Combination therapy of FASN inhibitors and thyroid hormone receptor agonists

Abstract

Therapeutic combinations of a fatty acid synthesis modulator and a thyroid hormone receptor agonist are provided. The combinations are useful in the treatment of conditions, including metabolic conditions and liver conditions, such as non-alcoholic steatohepatitis / metabolic dysfunction associated steatohepatitis (NASH / MASH).

Description

Cross-reference to related applications

[0001] This application claims priority and benefit to U.S. Provisional Application No. 63 / 509,267, filed June 20, 2023, the contents of which are hereby incorporated by reference in their entirety. Technical Field

[0002] This disclosure generally relates to a treatment combination of a fatty acid synthase inhibitor and a thyroid hormone receptor agonist for the treatment of liver disease. Background Technology

[0003] Metabolic dysfunction-associated fatty liver disease (MASLD) (formerly known as nonalcoholic liver disease (NAFLD)), a condition in which the liver contains more than 5% fat and is not caused by excessive alcohol consumption, currently affects approximately 20-30% of the population in the United States and throughout the Western world. It is significantly associated with an increased risk of cardiovascular disease (i.e., carotid atherosclerotic plaques and endothelial dysfunction), chronic kidney disease, and malignancies. Obesity, type 2 diabetes, and metabolic syndrome are the three main risk factors for NAFLD / MASLD, characterized by an imbalance between energy utilization and storage. This imbalance leads to metabolic pathway dysregulation and inflammatory responses, which further drive changes leading to liver damage and comorbidities. As metabolic syndrome progresses, NAFLD / MASLD can lead to more severe liver disease, initially metabolic dysfunction-associated steatohepatitis (MASH) (formerly known as nonalcoholic steatohepatitis (NASH)), and may then progress to severe cirrhosis and hepatocellular carcinoma.

[0004] In 2023, the Global Liver Medicine Association and patient groups officially decided to rename non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MASLD) and non-alcoholic steatohepatitis (NASH) as metabolic dysfunction-associated steatohepatitis (MASH). Additionally, the general term fatty liver disease (SLD) was established to encompass various types of liver diseases associated with fat accumulation in the liver.

[0005] The synthesis of fatty acids in the liver (a pathway known as de novo lipogenesis (DNL)) is increased in subjects with metabolic syndrome and NAFLD / MASLD (Donnelly, K. L 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, J. E 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 elevated hepatic triglyceride storage, but also produces saturated fatty acids, primarily palmitic acid, which contribute to increased liver inflammatory signaling events (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-Liver Conference, San Francisco, CA, USA, November 13–17, 2015). One of the key enzymes in the DNL pathway is fatty acid synthase (FASN), which is specifically responsible for synthesizing palmitic acid. Therefore, DNL is an important pathway for therapeutic interventions to reduce the consequences associated with metabolic syndrome and NAFLD / MASLD.

[0006] Inhibiting FASN may treat a wide range of diseases, including cancer, viral diseases, metabolic diseases, NAFLD / MASLD, NASH / MASH, and inflammatory diseases (i.e., rheumatoid arthritis, gout, pulmonary fibrosis, COPD, IBD, and transplant rejection). Additionally, FASN inhibition may offer therapeutic benefits for cardiovascular diseases, atherosclerosis, type II diabetes, and metabolic syndrome. Successful treatment of these diseases remains a highly unmet need.

[0007] FASN inhibition not only reduces hepatic fat but also acts directly on immune cells and hepatic stellate cells, thereby reducing inflammation and fibrosis. WO2012 / 122391, WO2014 / 008197, and WO2015 / 105860 describe heterocyclic FASN inhibitors, and WO2018 / 089904 describes the use of some of the aforementioned FASN inhibitors for the treatment of NAFLD / MASLD and NASH / MASH. The contents of the aforementioned disclosures are incorporated herein by reference. One of the compounds described in the aforementioned applications, denifanstat (TVB-2640), is a first-in-class FASN inhibitor that has been demonstrated in NASH / MASH trials to improve hepatic fat and biomarkers associated with inflammation and fibrosis.

[0008] Thyroid hormone receptor β (THRβ) agonists increase lipid oxidation, thereby reducing liver fat. The THRβ agonist resmetirom recently demonstrated significant NASH / MASH regression and fibrosis improvement in a phase III clinical trial and has been approved for the treatment of non-cirrhotic NASH / MASH. While the efficacy of the THRβ agonist resmetirom shows promise, its histological response rate has not yet reached 50%.

