tissue samples were saved for characterization using RNAseq. RNAseq was used to determine the expression levels of genes that showed differential expression and / or genes known to be associated with fibrosis in Compound 2 + second drug treated animals versus vehicle treated animals.

[0311] The combination of Compound 2 and Tropifexol reduced plasma total cholesterol in treated animals compared to vehicle to a greater extent than Compound 2 or Tropifexol alone (Figures 13 and 26). The P value for the combination of Compound 2 and Tropifexol was less than 0.001 when compared to vehicle or to Compound 2 or Tropifexol. The combination of Compound 2 and Tropifexol was also effective in reducing plasma triglycerides (Figure 14) (the P value for the combination of Compound 2 and Tropifexol was less than 0.05 when compared to vehicle or to Compound 2 or Tropifexol) and liver mass (Figure 15) in treated animals. Furthermore, the combination of Compound 2 and tropifexol was effective in reducing total liver cholesterol (Figure 16) (p-values ​​for the combination of Compound 2 and tropifexol were less than 0.05 when compared to vehicle or to Compound 2 or tropifexol), in reducing liver hydroxyproline (Figures 17 and 28) (p-values ​​for the combination of Compound 2 and tropifexol were less than 0.01 when compared to vehicle or to Compound 2 or tropifexol); and in reducing total liver lipids (Figure 29) (p-values ​​for the combination of Compound 2 and tropifexol were less than 0.001 when compared to vehicle or to Compound 2 or tropifexol).

[0312] Improved fibrosis scores were observed in Compound 2 + Tropifexol treated animals compared to vehicle treated animals (Figure 18), and reduced liver fibrosis was observed in Compound 2 + Tropifexol treated animals compared to vehicle treated animals and animals treated with Compound 2 or Tropifexol alone (Figures 19 and 30). Furthermore, improved NAFLD activity scores and steatosis scores were observed in Compound 2 + Tropifexol treated animals compared to vehicle treated animals or compared to treatment with either Compound 2 or Tropifexol alone (Figures 20-21). Similarly, Figures 23-24 show that treatment with a combination of Compound 2 and Tropifexol is effective in reducing liver collagen 1a1 (p-value for the combination of Compound 2 and Tropifexol was less than 0.05 when compared to vehicle or to Compound 2 or Tropifexol) and liver α-SMA levels.

[0313] Synergy analysis showed that the combination of Compound 2 and Tropifexor showed synergistic effects. The ratio of hepatic steatosis to vehicle was determined for the agents alone and in combination (Figure 22). Analysis of log-transformed data showed synergy with a p-value of 0.0004. Similarly, the ratio of hepatic triglycerides to vehicle was determined for the agents alone and in combination (Figure 31). The same analysis of log-transformed data also showed synergy with a p-value of 0.0018. Finally, analysis of the change from baseline in NALFD activity score for the agents alone and in combination using a general linear model (Figure 32) showed synergy with a p-value of 0.0297.

[0314] The combination of Compound 2 and semaglutide reduced plasma total cholesterol in treated animals to a greater extent than Compound 2 or semaglutide alone compared to vehicle (Figure 26). The combination of Compound 2 and semaglutide was also effective in reducing liver triglycerides in treated animals (Figure 27). Furthermore, the combination of Compound 2 and semaglutide was effective in reducing total liver cholesterol (Figure 16), liver hydroxyproline (Figure 28) and total liver lipids (Figure 29). Reduction in liver fibrosis was also observed in Compound 2 + semaglutide treated animals compared to vehicle treated animals. EXAMPLES

[0315] DIO-NASH mice are randomly assigned to treatment groups selected from vehicle, Compound 2 (e.g., 10 mg / kg), Liraglutide (e.g., 0.2 mg / kg), or Compound 2 (e.g., 10 mg / kg) and Liraglutide (e.g., 0.2 mg / kg). Absolute and relative body weights of mice are recorded daily. Mice undergo a 14-day titration period for a total treatment period of 12 weeks. Baseline steatosis score, fibrosis stage, and Col1a1 levels are determined 1 week prior to treatment. Body weights of mice are recorded daily. After 12 weeks of treatment, animals are sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol are measured, a terminal necropsy is performed for each liver, relative liver mass is determined as a percentage of body weight, whole liver biochemistry is assayed including total liver triglycerides and total liver cholesterol, and histological assessments of total liver hydroxyproline, NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, α-SMA, and galactin-3 levels are performed. Tissue samples are preserved for characterization using RNAseq. RNAseq is used to determine expression levels of genes showing differential expression and / or known to be associated with fibrosis in Compound 2 + liraglutide treated animals versus vehicle treated animals. EXAMPLES

