Combination therapy of thyroid hormone receptor agonists and FASN inhibitors

Abstract

This invention provides a therapeutic combination of a fatty acid synthesis modulator and a thyroid hormone receptor agonist. The combination can be used to treat disorders including metabolic disorders and liver damage, such as non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH).

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and interest in U.S. Provisional Application No. 63 / 509,267, filed on 20 June 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] This disclosure generally relates to therapeutic combinations of fatty acid synthase inhibitors and thyroid hormone receptor agonists for the treatment of liver disease. [Background technology]

[0003] Fatty liver disease associated with metabolic dysfunction (MASLD) (formerly known as non-alcoholic liver disease (NAFLD)) is a condition in which the liver contains more than 5% fat by weight, and is not caused by excessive alcohol consumption. It currently affects approximately 20-30% of the population in the United States and the general Western world, and is associated with a significant increase in the incidence of cardiovascular disease (i.e., carotid artery atherosclerosis and endothelial dysfunction), chronic kidney disease, and malignant tumors, not just liver problems. Obesity, type 2 diabetes, and metabolic syndrome are the three major risk factors for NAFLD / MASLD, characterized by an imbalance between energy utilization and storage. This imbalance leads to dysregulation of metabolic pathways and inflammatory responses, which in turn promote further changes leading to liver damage and comorbidities. As metabolic syndrome progresses, NAFLD / MASLD can lead to more advanced liver disease, starting with metabolic dysfunction-associated steatohepatitis (MASH) (formerly known as non-alcoholic steatohepatitis (NASH)), which can then progress to severe cirrhosis and hepatocellular carcinoma.

[0004] In 2023, the World Society for Liver Disease Medicine and patient groups formally decided to rename non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MASLD) and non-alcoholic steatohepatitis (NASH) to metabolic dysfunction-associated fatty liver disease (MASH). Furthermore, the comprehensive term fatty liver disease (SLD) was established to encompass multiple types of liver diseases associated with fat accumulation in the liver.

[0005] Fatty acid synthesis in the liver, through a pathway called de novo lipogenesis (DNL), is increased in individuals with metabolic syndrome and NAFLD / MASLD (Donnelly, KL, et al., “Sources of Fatty Acids Stored in Liver and Secreted via Lipoproteins in Patients with Nonalcoholic Fatty Liver Disease,” J. Clin. Invest. 115(5). 2005, 1343-51; Lambert, JE, et al., “Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals with Nonalcoholic Fatty Liver Disease,” Gastroenterology 146(3). 2014, 726-35). The DNL pathway not only produces fatty acids that contribute to increased triglyceride storage in the liver, but the fatty acids produced are saturated fatty acids, mainly palmitic acid, which contribute to signaling events that increase liver inflammation (Wei, Y., “Saturated Fatty Acids Induce Endoplasmic Reticulum Stress and Apoptosis Independently of Ceramide in Liver Cells,” Am.J.Physio.Endocrinol.Metab.291(2):2006,E275-81; Kakazu, E., et al., “Hepatocytes Release Ceramide-rich Proinflammatory Extracellular Vesicles in an IRE1alpha dependent manner,”Abstract 58.AASLD-The Liver Meeting, San Francisco, CA, USA, 13-17, November, 2015). One of the important enzymes in the DNL pathway is fatty acid synthase (FASN), which is solely responsible for the synthesis of palmitic acid.Therefore, DNL is an important pathway for therapeutic interventions to mitigate outcomes associated with metabolic syndrome and NAFLD / MASLD.

[0006] FASN inhibition holds potential as a treatment for a wide range of diseases, including cancer, viral diseases, metabolic disorders, NAFLD / MASLD, NASH / MASH, and inflammatory diseases (i.e., rheumatoid arthritis, gout, pulmonary fibrosis, COPD, IBD, and graft rejection). Furthermore, FASN inhibition may offer therapeutic effects in cardiovascular diseases, atherosclerosis, type II diabetes, and metabolic syndrome. Effective treatments for these diseases remain a significant unmet need.

[0007] FASN inhibition not only reduces hepatic fat but also acts directly on immune cells and hepatic stellate cells to alleviate inflammation and fibrosis. Heterocyclic FASN inhibitors are described in WO2012 / 122391, WO2014 / 008197, and WO2015 / 105860, and the use of some of the FASN inhibitors referenced above for the treatment of NAFLD / MASLD and NASH / MASH is described in WO2018 / 089904. The contents of the disclosures referenced above are incorporated herein by reference. Denifanstat (TVB-2640), one of the compounds described in the above referenced applications, is the first class of FASN inhibitors to demonstrate improvement in hepatic fat and biomarkers associated with inflammation and fibrosis in NASH / MASH studies.

[0008] Thyroid hormone receptor beta (THRβ) agonists reduce hepatic steatosis by increasing lipid oxidation, and the THRβ agonist resmethirome recently demonstrated significant resolution of NASH / MASH and improvement of fibrosis in a Phase III clinical trial and is approved for the treatment of non-cirrhotic NASH / MASH. While promising, the efficacy of the THRβ agonist resmethirome has not reached a histological response rate of 50%.

[0009] In fatty liver diseases such as NASH / MASH and NAFLD / MASLD, a combination of FASN inhibitors and other drugs, such as THRβ agonists, is necessary to complement and enhance the activity of FASN inhibitors. Furthermore, in fatty liver diseases such as NASH / MASH and NAFLD / MASLD, a combination of THRβ agonists and other drugs, such as FASN inhibitors, is necessary to complement and enhance the activity of THRβ agonists. [Overview of the project]

[0010] This disclosure addresses shortcomings in the treatment of metabolic diseases by providing novel therapeutic combinations of heterocyclic modulators of lipid synthesis and thyroid hormone receptor agonists. This provides multifaceted treatment for metabolic diseases with complex pathophysiologies. FASN inhibitors directly target inflammation (e.g., immune cells) and fibrosis (e.g., hepatic stellate cells), and indirectly target hepatic steatosis by inhibiting novel lipid synthesis. THR-β agonists may indirectly alleviate inflammation and fibrosis by reducing the effects of hepatic steatosis by increasing the breakdown of hepatic steatosis and / or beta-oxidation of fatty acids.

[0011] These different mechanisms can be additive or synergistic, potentially broadening or deepening the effectiveness response rate.

[0012] In a first aspect, the disclosure relates to a method for treating a disease (e.g., fatty liver disease, e.g., NAFLD / MASLD or NASH / MASH) to a subject in need of treatment for the disease, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor (THR) agonist (e.g., a thyroid hormone receptor-beta (THR-β) agonist).

[0013] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (IX-1): [ka] a compound, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, -CN, halogen, C1-C4 straight or branched alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 straight or branched alkyl), wherein, when R 1 is not H, -CN or halogen, it may be substituted with one or more halogens, each R 2 is independently H, halogen, or C1-C4 straight or branched alkyl, R 3 is H, -OH, or halogen, R 21 is H, halogen, C1-C4 straight or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl may contain an oxygen or nitrogen heteroatom, R 22 is H, halogen, or C1-C2 alkyl, R 24 is H, C1-C4 straight or branched alkyl, -(C1-C4 alkyl) t -OH, -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl), or -(C1-C4 alkyl) t -O-(C1-C4 straight or branched alkyl), wherein t is 0 or 1, the C3-C5 cycloalkyl may contain an oxygen or nitrogen heteroatom, L 1 is N, and L 2 is N.

[0014] In some embodiments of formula (IX-1), R 1 is H, -CN, halogen, or C1-C4 straight or branched alkyl, each R 2 is independently H, R 3 is H or halogen, R 21R is a C1-C4 linear or branched alkyl or a C3-C5 cycloalkyl, 22 is H or C1-C2 alkyl, and R 24 It is either H or a C1-C4 linear or branched alkyl group.

[0015] In some embodiments of equation (IX-1), R 1 is -CN, and each R 2 H is independent of R 3 H is R 21 It is a C3-C5 cycloalkyl group, and R 22 is H or C1-C2 alkyl, and R 24 These are C1-C4 linear or branched alkyl groups.

[0016] In some embodiments, the compound of formula (IX-1) has the following structure: [ka]

[0017] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XII-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently H, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 haloalkyl, -(C1~C4 alkyl)-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, Each R 241 These are independently H or C1-C2 alkyl, and R 25 These are halogens, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, C1-C4 haloalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), or cyclopropyl.

[0018] In some embodiments of equation (XII-1), L-Ar is [ka] And Ar is, [ka] And R 1 is H, -CN, halogen, or C1-C4 alkyl, and each R 2 H is independent of R 3 is H or F, and R 21 is H, halogen, or C1-C4 alkyl, and R 22 is H, halogen, or C1-C2 alkyl, and R 24 These are C1-C4 alkyl, C1-C4 haloalkyl, and -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), R 25 These are C1-C2 alkyl, C1-C4 haloalkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0019] In some embodiments of equation (XII-1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, and each R 2 H is independent of R 3 H is R 21 It is a C1-C4 alkyl group, and R 22 is H or C1-C2 alkyl, and R 24 This is a C1-C4 haloalkyl or -(C1-C4 alkyl) t -O u -(4-6 member complex ring), R 25 It is -(C1~C4 alkyl)-O-(C1~C4 alkyl).

[0020] In some embodiments, the compound of formula (XII-1) has the following structure: [ka]

[0021] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XIII-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 These are independently H, halogen, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, and -(C1~C4 alkyl)-N(R) 241 )2, -(C1~C4 alkyl) t -O u-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 membered heterocycle) or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl groups.

[0022] In some embodiments of equation (XIII-1), L-Ar is [ka] And Ar is, [ka] And R 1 is H, -CN, halogen, or C1-C4 alkyl, and each R 2 H is independent of R 3 is H or F, and R 21 is H, halogen, or C1-C4 alkyl, and R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 Each is independently a halogen, a C1-C4 alkyl, or -(C1-C4 alkyl) t It is -O-(C1~C4 alkyl).

[0023] In some embodiments of equation (XIII--1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, and each R 2 H is independent of R 3 H is R21 is C1-C4 alkyl, R 22 is H or C1-C2 alkyl, R 24 and R 25 are each independently halogen, C1-C4 alkyl, or -(C1-C4 alkyl) t -O-(C1-C4 alkyl).

[0024] In some embodiments, the compound of formula (XIII-1) has the following structure:

Chemical formula

[0025] In some embodiments, the fatty acid synthase inhibitor is of formula (XX-1):

Chemical formula

Chemical formula

Chemical formula

[0026] In some embodiments of formula (XX-1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, or -O-(C1~C4 alkyl) which may be substituted with one or more halogens, and each R 2 H is independent of R 3 is H or F, and R 21 is H or C1-C4 alkyl, and R 22 is H or C1-C2 alkyl, and R 24 R is -O-(C1~C4 alkyl), -O-(C1~C4 alkyl)-O-(C1~C4 alkyl), or -O-(4~6 member heterocycle), where R 24 R may be substituted with one or more hydroxyls or halogens, 25 This is H, a halogen, or a C1-C4 alkyl group.

[0027] In some embodiments of formula (XX-1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, or -O-(C1~C4 alkyl) which may be substituted with one or more halogens, and each R 2 H is independent of R 3 is H or F, and R 21 is H or C1-C4 alkyl, and R 22 is H or C1-C2 alkyl, and R 24 R is a -O-(C1~C4 alkyl) which may be substituted with one or more hydroxyls or halogens, 25 These are C1-C4 alkyl groups.

[0028] In some embodiments, the compound of formula (XX-1) has one of the following structures: [ka]

[0029] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (IX-1), (XII-1), (XIII-1), or (XX-1), or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152, 002-386, 002-242, 005-2, and 005-5, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152 and 005-2, or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the fatty acid synthase inhibitor is a compound selected from Table C-1, or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the fatty acid synthase inhibitor is a compound selected from Table C-2, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the fatty acid synthase inhibitor is a compound selected from Table C-3, or a pharmaceutically acceptable salt thereof.

[0035] In various embodiments, the Disclosure provides pharmaceutical compositions comprising one of the compounds disclosed herein and a pharmaceutically acceptable carrier, excipient, or diluent thereof.

[0036] In some embodiments, the thyroid hormone receptor agonist is expressed by formula (XXI): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, A A These are O, CH2, S, SO, or SO2. X A and Y A Each of these is independently selected from the group consisting of Br, Cl, and CH3. R 1A is, -(CH2) n COOH, -OCH2COOH, -NHC(=O)COOH, -NHCH2COOH, [ka] Selected from the group consisting of, Z A is H, or -C≡N, R 2A It is a lower alkyl having 1 to 4 C atoms, R 3 is H or a lower alkyl group. n is either 1 or 2. p is either 1 or 2.

[0037] In some embodiments, the thyroid hormone receptor agonist is expressed by formula (XXI-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 3A is H or CH2R 3B And, R 3B These are hydroxyl, O-linked amino acids, -OP(O)(OH)2, or -OC(O)R 3C And here, R 3C This includes lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or -(CH2) n -It is a heteroaryl, where n is 0 or 1. R 4A H is R 5A is either CH2COOH, C(O)CO2H, or its ester or amide, or R 4A and R 5 Together, -N=C(R 4B )-C(O)-NH-C(O)-, where R 4B is either H or cyano.

[0038] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] Compound A contains [compound A]. Compound A is also known as MGL-3196 or resmethilone and is marketed as Rezdifra® for the treatment of non-cirrhotic NASH.

[0039] In some embodiments of the combinations and methods of this disclosure, the fatty acid synthase inhibitor is (a) Formula (IX) [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are H, halogens, C1-C4 linear or branched alkyl groups, and C3-C5 cycloalkyl groups, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -OH, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), or -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. L 1 CR 23 or N; L 2 is CH or N, L 1 or L 2 At least one of them is N, and R 23 is H or a C1-C4 linear or branched alkyl, or (b) Formula (X): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, L 3 C(R 60 )2, O, or NR 50 And, Each R 60 These are independently H, -OH, -CN, and -O t -(C3-C5 cycloalkyl), -O-(C1-C4 linear or branched alkyl), or -C(O)-N(R 601 )2, and here, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. Each R 50 These are independently H, -C(O)-O t -(C1-C4 linear or branched alkyl), -C(O)-O t -(C3-C5 cyclic alkyl), C3-C5 cyclic alkyl which may contain an oxygen or nitrogen heteroatom, -C(O)-N(R 501 )2, C1-C4 linear or branched alkyl, where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. n is 1, 2, or 3. m is either 1 or 2. R 21 These are H, halogens, C1-C4 linear or branched alkyl groups, and C3-C5 cycloalkyl groups, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 These are H, halogen, and C1-C2 alkyl. Each R 26 These are independently -OH, -CN, halogen, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), -C(O)-O t -(C1~C4 alkyl), or -C(O)-N(R 501 )2, and here, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. s is 0, 1, or 2. R 601 and R 501 Each of these is independently H, or a C1-C4 linear or branched alkyl group. Here, R 26 , R 60 , R 50 , R 501 , and R 601 Two of these may be arbitrarily bonded to form a ring, where R 26 , R 60 , R 50 , R 501 , and R 601 Two of them are two R 26 , two R 60 , two R 50 , two R 501 , or two R's 601It may be so, or (c) Formula (VI-J) [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R 22 is H, halogen, or C1-C2 alkyl, R 35 is -C(O)-R 351 -C(O)-NHR 351 , -C(O)-OR 351 , or S(O)2R 351 And, R 351 is a C1-C6 linear or branched alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group, or (d) Equation (XII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, However, if u is 1, then t is 1, Each R 241 These are independently H or C1-C2 alkyl, and R 25These are halogens, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl or cyclopropyl, or (e) Formula (XIII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 These are independently H, halogen, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, and -(C1~C4 alkyl)-N(R) 241 )2, -(C1~C4 alkyl) t -Ou -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl, or (f) Formula (XIV): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 H, C1-C4 alkyl, -(C1-C4 alkyl)-OH, -(C1-C4 alkyl) t --N(R 241 )2, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O t -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl, or (g) Formula (XV): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L 3 -CH2-, -CHR 50 -, -O-, -NR 50 -, -NC(O)R 50 -, or -NC(O)OR 50 -and here, R 50 These are C1-C6 alkyl, C3-C5 cycloalkyl, or 4-6 membered heterocycles. n is 1, 2, or 3. m is either 1 or 2, where n+m≧3. L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, or, (h) Formula (XVI): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 Each of these is independently H, -C1~C4 alkyl, or halogen, or (i) Formula (XVII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 These are H, C1-C4 alkyl, -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, However, if u is 1, then t is 1, R 241 is H or C1-C6 alkyl, or (j) Formula (XVIII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, L 2 -NHR 35 or -C(O)NHR 351 And here, R 351 These are C1-C6 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl compounds. Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 member heterocycle), -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 35 is -C(O)R 351 -C(O)NHR 351 , C(O)OR 351 , or S(O)2R 351 And here, R 351 These are C1-C6 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl compounds, or (k) Formula (XIX): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, W, X, Y, and Z are each independently -N- or -CR 26 -, provided that two or fewer of W, X, Y, and Z are -N-, Each R 26 These are independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), and -N(R 27 )2, -S(O)2-(C1~C4 alkyl), or -C(O)-(C1~C4 alkyl), Each R 27 These are independently H or C1-C4 alkyl, or both R 27 These are C1-C4 alkyl groups, and together with the N atoms to which they are bonded, they form a 3-6 membered ring, where the ring may contain one oxygen atom as a member of the ring. Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 member heterocycle), -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, or, (l) Formula (XX): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24R is -O-(C1~C4 alkyl), -O-(C1~C4 alkyl)-O-(C1~C4 alkyl), -O-(C3~C5 cycloalkyl), or -O-(4~6 membered heterocycle), where R 24 It may be substituted with one or more hydroxyls or halogens, R 25 R is H, halogen, C1-C4 alkyl, or C3-C5 cycloalkyl, where R 25 may be substituted with one or more halogens, or (m) Formula (XI): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R 22 These are H, halogen, C1-C2 alkyl, and R 351 These are C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

[0040] In various embodiments, the Disclosure relates to a method for treating fatty liver disease in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for fatty liver disease. For example, in some embodiments, the Disclosure relates to a method for treating fatty liver disease in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for fatty liver disease. In some embodiments, the Disclosure relates to a method for treating fatty liver disease in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to a subject requiring treatment for fatty liver disease, wherein the fatty acid synthase inhibitor is [ka] Therefore, thyroid hormone receptor agonists are [ka] That is the case.