[0009] Combinations of FASN inhibitors with other agents (such as THRβ agonists) are needed to complement and enhance the activity of FASN inhibitors in fatty liver diseases (such as NASH / MASH and NAFLD / MASLD). Additionally, combinations of THRβ agonists with other agents (such as FASN inhibitors) are needed to complement and enhance the activity of THRβ agonists in fatty liver diseases (such as NASH / MASH and NAFLD / MASLD). Summary of the Invention

[0010] This disclosure addresses the deficiencies in the treatment of metabolic diseases by providing a novel therapeutic combination of a heterocyclic regulator of lipid synthesis and a thyroid hormone receptor agonist. This offers a multi-pronged approach to metabolic diseases with complex pathophysiology. FASN inhibitors directly target inflammation (e.g., immune cells) and fibrosis (e.g., hepatic stellate cells), and indirectly target inflammation and fibrosis by reducing hepatic steatosis through inhibition of de novo lipogenesis. THR-β agonists indirectly reduce inflammation and fibrosis by decreasing the hepatic steatosis effect through increased hepatic lipolysis and / or fatty acid β-oxidation.

[0011] These different mechanisms may produce additional or synergistic effects, and broaden or deepen the efficacy response rate.

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

[0013] In some implementations, the fatty acid synthase inhibitor is a compound of formula (IX-1):

[0014] (IX-1), or a pharmaceutically acceptable salt thereof, wherein:

[0015] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (4- to 6-membered heterocycle), or -O- (C1-C4 straight-chain or branched alkyl), wherein when R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0016] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[0017] R 3 It is H, -OH or halogen;

[0018] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0019] R 22 It is H, halogen, or C1-C2 alkyl;

[0020] R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0021] t is 0 or 1;

[0022] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0023] L 1 It is N; and

[0024] L 2 It is N.

[0025] In some implementations of formula (IX-1), R 1 It is H, -CN, halogen, or C1-C4 straight-chain or branched alkyl; each R 2 Independently for H; R 3 It is H or halogen; R 21 It is a C1-C4 straight-chain or branched alkyl group or a C3-C5 cycloalkyl group; R 22 It is H or C1-C2 alkyl; and R 24 It is an H or C1-C4 straight-chain or branched alkyl group.

[0026] In some implementations of formula (IX-1), R 1 It is -CN; each R 2 Independently for H; R 3 It is H; R 21 It is a C3-C5 cycloalkyl group; R 22 It is H or C1-C2 alkyl; and R 24 It is a C1-C4 straight-chain or branched alkyl group.

[0027] In some embodiments, the compound of formula (IX-1) has the following structure: (Compound 001-152).

[0028] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XII-1):

[0029] (XII-1), or a pharmaceutically acceptable salt thereof, wherein:

[0030] L-Ar is , or ;

[0031] Ar is , , , or ;

[0032] Het is a 5- to 6-membered heteroaryl group;

[0033] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0034] Each R 2 Independently, it is H, halogen, or C1-C4 alkyl;

[0035] R 3 It is H or F;

[0036] R 11 It is H or -CH3;

[0037] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0038] R 22 It is H, halogen, or C1-C2 alkyl;

[0039] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[0040] t is 0 or 1;

[0041] u is 0 or 1;

[0042] Each R 241 Independently H or C1-C2 alkyl; and

[0043] R 25 It is a halogen, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, C1-C4 haloalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl) or cyclopropyl.

[0044] In some implementations of formula (XII-1), L-Ar is Ar is R 1 It is H, -CN, halogen, or C1-C4 alkyl; each R 2 Independently for H; R 3 It is H or F; R 21 It is H, halogen, or C1-C4 alkyl; R 22 It is H, halogen, or C1-C2 alkyl; R 24 It is a C1-C4 alkyl, a C1-C4 haloalkyl, or -(C1-C4 alkyl). t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl); R 25 It is a C1-C2 alkyl, a C1-C4 haloalkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0045] In some implementations of formula (XII-1), L-Ar is Ar is R 1 It is -CN; each R 2 Independently for H; R 3 It is H; R 21 It is a C1-C4 alkyl group; R 22 It is H or C1-C2 alkyl; R 24 It is a C1-C4 haloalkyl or -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings), and R 25 It is -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[0046] In some embodiments, the compound of formula (XII-1) has the following structure: (Compound 002-386).