[0316] DIO-NASH mice are randomly assigned to treatment groups selected from vehicle, Compound 2 (e.g., 10 mg / kg), dual acting GLP-1 / glucagon agonist, or Compound 2 (e.g., 10 mg / kg) and dual acting GLP-1 / glucagon agonist. Absolute and relative body weights of mice are recorded daily. Mice undergo a 14-day titration period with a total treatment period of 12 weeks. Baseline steatosis score, fibrosis stage, and Col1a1 levels are determined 1 week prior to treatment. Body weights of mice are recorded daily. After 12 weeks of treatment, animals are sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol are measured, a terminal necropsy is performed for each liver, relative liver mass is determined as a percentage of body weight, whole liver biochemistry is assayed including total liver triglycerides and total liver cholesterol, and histological assessments of total liver hydroxyproline, NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, α-SMA, and galactin-3 levels are performed. Tissue samples are preserved for characterization using RNAseq. RNAseq is used to determine expression levels of genes showing differential expression and / or known to be associated with fibrosis in Compound 2 + dual acting GLP-1 / glucagon agonist treated animals versus vehicle treated animals. EXAMPLES

[0317] DIO-NASH mice are randomly assigned to treatment groups selected from vehicle, Compound 2 (e.g., 10 mg / kg), dual acting GLP-1 / GIP agonist, or Compound 2 (e.g., 10 mg / kg) and dual acting GLP-1 / GIP agonist. Absolute and relative body weights of mice are recorded daily. Mice undergo a 14-day titration period for a total treatment period of 12 weeks. Baseline steatosis score, fibrosis stage, and Col1a1 levels are determined 1 week prior to treatment. Body weights of mice are recorded daily. After 12 weeks of treatment, animals are sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol are measured, a terminal necropsy is performed for each liver, relative liver mass is determined as a percentage of body weight, whole liver biochemistry is assayed including total liver triglycerides and total liver cholesterol, and histological assessments of total liver hydroxyproline, NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, α-SMA, and galactin-3 levels are performed. Tissue samples are preserved for characterization using RNAseq. RNAseq is used to determine expression levels of genes showing differential expression and / or known to be associated with fibrosis in Compound 2 + dual acting GLP-1 / GIP agonist treated animals versus vehicle treated animals. EXAMPLES

[0318] DIO-NASH mice are randomly assigned to treatment groups selected from vehicle, Compound 2 (e.g., 10 mg / kg), DGAT inhibitor, or Compound 2 (e.g., 10 mg / kg) and DGAT inhibitor. Absolute and relative body weights of mice are recorded daily. Mice undergo a 14-day titration period for a total treatment period of 12 weeks. Baseline steatosis score, fibrosis stage, and Col1a1 levels are determined 1 week prior to treatment. Body weights of mice are recorded daily. After 12 weeks of treatment, animals are sacrificed. Plasma enzymes (P-ALT (alanine aminotransferase) and P-AST (aspartate aminotransferase)), total plasma triglycerides, and total plasma cholesterol are measured, a terminal necropsy is performed for each liver, relative liver mass is determined as a percentage of body weight, whole liver biochemistry is assayed including total liver triglycerides and total liver cholesterol, and histological assessments of total liver hydroxyproline, NAFLD activity score (performed pre- and post-treatment), fibrosis stage (also performed pre- and post-treatment), steatosis, Col1a1 levels, α-SMA, and galactin-3 levels are performed. Tissue samples are preserved for characterization using RNAseq. RNAseq is used to determine the expression levels of genes showing differential expression in Compound 2 + DGAT inhibitor treated animals versus vehicle treated animals and / or genes known to be associated with fibrosis.

[0319] 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.

[0320] 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."

[0321] 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.

[0322] 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.

[0323] 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 for preventing, treating or ameliorating one or more fatty liver diseases in a subject in need thereof, comprising administering to said subject in need thereof at least one TR-β agonist in combination with one or more second agents.

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