[0041] In various embodiments, the Disclosure relates to a method for treating non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in subjects requiring treatment of NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to subjects requiring treatment of NASH / MASH. For example, in some embodiments, the Disclosure relates to a method for treating non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in a subject requiring treatment for NASH / MASH, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for NASH / MASH. In some embodiments, the present disclosure relates to a method for treating non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in a subject requiring treatment for NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0042] In various embodiments, the Disclosure relates to a method for treating non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD) in subjects requiring treatment of NAFLD / MASLD, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to subjects requiring treatment of NAFLD / MASLD. For example, in some embodiments, the present disclosure relates to a method for treating non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD) in a subject requiring treatment for NAFLD / MASLD, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for NAFLD / MASLD. In some embodiments, the present disclosure relates to a method for treating non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD) in a subject requiring treatment for NAFLD / MASLD, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0043] In various embodiments, the Disclosure relates to a method for treating metabolic syndromes in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for metabolic syndromes. For example, in some embodiments, the Disclosure relates to a method for treating metabolic syndromes in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for metabolic syndromes. In some embodiments, the Disclosure relates to a method for treating metabolic syndromes in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to a subject requiring treatment for metabolic syndromes, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0044] In various embodiments, the Disclosure relates to a method for treating type II diabetes in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for type II diabetes. For example, in some embodiments, the Disclosure relates to a method for treating type II diabetes in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for type II diabetes. In some embodiments, the present disclosure relates to a method for treating type II diabetes in a subject requiring treatment for type II diabetes, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0045] In various embodiments, the Disclosure relates to a method for treating atherosclerosis in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for atherosclerosis. For example, in some embodiments, the Disclosure relates to a method for treating atherosclerosis in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for atherosclerosis. In some embodiments, the present disclosure relates to a method for treating atherosclerosis in a subject requiring treatment for atherosclerosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0046] In various embodiments, the Disclosure relates to a method for treating cirrhosis in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for cirrhosis. For example, in some embodiments, the Disclosure relates to a method for treating cirrhosis in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for cirrhosis. In some embodiments, the present disclosure relates to a method for treating cirrhosis in a subject requiring treatment for cirrhosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0047] In various embodiments, the Disclosure relates to a method for treating hepatic fibrosis in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for hepatic fibrosis. For example, in some embodiments, the Disclosure relates to a method for treating hepatic fibrosis in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for hepatic fibrosis. In some embodiments, the present disclosure relates to a method for treating hepatic fibrosis in a subject requiring treatment for hepatic fibrosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0048] In various embodiments, the Disclosure relates to a method for treating liver cancer in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject in need of treatment for liver cancer. For example, in some embodiments, the Disclosure relates to a method for treating liver cancer in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject in need of treatment for liver cancer. In some embodiments, the Disclosure relates to a method for treating liver cancer in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to a subject in need of treatment for liver cancer, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0049] In various embodiments, the Disclosure relates to a method for treating liver cancer in a subject requiring treatment for liver cancer arising from NAFLD / MASLD or NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to the subject. For example, in some embodiments, the Disclosure relates to a method for treating liver cancer in a subject requiring treatment for liver cancer arising from NAFLD / MASLD or NASH / MASH, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to the subject. In some embodiments, the present disclosure relates to a method for treating liver cancer in a subject requiring treatment for liver cancer arising from NAFLD / MASLD or NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0050] In various embodiments, the Disclosure relates to a method for treating hepatocellular carcinoma in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject in need of treatment for hepatocellular carcinoma. For example, in some embodiments, the Disclosure relates to a method for treating hepatocellular carcinoma in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject in need of treatment for hepatocellular carcinoma. In some embodiments, the present disclosure relates to a method for treating hepatocellular carcinoma in a subject requiring treatment for hepatocellular carcinoma, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0051] In various embodiments, the Disclosure relates to a method for treating hepatocellular carcinoma in a subject requiring treatment for hepatocellular carcinoma arising from NAFLD / MASLD or NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to the subject. For example, in some embodiments, the Disclosure relates to a method for treating hepatocellular carcinoma in a subject requiring treatment for hepatocellular carcinoma arising from NAFLD / MASLD or NASH / MASH, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to the subject requiring treatment for hepatocellular carcinoma arising from NAFLD / MASLD or NASH / MASH. In some embodiments, the present disclosure relates to a method for treating hepatocellular carcinoma in a subject requiring treatment for hepatocellular carcinoma arising from NAFLD / MASLD or NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0052] In various embodiments, the Disclosure relates to a method for treating cholangiocarcinoma in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject in need of treatment for cholangiocarcinoma. For example, in some embodiments, the Disclosure relates to a method for treating cholangiocarcinoma in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject in need of treatment for cholangiocarcinoma. In some embodiments, the present disclosure relates to a method for treating cholangiocarcinoma in a subject requiring treatment for cholangiocarcinoma, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0053] In various embodiments, the Disclosure relates to a method for treating a disease or condition in a subject requiring treatment for a disease or condition in which interleukin-1 beta (IL1β) levels are elevated, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to the subject. For example, in some embodiments, the Disclosure relates to a method for treating a disease or condition in a subject requiring treatment for a disease or condition in which interleukin-1 beta (IL1β) levels are elevated, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to the subject requiring treatment for a disease or condition in which interleukin-1 beta (IL1β) levels are elevated. In some embodiments, the present disclosure relates to a method for treating a disease or condition in a subject requiring treatment of a disease or condition in which interleukin-1 beta (IL1β) levels are elevated, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0054] In various embodiments, the Disclosure relates to a method for treating a disease or condition in a subject that requires treatment of a disease or condition regulated by interleukin-1 beta (IL1β), comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to the subject. For example, in some embodiments, the Disclosure relates to a method for treating a disease or condition in a subject that requires treatment of a disease or condition regulated by interleukin-1 beta (IL1β), comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to the subject. In some embodiments, the present disclosure relates to a method for treating a disease or condition in a subject requiring treatment of a disease or condition regulated by interleukin-1 beta (IL1β), comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0055] In various embodiments, the Disclosure relates to a method for treating a disease or condition in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for a disease or condition in which T helper (Th) cell levels are elevated. For example, in some embodiments, the Disclosure relates to a method for treating a disease or condition in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for a disease or condition in which T helper (Th) cell levels are elevated. In some embodiments, the present disclosure relates to a method for treating a disease or condition in a subject requiring treatment of a disease or condition in which T helper (Th) cell levels are elevated, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0056] In various aspects, this disclosure relates to regulatory T cells (T reg The present disclosure relates to a method for treating a disease or condition in a subject that requires treatment for a disease or condition in which regulatory T cells (T) are reduced or suppressed, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist). For example, in some embodiments, the present disclosure relates to a method for treating a disease or condition in a subject that requires treatment for a disease or condition in which regulatory T cells (T) are reduced or suppressed, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist). reg The present disclosure relates to a method for treating a disease or condition in a subject requiring treatment of a disease or condition in which regulatory T cells (T) are reduced or suppressed, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI). In some embodiments, the present disclosure relates to a method for treating a disease or condition in a subject requiring treatment of a disease or condition in which regulatory T cells (T) are reduced or suppressed, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI). regThe present invention relates to a method for treating a disease or condition in a subject that requires treatment for a disease or condition in which ) is reduced or suppressed, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0057] In various embodiments, the Disclosure relates to a method for improving established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in subjects requiring improvement of established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH), comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist). For example, in some embodiments, the Disclosure relates to a method for improving established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in subjects requiring improvement of established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH), comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI). In some embodiments, the present disclosure relates to a method for improving established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in subjects requiring improvement of established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH), wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0058] In various embodiments, the Disclosure relates to a method for reducing the expression of fibrosis-related genes in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring a reduction in the expression of fibrosis-related genes. For example, in some embodiments, the Disclosure relates to a method for reducing the expression of fibrosis-related genes in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring a reduction in the expression of fibrosis-related genes. In some embodiments, the present disclosure relates to a method for reducing the expression of fibrosis-related genes in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0059] In various embodiments, the Disclosure relates to a method for treating hepatic fibrosis in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for hepatic fibrosis. For example, in some embodiments, the Disclosure relates to a method for treating hepatic fibrosis in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for hepatic fibrosis. In some embodiments, the present disclosure relates to a method for treating hepatic fibrosis in a subject requiring treatment for hepatic fibrosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0060] In various embodiments, the Disclosure relates to a method for treating dermatofibrosis in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for dermatofibrosis. For example, in some embodiments, the Disclosure relates to a method for treating dermatofibrosis in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for dermatofibrosis. In some embodiments, the present disclosure relates to a method for treating dermatofibrosis in a subject requiring treatment of dermatofibrosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0061] In various embodiments, the Disclosure relates to a method for treating pulmonary fibrosis in a subject, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist) to a subject requiring treatment for pulmonary fibrosis. For example, in some embodiments, the Disclosure relates to a method for treating pulmonary fibrosis in a subject, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI) to a subject requiring treatment for pulmonary fibrosis. In some embodiments, the present disclosure relates to a method for treating pulmonary fibrosis in a subject requiring treatment for pulmonary fibrosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist to the subject, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0062] In various embodiments, the Disclosure relates to methods for reducing triglycerides in subjects requiring triglyceride reduction, such as in severe hypertriglyceridemia (sHTG), comprising administering fatty acid synthase inhibitors and thyroid hormone receptor agonists (e.g., thyroid hormone receptor-beta agonists). For example, in some embodiments, the Disclosure relates to methods for reducing triglycerides in subjects requiring triglyceride reduction, comprising administering fatty acid synthase inhibitors of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and thyroid hormone receptor agonists of formula (XXI). In some embodiments, the present disclosure relates to a method for reducing triglycerides in subjects requiring triglyceride reduction, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0063] In various embodiments, the Disclosure relates to a method for improving or restoring liver function in subjects requiring improvement or restoration of liver function, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist). For example, in some embodiments, the Disclosure relates to a method for improving or restoring liver function in subjects requiring improvement or restoration of liver function, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI). In some embodiments, the Disclosure relates to a method for improving or restoring liver function in subjects requiring improvement or restoration of liver function, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0064] In various embodiments, the Disclosure relates to a method for treating moderate to severe fibrosis-associated NASH / MASH in subjects requiring treatment of moderate to severe fibrosis-associated NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-beta agonist). For example, in some embodiments, the Disclosure relates to a method for treating moderate to severe fibrosis-associated NASH / MASH in subjects requiring treatment of moderate to severe fibrosis-associated NASH / MASH, comprising administering a fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI), and a thyroid hormone receptor agonist of formula (XXI). In some embodiments, the present disclosure relates to a method for treating moderate to severe fibrosis-associated NASH / MASH in subjects requiring treatment of moderate to severe fibrosis-associated NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist, wherein the fatty acid synthase inhibitor is compound 001-152 and the thyroid hormone receptor agonist is compound A.

[0065] In various embodiments, the disclosure further relates to pharmaceutical formulations comprising a FASN inhibitor or a pharmaceutically acceptable salt thereof and a thyroid hormone receptor agonist or a pharmaceutically acceptable salt thereof.

[0066] In another embodiment, the disclosure further relates to a pharmaceutical formulation comprising compound 001-152 or a pharmaceutically acceptable salt thereof and compound A or a pharmaceutically acceptable salt thereof.

[0067] In various other embodiments, the disclosure further relates to pharmaceutical formulations comprising compound 001-152 or pharmaceutically acceptable salts thereof, and form A of compound A.

[0068] In various other embodiments, the Disclosure relates to a method for treating the diseases and / or disorders described herein, comprising administering compound 001-152 or a pharmaceutically acceptable salt thereof and form A of compound A.

[0069] In various other embodiments, the Disclosure relates to a method for treating the diseases and / or disorders described herein, comprising administering a pharmaceutical formulation comprising compound 001-152 or a pharmaceutically acceptable salt thereof and form A of compound A.

[0070] In various aspects, this disclosure relates to fatty liver disease, non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH), non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NAFLD / MASLD), cirrhosis, hepatic fibrosis, liver cancer (e.g., liver cancer arising from NAFLD / MASLD or NASH / MASH), cholangiocarcinoma, or hepatocellular carcinoma (e.g., hepatocellular carcinoma arising from NAFLD / MASLD or NASH / MASH). With respect to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of drugs for the treatment of or for the improvement or restoration of liver function, the drugs are administered in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor beta-agonist, e.g., a compound of formula (XXI)).

[0071] In various aspects, this disclosure relates to diseases or conditions characterized by elevated interleukin-1 beta (IL1β) levels, diseases or conditions regulated by interleukin-1 beta (IL1β), diseases or conditions characterized by elevated T helper (Th) cell levels, or regulatory T cells (T regWith respect to fatty acid synthase inhibitors of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of a drug for the treatment of a disease or condition in which ) is reduced or suppressed, the drug is administered in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor beta-agonist, e.g., a compound of formula (XXI)).

[0072] In various embodiments, the present disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of a drug for improving established non-alcoholic steatohepatitis (NASH / MASH), wherein the drug is administered in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor beta-agonist, e.g., a compound of formula (XXI)).

[0073] In various embodiments, the present disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for the treatment of metabolic syndromes, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)).

[0074] In various embodiments, the present disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for the treatment of type II diabetes, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)).

[0075] In various embodiments, the present disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for the treatment of atherosclerosis, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)).

[0076] In various embodiments, the disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for reducing the expression of fibrosis-related genes, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)).

[0077] In various embodiments, the present disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for the treatment of hepatic fibrosis, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)).

[0078] In various embodiments, the disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for improving or restoring liver function, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)).

[0079] In various embodiments, the present disclosure relates to fatty acid synthase inhibitors of the structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for the treatment of NASH / MASH with moderate to severe fibrosis, wherein the agents are administered in combination with a THR β-agonist (e.g., a compound of formula (XXI)). In various embodiments, the Disclosure relates to fatty acid synthase inhibitors of structures (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) in the manufacture of agents for the treatment of dermatofibrosis or pulmonary fibrosis, wherein the agents are administered in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor beta-agonist, e.g., a compound of formula (XXI)).

[0080] In any of the embodiments and examples described above, the fatty acid synthase inhibitor of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) is a compound selected from Tables C-1 to C-3. [Brief explanation of the drawing]

[0081] [Figure 1A]This graph shows the effects of compounds 001-152 and A in a human liver microtissue model under de novo lipid production (DNL) conditions, as measured by tissue triglyceride content. Monotherapy with compound 001-152 (30 nM and 3 μM) reduces cellular triglycerides in vitro in the human liver microtissue model. The combination of compound 001-152 and compound A enhances the effect of compound A, resulting in an overall increased efficacy compared to the monotherapy. This liver microtissue model includes hepatocytes, Kupffer cells, and liver endothelial cells. Liver microtissues were treated for 7 days. To model increased lipid accumulation within hepatocytes, microtissues were treated with sugars and free fatty acids (FFA). Graphs show mean ± standard deviation (SD). A two-sided t-test with Welsh correction *p<0.05 was used. [Figure 1B] This graph shows the effects of compounds 001-152 and A on a human liver microtissue model under NASH conditions, as measured by tissue triglyceride content. The model includes stellate cells and incorporates pro-inflammatory stimulation with lipopolysaccharide (LPS). The liver microtissue model includes hepatocytes, hepatic endothelial cells, and hepatic stellate cells. Liver microtissues were treated for 10 days. Microtissues were treated with sugar, free fatty acids (FFA), and lipopolysaccharide (LPS) to model increased lipid accumulation in hepatocytes, inflammation, and fibrosis processes. Graphs show mean ± standard deviation (SD). A two-tailed t-test with Welsh correction *p<0.05 was used. [Figure 1C] This is a diagram showing the test timeline. [Figure 2]A is a graph showing NASH-induced intracellular triglyceride levels after administration of compound 001-152 as a monotherapy and in combination with other agents containing compound A. The graph shows that compound 001-152 monotherapy reduces cellular triglycerides in a human liver microtissue model. Other agents developed for NASH did not reduce triglycerides as effectively (see spotted bars). Compound 001-152 in combination with those agents (gray and black bars) reduced triglycerides more effectively. The combination of compound 001-152 with compound A (resmethirome or MGL-3196) reduced TG content to below basal levels. The graph shows median and interquartile ranges. B is a diagram showing the study timeline. [Figure 3] This table shows that, in a human liver microtissue model, the combination demonstrated improved and / or more consistent reductions in inflammatory markers MIP1a, IL-8, and TNFa (columns 7, 8), as well as IP10 (columns 5, 6), compared to monotherapy (compound A in columns 1 and 2, compounds 001-152 in columns 3 and 4). The combination also showed improved reduction in the fibrosis marker collagen 1 (columns 7 and 8) compared to monotherapy. These results suggest that the combination of compound 001-152 and compound A has the potential to improve the efficacy of the inflammatory and fibrotic pathways beyond the effects observed with monotherapy. In the table, "MGL" represents compound A, "U" represents an increased magnification change in NASH inflammation or fibrosis markers, and "D" represents a decreased magnification change in NASH inflammation or fibrosis markers. The magnitude of the effect is reflected in the grayscale tone of the field, with darker gray representing a more pronounced effect. Black fields indicate that data were not collected. [Figure 4A] This is a schematic diagram showing the test design. [Figure 4B]This graph shows the effect of the combination of compounds 001-152 and compound A on collagen 1α1 in human liver slices cultured under conditions mimicking human NASH. The graph demonstrates that the combination of compounds 001-152 and compound A improved the suppression of collagen 1α1, a fibrosis marker, compared to the single agents (see time points T72 and later). [Figure 5] This graph shows the effects of compounds 001-152 and A on collagen production in human primary hepatic stellate cells stimulated with 10 ng / ml TGF-beta over a 4-day treatment period. Compounds 001-152 directly inhibit collagen production (other cell types are not present in this model). * indicates p<0.05 compared to the vehicle control. [Figure 6] This is an X-ray powder diffraction (XRPD) map of compound A in form A. [Figure 7] This is the X-ray powder diffraction (XRPD) pattern of compound A in its anhydrous crystalline form (form A). [Figure 8] This is a differential scanning calorimetry (DSC) diagram of compound A in form A. [Figure 9] This is the XRPD pattern of the methyl isobutyl ketone (MIBK) solvate (form G) of compound A. [Figure 10] This is the XRPD pattern of the dimethylacetamide solvate (form K) of compound A. [Figure 11]Figure A shows the time course of plasma ALT in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast food diet (FFD) for 18 weeks to induce MASH features. The numerical values ​​represent the data mean + SD, and there are significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combinations n=14-15 (Example 11). Figure B shows the change in plasma ALT on day 28 of treatment in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast food diet (FFD) for 18 weeks to induce MASH features. The numerical values ​​represent the data mean + SD, and there are significant differences of *p<0.05, and ***p<0.001 compared to the FFD vehicle. Treatment group: Control normal feed n=8; Vehicle, TVB-3664, MGL-3196, combinations n=14-15 (Example 11). [Figure 12] Figure A shows the time course of plasma AST in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast food diet (FFD) for 18 weeks to induce MASH features. The numbers represent the data mean + SD, and there are significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combinations n=14-15 (Example 11). Figure B shows the change in plasma AST on day 28 of treatment in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast food diet (FFD) for 18 weeks to induce MASH features. The numbers represent the data mean + SD, and there are significant differences of *p<0.05 and ***p<0.001 compared to the FFD vehicle. Treatment group: Control normal feed n=8; Vehicle, TVB-3664, MGL-3196, combinations n=14-15 (Example 11). [Figure 13]This figure shows the time course of plasma triglycerides in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH characteristics. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combinations n=14-15 (Example 11). [Figure 14] This figure shows the time course of plasma cholesterol in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH characteristics. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combinations n=14-15 (Example 11). [Figure 15] This figure shows the changes in plasma lipoproteins in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH features. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combination n=14-15; for reference, lipoprotein profiles at the start of treatment for the FFD vehicle group are included (Example 11). [Figure 16]This figure shows changes in liver collagen in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH features. The data shown are after 10 weeks of treatment. Numerical values ​​represent the mean + SD of the data, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combination n=14-15; for reference, liver collagen profiles at the start of treatment for the FFD vehicle group are included (Example 11). [Figure 17] This figure shows the changes in total fatty liver by histopathological examination in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH characteristics. The data shown are from 10 weeks after treatment. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combination n=14-15; for reference, fatty liver profiles at the start of treatment for the FFD vehicle group are included (Example 11). The inset is an exemplary slide showing the differences between lean controls and MASH slides visualized in the experiment. [Figure 18]This figure shows the changes in microvesicular and macrovesicular fatty liver by histopathological examination in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH features. The data shown are from 10 weeks after treatment. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combination n=14-15; for reference, microvesicular and macrovesicular fatty liver profiles at the start of treatment in the FFD vehicle group are included (Example 11). The inset is an exemplary slide showing the differences between lean controls visualized in the experiment and MASH slides with microvesicular and macrovesicular fatty liver. [Figure 19] This figure shows the changes in inflammation as measured by histopathological examination in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH features. The data shown are from 10 weeks after treatment. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combination n=14-15; for reference, the inflammation profile at the start of treatment for the FFD vehicle group is included (Example 11). The inset is an exemplary slide showing the visualization of inflammation. [Figure 20]This figure shows the changes in abnormally enlarged hepatocytes (percentage of enlargement relative to surface area) as determined by histopathological examination in male LDL receptor knockout (Ldlr- / -) mice after being fed a fast-food diet (FFD) for 18 weeks to induce MASH characteristics. The data shown are from after 10 weeks of treatment. Numerical values ​​represent the data mean + SD, with significant differences of *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD vehicle. Treatment groups: control normal diet n=8; vehicle, TVB-3664, MGL-3196, combination n=14-15; for reference, the baseline profile of the FFD vehicle group is included (Example 11). [Figure 21] This figure shows the liver lipid levels at 6 weeks in a DIO (diet-induced obesity) MASH Gubra mouse model (Example 12). The groups are NC (normal diet control), VEH (MASH vehicle control), FASN (TVB-3664, a FASN inhibitor, a substitute for denifanstat), RES (resmethirome), and COMBO (a combination of TVB-3664 and resmethirome). [Figure 22] This figure shows the change in NAS score at 6 weeks in a DIO (diet-induced obesity) MASH Gubra mouse model (Example 12). The groups are NC (normal diet control), VEH (MASH vehicle control), FASN (TVB-3664, a FASN inhibitor, a substitute for denifanstat), RES (resmethirome), and COMBO (a combination of TVB-3664 and resmethirome). [Modes for carrying out the invention]

[0082] This disclosure addresses shortcomings in the treatment of conditions characterized by dysregulation of FASN function in subjects, such as liver damage, liver cancer (e.g., cholangiocarcinoma, hepatocellular carcinoma), and metabolic disorders (e.g., type II diabetes), by providing novel therapeutic methods including the administration of therapeutic combinations of fatty acid synthase inhibitors and thyroid receptor hormone agonists, and / or pharmaceutical formulations comprising fatty acid synthase inhibitors and thyroid receptor hormone agonists.

[0083] definition The chemical moieties referred to as monovalent (e.g., alkyl, aryl, etc.) also encompass structurally acceptable polyvalent moieties, as understood by those skilled in the art. For example, the "alkyl" moiety generally refers to a monovalent radical (e.g., CH3CH2-), but in appropriate contexts, the "alkyl" moiety can also refer to a divalent radical (e.g., -CH2CH2-, which is equivalent to the "alkylene" group). Similarly, where a divalent moiety is required, those skilled in the art will understand that the term "aryl" refers to the corresponding divalent arylene group.

[0084] It is understood that all atoms have a normal number of valences for bond formation (for example, depending on the oxidation state of the atom, carbon has 4, N has 3, O has 2, and S has 2, 4, or 6). In some cases, the part is, for example, (A) a It can be defined as B, where a is either 0 or 1. In such an example, if a is 0, the part is B, and if a is 1, the part is AB.

[0085] If substituents can have different numbers of the same type of atoms or groups (for example, alkyl groups can be C1, C2, C3, etc.), the number of repeating atoms or groups can be expressed within a range (for example, C1-C6 alkyl), and that range includes all numbers within that range and any subranges. For example, C1-C3 alkyl can be C1, C2, C3, C l-2 , C l-3 , and C 2-3 Contains alkyl.

[0086] "Alkanoyl" refers to a carbonyl group having a lower alkyl group as a substituent.

[0087] "Alkylamino" refers to an amino group that has been substituted with an alkyl group.

[0088] "Alkoxy" refers to an oxygen atom substituted with an alkyl group as defined herein, e.g., methoxy[-OCH3,C1 alkoxy]. 1-6The term "alkoxy" encompasses C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, and any sub-ranges thereof.

[0089] "Alkoxycarbonyl" refers to a carbonyl group that has an alkoxy group as a substituent.

[0090] "Alkyl," "alkenyl," and "alkynyl" refer to optionally substituted linear and branched aliphatic groups having 1 to 30 carbon atoms, preferably 1 to 15 carbon atoms, or more preferably 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, and propynyl. As used herein, the term "heteroalkyl" refers to alkyl groups having one or more heteroatoms.

[0091] "Alkylene" refers to a potentially substituted divalent radical, which is a branched or unbranched hydrocarbon fragment containing a specific number of carbon atoms and having two bonding sites. An example is propylene[-CH2CH2CH2-, C3 alkylene].

[0092] "Amino" refers to the -NH2 group.

[0093] "Aryl" refers to an optionally substituted aromatic group having at least one ring with a conjugated π-electron system, and includes carbocyclic aryl groups and biaryl groups, all of which may be substituted. Phenyl and naphthyl groups are preferred carbocyclic aryl groups.

[0094] "Aralkyl" or "arylalkyl" refers to an alkyl-substituted aryl group. Examples of aralkyl groups include butylphenyl, propylphenyl, ethylphenyl, methylphenyl, 3,5-dimethylphenyl, and tert-butylphenyl.

[0095] As used herein, "carbamoyl" is defined by the formula [ka] In order to establish the basis of the formula, R N is hydrogen, -OH, C1~C 12 Alkyl, C1-C 12 The group is selected from heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate, and sulfonamide.

[0096] "Carbonyl" is in the formula [ka] It refers to the base of.

[0097] A "cycloalkyl" refers to a ring that may be saturated or unsaturated, and may be monocyclic, bicyclic, or tricyclic, formed entirely from carbon atoms, and may be substituted. An example of a cycloalkyl group is the cyclopentenyl group (C5H7-), which is an unsaturated cycloalkyl group with five carbon atoms (C5).

[0098] A "heterocycle" refers to a substituted 5-7 membered cycloalkyl ring system containing 1, 2, or 3 heteroatoms (which may be the same or different, selected from N, O, or S, and may contain one double bond).

[0099] "Halogen" refers to a chloro, bromo, fluoro, or iodo atom radical. The term "halogen" also intends to be used in the terms "halo" or "halide."

[0100] A "heteroatom" refers to a non-carbon atom, and boron, nitrogen, oxygen, sulfur, and phosphorus are preferred heteroatoms, with nitrogen, oxygen, and sulfur being particularly preferred heteroatoms in the compounds of this disclosure.

[0101] A "heteroaryl" refers to an aryl group having 1 to 9 carbon atoms, which may be substituted, with the remaining atoms being heteroatoms. This includes those described in "Handbook of Chemistry and Physics," 49th edition, 1968, RCWeast, editor; The Chemical Rubber Co., Cleveland, Ohio. See Section C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems in particular. Suitable heteroaryls include thienyl, pyrrolyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinil, pyridadinyl, triazolyl, indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl, and benzothiadiazolyl.

[0102] The "may be substituted" portion may be substituted with 1 to 4, preferably 1 to 3, or more preferably 1 or 2, nonhydrogen substituents. Unless otherwise specified, when the substituent is on a carbon atom, the substituent may be -OH, -CN, -NO2, halogen, or C1-C 12 Alkyl, C1-C 12 The group consists of heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, and amino compounds, none of which are further substituted. Unless otherwise specified, when a substituent is on nitrogen, the substituent is C1-C 12 Alkyl, C1-C 12Selected from the group consisting of heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate, and sulfonamide, none of which are further substituted.

[0103] As used herein, "sulfonamide" is defined by the formula [ka] We intend to create a group having R in the formula. N is hydrogen, -OH, C1~C 12 Alkyl, C1-C 12 The group is selected from heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, and sulfonamide.

[0104] As used herein, the term "sulfonate" refers to the formula [ka] We intend to create a group having R in the formula. s is hydrogen, C1~C 10 Alkyl, C2~C 10 Alkenyl, C2~C 10 Alkinyl, C1~C 10 Alkanoyl, or C1-C 10 Selected from the group consisting of alkoxycarbonyls.

[0105] In this specification, "sulfonyl," used alone or as part of another group, refers to an SO2 group. The SO2 moiety may be substituted.

[0106] The compounds of this disclosure may exist as stereoisomers, in which case a chiral or asymmetric center is present. The stereoisomers are designated (R) or (S) depending on the arrangement of substituents around the chiral carbon atom. The terms (R) and (S) used herein refer to the arrangements defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., (1976), 45:13-30, which is incorporated herein by reference. This disclosure envisions a variety of stereoisomers and mixtures thereof, which are specifically included within the scope of this disclosure. Examples of stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds of this disclosure can be prepared synthetically from commercially available starting materials having a chiral or asymmetric center, or they can be prepared by preparing racemic mixtures and then using resolution methods well known to those skilled in the art. Examples of these separation methods include (1) combining the enantiomer mixture with an auxiliary substance, separating the resulting diastereomer mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary substance, or (2) directly separating the optical enantiomer mixture using a chiral liquid chromatography column.

[0107] Furthermore, the portion disclosed herein, which exists as multiple tautomer forms, includes all such forms encompassed by a given tautomer formula. For example, [ka] Compound 001-152, as described above, is also, for example, [ka] It is understood that this also includes.

[0108] A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion involves a formal transfer of hydrogen atoms, with the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of sets of tautomers in solution. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. One example of a moiety that exists in several tautomeric forms is 1,2,4-triazole, which exists in tautomeric forms known as 1H-1,2,4-triazole, 4H-1,2,4-triazole, and 3H-1,2,4-triazole, which rapidly interconvert. [ka]

[0109] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and hydrogen atoms occurs. Ring chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic form, such as that exhibited by glucose.

[0110] Common tautomer pairs include ketone-enol, amide-nitrile, lactam-lactim, amide-imido acid tautomerism, imine-enamine, and enamine-enamine in heterocyclic rings (e.g., nucleic acid bases such as guanine, thymine, and cytosine). An example of keto-enol equilibrium is between pyridine-2(1H)-one and the corresponding pyridine-2-ol, as shown below. [ka]

[0111] The individual atoms in the disclosed compound may be any isotope of that element. For example, hydrogen may be in the form of deuterium.

[0112] "Pharmacopoeia-acceptable" means that a substance is approved, or may be approved, by a federal or state regulatory agency for use in animals, more specifically, in humans, or is listed in the United States Pharmacopeia or any other generally accepted pharmacopoeia. A substance that is "pharmacopoeia-acceptable" may be biologically undesirable or otherwise undesirable, i.e., it may be administered to an individual without causing an undesirable biological effect or without harmful interaction with any component of a composition containing it.

[0113] The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include, for example, acid addition salts and base addition salts.

[0114] The “acid addition salts” described in this disclosure are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or with organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfic acid It is formed together with honic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]octo-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.

[0115] The “base addition salts” described herein are formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when it coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, and N-methylglucamine. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide. It should be understood that references to pharmaceutically acceptable salts include their solvation or crystalline form, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. If the solvent is water, a hydrate is formed; if the solvent is an alcohol, an alcoholate is formed. Polymorphs include different crystalline packing configurations of the same elemental composition of the compound. Polymorphs typically exhibit different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Due to various factors such as recrystallization solvent, crystallization rate, and storage temperature, the single-crystal form may become dominant.

[0116] The term “to treat” includes administering the compounds or agents of the present invention to a subject in order to prevent, delay, alleviate, halt, or suppress the onset of symptoms or conditions associated with fatty acid synthase-related disorders (e.g., cancer-related tumor growth). A skilled healthcare professional would know how to determine whether a patient has a fatty acid synthase-related disorder using standard methods, for example, by examining the patient and determining whether the patient has a disorder known to be associated with fatty acid synthase activity, or by measuring fatty acid synthase levels in the plasma or tissue of an individual suspected of having a fatty acid synthase-related disorder and comparing the fatty acid synthase levels in the plasma or tissue of an individual suspected of having a fatty acid synthase-related disorder with fatty acid synthase levels in the plasma or tissue of a healthy individual. Accordingly, the present invention provides, among other things, a method for administering the compounds of the present invention to a subject and measuring the fatty acid synthase activity in the subject. The fatty acid synthase activity in the subject can be determined before and / or after administration of the compound.

[0117] A "therapeutic dose" or "pharmaceutically effective dose" refers to the amount administered to a subject that produces the intended effect. For example, a "therapeutic dose" is sufficient to inhibit fatty acid synthase activity when administered to a subject to inhibit fatty acid synthase activity. When administered to a subject to treat a disease, a "therapeutic dose" is sufficient to treat that disease.

[0118] In some embodiments, the term “therapeutic dose” refers to a synergistically effective dose or a dose that is treated synergistically.

[0119] "Synergistic" means that the therapeutic effect of a FASN inhibitor when administered in combination with a THR agonist (e.g., a THR-β agonist) as described herein is greater than the predicted additive therapeutic effect when the FASN inhibitor and the THR agonist (e.g., a THR-β agonist) are administered individually. The terms "synergistic therapeutic dose" or "synergically effective dose" refer to a dose less than the standard therapeutic dose of one or both drugs, meaning that the amount required for the desired effect is less than when the drugs are used individually. A synergistic therapeutic dose may include cases where one drug is administered at a standard therapeutic dose and the other drug is administered at a dose less than the standard therapeutic dose. For example, a synergistic effect can be obtained by administering a therapeutic dose of a FASN inhibitor and a standard or less-than-standard therapeutic dose of a THR agonist (e.g., a THR-β agonist), and vice versa.

[0120] The term "therapeutic combination" is intended to encompass the sequential administration of two or more therapeutic agents (e.g., a fatty acid synthase inhibitor and a THR-β agonist of the Disclosure), where each therapeutic agent may be administered at different time points, and these therapeutic agents, or at least two of them, may be administered simultaneously or substantially simultaneously. Simultaneous administration can be achieved, for example, by administering a single capsule containing a fixed ratio of each therapeutic agent (e.g., a fatty acid synthase inhibitor and a THR-β agonist of the Disclosure), or multiple single capsules of each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent (e.g., a fatty acid synthase inhibitor and a THR-β agonist of the Disclosure) can be achieved by any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents may be administered by the same or different routes. For example, the first therapeutic agent of a selected combination may be administered by intravenous injection, while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. The therapeutic agents may also be administered alternately.

[0121] Unless otherwise specified, the terms “subject” or “patient” are used interchangeably and refer to human patients and mammals such as non-human primates, as well as laboratory animals such as rabbits, rats, and mice, and other animals. Therefore, as used herein, the terms “subject” or “patient” mean any mammalian patient or subject to whom the compounds of the present invention can be administered. In exemplary embodiments of the present invention, commonly used screening methods are used to determine risk factors associated with the target or suspected disease or condition, or to identify a pre-existing disease or condition, in order to identify a target patient for treatment by the method of the present invention. Examples of these screening methods include conventional workups for determining risk factors associated with the target or suspected disease or condition. These methods and other routine methods enable clinicians to select patients who require treatment with the methods and formulations of the present invention.

[0122] FASN Route Modulator In some embodiments, the fatty acid synthase inhibitor is of formula (I): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, X, Y, and Z are each independently CR or NR', where R is hydrogen or C 1-6 It is an alkyl group, where R' is hydrogen, C 1-6 Alkyl, or absent, A is either CH or N, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino, R 17 and R 18 Each of these may be a hydrogen atom or an alkyl group independently, or they may be bonded together to form a bond. n is either 1 or 2. m is either 0 or 1.

[0123] In a particular embodiment of equation (I), R3 is F.

[0124] In a particular embodiment of formula (I), A is CH.

[0125] In a particular embodiment of formula (I), A is N.

[0126] In a particular embodiment of formula (I), X, Y, and Z are NR'.

[0127] In certain embodiments of formula (I), R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 It is alkoxy, or R4 and R11 These atoms bond together with the atoms they are bonded to, forming a heteroaryl group.

[0128] In a particular embodiment of formula (I), R5 is hydrogen and R6 is an aryl or heteroaryl compound.

[0129] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following formula (IA) or (IB): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z are each independently CR or NR', where R is hydrogen or C 1-6 It is an alkyl group, where R' is hydrogen, C 1-6 Alkyl, or absent, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino, and R 17 and R 18 Each of these elements may be independently hydrogen or alkyl, or they may be bonded together to form a bond.

[0130] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following formula (IC) or (ID): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z are each independently CR or NR', where R is hydrogen or C 1-6 It is an alkyl group, where R' is hydrogen, C 1-6 Alkyl, or absent, R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 20 is hydrogen or C 1-6 Alkyl, C1-6 Alkoxy, or -N(R 13 )(R 14 ) and R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, and R 10 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0131] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following: (IE), (IF), (IG), and (IH): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0132] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following: (II), (IJ), and (IK): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, X and Y are independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, R5, R6, R7, R8, R9, and R 10 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0133] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following formula (IL) or (IM): [ka] Having or having a pharmaceutically acceptable salt thereof, in the formula, X and Y are independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 20is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, and R 10 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0134] In certain embodiments, the fatty acid synthase inhibitor is compound 001-346 or 001-495 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0135] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following formula (IP): [ka] Having or having a pharmaceutically acceptable salt thereof, in the formula, R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C1-6 Alkyl, or C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0136] In certain embodiments, the fatty acid synthase inhibitor is compound 001-385, 001-387, or 001-496 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following formula (IT): [ka] Having or having a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z are each independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C1-6 Alkoxy, C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0138] In certain embodiments, the fatty acid synthase inhibitor is compound 001-118 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the fatty acid synthase inhibitor of formula (I) is the following formula (IV): [ka] Having or having a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z are each independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, C1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14 These are H and C, which are independent of each other.1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0140] In certain embodiments, the fatty acid synthase inhibitor is one of the compounds 001-40 in Table C-1, or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-500, 001-27, 001-73, 001-348, 001-349, 001-123, 001-497, 001-383, 001-280, 001-121, and 001-289 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (II): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, X, Y, and Z are each independently CR or NR', where R is hydrogen or C 1-6 It is an alkyl group, where R' is hydrogen, C 1-6 Alkyl, or absent, L and D are independently C or N. R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14), CF3, -OCF3, or -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino, R 17 and R 18 Each of these may be a hydrogen atom or an alkyl group independently, or they may be bonded together to form a bond. n is either 1 or 2. m is either 0 or 1.

[0143] In a particular embodiment, the fatty acid synthase inhibitor of formula (II) is the following formula (II-A): [ka] Having or having a pharmaceutically acceptable salt thereof, in the formula, X, Y, and Z are each independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R2 is hydrogen, halo, C 1-6 Alkoxy, C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They either bond together with the atoms they are bonded to to form a heteroaryl group, or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 12 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is or R 11 and R 12 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, R 10 , R 13 , and R14 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0144] In certain embodiments, the fatty acid synthase inhibitor of formula (II) is the following formula (II-B): [ka] Having or having a pharmaceutically acceptable salt thereof, in the formula, X and Y are independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C 1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 20 is hydrogen or C1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, and R 10 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0145] In certain embodiments, the fatty acid synthase inhibitor of formula (II) is the following: (II-C), (II-D), and (II-E): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, X and Y are independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 Either they are alkyl, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 Either they are alkoxy, or R2 and R3, together with the atom to which they are bonded, form a 5-membered heterocycline. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R5, R6, R7, R8, R9, and R 10 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0146] In certain embodiments, the fatty acid synthase inhibitor is compound 001-347 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (III): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, X, Y, and Z are each independently CR or NR', where R is hydrogen or C 1-6 It is an alkyl group, where R' is hydrogen, C 1-6alkyl, or absent, Q is C or N, R3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, C 1-6 alkoxy, or when Q is N, R3 is absent, R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 )、C 1-6 alkyl, C 1-6 alkoxy, or -S(=O)2R 20 or R4 and R 11 are joined together with the atoms to which they are attached to form heteroaryl, R 11 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, -N(R 13 R 14 )、CF3、-OCF3、-S(=O)2R 20 or R4 and R 11 are joined together with the atoms to which they are attached to form heteroaryl, or R 11 and R 12 are joined together with the atoms to which they are attached to form heteroaryl, R [[ID=’43]] 12 is hydrogen, halo, cyano, C 1-6 alkyl, C 1-6 alkoxy, -N(R 13 R 14 )、CF3、-OCF3、or -S(=O)2R 20 or R 11 and R [[ID=5’7]] 12 are joined together with the atoms to which they are attached to form heteroaryl, R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or -N(R 13 )(R 14 ) and R5, R6, R7, R8, R9, R10 , R 13 , and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino, R 17 and R 18 Each of these may be a hydrogen atom or an alkyl group independently, or they may be bonded together to form a bond. R 19 These are aryl, heteroaryl, cycloalkyl, or heterocyclyl compounds. n is 0, 1, or 2. m is either 0 or 1.

[0148] In certain embodiments, the fatty acid synthase inhibitor of formula (III) is the following: (III-A), (III-B), and (III-C): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, X and Y are independently CR or NR', where R is H or C 1-6 It is an alkyl group, and R' is H, C 1-6 Alkyl, or absent, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R4 is hydrogen, heteroaryl, heterocyclyl, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R 10 ), C 1-6 Alkyl, C1-6 Alkoxy, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R 11 These are hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, -N(R 13 R 14 ), CF3, -OCF3, or -S(=O)2R 20 is either R4 and R 11 They bond together with the atoms they are bonded to, forming a heteroaryl group. R5, R6, R7, R8, R9, and R 10 These are H and C, which are independent of each other. 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, or -N(R) 15 R 16 ) and R 15 and R 16 These are H and C, which are independent of each other. 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino.

[0149] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-50, 001-51, and 001-326 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0150] In some embodiments, the fatty acid synthase inhibitor is of formula (IV-A), (IV-B), or (IV-C): [ka] The compound, or a pharmaceutically acceptable salt thereof, in the formula, L1, L2, L3, L4, and A are each independently CH or N. R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C1-6 alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 where q is 0, 1, 2, 3, or 4, R 20 is hydrogen or C 1-6 alkyl, C 1-6 alkoxy, or -N(R 13 )(R 14 ), R2 is hydrogen, halo, C 1-6 alkoxy, or C 1-6 alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 alkyl, or C 1-6 alkoxy, R 21 and R​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​These atoms bond together with the atoms they are attached to to form heterocyclyl, heteroaryl, or cycloalkyl groups. R 26 These are hydrogen, heteroaryl, heterocyclyl, -N(R 13 )(R 14 ), or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 25 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, and R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 They are alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

[0151] In certain embodiments, the fatty acid synthase inhibitor of formula (IV) is the following: (IV-D) and (IV-E): [ka] It has one of the following, or a pharmaceutically acceptable salt thereof.

[0152] R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 26 These are hydrogen, heteroaryl, heterocyclyl, -N(R 13 )(R 14 ), or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 25 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, and R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 They are alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

[0153] In certain embodiments, the fatty acid synthase inhibitor of formula (IV) is the following: (IV-F) and (IV-G): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 25 is hydrogen, C1-6 Alkyl, or C 1-6 It is an alkoxy, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 They are alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, s is 0, 1, or 2. L5 is CH2, NH, S, or O. L6 is CH or N, R 27 These are hydrogen, -C(=O)R'', and -S(=O)2R''. 20 And, R 28 These are hydrogen, -C(=O)R'', and -S(=O)2R''. 20 If L6 is O, then it does not exist, and R stands for hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), or -N(R 13 )(R 14 )

[0154] In a particular embodiment of formula (IV), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or -C(=O)N(R) 13 )(R 14 )

[0155] In a particular embodiment of formula (IV), R1 is cyanoacrylate.

[0156] In a particular embodiment of formula (IV), R2 is hydrogen or a halo, and R2 is hydrogen.

[0157] In a particular embodiment of formula (IV), R3 is hydrogen.

[0158] In a particular embodiment of formula (IV), R 21and R 22 Each of them independently consists of hydrogen or C 1-6 It is alkyl.

[0159] In a particular embodiment of formula (IV), R 21 and R 22 Each of them is independent of C 1-6 It is alkyl.

[0160] In a particular embodiment of formula (IV), R 25 It is hydrogen.

[0161] In a particular embodiment of equation (IV), L2 is N.

[0162] In a particular embodiment of formula (IV), L1 is CH.

[0163] In a particular embodiment of formula (IV), L3 is CH.

[0164] In a particular embodiment of formula (IV), L4 is CH.

[0165] In a particular embodiment of formula (IV), A is N.

[0166] In a particular embodiment of formula (IV), A is CH.

[0167] In a particular embodiment of formula (IV), R 26 It is a heterocycline.

[0168] In a particular embodiment of formula (IV), R 24 is -N(R 13 )(R 14 )

[0169] In a particular embodiment of formula (IV), L5 and L6 are each independently N. In a particular embodiment of formula (IV), s is 1.

[0170] In a particular embodiment of equation (IV), s is 0.

[0171] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-1, 001-3, 001-4, 001-14, 001-20, 001-27, 001-31, and 001-36 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (V): [ka] The compound, or a pharmaceutically acceptable salt thereof, in the formula, L7 is either N or O, and if L7 is O, then R 30 It does not exist. A is either CH or N, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is Halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20And, R 29 and R 30 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, -N(R 15 R 16 ), -C(=O)R 46 , or -R 48 C(=O)R 47 is or R 29 and R 30 These atoms bond together with the atoms they are bonded to to form a heteroaryl or heterocycline, where L7 is O, R 30 It does not exist. R 46 and R 47 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 48 It is either alkyl or absent. R 31 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, and v is either 0 or 1.

[0173] In certain embodiments, the fatty acid synthase inhibitor of formula (V) is the following: (VA), (VB), (VC), and (VD): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is Halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 30 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, -N(R 15 R 16 ), -C(=O)R 46 , or -R 48 C(=O)R 47 And here, if L7 is O, then R30 It does not exist. R 46 and R 47 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 48 It is either alkyl or absent. R 31 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, L8, L9, and L 10 Each of these is independently CH2, NH, or O. L 11 and L 12 Each is independently either CH or N, R 32 and R 33 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2R 20 -C(=O)R 46 , hydroxyalkyl, hydroxyl, or absent, u is 0, 1, or 2, t is 0, 1, or 2.

[0174] In a particular embodiment of equation (V), L7 is N.

[0175] In a particular embodiment of formula (V), L7 is O.

[0176] In a particular embodiment of equation (V), A is N.

[0177] In a particular embodiment of formula (V), A is CH.

[0178] In a particular embodiment of formula (V), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or -C(=O)N(R) 13 )(R 14 )

[0179] In a particular embodiment of formula (V), R1 is cyanoacrylate.

[0180] In a particular embodiment of formula (V), R2 is hydrogen or a halo.

[0181] In a particular embodiment of formula (V), R2 is hydrogen.

[0182] In a particular embodiment of formula (V), R3 is fluorine.

[0183] In a particular embodiment of formula (V), R 21 and R 22 Each of them independently consists of hydrogen or C 1-6 It is alkyl.

[0184] In a particular embodiment of formula (V), R 21 and R 22 Each of them is independent of C 1-6 It is alkyl.

[0185] In a particular embodiment of formula (V), R 31 It is hydrogen.

[0186] In a particular embodiment of formula (V), R30 It is hydrogen.

[0187] In a particular embodiment of equation (V), L8 is O.

[0188] In a particular embodiment of equation (V), L9 is O.

[0189] In a particular embodiment of formula (V), L 10 is O, L 11 It is N.

[0190] In a particular embodiment of formula (V), L 12 It is N.

[0191] In a particular embodiment of formula (V), R 32 and R 33 Each of them is an independent hydrogen atom.

[0192] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-64, 001-65, 001-70, 001-78, 001-498, 001-336, and 001-338 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0193] In some embodiments, the fatty acid synthase inhibitor is of formula (VI-A) or (VI-B): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L 13 , L 14 , L 15 , and A are each independently CH or N, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is Halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 34 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF3, -OCF3, -S(=O)2R 20 , or -N(R 15 R 16 ) and R 35 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 36 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 15 R 16 ), heterocyclyl, or heteroaryl, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R16 ), or -S(=O)2R 20 and R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 They are alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

[0194] In certain embodiments, the fatty acid synthase inhibitor of formula (VI) is the following formula (VI-C) or (VI-D): [ka] Having one of the following, or having a pharmaceutically acceptable salt thereof, in the formula, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is Halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 35 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 36 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -N(R 15 R 16 ), heterocyclyl, or heteroaryl, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 It is an alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, and R 37 and R 38 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 It is an alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, or R 37 and R 38 These atoms bond together with the atoms they are attached to, forming heteroaryl or heterocycline compounds.

[0195] In a particular embodiment of formula (VI), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or -C(=O)N(R) 13 )(R 14 )

[0196] In a particular embodiment of formula (VI), R1 is cyanoacrylate.

[0197] In certain embodiments of formula (VI), R2 is hydrogen or a halo.

[0198] In a particular embodiment of formula (VI), R2 is hydrogen.

[0199] In a particular embodiment of formula (VI), R3 is fluorine.

[0200] In a particular embodiment of formula (VI), R 21 and R 22 Each of them independently consists of hydrogen or C 1-6 It is alkyl.

[0201] In a particular embodiment of formula (VI), R 21 and R 22 Each of them is independent of C 1-6 It is alkyl.

[0202] In a particular embodiment of formula (VI), R 35 It is hydrogen.

[0203] In a particular embodiment of formula (VI), R 34 It is a heteroaryl compound.

[0204] In a particular embodiment of formula (VI), R 34 These are thienyl, pyril, furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridadinyl, indolyl, isoindolyl, indolidinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, or imidazopyridyl.

[0205] In a particular embodiment of formula (VI), L 13 It is N.

[0206] In a particular embodiment of formula (VI), L 14 and L15 Each of these is independently a CH.

[0207] In a particular embodiment of formula (VI), A is N.

[0208] In a particular embodiment of formula (VI), A is CH.

[0209] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-42, 001-43, 001-48, 001-62, and 001-322 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (VI-J): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1 Here, is H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), or -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R 22 is H, halogen, or C1-C2 alkyl, R 35 is -C(O)-R 351 -C(O)-NHR 351 , -C(O)-OR 351, or S(O)2R 351 And, R 351 These are C1-C6 linear or branched alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups.

[0211] In some embodiments of formula (VI-J), R 3 This is H or a halogen.

[0212] In some embodiments of formula (VI-J), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0213] In some embodiments of formula (VI-J), R 22 These are C1-C2 alkyl groups.

[0214] In some embodiments of formula (VI-J), R 21 It is cyclobutyl, and R 22 These are C1-C2 alkyl groups.

[0215] In some embodiments of formula (VI-J), R 21 It is cyclobutyl.

[0216] In some embodiments of formula (VI-J), R 3 It is either H or F.

[0217] In some embodiments of formula (VI-J), R 1 is -CN.

[0218] In some embodiments of formula (VI-J), R 1 It is -CF3.

[0219] In some embodiments of formula (VI-J), R 22 It is H, methyl, or ethyl.

[0220] In some embodiments of formula (VI-J), R 22 H is H.

[0221] In some embodiments of formula (VI-J), R 22 It is methyl.

[0222] In some embodiments of formula (VI-J), R 35 -C(O)-NHR 351 That is the case.

[0223] In some embodiments of formula (VI-J), R 351 These are isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

[0224] In some embodiments of formula (VI-J), R 351 This is (R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

[0225] In some embodiments of formula (VI-J), R 1 is -CN, and each R 2 is hydrogen, R 3 is H or F, and R 21 R is a C3-C4 cycloalkyl group, 22 H is R 35 -C(O)-NHR 351 And here, R 351 These are isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

[0226] In some embodiments of formula (VI-J), R 35 is -C(O)-OR351 That is the case.

[0227] In some embodiments of formula (VI-J), R 351 These are isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

[0228] In some embodiments of formula (VI-J), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 R is a C3-C4 cycloalkyl group, 22 H is R 35 is -C(O)-OR 351 And here, R 351 These are isopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

[0229] In some embodiments of formula (VI-J), R 351 This is (R)-3-tetrahydrofuranyl or (S)-3-(tetrahydrofuranyl).

[0230] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-443, 001-444, 001-490, 001-491, 001-492, and 001-493 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (VII-A) or (VII-B): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L 16 is C or N, L 16 If R is N, 41 It does not exist. L 17 , L 18 , and A are each independently CH or N, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 40 , R 42 , and R 43 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2R 20-C(=O)R, hydroxyalkyl, hydroxyl, or -N(R 13 R 14 ) or R 41 and R 42 These then bond together with the atoms they are bonded to, forming heteroaryl or heterocycline compounds. R 41 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, -S(=O)2R 20 -C(=O)R, hydroxyalkyl, hydroxyl, or -N(R 13 R 14 ) or L 16 If R is N, 41 It does not exist, or R 41 and R 42 These then bond together with the atoms they are bonded to, forming heteroaryl or heterocycline compounds. R is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 39 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 and R 15 and R 16 These are, independently, hydrogen and C 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

[0232] In a particular embodiment of formula (VII), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, or -C(=O)N(R) 13 )(R 14 )

[0233] In a particular embodiment of formula (VII), R1 is cyanoacrylate.

[0234] In certain embodiments of formula (VII), R2 is hydrogen or a halo.

[0235] In a particular embodiment of formula (VII), R2 is hydrogen.

[0236] In a particular embodiment of formula (VII), R3 is hydrogen.

[0237] In a particular embodiment of equation (VII), R 21 and R 22 Each of them independently consists of hydrogen or C 1-6 It is alkyl.

[0238] In a particular embodiment of equation (VII), R 21 and R 22 Each of them is independent of C 1-6 It is alkyl.

[0239] In a particular embodiment of equation (VII), R 39 It is hydrogen.

[0240] In a particular embodiment of equation (VII), R 40 It is hydrogen.

[0241] In a particular embodiment of formula (VII), L 16 It is N.

[0242] In a particular embodiment of formula (VII), L 17 It is N.

[0243] In a particular embodiment of formula (VII), L 18It is CH.

[0244] In a particular embodiment of formula (VII), L 18 It is N.

[0245] In a particular embodiment of formula (VII), A is N.

[0246] In a particular embodiment of formula (VII), A is CH.

[0247] In a particular embodiment of equation (VII), R 42 is C 1-6 It is alkyl.

[0248] In a particular embodiment of equation (VII), R 41 is C 1-6 It is alkyl.

[0249] In certain embodiments, the fatty acid synthase inhibitor is compound 001-161 or 001-499 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0250] In some embodiments, the fatty acid synthase inhibitor is expressed by formulas VIII-A), (VIII-B), and (VIII-C): [ka] One of the compounds, or a pharmaceutically acceptable salt thereof, in the formula, L 19 And A are, independently, CH or N, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 39 is hydrogen, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 44 and R 45 These are, independently, hydrogen and C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, -S(=O)2R 20 -C(=O)R, or -N(R 13 R 14 ) and R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 and R 15 and R 16 These are, independently, hydrogen and C 1-6 They are alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino.

[0251] In a particular embodiment of formula (VIII), R1 is cyanoacrylate.

[0252] In certain embodiments of formula (VIII), R2 is hydrogen or a halo.

[0253] In a particular embodiment of formula (VIII), R2 is hydrogen.

[0254] In a particular embodiment of formula (VIII), R3 is hydrogen.

[0255] In a particular embodiment of formula (VIII), R 21 and R 22 Each of them independently consists of hydrogen or C 1-6 It is alkyl.

[0256] In a particular embodiment of formula (VIII), R 21 and R 22 Each of them is independent of C 1-6 It is alkyl.

[0257] In a particular embodiment of formula (VIII), R 39 It is hydrogen.

[0258] In a particular embodiment of formula (VIII), L 19 It is N.

[0259] In a particular embodiment of formula (VIII), A is N.

[0260] In a particular embodiment of formula (VIII), A is CH.

[0261] In certain embodiments, the fatty acid synthase inhibitor is compound 001-498 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (IX): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1 Here, is H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), or -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 This is H, a halogen, a C1-C4 linear or branched alkyl group, or a C3-C5 cycloalkyl group, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -OH, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), or -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. L 1 CR 23 or N; L 2 is CH or N, L 1 or L 2 At least one of them is N, and R 23It is either H or a C1-C4 linear or branched alkyl group.

[0263] In some embodiments of equation (IX), R 24 This is a C1-C4 linear or branched alkyl group, or -(C1-C4 alkyl group) t -O-(C1~C4 linear or branched alkyl), where t is 0 or 1.

[0264] In some embodiments of equation (IX), R 21 This includes halogens, C1-C4 linear or branched alkyl groups, C3-C5 cycloalkyl groups (where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom), or -S(O) u -(C1-C4 linear or branched alkyl) (where u is 0 or 2), or -S(O) u -(C3~C5 cycloalkyl) (where u is 0 or 2).

[0265] In some embodiments of equation (IX), R 3 This is H or a halogen.

[0266] In some embodiments of equation (IX), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0267] In some embodiments of equation (IX), L1 and L2 Both are N.

[0268] In some embodiments of equation (IX), R 21 R is a C1-C2 alkyl or C3-C5 cycloalkyl, 22 These are C1-C2 alkyl groups.

[0269] In some embodiments of equation (IX), R 21 R is a C3-C5 cycloalkyl group, 22 These are C1-C2 alkyl groups.

[0270] In some embodiments of equation (IX), R 24 is -(C1~C2 alkyl) t It is -O-(C1~C2 alkyl), where t is 0 or 1.

[0271] In some embodiments of equation (IX), R 21 R is a C3-C5 alkyl group, 22 R is a C1-C2 alkyl group, 24 These are C1-C2 alkyl groups.

[0272] In some embodiments of equation (IX), R 21 It is cyclobutyl, and R 22 R is a C1-C2 alkyl group, 24 These are C1-C2 alkyl groups.

[0273] In some embodiments of equation (IX), R 21 It is cyclobutyl.

[0274] In some embodiments of equation (IX), R 3 It is either H or F.

[0275] In some embodiments of equation (IX), R 1 is -CN.

[0276] In some embodiments of equation (IX), R 1 It is -CF3.

[0277] In some embodiments of equation (IX), R 22 It is H, methyl, or ethyl.

[0278] In some embodiments of equation (IX), R 22 H is H.

[0279] In some embodiments of equation (IX), R 22 It is methyl.

[0280] In some embodiments of equation (IX), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is a C3-C4 cycloalkyl group, and R 22 It is methyl, and L 1 and L 2 N is R 24 These are methyl, ethyl, hydroxymethyl, methoxymethyl, and 2-methoxyethyl.

[0281] In some embodiments of equation (IX), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is a C3-C4 cycloalkyl group, and R 22 It is methyl, and L 1 and L 2 N is R 24 It is either methoxy or ethoxy.

[0282] In some embodiments of equation (IX), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is a C3-C4 cycloalkyl group, and R 22 It is methyl, and L 1 CH is L 2 N is R 24 These are methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

[0283] In some embodiments of equation (IX), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is a C3-C4 cycloalkyl group, and R 22 It is methyl, and L 1 N is L 2 CH is, R24 These are methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

[0284] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152, 001-154, 001-156, and 001-246 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (IX-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1 R is H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 linear or branched alkyl), where R 1 If it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are H, halogens, C1-C4 linear or branched alkyl groups, and C3-C5 cycloalkyl groups, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -OH, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), or -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. L 1 is N, and L 2 It is N.

[0286] In some embodiments of equation (IX-1), R 1 is H, -CN, halogen, or a linear or branched alkyl group of C1-C4, and each R 2 H is independent of R 3 is H or halogen, and R 21 R is a C1-C4 linear or branched alkyl or a C3-C5 cycloalkyl, 22 is H or C1-C2 alkyl, and R 24 It is either H or a C1-C4 linear or branched alkyl group.

[0287] In some embodiments of equation (IX-1), R 1 is -CN, and each R 2 H is independent of R 3 H is R 21 It is a C3-C5 cycloalkyl group, and R 22 is H or C1-C2 alkyl, and R 24 These are C1-C4 linear or branched alkyl groups.

[0288] In some embodiments, the fatty acid synthase inhibitor of formula (IX-1) has the following structure: [ka]

[0289] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (X): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1Here, is H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), or -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, L 3 C(R 60 )2, O, or NR 50 And, Each R 60 These are independently H, -OH, -CN, and -O t -(C3-C5 cycloalkyl), -O-(C1-C4 linear or branched alkyl), or -C(O)-N(R 601 )2, and here, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. Each R 50 These are independently H, -C(O)-O t -(C1-C4 linear or branched alkyl), -C(O)-O t -(C3-C5 cyclic alkyl), C3-C5 cyclic alkyl which may contain an oxygen or nitrogen heteroatom, -C(O)-N(R 501 )2, or a C1-C4 linear or branched alkyl group, where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. n is 1, 2, or 3. m is either 1 or 2. R 21This is H, a halogen, a C1-C4 linear or branched alkyl group, or a C3-C5 cycloalkyl group, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 is H, halogen, or C1-C2 alkyl, Each R 26 These are independently -OH, -CN, halogen, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), -C(O)-O t -(C1~C4 alkyl), or -C(O)-N(R 501 )2, and here, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. s is 0, 1, or 2. R 601 and R 501 Each of these is independently H, or a C1-C4 linear or branched alkyl group. Here, R 26 , R 60 , R 50 , R 501 , and R 601 Two of these may be arbitrarily bonded to form a ring, where R 26 , R 60 , R 50 , R 501 , and R 601 Two of them are two R 26 , two R 60 , two R 50 , two R 501 , or two R's 601 That's fine.

[0290] In some embodiments of equation (X), R 21 These are halogens, C1-C4 linear or branched alkyl groups, or C3-C5 cycloalkyl groups.

[0291] In some embodiments of equation (X), R 3 This is H or a halogen.

[0292] In some embodiments of equation (X), R 1 These are -CN or C1-C2 haloalkyl groups.

[0293] In some embodiments of equation (X), R 3 It is either H or F.

[0294] In some embodiments of equation (X), R 1 is -CN.

[0295] In some embodiments of equation (X), R 1 It is -CF3.

[0296] In some embodiments of equation (X), n is 1.

[0297] In some embodiments of equation (X), n is 2.

[0298] In some embodiments of equation (X), m is 1.

[0299] In some embodiments of equation (X), m is 2.

[0300] In some embodiments of equation (X), R 21 R is a C1-C2 alkyl or C3-C5 cycloalkyl, 22 These are C1-C2 alkyl groups.

[0301] In some embodiments of equation (X), R 21 R is a C3-C5 cycloalkyl group, 22 These are C1-C2 alkyl groups.

[0302] In some embodiments of equation (X), n is 2, m is 1, and L 3 It is -NC(O)-O-(C1~C2 alkyl).

[0303] In some embodiments of equation (X), L 3 is NR 50 And R 50 It is a C1-C2 alkyl group, and R 21 It is cyclobutyl, and R 22 is H or methyl, and R 3 H is R 1 , -CN, m is 2, and n is 1 or 2.

[0304] In some embodiments of equation (X), n is 2, m is 1, and L 3 is O, and s is 0.

[0305] In some embodiments of equation (X), R 22 It is H, methyl, or ethyl.

[0306] In some embodiments of equation (X), R 22 It is methyl.

[0307] In some embodiments of equation (X), R 22 H is H.

[0308] In some embodiments of equation (X), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is a C3-C4 cycloalkyl group, and R 22 is methyl, n is 2, L 3 is NR 50 And here, R 50 It is either methyl or ethyl.

[0309] In some embodiments of equation (X), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is a C3-C4 cycloalkyl group, and R 22is methyl, n is 2, L 3 It is O.

[0310] In certain embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-406, 001-440, and 001-439 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XI): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 1 Here, is H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), or -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R 22 These are H, halogen, C1-C2 alkyl, and R 351 These are C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

[0312] In some embodiments of equation (XI), R 3 This is H or a halogen.

[0313] In some embodiments of equation (XI), R 1These are halogens, -CN, or C1-C2 haloalkyl groups.

[0314] In some embodiments of equation (XI), R 21 R is a C3-C4 cycloalkyl group, 22 These are C1-C2 alkyl groups.

[0315] In some embodiments of equation (XI), R 21 It is cyclobutyl, and R 22 These are C1-C2 alkyl groups.

[0316] In some embodiments of equation (XI), R 21 It is cyclobutyl.

[0317] In some embodiments of equation (XI), R 3 It is either H or F.

[0318] In some embodiments of equation (XI), R 1 is -CN.

[0319] In some embodiments of equation (XI), R 1 It is -CF3.

[0320] In some embodiments of equation (XI), R 22 It is H, methyl, or ethyl.

[0321] In some embodiments of equation (XI), R 22 H is H.

[0322] In some embodiments of equation (XI), R 22 It is methyl.

[0323] In some embodiments of equation (XI), R 1 is -CN, and each R 2 H is R 3 is H or F, and R 21 It is cyclobutyl, and R 22 It is methyl, and R351 It is either methyl or ethyl.

[0324] In certain embodiments, the fatty acid synthase inhibitor is compound 001-254 or 001-256 of Table C-1, or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XII): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24These are H, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 haloalkyl, -(C1~C4 alkyl)-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, However, if u is 1, then t is 1, Each R 241 These are independently H or C1-C2 alkyl, and R 25 These are halogens, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, C1-C4 haloalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), or cyclopropyl.

[0326] In some embodiments of equation (XII), L-Ar is [ka] And Ar is, [ka] isn't it.

[0327] In some embodiments of equation (XII), L-Ar is [ka] And Ar is, [ka] That is the case.

[0328] In some embodiments of equation (XII), L-Ar is [ka] And Ar is, [ka] That is the case.

[0329] In some embodiments of equation (XII), Ar is [ka] That is the case.

[0330] In some embodiments of equation (XII), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0331] In some embodiments of equation (XII), R 1 is -CN.

[0332] In some embodiments of equation (XII), R 2 H is H.

[0333] In some embodiments of equation (XII), R 21 These are halogens, C1-C4 alkyls, or C3-C5 cycloalkyls.

[0334] In some embodiments of equation (XII), R 21 These are C1-C4 alkyl or C3-C5 cycloalkyl groups.

[0335] In some embodiments of equation (XII), R 21 These are C1-C2 alkyl or C3-C5 cycloalkyl groups.

[0336] In some embodiments of equation (XII), R 21 These are C1-C2 alkyl groups.

[0337] In some embodiments of equation (XII), R 21It is -CH3.

[0338] In some embodiments of equation (XII), R 22 It is either H or a C1-C2 alkyl group.

[0339] In some embodiments of equation (XII), R 22 This is either H or -CH3.

[0340] In some embodiments of equation (XII), R 22 It is -CH3.

[0341] In some embodiments of equation (XII), R 24 These are H, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, -(C1~C4 alkyl)-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0342] In some embodiments of equation (XII), R 24 H, -(C1~C4 alkyl), -(C1~C4 alkyl)-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0343] In some embodiments of equation (XII), R 24 The group is C1-C4 alkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0344] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XII), where R 24 It is -(C1~C2 alkyl)-O-(C1~C2 alkyl).

[0345] In some embodiments of equation (XII), R 24 It is -CH2-O-CH3.

[0346] In some embodiments of equation (XII), R 24 These are C1-C2 alkyl groups.

[0347] In some embodiments of equation (XII), R 24 It is -CH3.

[0348] In some embodiments of equation (XII), R 24 These are C3-C6 cycloalkyl groups.

[0349] In some embodiments of equation (XII), R 24 It is -CN or -(C1~C2 alkyl)-CN.

[0350] In some embodiments of equation (XII), R 24 is -CN.

[0351] In some embodiments of equation (XII), R 24 It is -(C1-C2 alkyl)-CN.

[0352] In some embodiments of equation (XII), R 24 These are H, -CH3, -CH2OH, -CH2OCH3, -(CH2)2OH, -(CH2)2OCH3, or -(CH2)2N(CH3)2.

[0353] In some embodiments of equation (XII), R 24 These are methyl, isopropyl, cyclopropyl, -CN, or -(C1~C2 alkyl)-CN.

[0354] In some embodiments of equation (XII), R 24 It is substituted with one or more substituents selected from C1-C2 alkyl, oxo, -CN, halogen, alkanoyl, alkoxycarbonyl, -OH, and C1-C2 alkoxy groups.

[0355] In some embodiments of equation (XII), R 24 It is substituted with one or more substituents selected from methyl, -F, methoxy, -C(=O)CH3, and -C(=O)-OCH3.

[0356] In some embodiments of equation (XII), R 24 It is substituted with two identical or different substituents.

[0357] In some embodiments of equation (XII), R 24 It is substituted with three identical or different substituents.

[0358] In some embodiments of equation (XII), R 25 These are halogens, -CN, C1-C2 alkyl groups, or cyclopropyl groups.

[0359] In some embodiments of equation (XII), R 25 These are halogens, C1-C2 alkyl groups, or cyclopropyl groups.

[0360] In some embodiments of equation (XII), R 25 It is -CN, -Cl, or -CH3.

[0361] In some embodiments of equation (XII), R 25 It is -Cl.

[0362] In some embodiments of equation (XII), R 25 It is -CH3.

[0363] In some embodiments of equation (XII), R 25It is substituted with one or more substituents selected from -OH, halogens, C1-C2 alkyls, and alkylcarbonyloxys.

[0364] In some embodiments of equation (XII), R 25 It is substituted with one or more substituents selected from -F, methyl, and -OC(=O)-CH3.

[0365] In some embodiments of equation (XII), R 25 It is substituted with two identical or different substituents.

[0366] In some embodiments of equation (XII), R 25 It is substituted with three identical or different substituents.

[0367] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XII-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-Ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently H, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 haloalkyl, -(C1~C4 alkyl)-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle), or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, Each R 241 These are independently H or C1-C2 alkyl, and R 25 These are halogens, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, C1-C4 haloalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl), or cyclopropyl.

[0368] In some embodiments of equation (XII-1), L-Ar is [ka] And Ar is, [ka] And R 1 is H, -CN, halogen, or C1-C4 alkyl, and each R 2 H is independent of R 3 is H or F, and R 21is H, halogen, or C1-C4 alkyl, and R 22 is H, halogen, or C1-C2 alkyl, and R 24 These are C1-C4 alkyl, C1-C4 haloalkyl, and -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), R 25 These are C1-C2 alkyl, C1-C4 haloalkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0369] In some embodiments of equation (XII-1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, and each R 2 H is independent of R 3 H is R 21 It is a C1-C4 alkyl group, and R 22 is H or C1-C2 alkyl, and R 24 This is a C1-C4 haloalkyl or -(C1-C4 alkyl) t -O u -(4-6 member complex ring), R 25 It is -(C1~C4 alkyl)-O-(C1~C4 alkyl).

[0370] In some embodiments, the compound of formula (XII-1) has the following structure: [ka]

[0371] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XIII): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 These are independently H, halogen, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, and -(C1~C4 alkyl)-N(R) 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl groups.

[0372] In some embodiments of formula (XIII), L-Ar [ka] If that is the case, Ar is [ka] isn't it.

[0373] In some embodiments of equation (XIII), L-Ar is [ka] And Ar is, [ka] That is the case.

[0374] In some embodiments of equation (XIII), L-Ar is [ka] And Ar is, [ka] That is the case.

[0375] In some embodiments of equation (XIII), Ar is [ka] That is the case.

[0376] In some embodiments of equation (XIII), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0377] In some embodiments of equation (XIII), R 1 is -CN.

[0378] In some embodiments of equation (XIII), R 2 H is H.

[0379] In some embodiments of equation (XIII), R 21 These are halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles.

[0380] In some embodiments of equation (XIII), R 21 These are C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles.

[0381] In some embodiments of equation (XIII), R 21 These are C1-C2 alkyl or C3-C5 cycloalkyl groups.

[0382] In some embodiments of equation (XIII), R 21 These are C1-C2 alkyl groups.

[0383] In some embodiments of equation (XIII), R 21 It is -CH3.

[0384] In some embodiments of equation (XIII), R 22 It is either H or a C1-C2 alkyl group.

[0385] In some embodiments of equation (XIII), R 22 This is either H or -CH3.

[0386] In some embodiments of equation (XIII), R 22 It is -CH3.

[0387] In some embodiments of equation (XIII), R 24 and R 25These are H, -(C1~C4 alkyl), -(C1~C4 alkyl)-OH, and -(C1~C4 alkyl)-N(R) respectively, independently. 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0388] In some embodiments of equation (XIII), R 24 and R 25 These are H, C1-C4 alkyl, and -(C1-C4 alkyl) respectively, independently. t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0389] In some embodiments of equation (XIII), R 24 These are H, C1-C4 alkyl, -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0390] In some embodiments of equation (XIII), R 24 These are -CN, -Cl, C1~C4 alkyl, or -(C1~C4 alkyl)-O-(C1~C4 alkyl).

[0391] In some embodiments of equation (XIII), R 24 The group is C1-C4 alkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0392] In some embodiments of equation (XIII), R 24It is -(C1~C2 alkyl)-O-(C1~C2 alkyl).

[0393] In some embodiments of equation (XIII), R 24 These are C1-C4 alkyl groups.

[0394] In some embodiments of equation (XIII), R 24 It is -CH3.

[0395] In some embodiments of equation (XIII), R 24 It is hydrogen.

[0396] In some embodiments of equation (XIII), R 24 It is substituted with one or more substituents selected from halogens, C3-C5 cycloalkyls, and C1-C2 alkoxys.

[0397] In some embodiments of equation (XIII), R 24 It is substituted with one or more substituents selected from -F, cyclopropyl, and -OCH3.

[0398] In some embodiments of equation (XIII), R 24 It is substituted with two identical or different substituents.

[0399] In some embodiments of equation (XIII), R 24 It is substituted with three identical or different substituents.

[0400] In some embodiments of equation (XIII), R 25 These are halogens, methyl, ethyl, or cyclopropyl compounds.

[0401] In some embodiments of equation (XIII), R 25 -CN, -Cl, C1~C4 alkyl, -(C1~C4 alkyl) t -O-(C3-C5 cycloalkyl), or -(C1-C4 alkyl) tIt is -O-(C1~C4 alkyl).

[0402] In some embodiments of equation (XIII), R 25 These are -CN, -Cl, -CH3, -O-(C3-C5 cycloalkyl), or -O-(C1-C2 alkyl).

[0403] In some embodiments of equation (XIII), R 25 These are -CN, -Cl, or C1-C4 alkyl groups.

[0404] In some embodiments of equation (XIII), R 25 It is -CH3.

[0405] In some embodiments of equation (XIII), R 25 It is -Cl.

[0406] In some embodiments of equation (XIII), R 25 It is replaced by one or more halogens.

[0407] In some embodiments of equation (XIII), R 25 It is replaced by one or more -F.

[0408] In some embodiments of equation (XIII), R 25 It is substituted with two substituents.

[0409] In some embodiments of equation (XIII), R 25 It is substituted with three substituents.

[0410] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XIII-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-Ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 These are independently H, halogen, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, and -(C1~C4 alkyl)-N(R) 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl groups.

[0411] In some embodiments of equation (XIII-1), L-Ar is [ka] And Ar is, [ka] And R 1 is H, -CN, halogen, or C1-C4 alkyl, and each R 2 H is independent of R 3 is H or F, and R 21 is H, halogen, or C1-C4 alkyl, and R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 Each is independently a halogen, a C1-C4 alkyl, or -(C1-C4 alkyl) t It is -O-(C1~C4 alkyl).

[0412] In some embodiments of equation (XIII--1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, and each R 2 H is independent of R 3 H is R 21 It is a C1-C4 alkyl group, and R 22 is H or C1-C2 alkyl, and R 24 and R 25 Each is independently a halogen, a C1-C4 alkyl, or -(C1-C4 alkyl) t It is -O-(C1~C4 alkyl).

[0413] In some embodiments, the fatty acid synthase inhibitor of formula (XIII-1) has the following structure: [ka]

[0414] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XIV): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 These are H, C1-C4 alkyl, C1-C4 haloalkyl-(C1-C4 alkyl)-OH, -(C1-C4 alkyl) t --N(R 241 )2, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O t -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl groups.

[0415] In some embodiments of equation (XIV), L-Ar is [ka] And Ar is, [ka] That is the case.

[0416] In some embodiments of equation (XIV), L-Ar is [ka] And Ar is, [ka] That is the case.

[0417] In some embodiments of equation (XIV), Ar is [ka] That is the case.

[0418] In some embodiments of equation (XIV), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0419] In some embodiments of equation (XIV), R 1 is -CN.

[0420] In some embodiments of equation (XIV), R 2 H is H.

[0421] In some embodiments of equation (XIV), R 21 These are halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles.

[0422] In some embodiments of equation (XIV), R 21 These are H, C1-C4 alkyl, C3-C5 cycloalkyl, or 4-6 membered heterocycles.

[0423] In some embodiments of equation (XIV), R 21 These are C1-C2 alkyl or C3-C5 cycloalkyl groups.

[0424] In some embodiments of equation (XIV), R 21 These are C1-C2 alkyl groups.

[0425] In some embodiments of equation (XIV), R 21 These are C3-C5 cycloalkyl groups.

[0426] In some embodiments of equation (XIV), R 22 It is either H or a C1-C2 alkyl group.

[0427] In some embodiments of equation (XIV), R 22 H is H.

[0428] In some embodiments of equation (XIV), R 22 These are C1-C2 alkyl groups.

[0429] In some embodiments of equation (XIV), R 22 It is -CH3.

[0430] In some embodiments of equation (XIV), R 24 This is C1-C4 alkyl, or -(C1-C4 alkyl) t It is -O-(C1~C4 alkyl).

[0431] In some embodiments of equation (XIV), R 24 is -(C1~C2 alkyl) t It is -O-(C1~C2 alkyl).

[0432] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XV): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L 3 -CH2-, -CHR 50 -, -O-, -NR 50 -, -NC(O)R 50 -, or -NC(O)OR 50 -and here, R 50 These are C1-C6 alkyl, C3-C5 cycloalkyl, or 4-6 membered heterocycles. n is 1, 2, or 3. m is either 1 or 2, where n+m≧3. L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, In some embodiments of equation (XV), L-Ar is [ka] And Ar is, [ka] That is the case.

[0433] In some embodiments of equation (XV), L-Ar is [ka] And Ar is, [ka] That is the case.

[0434] In some embodiments of equation (XV), R 1 R is H, -CN, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H or -CN, R 1 It may be replaced with one or more halogens.

[0435] In some embodiments of equation (XV), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0436] In some embodiments of equation (XV), R 1 These are -CN or C1-C2 haloalkyl groups.

[0437] In some embodiments of equation (XV), R 1 is -CN.

[0438] In some embodiments of equation (XV), R 1 It is -Cl.

[0439] In some embodiments of equation (XV), R 2 H is H.

[0440] In some embodiments of equation (XV), R 21 These are halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles.

[0441] In some embodiments of equation (XV), R 21 These are C1-C2 alkyl or C3-C5 cycloalkyl groups.

[0442] In some embodiments of equation (XV), R 21 These are C3-C5 cycloalkyl groups.

[0443] In some embodiments of equation (XV), R 22It is either H or a C1-C2 alkyl group.

[0444] In some embodiments of equation (XV), R 22 H is H.

[0445] In some embodiments of equation (XV), R 22 These are C1-C2 alkyl groups.

[0446] In some embodiments of equation (XV), R 22 It is -CH3.

[0447] In some embodiments of equation (XV), L 3 It is -N(CH3)-.

[0448] In some embodiments of equation (XV), n is 2 and m is 2.

[0449] In some embodiments of equation (XV), n is 1 or 2.

[0450] In some embodiments of equation (XV), n is 1 and m is 2.

[0451] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XVI): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 Each of these is independently H, -C1~C4 alkyl, or halogen.

[0452] In some embodiments of equation (XVI), L-Ar is [ka] And Ar is, [ka] That is the case.

[0453] In some embodiments of equation (XVI), L-Ar is [ka] And Ar is, [ka] That is the case.

[0454] In some embodiments of equation (XVI), R 1These are halogens, -CN, or C1-C2 haloalkyl groups.

[0455] In some embodiments of equation (XVI), R 21 These are halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles.

[0456] In some embodiments of equation (XVI), R 21 It is -CH3.

[0457] In some embodiments of equation (XVI), R 22 H is H.

[0458] In some embodiments, the fatty acid synthase inhibitor is of formula (XVII): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl, R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 These are H, C1-C4 alkyl, -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, However, if u is 1, then t is 1, R 241 It is either H or a C1-C6 alkyl group.

[0459] In some embodiments of equation (XVII), L-Ar is [ka] And Ar is, [ka] That is the case.

[0460] In some embodiments of equation (XVII), R 1 These are halogens, -CN, or C1-C2 haloalkyl groups.

[0461] In some embodiments of equation (XVII), R 1 is -CN.

[0462] In some embodiments of equation (XVII), R 2 H is H.

[0463] In some embodiments of equation (XVII), R 21 These are halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles.

[0464] In some embodiments of equation (XVII), R 21 These are C1-C2 alkyl or C3-C5 cycloalkyl groups.

[0465] In some embodiments of equation (XVII), R 21 These are C1-C2 alkyl groups.

[0466] In some embodiments of equation (XVII), R 21 These are C3-C5 cycloalkyl groups.

[0467] In some embodiments of equation (XVII), R 22 It is either H or a C1-C2 alkyl group.

[0468] In some embodiments of equation (XVII), R 22 H is H.

[0469] In some embodiments of equation (XVII), R 22 These are C1-C2 alkyl groups.

[0470] In some embodiments of equation (XVII), R 22 It is -CH3.

[0471] In some embodiments of equation (XVII), R 24 The group is C1-C4 alkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0472] In some embodiments of equation (XVII), R 24 It is -(C1~C2 alkyl)-O-(C1~C2 alkyl).

[0473] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XVIII): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, L 2 -NHR 35 or -C(O)NHR 351 And here, R 351 These are C1-C6 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl compounds. Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 35 is -C(O)R 351 -C(O)NHR 351 , C(O)OR 351 , or S(O)2R 351 And here, R 351 These are C1-C6 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl compounds.

[0474] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XVIII), where L-Ar is [ka] And Ar is [ka] isn't it.

[0475] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XVIII), where L 2 Ha-NHR 35 That is the case.

[0476] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XVIII), where L 2 is -C(O)NH 351 That is the case.

[0477] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XIX): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, W, X, Y, and Z are each independently -N- or -CR 26 -, provided that two or fewer of W, X, Y, and Z are -N-, Each R 26 These are independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), and -N(R 27 )2, -S(O)2-(C1~C4 alkyl), or -C(O)-(C1~C4 alkyl), Each R 27 These are independently H or C1-C4 alkyl, or both R 27 These are C1-C4 alkyl groups, and together with the N atoms to which they are bonded, they form a 3-6 membered ring, where the ring may contain one oxygen atom as a member of the ring. Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 This is H, a halogen, or a C1-C2 alkyl group.

[0478] In some embodiments of equation (XIX), Ar is [ka] That is the case.

[0479] In some embodiments of formula (XIX), Y is -CR 26 -and here, R 26 is -N(R 27 )2.

[0480] In some embodiments of equation (XIX), X is -N-.

[0481] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XX): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, L-ar is [ka] And, Ar is [ka] And, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R22 is H, halogen, or C1-C2 alkyl, R 24 R is -O-(C1~C4 alkyl), -O-(C1~C4 alkyl)-O-(C1~C4 alkyl), -O-(C3~C5 cycloalkyl), or -O-(4~6 membered heterocycle), where R 24 It may be substituted with one or more hydroxyls or halogens, R 25 R is H, halogen, C1-C4 alkyl, or C3-C5 cycloalkyl, where R 25 It may be substituted with one or more halogens.

[0482] In some embodiments of formula (XX), L-Ar is [ka] That is the case.

[0483] In some embodiments of formula (XX), L-Ar is [ka] That is the case.

[0484] In some embodiments of formula (XX), L-Ar is [ka] That is the case.

[0485] In some embodiments of equation (XX), R 3 H is H.

[0486] In some embodiments of equation (XX), R 1 is -CN or -O-(C1-C4 alkyl), where R 1 If it is not -CN, R 1 It may be replaced with one or more halogens.

[0487] In some embodiments of equation (XX), R1 is -CN.

[0488] In some embodiments of equation (XX), R 1 This is a -O-(C1~C4 alkyl) which may be substituted with one or more halogens.

[0489] Several embodiments of formula (XX), each R 2 It is hydrogen.

[0490] In some embodiments of equation (XX), R 21 These are C1-C4 alkyl groups.

[0491] In some embodiments of equation (XX), R 22 It is either H or a C1-C2 alkyl group.

[0492] In some embodiments of equation (XX), R 24 is a -O-(C1-C4 alkyl) which may be substituted with one or more hydroxyls or halogens.

[0493] In some embodiments of equation (XX), R 24 is a -O-(C1-C4 alkyl) which may be substituted with one or more hydroxyls.

[0494] In some embodiments of equation (XX), R 25 It is -CH3.

[0495] In some embodiments, the fatty acid synthase inhibitor is expressed by formula (XX-1): [ka] The compound, or a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24 R is -O-(C1~C4 alkyl), -O-(C1~C4 alkyl)-O-(C1~C4 alkyl), -O-(C3~C5 cycloalkyl), or -O-(4~6 membered heterocycle), where R 24 It may be substituted with one or more hydroxyls or halogens, R 25 R is H, halogen, C1-C4 alkyl, or C3-C5 cycloalkyl, where R 25 It may be substituted with one or more halogens.

[0496] In some embodiments of formula (XX-1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, or -O-(C1~C4 alkyl) which may be substituted with one or more halogens, and each R2 H is independent of R 3 is H or F, and R 21 is H or C1-C4 alkyl, and R 22 is H or C1-C2 alkyl, and R 24 R is -O-(C1~C4 alkyl), -O-(C1~C4 alkyl)-O-(C1~C4 alkyl), or -O-(4~6 member heterocycle), where R 24 R may be substituted with one or more hydroxyls or halogens, 25 This is H, a halogen, or a C1-C4 alkyl group.

[0497] In some embodiments of formula (XX-1), L-Ar is [ka] And Ar is, [ka] And R 1 is -CN, or -O-(C1~C4 alkyl) which may be substituted with one or more halogens, and each R 2 H is independent of R 3 is H or F, and R 21 is H or C1-C4 alkyl, and R 22 is H or C1-C2 alkyl, and R 24 R is a -O-(C1~C4 alkyl) which may be substituted with one or more hydroxyls or halogens, 25 These are C1-C4 alkyl groups.

[0498] In some embodiments, the compound of formula (XX-1) has one of the following structures: [ka]

[0499] In some embodiments, the disclosure provides pharmaceutical compositions comprising one of the fatty acid synthase inhibitors of formula (IX-1), (XII-1), (XIII-1), (XX-1), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIV), or (XX), and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the fatty acid synthase inhibitor is a compound of formula (IX-1), (XII-1), (XIII-1), or (XX-1), or a pharmaceutically acceptable salt thereof.

[0500] In some embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152, 002-386, 002-242, 005-2, and 005-5, or a pharmaceutically acceptable salt thereof.

[0501] In some embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152 and 005-2, or a pharmaceutically acceptable salt thereof.

[0502] In some embodiments, the fatty acid synthase inhibitor is a compound selected from Table C-1, or a pharmaceutically acceptable salt thereof.

[0503] In some embodiments, the fatty acid synthase inhibitor is a compound selected from Table C-2, or a pharmaceutically acceptable salt thereof.

[0504] In some embodiments, the fatty acid synthase inhibitor is a compound selected from Table C-3, or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 Table 2-24 Table 2-25 Table 2-26 Table 2-27 Table 2-28 Table 2-29 Table 2-30 Table 2-31 Table 2-32 Table 2-33 Table 2-34 Table 2-35 Table 2-36 Table 2-37 Table 2-38 [Table 2-39] [Table 2-40] [Table 3-1] [Table 3-2]

[0505] Thyroid hormone receptor agonists Examples of thyroid hormone receptor agonists that may be used in the methods and compositions disclosed herein are described below.

[0506] In some embodiments, thyroid hormone receptor (THR) agonists (e.g., THHβ agonists) are used. [ka] and Select from ALG-055009.

[0507] In some embodiments, the thyroid hormone receptor agonist is expressed by formula (XXI): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, A A These are O, CH2, S, SO, or SO2. X A and Y A Each of these is independently selected from the group consisting of Br, Cl, and CH3. R 1A is, -(CH2) n COOH, -OCH2COOH, -NHC(=O)COOH, -NHCH2COOH, [ka] Selected from the group consisting of, Z A is H, or -C≡N, R 2A It is a lower alkyl having 1 to 4 C atoms, R 3 is H or a lower alkyl group. n is either 1 or 2. p is either 1 or 2.

[0508] In some embodiments, the thyroid hormone receptor agonist is expressed by formula (XXI-1): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which, R 3A is H or CH2R 3B And, R 3B These are hydroxyl, O-linked amino acids, -OP(O)(OH)2, or -OC(O)R 3C And here, R 3C This includes lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or -(CH2) n -It is a heteroaryl, where n is 0 or 1. R 4A H is R 5A is either CH2COOH, C(O)CO2H, or its ester or amide, or R 4A and R 5 Together, -N=C(R 4B )-C(O)-NH-C(O)-, where R 4B is either H or cyano.

[0509] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It has (compound A).

[0510] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0511] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0512] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0513] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0514] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0515] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0516] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0517] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0518] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0519] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0520] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0521] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0522] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0523] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0524] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0525] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0526] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0527] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0528] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0529] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0530] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0531] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0532] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0533] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0534] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0535] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0536] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0537] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0538] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0539] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0540] In some embodiments, the thyroid hormone receptor agonist of formula (XXI) has the following structure: [ka] It holds.

[0541] In some embodiments, the crystalline polymorph (morph A) of compound A is characterized by an X-ray powder diffraction pattern including peaks at approximately 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2θ, obtained using a Cu-Ka radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern further includes peaks at approximately 8.2, 11.2, 15.7, 16.4, 17.7, 30.0, and 32.2 degrees 2θ. In some embodiments, the X-ray powder diffraction pattern of morph A may further include one or more peaks from Table P-1. In some embodiments, morph A has an X-ray diffraction pattern substantially similar to that shown in Figure 6. In some embodiments, morph A has an X-ray diffraction pattern substantially similar to that shown in Figure 7. In embodiments, morph A is characterized by a differential scanning calorimetry (DSC) figure including an onset melting temperature of approximately 321°C and an endothermic peak at approximately 329°C. In this embodiment, the DSC diagram is substantially the same as that shown in Figure 8.

[0542] In some embodiments, the crystalline form of compound A is a hydrate. In some embodiments, the hydrate is a monohydrate. In some embodiments, the hydrate is a dihydrate.

[0543] In some embodiments, the crystalline polymorph (morph G) of compound A is characterized by an X-ray powder diffraction pattern containing peaks at approximately 9.50, 12.9, 16.7, 17.3, 19.5, 20.2, 25.6, and 28.3 degrees 2θ, the X-ray powder diffraction pattern obtained using a Cu-Ka radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of morph G may further include one or more peaks from Table P-2. In some embodiments, morph G has an X-ray diffraction pattern substantially similar to that shown in Figure 9.

[0544] In some embodiments, the crystalline polymorph (morph K) of compound A is characterized by an X-ray powder diffraction pattern containing peaks at approximately 8.42, 11.4, 14.5, 18.9, 21.1, and 21.6 degrees 2θ, the X-ray powder diffraction pattern obtained using a Cu-Ka radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of morph K may further include one or more peaks shown in Table 3. In some embodiments, morph K has an X-ray diffraction pattern substantially similar to that shown in Figure 10. [Table 4] [Table 5] [Table 6]

[0545] Dosage and administration of thyroid hormone receptor agonists Thyroid hormone receptor beta-agonists intended by the methods described herein may be administered orally or parenterally (e.g., subcutaneously). Thyroid hormone receptor beta-agonists approved by the U.S. Food and Drug Administration for at least one indication may be administered via the route described on their FDA-approved labels. In some embodiments, thyroid hormone receptor beta-agonists are administered orally.

[0546] Thyroid hormone receptor beta-agonists, including those intended by the methods described herein, are currently in use and, in some cases, approved by the U.S. Food and Drug Administration for use in the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).

[0547] In some embodiments of the methods described herein, thyroid hormone receptor beta-agonists are administered in doses equivalent to the dose indicated on their labels as the recommended dose for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments of the methods described herein, thyroid hormone receptor beta-agonists are administered in doses lower than the dose indicated on their labels as the recommended dose for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH) (i.e., doses equivalent to a specific percentage of the dose indicated on their labels as the recommended dose for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH)). In some aspects of the methods described herein, thyroid hormone receptor beta-agonists are used in doses of 10%-90%, 20%-90%, 30%-90%, 40%-90%, 50%-90%, 60%-90%, 70%-90%, 80%-90%, 10%-80%, 20%-80%, 30%-80%, 40%-80%, 50%-80%, and 60% of the doses indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrodermic NASH). It is administered in doses of ~80%, 70%~80%, 10%~70%, 20%~70%, 30%~70%, 40%~70%, 50%~70%, 60%~70%, 10%~60%, 20%~60%, 30%~60%, 40%~60%, 50%~60%, 10%~50%, 20%~50%, 30%~50%, 40%~50%, 10%~40%, 20%~40%, 30%~40%, 10%~30%, 20%~30%, and 10%~20%.

[0548] In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 20% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 30% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 40% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 50% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 60% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 70% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 80% to 90% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 20% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 30% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).In some embodiments, thyroid hormone receptor beta-agonists are administered at 40% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 50% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 60% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 70% to 80% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 70% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 20% to 70% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 30% to 70% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 40% to 70% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 50% to 70% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 60% to 70% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 10% to 60% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).In some embodiments, thyroid hormone receptor beta-agonists are administered at 20% to 60% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 30% to 60% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 40% to 60% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at 50% to 60% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 50% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 20% to 50% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 30% to 50% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 40% to 50% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 40% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 20% to 40% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 30% to 40% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 30% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 20% to 30% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered at doses of 10% to 20% of the dose indicated for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).

[0549] Thyroid hormone receptor beta-agonists can be administered at various frequencies as part of the methods described herein. In certain embodiments, thyroid hormone receptor beta-agonists are administered at the frequencies indicated on their labels for the treatment of one of the approved indications. In certain embodiments, thyroid hormone receptor beta-agonists are administered at the frequencies indicated on their labels as maintenance therapy in the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some embodiments, thyroid hormone receptor beta-agonists are administered daily (e.g., once or twice daily) or intermittently (e.g., every other day, on a Mon / Wed / Fri schedule, weekly, bi-weekly, monthly, bi-monthly, etc.). In some embodiments, thyroid hormone receptor beta-agonists are administered daily (e.g., once or twice daily). In some embodiments, thyroid hormone receptor beta-agonists are administered intermittently (e.g., every other day, on a Mon / Wed / Fri schedule, weekly, bi-weekly, monthly, bi-monthly, etc.).

[0550] In some embodiments, the thyroid hormone receptor beta-agonist is resmethilone, and the dose indicated for the treatment of NASH (e.g., non-cirrhotic NASH) is 80 mg once daily for patients weighing 100 kg or less, and 100 mg once daily for patients weighing 100 kg or more.

[0551] Treatment method In some embodiments, embodiments provided herein relate to a method for treating fatty liver disease in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for fatty liver disease.

[0552] In some embodiments, embodiments provided herein relate to a method for treating non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH). In some embodiments, NASH / MASH is NASH / MASH with moderate to severe fibrosis (e.g., fibrosis score 2 or 3). In some embodiments, treating non-alcoholic steatohepatitis involves preventing the progression of at least one symptom of non-alcoholic steatohepatitis. In some embodiments, the symptom is selected from elevated AST levels, elevated ALT levels, elevated GGT levels, elevated liver triglyceride levels, elevated cholesterol levels, fatty liver, liver inflammation, liver ballooning, liver fibrosis, and NAFLD activity score. In some embodiments, treating NASH / MASH includes improving the target liver fibrosis by one or more stages without worsening NASH / MASH.

[0553] In some embodiments, treating NASH / MASH includes resolving NASH / MASH without exacerbating the fibrosis in question.

[0554] In some embodiments, embodiments provided herein relate to a method for treating non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD) in a subject requiring treatment of non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD), comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment of non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD).

[0555] In some embodiments, embodiments provided herein relate to a method for treating metabolic syndromes in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for metabolic syndromes.

[0556] In some embodiments, embodiments provided herein relate to a method for treating type II diabetes in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for type II diabetes.

[0557] In some embodiments, embodiments provided herein relate to a method for treating atherosclerosis in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for atherosclerosis.

[0558] In some embodiments, embodiments provided herein relate to a method for treating cirrhosis in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for cirrhosis.

[0559] In some embodiments, embodiments provided herein relate to a method for treating liver cancer (e.g., hepatocellular carcinoma) in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject in need of treatment for liver cancer (e.g., hepatocellular carcinoma). In some embodiments, the liver cancer develops from NASH / MASH or NAFLD / MASLD. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the liver cancer is cholangiocarcinoma.

[0560] In some embodiments, embodiments provided herein relate to a method for treating a disease or condition in which interleukin-1 beta (IL1β) levels are elevated, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for a disease or condition in which interleukin-1 beta (IL1β) levels are elevated. In some embodiments, the disease or condition is familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrenosum, acne (PAPA), cryopyrin-associated periodic syndromes (CAPS), hyper-IgD syndrome (HIDS), adult and juvenile Still's disease, Schnitzler syndrome, TNF receptor-associated periodic syndromes (TRAPS), Blau syndrome; Sweet's syndrome, IL-1 receptor antagonist deficiency (DIRA), relapsing idiopathic pericarditis, macrophage activation syndrome (MAS), urticarial vasculitis, antisynthetase syndrome, The following conditions are selected: relapsing polychondritis, Behçet's disease, Erdheim-Chester syndrome (histiocytosis), synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, lymphadenitis syndrome (Adenitis syndrome (PFAPA)), uric acid crystalline arthritis (gout), type 2 diabetes mellitus, smoldering multiple myeloma, post-myocardial infarction heart failure, osteoarthritis, transfusion-related acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. In some embodiments, the disease or condition is acne.

[0561] In some embodiments, the embodiments provided herein involve a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein, thereby controlling regulatory T cells (T reg The present invention relates to a method for treating a disease or condition in which regulatory T cells (Tregs) are reduced or suppressed in a subject, comprising administering to a subject who requires treatment for a disease or condition in which regulatory T cells (Tregs) are reduced or suppressed.In some embodiments, T reg The cells are suppressed.

[0562] In some embodiments, the embodiments provided herein involve a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein, with T helper (T h The present invention relates to a method for treating a disease or condition in which T helper (Th) cell levels are elevated in a subject, comprising administering to the subject who requires treatment for a disease or condition in which T helper (Th) cell levels are elevated.In some embodiments, the elevated T helper cells are T h 1. T h 2, T h 9, or T h 17. In some embodiments, the elevated T helper cells are T 17 In some embodiments, the disease or condition is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and graft rejection.

[0563] In some embodiments, embodiments provided herein relate to a method for improving established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring improvement of established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH).

[0564] In some embodiments, embodiments provided herein relate to a method for treating hepatic fibrosis in a subject, comprising administering a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor beta-agonist as defined in any of the embodiments described herein to a subject requiring treatment for hepatic fibrosis.

[0565] In some embodiments, embodiments provided herein relate to a method for reducing the expression of fibrosis-related genes in a subject, comprising administering a combination of a FASN inhibitor, as defined in any of the embodiments described herein, and a thyroid hormone receptor beta-agonist, as defined in any of the embodiments described herein, to a subject requiring a reduction in the expression of fibrosis-related genes.

[0566] In some embodiments, embodiments provided herein relate to a method for reducing triglycerides in a subject, comprising administering a combination of a FASN inhibitor, as defined in any of the embodiments described herein, and a thyroid hormone receptor beta-agonist, as defined in any of the embodiments described herein, to a subject requiring a reduction in triglycerides.

[0567] In some embodiments, the combination of a FASN inhibitor and a thyroid hormone receptor β-agonist is synergistic.

[0568] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is: (a) Formula (IX) [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R3 is H, -OH, or halogen, R 21 These are H, halogens, C1-C4 linear or branched alkyl groups, and C3-C5 cycloalkyl groups, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -OH, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), or -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. L 1 CR 23 or N; L 2 is CH or N, L 1 or L 2 At least one of them is N, and R 23 is H or a C1-C4 linear or branched alkyl, or (b) Formula (X): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, L 3 C(R 60 )2, O, or NR 50 And, Each R 60 These are independently H, -OH, -CN, and -O t -(C3-C5 cycloalkyl), -O-(C1-C4 linear or branched alkyl), or -C(O)-N(R 601 )2, and here, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. Each R 50 These are independently H, -C(O)-O t -(C1-C4 linear or branched alkyl), -C(O)-O t -(C3-C5 cyclic alkyl), C3-C5 cyclic alkyl which may contain an oxygen or nitrogen heteroatom, -C(O)-N(R 501 )2, C1-C4 linear or branched alkyl, where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. n is 1, 2, or 3. m is either 1 or 2. R 21 These are H, halogens, C1-C4 linear or branched alkyl groups, and C3-C5 cycloalkyl groups, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 These are H, halogen, and C1-C2 alkyl. Each R 26 These are independently -OH, -CN, halogen, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t-O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), -C(O)-O t -(C1~C4 alkyl), or -C(O)-N(R 501 )2, and here, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. s is 0, 1, or 2. R 601 and R 501 Each of these is independently H, or a C1-C4 linear or branched alkyl group. Here, R 26 , R 60 , R 50 , R 501 , and R 601 Two of these may be arbitrarily bonded to form a ring, where R 26 , R 60 , R 50 , R 501 , and R 601 Two of them are two R 26 , two R 60 , two R 50 , two R 501 , or two R's 601 It may be so, or (c) Formula (VI-J) [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R 22 is H, halogen, or C1-C2 alkyl, R 35 is -C(O)-R 351 -C(O)-NHR 351 , -C(O)-OR 351 , or S(O)2R 351 And, R 351 is a C1-C6 linear or branched alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group, or (d) Equation (XII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24 These are H, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, -(C1~C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C6 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, However, if u is 1, then t is 1, Each R 241 These are independently H or C1-C2 alkyl, and R 25 These are halogens, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl or cyclopropyl, or (e) Formula (XIII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 These are independently H, halogen, -CN, -(C1~C4 alkyl)-CN, C1~C4 alkyl, C1~C4 alkyl-OH, and -(C1~C4 alkyl)-N(R) 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl, or (f) Formula (XIV): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 H, C1-C4 alkyl, -(C1-C4 alkyl)-OH, -(C1-C4 alkyl) t --N(R 241 )2, -(C1~C4 alkyl) t -O t-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O t -(4-6 member heterocycle), or -(C1-C4 alkyl) t -O-(C1~C4 alkyl), where, Each t is independently either 0 or 1. Each R 241 These are independently H or C1-C2 alkyl, or (g) Formula (XV): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L 3 -CH2-, -CHR 50 -, -O-, -NR 50 -, -NC(O)R 50 -, or -NC(O)OR 50 -and here, R 50 These are C1-C6 alkyl, C3-C5 cycloalkyl, or 4-6 membered heterocycles. n is 1, 2, or 3. m is either 1 or 2, where n+m≧3. L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, or, (h) Formula (XVI): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 and R 25 Each of these is independently H, -C1~C4 alkyl, or halogen, or (i) Formula (XVII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 24 These are H, C1-C4 alkyl, -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-N(R 241 )2, -(C1~C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4-6 member heterocycle) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), where, t is either 0 or 1, u is either 0 or 1, However, if u is 1, then t is 1, R 241 is H or C1-C6 alkyl, or (j) Formula (XVIII): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] However, L-Ar [ka] If so, Ar [ka] Instead, L 2 -NHR 35 or -C(O)NHR 351 And here, R 351 These are C1-C6 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl compounds. Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 member heterocycle), -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, and R 35 is -C(O)R 351 -C(O)NHR 351 , C(O)OR 351 , or S(O)2R 351 And here, R 351 These are C1-C6 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl compounds, or (k) Formula (XIX): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, W, X, Y, and Z are each independently -N- or -CR 26 -, provided that two or fewer of W, X, Y, and Z are -N-, Each R 26 These are independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), and -N(R 27 )2, -S(O)2-(C1~C4 alkyl), or -C(O)-(C1~C4 alkyl), Each R 27 These are independently H or C1-C4 alkyl, or both R 27 These are C1-C4 alkyl groups, and together with the N atoms to which they are bonded, they form a 3-6 membered ring, where the ring may contain one oxygen atom as a member of the ring. Ar is [ka] And, Het is a 5-6 member heteroaryl, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 member heterocycle), -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 11 is H or -CH3, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, or, (l) Formula (XX): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-ar is [ka] And, Ar is [ka] And, R 1 R is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4-6 membered heterocycle), or -O-(C1-C4 alkyl), where R 1 If it is not H, -CN, or halogen, R 1 It may be replaced by one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 alkyl. R 3 is H or F, R 21 These are H, halogens, C1-C4 alkyl groups, C3-C5 cycloalkyl groups, or 4-6 membered heterocycles. R 22 is H, halogen, or C1-C2 alkyl, R 24 R is -O-(C1~C4 alkyl), -O-(C1~C4 alkyl)-O-(C1~C4 alkyl), -O-(C3~C5 cycloalkyl), or -O-(4~6 membered heterocycle), where R 24 It may be substituted with one or more hydroxyls or halogens, R 25 R is H, halogen, C1-C4 alkyl, or C3-C5 cycloalkyl, where R 25 may be substituted with one or more halogens, or (m) Formula (XI): [ka] Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently H, halogens, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R 22 These are H, halogen, C1-C2 alkyl, and R 351 These are C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

[0569] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is: [ka] It is a compound selected from the group consisting of the following:

[0570] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is: [ka] It is a compound selected from the group consisting of the following:

[0571] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is: [ka] That is the case.

[0572] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is: [ka] That is the case.

[0573] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is denifanstat or a pharmaceutically acceptable salt thereof, and includes all possible tautomers of denifanstat.

[0574] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is TVB-3664 or a pharmaceutically acceptable salt thereof.

[0575] In some embodiments of the methods provided herein, such as those described above (or below), the thyroid hormone receptor beta-agonist is [ka] and Select from ALG-055009.

[0576] In some embodiments of the methods provided herein, such as those described above (or below), the thyroid hormone receptor beta-agonist is of formula (XXI): [ka] The compound, or a pharmaceutically acceptable salt thereof, in the formula, A A These are O, CH2, S, SO, or SO2. X A and Y A Each of these is independently selected from the group consisting of Br, Cl, and CH3. R 1A is, -(CH2) n COOH, -OCH2COOH, -NHC(=O)COOH, -NHCH2COOH, [ka] Selected from the group consisting of, Z A is H, or -C≡N, R 2A It is a lower alkyl having 1 to 4 C atoms, R 3 is H or a lower alkyl group. n is either 1 or 2. p is either 1 or 2.

[0577] In some embodiments of the methods provided herein, such as those described above (or below), the thyroid hormone receptor beta-agonist is resmethylome (also known as MGL-3196): [ka]

[0578] Throughout this disclosure, references to “therapeutic methods” include the use of the compounds, compositions, and combinations described herein in therapeutic methods, the use of the compounds, compositions, and combinations for use in the treatment of the diseases described herein, and the use of the compounds, compositions, and combinations described herein in the manufacture of agents for the treatment of the diseases described herein.

[0579] Compound Synthesis Furthermore, this specification also describes methods for synthesizing the fatty acid synthase inhibitors of this disclosure. The fatty acid synthase inhibitors of this disclosure can be synthesized as shown in the following synthesis schemes 1 to 13. Scheme 1 [ka] During the ceremony, R is either hydrogen or alkyl. R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, and R 17 It is hydrogen or alkyl. Scheme 2 [ka] During the ceremony, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, R 23 is hydrogen, -N(R 13 )(R 14 ), C 1-6 Alkyl, C 1-6 It is either an alkoxy, or absent if L1 is N, or R 23 and R 24 These combine with the atoms to which they are bonded to form heterocyclyl, heteroaryl, or cycloalkyl groups, and R 24 is hydrogen, -N(R 13 )(R 14 ), C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkoxy)(heterocyclyl), heterocyclyl, or R 23 and R 24 These atoms bond together with the atoms they are attached to to form heterocyclyl, heteroaryl, or cycloalkyl groups. Scheme 3 [ka] During the ceremony, LG is a leaving group, Nu is a nucleophile, L2, L3, L4, and L 4’ Each is independently either CH or N, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, and R 17 It is hydrogen or alkyl. Scheme 4 [ka] Here, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R 16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, R 17 is hydrogen or alkyl, and R 24is hydrogen, -N(R 13 )(R 14 ), C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 It is an alkoxy (heterocyclyl), or a heterocyclyl. Scheme 5 [ka] Here, R1 is hydrogen, cyano, halo, C 1-6 Alkyl, C 1-6 Alkoxy, -C(=O)N(R 13 )(R 14 ), -(CH2) q C(=O)N(R 13 )(R 14 ), CF3, -OCF3, or -S(=O)2R 20 And, q is 0, 1, 2, 3, or 4. R 20 is hydrogen or C 1-6 Alkyl, C 1-6 Alkoxy, or -N(R 13 )(R 14 ) and R2 is hydrogen, halo, C 1-6 Alkoxy, or C 1-6 It is alkyl, R3 is hydrogen, hydroxyl, halo, C 1-6 Alkyl, or C 1-6 It is an alkoxy, R 21 and R 22 These are, independently, hydrogen, halo, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, CF3, -OCF3, or -S(=O)2R 20 And, R 13 and R 14 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, alkylamino, -N(R 15 R16 ), or -S(=O)2R 20 And, R 15 and R 16 These are, independently, hydrogen and C 1-6 Alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or alkylamino, R 17 is hydrogen or alkyl, R 24 is hydrogen, -N(R 13 )(R 14 ), C 1-6 Alkyl, C 1-6 Alkoxy, -(C 1-6 Alkoxy) (heterocyclyl), or heterocyclyl, R 29 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, -N(R 15 R 16 ), -C(=O)R 46 , or -R 48 C(=O)R 47 And, R 34 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, hydroxyl, hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF3, -OCF3, -S(=O)2R 20 , or -N(R 15 R 16 ) and m is 0, 1, or 2.

[0580] Schemes 6-13 provide the synthesis of exemplary compounds of formula IX, where, R 1 These are H, -CN, halogen, C1-C4 linear or branched alkyl, -O-(C3-C5 cycloalkyl), and -O-(C1-C4 linear or branched alkyl), where, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. R 1 However, if it is not H, -CN, or a halogen, it may be substituted with one or more halogens. Each R 2 These are independently hydrogen, halogen, or C1-C4 linear or branched alkyl groups. R 3 is H, -OH, or halogen, R 21 These are H, halogens, C1-C4 linear or branched alkyl groups, and C3-C5 cycloalkyl groups, where the C3-C5 cycloalkyl group may contain an oxygen or nitrogen heteroatom. R 22 is H, halogen, or C1-C2 alkyl, R 23 is H or a C1-C4 linear or branched alkyl group. R 24 These are H, C1-C4 linear or branched alkyl, and -(C1-C4 alkyl). t -OH, -(C1~C4 alkyl) t -O t -(C3-C5 cycloalkyl), or -(C1-C4 alkyl) t -O-(C1~C4 linear or branched alkyl), where, t is either 0 or 1, C3-C5 cycloalkyl groups may contain oxygen or nitrogen heteroatoms. Scheme 6 [ka] Scheme 7 [ka] Scheme 8 [ka] Scheme 9 [ka] Scheme 10 [ka] Scheme 11 [ka] Scheme 12 [ka] Scheme 13 [ka]

[0581] Examples provide additional methods for producing the specific compounds described herein. Those skilled in the art will recognize that other compounds of the structure can be produced by modifications to the specifically disclosed scheme using methods known to those skilled in the art. Additional examples can be found in Tables C-1, C-2, and C-3.

[0582] Many such techniques are well known in the field. However, many of the known techniques are described in detail in the Compendium of Organic Synthetic Methods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5, 1984; and Vol. 6, as well as March in Advanced Organic Chemistry (1985); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes (1993); Advanced Organic Chemistry Part B: Reactions and Synthesis, Second Edition (1983); Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Second Edition (1977); Protecting Groups in Organic Synthesis, Second Edition; and Comprehensive Organic Transformations (1999)).

[0583] Fatty acid synthesis pathway Various aspects of this disclosure relate to compositions and methods for modulating the activity of the fatty acid synthesis pathway to treat viral infections or cancer. The human fatty acid synthesis pathway can utilize four enzymes: 1) acetyl-CoA carboxylase (ACC) capable of synthesizing malonyl-CoA, 2) malate enzyme capable of producing NADPH, 3) citrate lyase capable of synthesizing acetyl-CoA, and 4) fatty acid synthase capable of catalyzing the NADPH-dependent synthesis of fatty acids from acetyl-CoA and malonyl-CoA. In various aspects, this disclosure relates to the treatment of viral infections and cancer by modulating the activity of fatty acid synthase proteins.

[0584] The final product of fatty acid synthase is a free fatty acid that can be used for separate enzymatic derivatization with coenzyme A for incorporation into other products. In humans, fatty acid synthesis can occur in two sites: one is the liver, where palmitic acid can be produced (Roncari, (1974) Can. J. Biochem., 52:221-230); the other is the mammary gland during lactation, where C 10 ~C 14 Fatty acids can be produced (Thompson, et al., (1985) Pediatr. Res., 19:139-143).

[0585] Fatty acids can be synthesized from acetyl-CoA in the cytoplasm. Acetyl-CoA can be produced from pyruvate by pyruvate dehydrogenase (PDH) and by β-oxidation of fatty acids in mitochondria. The "citrate shuttle" can transport acetyl-CoA from mitochondria to the cytoplasm. Acetyl-CoA can react with oxaloacetate to produce citrate, and tricarboxylic acid translocase can transport citrate from mitochondria to the cytosol. In the cytoplasm, citrate can be converted back to oxaloacetate and acetyl-CoA, a reaction that can be catalyzed by ATP-citrate lyase. Oxaloacetate can be converted back to pyruvate for re-entry into mitochondria.

[0586] Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxylase (ACC) is a complex, polyfunctional biotin-containing enzyme system that can catalyze the carboxylation of acetyl-CoA to malonyl-CoA. This conversion is an irreversible rate-limiting step in fatty acid synthesis. ACC can perform three functions: biotin carboxyl carrier protein, biotin carboxylase, and carboxyltransferase. Following ATP-dependent carboxylation of biotin, a prosthetic group (cofactor), it can transfer the carboxyl group to acetyl-CoA. HCO3 - +ATP+acetyl-CoA->ADP+Pi +Maronyl-CoA

[0587] Two distinct ACC forms, alpha and beta, exist, encoded by two different genes, ACC-alpha (also known as ACC, ACAC, ACC1, ACCA, and ACACA), which may encode proteins highly enriched in adipose tissues. For this gene, multiple alternatively spliced ​​transcript variants have been found, with branched sequences encoding distinct isoforms. ACC-beta (also called ACC2, ACCB, HACC275, and ACACB) may encode a protein thought to regulate fatty acid oxidation by the ability of malonyl-CoA to inhibit carnitine-palmitoyl-CoA transferase I. Carnitine-palmitoyl-CoA transferase I is the rate-limiting step in mitochondrial fatty acid uptake and oxidation. ACC-beta may be more involved in regulating fatty acid oxidation than in fatty acid biosynthesis. There is evidence for the existence of two ACC-beta isoforms.

[0588] ACC can be regulated by phosphorylation / dephosphorylation of targeted serine residues. For example, AMP-activated kinase (AMPK) can phosphorylate ACC, and this phosphorylation may inhibit ACC's ability to produce malonyl-CoA. In ACACA, AMPK can phosphorylate Ser79, Ser1200, and Ser1215 (Park SH et al. (2002) J. Appl. Physiol. 92:2475-82). AMPK can phosphorylate Ser218 on ACACB (Hardie DG (1992) Biochim. Biophys. Acta 1123:231-8). In addition, cAMP-dependent protein kinase (protein kinase A, i.e., PKA) can phosphorylate ACC.

[0589] ACC can be regulated by allosteric conversion with citrate or palmitoyl-CoA. For example, citrate can be a positive effector (i.e., citrate can allosterically activate ACC). Citrate concentrations can be high when sufficient acetyl-CoA enters the Krebs cycle. Excess acetyl-CoA can then be converted to fatty acids via malonyl-CoA. Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA, a product of fatty acid synthase (FASN), can promote the inactive conformation of ACC, thereby reducing the production of malonyl-CoA (feedback inhibition process). AMP can regulate fatty acid synthesis by regulating the availability of malonyl-CoA. When insulin binds to its receptor, phosphatases are activated to dephosphorylate ACC, potentially eliminating the inhibitory effect.

[0590] The fatty acid synthase gene (FAS, OA-519, SDR27X1; MGC14367; MGC15706; also known as FASN) is involved in fatty acid synthesis. The enzyme encoded by this gene is a multifunctional protein of approximately 272 kDa with multiple domains, each possessing distinct enzymatic activity that can play a role in fatty acid biosynthesis. FASN can catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA to long-chain saturated fatty acids in the presence of NADPH. In some cancer cell lines, the FASN protein has been found to be fused with the estrogen receptor alpha (ER-alpha), where the N-terminus of FASN is fused in-frame with the C-terminus of ER-alpha.

[0591] The FASN protein can exist in the cytosol as a dimer of identical subunits. FASN consists of three catalytic domains in its N-terminal section: ketoacyl synthase (KS), malonyl / acetyltransferase (MAT), and dehydrase (DH). The N-terminal section is separated from four C-terminal domains (enoyl reductase (ER), ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE)) by a core region of approximately 600 amino acids. Crystal structures of mammalian fatty acid synthases have been reported (Maier T. et al. (2008) Science 321:1315-1322). Each of the catalytic domains of FASN can be targeted in the methods for treating viral infections of the invention provided.

[0592] The enzymatic steps of fatty acid synthesis may include decarboxyl condensation, reduction, dehydration, and further reduction, which can result in a saturated acyl moiety. NADPH can be a charge donor in reduction reactions.

[0593] Usefulness in metabolic disorders In various aspects, the therapeutic combinations described herein may be useful in the treatment of metabolic diseases. FASNs have been demonstrated to be involved in the regulation of glucose, lipid, and cholesterol metabolism. Mice with liver-specific inactivation of FASNs have normal physiological function unless fed a fat-free diet, in which case they develop hypoglycemia and fatty liver, both of which are reversible with dietary fat. (Chakravarhy, MV, et al. (2005) Cell Metabolism 1:309-322). Db / + mice fed a high-fructose diet showed reduced liver triglyceride levels and improved insulin sensitivity when treated for 28 days with platensimycin, a covalent inhibitor of FASNs. (Wu, M. et al. (2011) PNAS 108(13):5378-5383). Ambient glucose levels also decreased in db / db mice after treatment with platensimycin. These results provide evidence that inhibiting FASN may yield therapeutic benefits in animal models of diabetes and related metabolic disorders. Therefore, the disclosed FASN inhibitors may be useful in treating disorders characterized by dysregulation in these systems, including, but not limited to, steatosis and diabetes.

[0594] Non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD) is a condition in which the liver contains more than 5% fat by weight and is not caused by alcohol consumption. It currently affects approximately 20-30% of the population in the United States and the general Western world, and is associated with a significant increase in the incidence of cardiovascular disease, chronic kidney disease, and malignant tumors, not just liver disease. Obesity and metabolic syndrome are two major risk factors for NAFLD / MASLD, characterized by an imbalance between energy utilization and storage. This imbalance leads to dysregulation of metabolic pathways and inflammatory responses, which in turn promote further changes leading to liver damage and comorbidities. As metabolic syndrome progresses, NAFLD / MASLD can lead to more advanced liver disease, starting with non-alcoholic steatohepatitis / metabolic disorder-associated fatty liver disease (NASH / MASH), and subsequently progressing to severe liver diseases such as cirrhosis and hepatocellular carcinoma.

[0595] The synthesis of fatty acids in the liver, via a pathway called hepatic de novo lipidogenesis (DNL), is increased in individuals with metabolic syndrome and NAFLD / MASLD. The DNL pathway not only produces fatty acids that contribute to increased hepatic triglyceride storage, but the fatty acids produced, primarily saturated fatty acids, mainly palmitic acid (C16:0), contribute to signaling events that increase hepatic inflammation. Free palmitic acid fatty acids are also involved in hepatic inflammatory processes, including macrophage recruitment and activation of the endoplasmic reticulum stress response.

[0596] Thyroid hormones play a central role in liver function, influencing a range of health parameters from serum cholesterol and triglyceride levels to pathological fat accumulation in the liver, through the activation of their β-receptors in hepatocytes. THR-β action is key to proper liver function, including the regulation of mitochondrial activity such as hepatic fat breakdown and the control of normal, healthy mitochondrial levels. Patients with NASH / MASH have reduced THR-β receptor activity in the liver.

[0597] Accordingly, in various embodiments, the present disclosure provides methods for treating NASH / MASH or symptoms of NASH / MASH in subjects, the methods comprising administering to a subject in need of such treatment an effective amount of a fatty acid synthase inhibitor in combination with a thyroid hormone receptor agonist (e.g., a THR-beta agonist), wherein the thyroid hormone receptor agonist has formula (XXI), and the fatty acid synthase inhibitor has formulas (I), (II), (III), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or those shown in Table C-1, Table C-2, or Table C-3. In further embodiments, therapeutic combinations may be used for the manufacture of agents for treating NASH / MASH or the symptoms of NASH / MASH. In further embodiments, therapeutic combinations may be used to treat NASH / MASH or the symptoms of NASH / MASH. In some embodiments, NASH / MASH is established in the subject, and treatment with the compounds of the Disclosure may reduce or eliminate the symptoms and etiologies of NASH / MASH, such as systemic steatosis, fatty liver, steatohepatitis, inflammation, inflammation of the liver, lysosomal acid lipase deficiency, and cirrhosis. In other embodiments, the treatment may be used prophylactically to prevent the onset of non-alcoholic fatty liver disease / metabolic dysfunction-associated fatty liver disease (NAFLD / MASLD), the onset of NASH / MASH, the progression from NAFLD / MASLD to NASH / MASH, or to halt the progression of NASH / MASH disease. Whether prophylactic or in the case of established NAFLD / MASLD or NASH / MASH disease, treatment of fatty liver disease reduces risk factors associated with the establishment or progression of diabetes, liver cancer, cardiovascular disease, high triglycerides, kidney disease, and metabolic syndrome.

[0598] Accordingly, in some embodiments, the present disclosure provides a method for treating non-alcoholic steatohepatitis, comprising administering a fatty acid synthase inhibitor in combination with a thyroid hormone receptor agonist (e.g., a THR-beta agonist) to subjects in need of treatment for non-alcoholic steatohepatitis, wherein the thyroid hormone receptor agonist has formula (XXI), and the fatty acid synthase inhibitor has formula (I), (II), (III), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or those shown in Table C-1, Table C-2, or Table C-3, and the method comprises improving at least one symptom of established non-alcoholic steatohepatitis. In some embodiments, the method includes preventing the progression of at least one symptom of non-alcoholic steatohepatitis. In some embodiments, the symptom is selected from elevated AST levels, elevated ALT levels, elevated GGT levels, elevated liver triglyceride levels, elevated cholesterol levels, fatty liver, liver inflammation, liver ballooning, liver fibrosis, and NAFLD activity score.

[0599] Furthermore, as described in Example 6, the compounds of this disclosure (e.g., compound 002-386) have been found to reduce the expression of fibrosis-related genes in human hepatocytes. Thus, in some embodiments, the therapeutic combinations of this disclosure can reduce the expression of fibrosis-related genes (e.g., Col 1a1, αSMA, βPDGFR, TGFbR1, TIMP1, TIMP2, and / or MMP2). In some embodiments, gene expression may return after withdrawal of the compound (e.g., compound 002-386). Therefore, although we do not wish to be bound by theory, downregulation of fibrosis-related genes is not a toxic effect of the compounds of this disclosure.

[0600] Accordingly, in various embodiments, the Disclosure provides a method for reducing the expression of fibrosis-related genes in a subject (e.g., hepatocytes of the subject), the method comprising administering to a subject requiring such treatment an effective amount of a fatty acid synthase inhibitor in combination with a thyroid hormone receptor agonist (e.g., a THR-beta agonist), where the thyroid hormone receptor agonist has formula (XXI), and the fatty acid synthase inhibitor has formulas (I), (II), (III), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or those shown in Table C-1, Table C-2, or Table C-3. In further embodiments, the therapeutic combination may be used to manufacture a drug for reducing the expression of fibrosis-related genes (e.g., in hepatocytes). In a further embodiment, the therapeutic combination may be used to reduce the expression of fibrosis-related genes (for example, in hepatocytes).

[0601] Cardiovascular disease is closely linked to the progression of metabolic syndrome. However, NAFLD / MASLD is also a strong predictor of cardiovascular disease, independently of the presence of metabolic syndrome, including an increased risk of carotid artery atherosclerosis and endothelial dysfunction (Francis WB, et al., “De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose.” Biol. Rev. (2016), 91, pp. 452-468). NAFLD / MASLD has also been identified as an independent contributing factor to the development of type II diabetes. The incidence of prediabetes or type 2 diabetes is 2.6 times higher in individuals with NAFLD / MASLD, suggesting an independent role in the pathogenesis of type 2 diabetes other than early insulin resistance (Francis WB, Biol. Rev. (2016), pp. 452-468; Bae, JC, et al., “Combined effect of nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes.” Diabetes Care, 2011, 34, 727-729). Therefore, DNL is an important pathway for therapeutic interventions to mitigate outcomes associated with metabolic syndrome and NAFLD / MASLD (Bae, JC, Diabetes Care, 2011, 727-729).

[0602] NAFLD / MASLD and NASH / MASH are associated with obesity and diabetes in people who consume high-fat, high-calorie diets. Fatty acid synthesis in the liver (i.e., synthesized via the hepatic denominative lipogenesis (DNL) pathway) is increased in subjects with metabolic syndrome and NAFLD / MASLD. One of the key enzymes in DNL is fatty acid synthase (FASN). While there is a promising link between FASN, DNL, ​​and NAFLD / MASLD, there is little evidence that direct inhibition of FASN is an effective mechanism for treating NAFLD / MASLD or controlling the progression of fatty liver. Several literature reports on direct intervention of FASN with gene knockout inhibitors or small molecule inhibitors have yielded results suggesting exacerbation of fatty liver, which is the opposite of the effect needed to treat NAFLD / MASLD or NASH / MASH. These results suggest that FASN inhibition is not expected to alleviate fatty liver disease, nor is it an appropriate mechanism for controlling the underlying metabolic dysregulation or inflammatory signaling that promotes the progression of fatty liver disease.

[0603] For example, liver-specific FASN knockout mice have been shown to have normal livers when maintained on a standard diet. Unexpectedly, when fed a zero-fat / high-carbohydrate diet, the mice developed fatty liver (hepatic steatohepatia) and hypoglycemia, and it has been shown that complete inhibition of FASN in the liver of mammals fed a fat-restricted diet leads to the development of NAFLD / MASLD, a precursor to NASH / MASH (Chakravarthy, MV, et al., “New hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis,” Cell Metabol. 1(5), 2005, 309-322). When knockout mice were fed a normal diet, no effects on metabolism or the development of fatty liver due to complete inhibition of FASN by the knockout were observed. This indicates that FASN inhibition in the liver does not affect mammals consuming a fat-containing diet, or that it induces fatty liver conditions (leading to NAFLD / MASLD and NASH / MASH) in mammals consuming a low-fat / high-carbohydrate diet and provides the counter-effect necessary for treating NASH / MASH.

[0604] Small molecule inhibitors of FASNs have been used to assess insulin resistance and fatty liver. Recent studies in obese, insulin-resistant Zucker rats (a type II diabetes model) have shown that inhibition of de novo lipogenesis by small molecule FASN inhibitors did not improve insulin sensitivity and actually increased hepatic fat levels (i.e., hepatic steatohepatism). While FASN inhibitors have also been shown to inhibit de novo lipogenesis in the liver, they result in hepatic steatohepatism or increased fat deposition in the liver ("A Novel Fatty Acid Synthase Inhibitor (FASi) Suppresses De Novo Lipogenesis but induces Hepatic Steatosis, Dermatitis and does not enhance Insulin Sensitivity in Obese Zucker Rats," Am. Diabetes Assoc. 68th Scientific Sessions, June 6-10, 2008, San Francisco, CA, poster 58LB; WO2008059214). These studies have shown that direct inhibition of FASN reduces lipoprotein synthesis in the liver, but accelerates the development of NAFLD / MASLD and NASH / MASH in obese, diabetic mammals. Therefore, FASN inhibition is not expected to have a therapeutic effect on fatty liver disease in obese and diabetic individuals who are at the highest risk of developing NAFLD / MASLD and NASH / MASH.

[0605] The therapeutic methods and combinations described in this application control NAFLD / MASLD in rodents and reduce pro-inflammatory cytokines such as IL-1β, and Th 17 Anti-inflammatory T cells are produced from pro-inflammatory cells such as cellular cells. regIt is useful in regulating the differentiation of T cells into other cells. The FASN inhibitors of this application can be used to treat various forms of metabolic syndrome, including non-alcoholic liver disease (NAFLD / MASLD) and the more advanced non-alcoholic steatohepatitis (NASH / MASH). If left untreated, these liver dysfunction conditions can progress to serious liver diseases, including cirrhosis, in which fatty deposits, inflammation, fibrosis, and steatohepatitis are observed in the liver, and can eventually progress to liver cancer (hepatocellular carcinoma). Cirrhosis can cause direct health effects due to liver dysfunction, specifically spider angiomas or nevi, palmar erythema, gynecomastia, hypogonadism, ascites, hepatic halitosis, jaundice, splenomegaly, esophageal varices, Medusa's head, hepatic encephalopathy, and portal hypertension, which can lead to acute kidney injury (especially hepatorenal syndrome). In some embodiments, the therapeutic combinations of the present disclosure can be used to treat metabolic syndrome, non-alcoholic liver disease (NAFLD / MASLD), non-alcoholic steatohepatitis (NASH / MASH), cirrhosis, hepatic fibrosis, and / or liver cancer (hepatocellular carcinoma, cholangiocarcinoma). In some embodiments, the therapeutic combinations of the present disclosure may be used to treat type II diabetes. In some embodiments, the therapeutic combinations of the present disclosure may be used to treat atherosclerosis.

[0606] The therapeutic methods and combinations of this application can also be used to treat inflammatory diseases by inducing changes in inflammation-inducing cytokines. Examples of inflammatory diseases that can be treated with the therapeutic combinations of this application include, but are not limited to, IL-1 beta-containing inflammatory diseases such as diseases that respond to IL-1 beta blockade or diseases associated with increased IL-1 beta expression. In some embodiments, diseases or conditions in which IL-1 beta is elevated or regulated by IL-1 beta include: Familial Mediterranean Fever (FMF); Septic Arthritis, Pyoderma Gangrenosum, Acne (PAPA); Cryopyrin-Associated Periodic Syndromes (CAPS); High IgD Syndrome (HIDS); Adult and Juvenile Still's Disease; Schnitzler Syndrome; TNF Receptor-Associated Periodic Syndromes (TRAPS); Blau Syndrome; Sweet's Syndrome; IL-1 Receptor Antagonist Deficiency (DIRA); Relapsing Idiopathic Pericarditis; Macrophage Activation Syndrome (MAS); Urticarial Vasculitis The following are selected: antisynthetase syndrome; relapsing polychondritis; Behçet's disease; Erdheim-Chester syndrome (histiocytosis); synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO); rheumatoid arthritis; periodic fever, aphthous stomatitis, pharyngitis, lymphadenitis syndrome (Adenitis syndrome (PFAPA)); uric acid crystalline arthritis (gout); type 2 diabetes mellitus; smoldering multiple myeloma; post-myocardial infarction heart failure; osteoarthritis; transfusion-associated acute lung injury; ventilator-induced lung injury; pulmonary fibrosis including idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease (COPD); and asthma. In some embodiments, the disease or condition in which IL-1 beta is elevated or modulated by IL-1 beta is acne.

[0607] The therapeutic methods and combinations described herein treat diseases or conditions associated with elevated levels of inflammatory T cells and / or reduced or insufficient levels of anti-inflammatory T cells, or by diverting the differentiation of leukocytes (i.e., T cells) away from helper T cells and promoting the development of anti-inflammatory regulatory T cells (T cells). reg It can also be used to treat diseases or conditions in which increasing the number of cells is beneficial. reg Cells are essential for immune tolerance, and T helper cells (i.e., Th1, Th2, Th9, Th)17 They play a crucial role in limiting excessive immune and inflammatory responses carried out by (etc.). Therefore, shunting the differentiation of T helper cells into regulatory T cells by FASN inhibition can be used to treat inflammatory diseases.

[0608] The therapeutic method or combination of treatments described herein inhibits the maturation of T cells into T helper inflammatory cells (T helper cells that may be inhibited include Th1, Th2, Th9, and Th1). 17 Examples include, but are not limited to, T reg It can promote their differentiation into cells. Naive CD4+ cells differentiate into T helper and regulatory T cells to perform their immunological functions. Differentiation depends on the presence of cytokines. 17 T helper cells, such as those found in cellular cells, play a crucial role in the protective immune response against intracellular pathogens. However, excessive immune responses exerted by these T helper cells can also cause autoimmune and inflammatory diseases. Examples of immune-mediated diseases that can be treated with the FASN inhibitors of this application include, but are not limited to, psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease (IBD), chronic obstructive pulmonary disease (COPD), asthma, tumorigenesis, and graft rejection (Laura, A., et.al., “Th17 cells in human disease,” Immunol. Rev. 223, 2008, 87-113; Lee, Y., et.al., “Unexpected targets and triggers of autoimmunity.” J. Clin. Immunol., 34 Suppl 1, 2014, S56-60).

[0609] In various embodiments, the disclosed therapeutic methods and combinations are useful for the treatment of non-alcoholic fatty acid disease (NAFLD / MASLD), non-alcoholic steatohepatitis (NASH / MASH), steatosis, and diabetes. In one embodiment, the disclosure relates to a method for treating non-alcoholic steatohepatitis (NASH / MASH) in combination with a FASN inhibitor compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) in combination with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0610] In another embodiment, the Disclosure relates to a method for treating non-alcoholic steatohepatitis (NASH / MASH) in combination with a FASN inhibitor compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0611] In another embodiment, the Disclosure relates to a method for treating metabolic syndrome. In one embodiment, the Disclosure relates to a method for treating metabolic syndrome in combination with a compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0612] In another embodiment, the Disclosure relates to a method for treating type II diabetes. In one embodiment, the Disclosure relates to a method for treating type II diabetes in combination with a compound of the Disclosure (e.g., a compound of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0613] In another embodiment, the Disclosure relates to a method for treating atherosclerosis. In one embodiment, the Disclosure relates to a method for treating atherosclerosis by combining a compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0614] In another embodiment, the Disclosure relates to a method for treating cirrhosis of the liver. In one embodiment, the Disclosure relates to a method for treating cirrhosis of the liver by combining a compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0615] In another embodiment, the Disclosure relates to a method for treating hepatic fibrosis. In one embodiment, the Disclosure relates to a method for treating hepatic fibrosis in combination with a compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0616] In another embodiment, the Disclosure relates to a method for treating inflammation. In one embodiment, the Disclosure relates to a method for treating inflammation by combining a compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)).

[0617] In another embodiment, the Disclosure relates to a method for treating a disease or condition in which interleukin-1-beta (IL1β) levels are elevated. In one embodiment, the Disclosure relates to a method for treating a disease or condition in which interleukin-1-beta (IL1β) levels are elevated by combining a compound of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (i.e., one of formula (XXI)). In some embodiments, diseases or conditions with elevated interleukin-1 beta (IL1β) levels include familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrenosum, and acne (PAPA), cryopyrin-associated periodic syndromes (CAPS), hyper-IgD syndrome (HIDS), adult- and juvenile Still's disease, Schnitzler syndrome, TNF receptor-associated periodic syndromes (TRAPS), Blau syndrome; Sweet's syndrome, IL-1 receptor antagonist deficiency (DIRA), relapsing idiopathic pericarditis, macrophage activation syndrome (MAS), and urticarial vasculitis. The following conditions are selected: antisynthetase syndrome, relapsing polychondritis, Behçet's disease, Erdheim-Chester syndrome (histiocytosis), synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, lymphadenitis syndrome (Adenitis syndrome (PFAPA)), uric acid crystalline arthritis (gout), type 2 diabetes mellitus, smoldering multiple myeloma, post-myocardial infarction heart failure, osteoarthritis, transfusion-related acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

[0618] In another embodiment, the present disclosure relates to the T helper (T h)The present disclosure relates to a method for treating a disease or condition in which cellular levels are elevated.In one embodiment, the present disclosure describes a compound of the present disclosure (e.g., a compound of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) in combination with a thyroid receptor hormone agonist (i.e., one of formula (XXI)) to form a T helper (T h This relates to a method for treating a disease or condition in which cellular levels are elevated. In some embodiments, T helper (T h Diseases or conditions in which cellular levels are elevated are selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and graft rejection.

[0619] In another embodiment, the present disclosure relates to regulatory T cells (T reg The present disclosure relates to a method for treating a disease or condition in which regulatory T cells (T) are reduced or suppressed. In one embodiment, the present disclosure describes a compound of the present disclosure (e.g., a compound of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) in combination with a thyroid receptor hormone agonist (i.e., one of formula (XXI)) to treat regulatory T cells (T) reg The present invention relates to a method for treating a disease or condition in which regulatory T cells (T) are reduced or suppressed. In some embodiments, regulatory T cells (T) are used. reg Diseases or conditions in which ) are reduced or suppressed are selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and graft rejection.

[0620] Anticancer activity In various embodiments, the therapeutic combinations disclosed are useful for the treatment of liver cancer. In one embodiment, the disclosure relates to a method for treating liver cancer in combination with a fatty acid synthase inhibitor of the Disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) a thyroid receptor hormone agonist (e.g., a compound of formula (XXI)). In some embodiments, the liver cancer is liver cancer that develops from NAFLD / MASLD or NASH / MASH. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma that develops from NAFLD / MASLD or NASH / MASH. In some embodiments, the liver cancer is cholangiocarcinoma.

[0621] Rapidly proliferating cancer cells activate the fatty acid synthesis pathway to supply high levels of lipids necessary for membrane assembly and oxidative metabolism (Flavin, R. et al. (2010) Future Oncology. 6(4):551-562). Inhibitors of fatty acid synthesis have shown in vivo activity in preclinical cancer models (Orita, H. et al. (2007) Clinical Cancer Research. 13(23):7139-7145, and Puig, T. et al. (2011) Breast Cancer Research, 13(6):R131). Furthermore, fatty acid synthesis assists in new angiogenesis, and inhibitors of this pathway have activity in in vitro models of angiogenesis (Browne, CD, et al. (2006) The FASEB Journal, 20(12):2027-2035). The compounds of this disclosure demonstrated the ability to selectively induce cell cycle arrest in HUVEC cells without causing systemic cell death by apoptosis. Please refer to the examples.

[0622] The cancer treatment of the present invention includes an antitumor effect that can be evaluated by conventional means such as response rate, time to disease progression, and / or survival rate. The antitumor effect of the present invention includes, but is not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor reduction, increased time to tumor regrowth after discontinuation of treatment, and deceleration of disease progression. For example, when the combination of the present invention is administered to a warm-blooded animal such as a human requiring treatment for cancer with solid tumors, such a treatment method would produce an effect that can be measured, for example, by one or more of the degree of antitumor effect, response rate, time to disease progression, and survival rate.

[0623] In various embodiments, the disclosed therapeutic combinations are useful for reducing triglycerides in subjects requiring a reduction in triglycerides. In one embodiment, the disclosure relates to a method for reducing triglycerides by combining a fatty acid synthase inhibitor of the disclosure (e.g., compounds of formula (I), (II), (III), (IV), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX)) with a thyroid receptor hormone agonist (e.g., a compound of formula (XXI)).

[0624] Inhibition of fatty acid synthesis Reducing the activity of the fatty acid synthesis pathway, such as FASN gene expression or FASN protein activity, is also called "inhibiting" the fatty acid synthesis pathway, such as FASN gene expression or FASN protein activity. The term "inhibit" and its grammatical conjugations, such as "inhibitory," refer to a reduction in fatty acid synthesis activity, such as FASN gene expression or FASN protein activity, without requiring complete inhibition. In another aspect, such a reduction is at least 50%, at least 75%, at least 90%, and can reach at least 95% of the enzyme activity in the absence of an inhibitor, for example. Conversely, the phrase "not inhibit" and its grammatical conjugations refer to a situation in which enzyme activity is reduced by less than 20%, less than 10%, and possibly less than 5%, in the presence of a drug. Furthermore, the phrase "substantially not inhibit" and its grammatical conjugations refer to a situation in which enzyme activity is reduced by less than 30%, less than 20%, and possibly less than 10%, in the presence of a drug.

[0625] Increasing the activity of the fatty acid synthesis pathway, for example, FASN gene expression or FASN protein activity, is also called "activating" the fatty acid synthesis pathway, for example, FASN gene expression or FASN protein activity. The term "activated" and its grammatical conjugations such as "activate" refer to an increase in the activity of the fatty acid synthesis pathway, for example, FASN gene expression or FASN protein activity, without requiring complete activation. In another aspect, such an increase is at least 50%, at least 75%, at least 90%, and can reach at least 95% of the enzyme activity in the absence of an activating effect, for example, in the absence of an activator. Conversely, the phrase "not activated" and its grammatical conjugations refer to a situation in which enzyme activity increases by less than 20%, less than 10%, and possibly less than 5%, in the presence of a drug. Furthermore, the phrase "substantially unactivated" and its grammatical conjugations refer to a situation in which enzyme activity increases by less than 30%, less than 20%, and possibly less than 10%, in the presence of a drug.

[0626] The ability to reduce enzyme activity is a measure of how potent or active a drug or combination of drugs is against that enzyme. Efficacy is measured by cell-free, whole-cell, and / or in vivo assays using IC50, K50, and K50. i It can be measured with respect to the and / or ED50 value. The IC50 value represents the concentration of the drug required to inhibit enzyme activity by half (50%) under a given set of conditions. i The value represents the equilibrium affinity constant for the binding of the inhibitor to the enzyme. The ED50 value represents the dose of the drug required to produce a maximum half-dose response in a biological assay. Further details of these measures are understood by those skilled in the art and can be found in standard textbooks on biochemistry, enzymology, etc.

[0627] Formulation, route of administration, and effective dose Yet another aspect of the present invention relates to formulations, routes of administration, and effective doses of the compounds of the present invention.

[0628] In some embodiments of the method of the present disclosure, a fatty acid synthase inhibitor and a thyroid receptor hormone agonist (e.g., a thyroid receptor hormone-beta agonist, e.g., a compound of formula (XXI)) are administered sequentially.

[0629] In some embodiments of the methods of the present disclosure, a fatty acid synthase inhibitor and a thyroid receptor hormone agonist (e.g., a thyroid receptor hormone-beta agonist, e.g., a compound of formula (XXI)) are administered simultaneously.

[0630] In some embodiments of the methods of the present disclosure, a fatty acid synthase inhibitor and a thyroid receptor hormone agonist (e.g., a thyroid receptor hormone-beta agonist, e.g., a compound of formula (XXI)) are formulated into separate dosage forms.

[0631] In some embodiments of the methods of the present disclosure, the fatty acid synthase inhibitor and the thyroid receptor hormone agonist (e.g., a thyroid receptor hormone-beta agonist, e.g., a compound of formula (XXI)) are formulated into the same dosage form.

[0632] The dosage forms intended herein may include any of the doses and combinations of doses listed in the methods described herein.

[0633] The compounds of the present invention can be administered as pharmaceutical formulations suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal patch, pulmonary, vaginal, suppository, or parenteral (including intramuscular, intra-arterial, intrathecal, intradermal, intraperitoneal, subcutaneous, and intravenous) administration, or as forms suitable for aerosolization, inhalation, or inhalation. General information regarding drug delivery systems is described in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lipencot Williams & Wilkins, Baltimore Md. (1999)).

[0634] In various embodiments, the pharmaceutical composition includes carriers and excipients (including, but not limited to, buffers, carbohydrates, mannitol, proteins, polypeptides, or amino acids such as glycine, antioxidants, bacteriostatic agents, chelating agents, suspending agents, thickeners, and / or preservatives), water, petroleum-derived, animal-derived, plant-derived, or synthetic oils (such as peanut oil, soybean oil, mineral oil, and sesame oil), physiological saline, glucose aqueous solutions, and glycerol solutions...

Claims

1. A method for treating fatty liver disease in a subject requiring treatment for the disease, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

2. A method for treating non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in a subject requiring treatment for the same condition, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist.

3. The method according to claim 2, wherein treating the non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) includes preventing the progression of at least one symptom of the non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH).

4. The method according to claim 2 or 3, wherein the symptoms are selected from elevated AST levels, elevated ALT levels, elevated GGT levels, elevated liver triglyceride levels, elevated cholesterol levels, fatty liver, liver inflammation, liver ballooning, liver fibrosis, and NAFLD activity score.

5. A method for treating non-alcoholic fatty liver disease / metabolic disorder-associated fatty liver disease (NAFLD / MASLD) in a subject requiring treatment for the same condition, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist.

6. A method for treating metabolic syndrome in a subject requiring treatment for metabolic syndrome, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

7. A method for treating type II diabetes in a subject requiring treatment for type II diabetes, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

8. A method for treating atherosclerosis in a subject requiring treatment for atherosclerosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

9. A method for treating liver cirrhosis in a subject requiring treatment for liver cirrhosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

10. A method for treating liver cancer in a subject requiring treatment for liver cancer, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

11. The method according to claim 10, wherein the liver cancer originates from NASH / MASH or NAFLD / MASLD.

12. The method according to claim 11, wherein the liver cancer is hepatocellular carcinoma.

13. The method according to claim 12, wherein the hepatocellular carcinoma originates from NASH / MASH or NAFLD / MASLD.

14. The method according to claim 11, wherein the liver cancer is bile duct cancer.

15. A method for treating a disease or condition in a subject requiring treatment for a disease or condition in which interleukin-1 beta (IL-1β) levels are elevated, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist.

16. The aforementioned diseases or conditions include Familial Mediterranean Fever (FMF), Septic Arthritis, Pyoderma Gangrenospa, Acne (PAPA), Cryopyrin-Associated Periodic Syndrome (CAPS), Hypertension Infectious Disease (HIDS), Adult and Juvenile Still's Disease, Schnitzler Syndrome, TNF Receptor-Associated Periodic Syndrome (TRAPS), Blau Syndrome; Sweet's Syndrome, IL-1 Receptor Antagonist Deficiency (DIRA), Relapsing Idiopathic Pericarditis, Macrophage Activation Syndrome (MAS), Urticarial Vasculitis, Antisynthetase Syndrome, Relapsing Polychondritis, and B. The method according to claim 15, selected from Chet's disease, Erdheim-Chester syndrome (histiocytosis), synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, lymphadenitis syndrome (Adenitis syndrome (PFAPA)), uric acid crystalline arthritis (gout), type 2 diabetes mellitus, smoldering multiple myeloma, post-myocardial infarction heart failure, osteoarthritis, transfusion-associated acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

17. Regulatory T cells (T ｒｅｇ A method for treating a disease or condition in a subject requiring treatment, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject, wherein the aforementioned disease or condition is reduced or suppressed.

18. Said T ｒｅｇ The method according to claim 17, wherein cells are suppressed.

19. T Helper (T ｈ A method for treating a disease or condition in a subject requiring treatment of a disease or condition in which cellular levels are elevated, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

20. The aforementioned elevated T helper cells, ｈ 1. T ｈ 2. T ｈ 9, or T ｈ The method according to claim 19, wherein the method is 17.

21. The method according to claim 20, wherein the elevated T helper cells are T17.

22. The method according to any one of claims 17 to 21, wherein the disease or condition is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumor formation, and graft rejection.

23. A method for improving established non-alcoholic steatohepatitis / metabolic disorder-associated steatohepatitis (NASH / MASH) in subjects requiring improvement of said subject.

24. A method for treating liver fibrosis in a subject requiring treatment for liver fibrosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

25. A method for reducing the expression of fibrosis-related genes in a subject requiring a reduction in the expression of said fibrosis-related genes, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

26. A method for reducing triglycerides in a subject requiring a reduction in triglycerides, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

27. A method for improving or restoring liver function in a subject requiring improvement or restoration of liver function, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subject.

28. A method for treating moderate to severe fibrosis-associated NASH / MASH in subjects requiring treatment of NASH / MASH with moderate to severe fibrosis, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-beta agonist to the subjects.

29. The method according to claim 28, wherein the subject improved liver fibrosis by one or more stages without worsening NASH / MASH.

30. The method according to claim 28, wherein the subject has resolved NASH / MASH without worsening fibrosis.

31. The aforementioned thyroid hormone receptor-beta agonist is given by formula (XXI): 【Chemistry 1】 or having a pharmaceutically acceptable salt thereof, in the formula, A Ａ is O, CH ２ , S, SO, or SO ２ and X Ａ and Y Ａ These are, independently, Br, Cl, and CH ３ Selected from the group consisting of, R １Ａ is, -(CH ２ ) ｎ COOH, -OCH ２ COOH, -NHC(=O)COOH, -NHCH ２ COOH, 【Chemistry 2】 Selected from the group consisting of, Z Ａ is H, or -C≡N, R ２Ａ It is a lower alkyl having 1 to 4 carbon atoms. R ３ is H or a lower alkyl, n is either 1 or 2, The method according to any one of claims 1 to 30, wherein p is 1 or 2.

32. The aforementioned fatty acid synthase inhibitor (a) Formula (IX) 【Transformation 3】 Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R １ H, -CN, halogen, C １ ~C ４ Linear or branched alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O-(C １ ~C ４ (Linear or branched alkyl), where, C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. The aforementioned R １ However, if it is not H, -CN, or halogen, it may be substituted with one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is a linear or branched alkyl group. R ３ is H, -OH, or a halogen, R ２１ H, halogen, C １ ~C ４ Linear or branched alkyl, C ３ ~C ５ It is a cycloalkyl, where the C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. R ２２ is H, halogen, or C １ ~C ２ It is alkyl, R ２４ H, C １ ~C ４ Linear or branched alkyl, -(C １ ~C ４ Alkyl) ｔ -OH, -(C １ ~C ４ Alkyl) ｔ -O ｔ - (C ３ ~C ５ Cycloalkyl), or -(C １ ~C ４ Alkyl) ｔ -O-(C １ ~C ４ (Linear or branched alkyl), where, t is either 0 or 1. Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. L １ CR ２３ or N; L ２ is CH or N, L １ or L ２ At least one of them is N, and R ２３ is H or C １ ~C ４ It is a linear or branched alkyl group, or (b) Formula (X): 【Chemistry 4】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R １ H, -CN, halogen, C １ ~C ４ Linear or branched alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O-(C １ ~C ４ (Linear or branched alkyl), where, Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. The aforementioned R １ However, if it is not H, -CN, or halogen, it may be substituted with one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is a linear or branched alkyl group. R ３ is H, -OH, or a halogen, L ３ is C(R ６０ ) ２ , O, or NR ５０ and Each R ６０ is independently H, -OH, -CN, -O ｔ -(C ３ ~C ５ cycloalkyl), -O-(C １ ~C ４ linear or branched alkyl), or -C(O)-N(R ６０１ ) ２ wherein t is either 0 or 1. Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. Each R ５０ These are independently H, -C(O)-O ｔ - (C １ ~C ４ (Linear or branched alkyl), -C(O)-O ｔ - (C ３ ~C ５ C may contain a cyclic alkyl group, oxygen, or nitrogen heteroatom. ３ ~C ５ Cyclic alkyl, -C(O)-N(R ５０１ ) ２ , C １ ~C ４ It is a linear or branched alkyl group, where, t is either 0 or 1. Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. n is 1, 2, or 3. m is either 1 or 2. R ２１ H, halogen, C １ ~C ４ Linear or branched alkyl, C ３ ~C ５ It is a cycloalkyl, where the C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. R ２２ H, halogen, C １ ~C ２ It is alkyl, Each R ２６ These are independently -OH, -CN, halogen, and C １ ~C ４ Linear or branched alkyl, -(C １ ~C ４ Alkyl) ｔ -O ｔ - (C ３ ~C ５ Cycloalkyl), - (C １ ~C ４ Alkyl) ｔ -O-(C １ ~C ４ (Linear or branched alkyl), -C(O)-O ｔ - (C １ ~C ４ Alkyl), or -C(O)-N(R ５０１ ) ２ And here, t is either 0 or 1. Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. s is 0, 1, or 2. R ６０１ and R ５０１ These are H or C, each independently. １ ~C ４ It is a linear or branched alkyl group. Here, R ２６ , R ６０ , R ５０ , R ５０１ , and R ６０１ Two of these may be arbitrarily bonded to form a ring, where R ２６ , the R ６０ , the R ５０ , the R ５０１ , and the R ６０１ Two of them are two R ２６ , two R ６０ , two R ５０ , two R ５０１ , or two R's ６０１ It may be so, or (c) Formula (VI-J) 【Transformation 5】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R １ H, -CN, halogen, C １ ~C ４ Linear or branched alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O-(C １ ~C ４ (Linear or branched alkyl), where, Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. The aforementioned R １ However, if it is not H, -CN, or halogen, it may be substituted with one or more halogens. Each R ２ These are independently H, halogen, or C １ ~C ４ It is a linear or branched alkyl group. R ３ is H, -OH, or a halogen, R ２１ These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R ２２ is H, halogen, or C １ ~C ２ It is alkyl, R ３５ is -C(O)-R ３５１ , -C(O)-NHR ３５１ , -C(O)-OR ３５１ , or S(O) ２ R ３５１ And, R ３５１ C １ ~C ６ They are linear or branched alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or (d) Equation (XII): 【Transformation 6】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Transformation 7】 And, Ar is, 【Transformation 8】 And, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, R ２４ is H, -CN, -(C １ ~C ４ Alkyl)-CN,C １ ~C ４ Alkyl, C １ ~C ４ Alkyl-OH,-(C １ ~C ４ Alkyl)-N(R ２４１ ) ２ , - (C １ ~C ４ Alkyl) ｔ -O ｕ - (C ３ ~C ６ Cycloalkyl), - (C １ ~C ４ Alkyl) ｔ -O ｕ - (4- to 6-membered heterogeneous ring) or - (C １ ~C ４ Alkyl)-O-(C １ ~C ４ It is alkyl, and here, t is either 0 or 1. u is either 0 or 1, However, if u is 1, then t is 1, Each R ２４１ H or C １ ~C ２ It is alkyl, and R ２５ is halogen, -CN, -(C １ -C ４ Alkyl)-CN,C １ ~C ２ Alkyl or cyclopropyl, or (e) Formula (XIII): 【Chemistry 9】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Chemistry 10】 And, Ar is, 【Chemistry 11】 And, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, and R ２４ and R ２５ These are H, halogen, -CN, and -(C) respectively, independently. １ ~C ４ Alkyl)-CN,C １ ~C ４ Alkyl, C １ ~C ４ Alkyl-OH,-(C １ ~C ４ Alkyl)-N(R ２４１ ) ２ , - (C １ ~C ４ Alkyl) ｔ -O ｕ - (C ３ ~C ５ Cycloalkyl), - (C １ ~C ４ Alkyl) ｔ -O ｕ - (4- to 6-membered complex ring), or - (C １ ~C ４ Alkyl) ｔ -O-(C １ ~C ４ It is alkyl, and here, Each t is independently either 0 or 1. Each u is independently either 0 or 1. Each R ２４１ H or C １ ~C ２ It is alkyl, or (f) Formula (XIV): 【Chemistry 12】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Chemistry 13】 And, Ar is, 【Chemistry 14】 However, the above L-Ar is 【Chemistry 15】 If so, Ar is 【Chemistry 16】 Instead, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, and R ２４ H, C １ ~C ４ Alkyl, -(C １ ~C ４ Alkyl)-OH,-(C １ ~C ４ Alkyl) ｔ --N(R) ２４１ ) ２ , - (C １ ~C ４ Alkyl) ｔ -O ｔ - (C ３ ~C ５ Cycloalkyl), - (C １ ~C ４ Alkyl) ｔ -O ｔ - (4- to 6-membered complex ring), or - (C １ ~C ４ Alkyl) ｔ -O-(C １ ~C ４ It is alkyl, and here, Each t is independently either 0 or 1. Each R ２４１ H or C １ ~C ２ It is alkyl, or (g) Formula (XV): 【Chemistry 17】 Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L ３ is, -CH ２ -----CHR ５０ -, -O-, -NR ５０ -, -NC(O)R ５０ - or -NC(O)OR ５０ - and here, R ５０ is C １ ~C ６ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, n is 1, 2, or 3. m is either 1 or 2, where n + m ≥ 3. L-Ar is [Chemistry 18] And, Ar is, 【Chemistry 19】 However, the above L-Ar is 【Chemistry 20】 If so, Ar is 【Chemistry 21】 Instead, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, or, (h) Formula (XVI): 【Chemistry 22】 Does it have the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Chemistry 23】 And, Ar is, 【Chemistry 24】 And, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, and R ２４ and R ２５ These are H and -C, respectively, independently. １ ~C ４ Alkyl, or halogen, or (i) Formula (XVII): 【Chemistry 25】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Chemistry 26】 And, Ar is, 【Chemistry 27】 However, the above L-Ar is 【Chemistry 28】 If so, Ar is 【Chemistry 29】 Instead, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, and R ２４ H, C １ ~C ４ Alkyl, -(C １ ~C ４ Alkyl)-OH,-(C １ ~C ４ Alkyl)-N(R ２４１ ) ２ , - (C １ ~C ４ Alkyl) ｔ -O ｕ - (C ３ ~C ５ Cycloalkyl), - (C １ ~C ４ Alkyl) ｔ -O ｕ - (4- to 6-membered complex ring), or - (C １ ~C ４ Alkyl)-O-(C １ ~C ４ It is alkyl, and here, t is either 0 or 1. u is either 0 or 1, However, if u is 1, then t is 1, R ２４１ is H or C １ ~C ６ It is alkyl, or (j) Formula (XVIII): 【Transformation 30】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Chemistry 31】 And, Ar is, 【Chemistry 32】 However, the above L-Ar is 【Transformation 33】 If so, Ar is 【Transformation 34】 Instead, L ２ -NHR ３５ or -C(O)NHR ３５１ And here, R ３５１ C １ ~C ６ Alkyl, C ３ ~C ５ They are cycloalkyl, 4-6 membered heterocyclic, aryl, or heteroaryl. Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, and R ３５ is -C(O)R ３５１ , -C(O)NHR ３５１ , C(O)OR ３５１ , or S(O) ２ R ３５１ And here, R ３５１ C １ ~C ６ Alkyl, C ３ ~C ５ It is a cycloalkyl, a 4- to 6-membered heterocyclic, aryl, or heteroaryl, or (k) Formula (XIX): 【Chemistry 35】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, W, X, Y, and Z are each independently -N- or -CR ２６ -, provided that two or fewer of the above W, X, Y, and Z are -N-, Each R ２６ H and C are independent. １ ~C ４ Alkyl, -O-(C １ ~C ４ Alkyl), -N(R ２７ ) ２ , -S(O) ２ - (C １ ~C ４ Alkyl), or -C(O)-(C １ ~C ４ It is alkyl, Each R ２７ These are, independently, H or C １ ~C ４ Alkyl or both R ２７ C １ ~C ４ They are alkyl groups, and together with the N atoms to which they are bonded, they form a 3-6 membered ring, where the ring may contain one oxygen atom as a member of the ring. Ar is, 【Transformation 36】 And, Het is a 5-6 member heteroaryl compound. R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R １１ is H or -CH ３ And, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, or, (l) Formula (XX): 【Chemistry 37】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, L-Ar is 【Transformation 38】 And, Ar is, 【Chemistry 39】 And, R １ H, -CN, halogen, C １ ~C ４ Alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O- (4-6 membered heterocycle), or -O- (C １ ~C ４ Alkyl) and here, R １ If is not H, -CN, or halogen, then R １ It may be replaced by one or more halogens. Each R ２ These are independently hydrogen, halogen, or C １ ~C ４ It is alkyl, R ３ is H or F, R ２１ H, halogen, C １ ~C ４ Alkyl, C ３ ~C ５ It is a cycloalkyl or a 4-6 membered heterocycle, R ２２ is H, halogen, or C １ ~C ２ It is alkyl, R ２４ is, -O-(C １ ~C ４ Alkyl), -O-(C １ ~C ４ Alkyl)-O-(C １ ~C ４ Alkyl), -O-(C ３ ~C ５ Cycloalkyl), or -O- (4-6 membered heterocycle), where R ２４ may be substituted with one or more hydroxyls or halogens, R ２５ H, halogen, C １ ~C ４ Alkyl, or C ３ ~C ５ It is a cycloalkyl, where R ２５ may be substituted with one or more halogens, or (m) Formula (XI): 【Chemistry 40】 It has the formula, or having a pharmaceutically acceptable salt thereof, in the formula, R １ H, -CN, halogen, C １ ~C ４ Linear or branched alkyl, -O-(C ３ ~C ５ Cycloalkyl), -O-(C １ ~C ４ (Linear or branched alkyl), where, Said C ３ ~C ５ Cycloalkyls may contain oxygen or nitrogen heteroatoms. The aforementioned R １ However, if it is not H, -CN, or halogen, it may be substituted with one or more halogens. Each R ２ These are independently H, halogen, or C １ ~C ４ It is a linear or branched alkyl group. R ３ is H, -OH, or a halogen, R ２１ These are cyclobutyl, azetidine-1-yl, or cyclopropyl. R ２２ H, halogen, C １ ~C ２ It is alkyl, and R ３５１ C １ ~C ２ Alkyl or C ２ -O-(C １ Or C ２ The method according to any one of claims 1 to 31, wherein the alkyl group is...

33. The aforementioned fatty acid synthase inhibitor 【Chemistry 41】 The method according to any one of claims 1 to 32.

34. The aforementioned fatty acid synthase inhibitor 【Chemistry 42】 The method according to any one of claims 1 to 32.

35. The method according to any one of claims 1 to 34, wherein the thyroid hormone receptor-beta agonist is selected from resmethilone, VK2809, TERN-501, and ALG-055009.

36. The aforementioned thyroid hormone receptor-beta agonist is given by formula: 【Chemistry 43】 The method according to any one of claims 1 to 34, wherein the resmethionine is having the properties of the resmethionine.

37. The method according to any one of claims 1 to 36, wherein the fatty acid synthase inhibitor and the thyroid hormone receptor-beta agonist are administered sequentially.

38. The method according to any one of claims 1 to 36, wherein the fatty acid synthase inhibitor and the thyroid hormone receptor-beta agonist are administered simultaneously.

39. The method according to claim 38, wherein the FASN inhibitor and the thyroid hormone receptor-beta agonist are administered on the same administration schedule.

40. The method according to claim 38, wherein the FASN inhibitor and the thyroid hormone receptor-beta agonist are administered according to different administration schedules.

41. The method according to any one of claims 1 to 40, wherein the fatty acid synthase inhibitor and the thyroid hormone receptor-beta agonist are formulated into separate dosage forms.

42. The method according to any one of claims 1 to 38, wherein the fatty acid synthase inhibitor and the thyroid hormone receptor-beta agonist are formulated into the same dosage form.

43. The method according to any one of claims 1 to 39, wherein the resmethylome is a polymorph of form A.

44. The method according to any one of claims 1 to 43, wherein the FASN inhibitor and the thyroid hormone receptor beta-agonist are administered in synergistically effective amounts.

45. The method according to any one of claims 1 to 44, wherein the FASN inhibitor is administered in a dose of 10 to 100 mg.

46. The method according to any one of claims 1 to 44, wherein the FASN inhibitor is administered in a dose of 10 to 50 mg.

47. The method according to any one of claims 1 to 44, wherein the FASN inhibitor is administered in a dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.

48. The method according to any one of claims 1 to 44, wherein the FASN inhibitor is administered in a dose of 50 mg.

49. The method according to any one of claims 1 to 48, wherein the FASN inhibitor is administered once or twice daily.

50. The method according to any one of claims 1 to 48, wherein the FASN inhibitor is administered once daily.

51. The method according to any one of claims 1 to 50, wherein the FASN inhibitor is administered orally.

52. The method according to any one of claims 1 to 51, wherein the thyroid hormone receptor beta-agonist is administered in a dose equivalent to that of a monotherapy dose indicated for treating NASH / MASH.

53. The method according to any one of claims 1 to 51, wherein the thyroid hormone receptor beta-agonist is administered at a dose of 10% to 90% of the monotherapy dose indicated for treating NASH / MASH.

54. The method according to any one of claims 1 to 51, wherein the thyroid hormone receptor beta-agonist is administered at a dose of 80 mg once daily to patients weighing 100 kg or less, and at a dose of 100 mg once daily to patients weighing 100 kg or more.

55. The method according to any one of claims 1 to 54, wherein the subject is diagnosed with a co-existing disease.

56. The method according to claim 55, wherein the comorbidity is obesity, type 2 diabetes, or a combination thereof.

57. The method according to claim 55, wherein the co-existing condition is obesity.

58. The method according to claim 55, wherein the comorbidity is type 2 diabetes.

59. The method according to claim 55, wherein the comorbidity is a combination of obesity and type 2 diabetes.

60. A pharmaceutical preparation comprising compound 001-152 (denifanstat) or a pharmaceutically acceptable salt thereof, and compound A (resmethirome) or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical preparation comprising compound 001-152 (denifanstat) or a pharmaceutically acceptable salt thereof, and a polymorph of form A of compound A (resmethirome).

62. A pharmaceutical preparation comprising a FASN inhibitor or a pharmaceutically acceptable salt thereof, and a thyroid hormone receptor agonist or a pharmaceutically acceptable salt thereof.

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