[0047] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XIII-1):

[0048] (XIII-1), or a pharmaceutically acceptable salt thereof, wherein:

[0049] L-Ar is , or ;

[0050] Ar is , , , or ;

[0051] Het is a 5- to 6-membered heteroaryl group;

[0052] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0053] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0054] R 3 It is H or F;

[0055] R 11 It is H or -CH3;

[0056] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0057] R 22 It is H, halogen, or C1-C2 alkyl; and

[0058] Each R 24 and R 25 Independently, it can be H, halogen, -CN, -(C1-C4 alkyl)-CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-N(R). 241 2, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[0059] Each t is independently 0 or 1;

[0060] Each u is independently 0 or 1; and

[0061] Each R 241 It is independently H or C1-C2 alkyl.

[0062] In some implementations of formula (XIII-1), L-Ar is Ar is R1 It is H, -CN, halogen, or C1-C4 alkyl; each R 2 Independently for H; R 3 It is H or F; R 21 It is H, halogen, or C1-C4 alkyl; R 22 It is H, halogen, or C1-C2 alkyl; and each R 24 and R 25 It can be independently halogenated, C1-C4 alkyl, or -(C1-C4 alkyl). t -O-(C1-C4 alkyl).

[0063] In some implementations of formula (XIII-1), L-Ar is Ar is R 1 It is -CN; each R 2 Independently for H; R 3 It is H; R 21 It is a C1-C4 alkyl group; R 22 It is H or C1-C2 alkyl; and each R 24 and R 25 It can be independently halogenated, C1-C4 alkyl, or -(C1-C4 alkyl). t -O-(C1-C4 alkyl).

[0064] In some embodiments, the compound of formula (XIII-1) has the following structure: (Compound 002-242).

[0065] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XX-1):

[0066] (XX-1),

[0067] Or its pharmaceutically acceptable salt, wherein:

[0068] L-Ar is , or ;

[0069] Ar is ;

[0070] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0071] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0072] R 3 It is H or F;

[0073] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0074] R 22 It is H, halogen, or C1-C2 alkyl;

[0075] R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl), -O-(C3-C5 cycloalkyl) or -O-(4- to 6-membered heterocycle), wherein R 24 Optionally substituted with one or more hydroxyl groups or halogens; and

[0076] R 25 It is H, halogen, C1-C4 alkyl or C3-C5 cycloalkyl, wherein R 25 It may be optionally replaced by one or more halogens.

[0077] In some implementations of formula (XX-1), L-Ar is Ar is R 1 It is -CN or -O-(C1-C4 alkyl) optionally substituted with one or more halogens; each R 2 Independently for H; R 3 It is H or F; R 21 It is H or C1-C4 alkyl; R 22 It is H or C1-C2 alkyl; R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl) or -O-(4- to 6-membered heterocycle), where R 24 Optionally substituted with one or more hydroxyl groups or halogens; and R 25 It is H, halogen, or C1-C4 alkyl.

[0078] In some implementations of formula (XX-1), L-Ar is Ar is R 1 It is -CN or -O-(C1-C4 alkyl) optionally substituted with one or more halogens; each R 2 Independently for H; R 3 It is H or F; R 21 It is H or C1-C4 alkyl; R 22 It is H or C1-C2 alkyl; R24 It is an -O-(C1-C4 alkyl) substituted with one or more hydroxyl groups or halogens; and R 25 It is a C1-C4 alkyl group.

[0079] In some embodiments, the compound of formula (XX-1) has one of the following structures:

[0080] (Compound 005-2)

[0081] (Compound 005-5).

[0082] 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.

[0083] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compound 001-152, compound 002-386, compound 002-242, compound 005-2 and compound 005-5, or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152 and 005-2, or their pharmaceutically acceptable salts.

[0085] In some implementations, the fatty acid synthase inhibitor is a compound selected from Table C-1 or a pharmaceutically acceptable salt thereof.

[0086] In some implementations, the fatty acid synthase inhibitor is a compound selected from Table C-2 or a pharmaceutically acceptable salt thereof.

[0087] In some implementations, the fatty acid synthase inhibitor is a compound selected from Table C-3 or a pharmaceutically acceptable salt thereof.

[0088] In all respects, this disclosure provides pharmaceutical compositions comprising any of the compounds disclosed herein, as well as pharmaceutically acceptable carriers, excipients, or diluents.

[0089] In some implementations, the thyroid hormone receptor agonist is a compound of formula (XXI):

[0090] (XXI), or a pharmaceutically acceptable salt thereof, wherein:

[0091] A A It is O, CH2, S, SO or SO2;

[0092] X Aand Y A Each group is independently selected from the groups composed of Br, Cl, and CH3;

[0093] R 1A Choose from the following groups: -(CH2) n COOH, -OCH2COOH, -NHC(═O)COOH, -NHCH2COOH, and ;

[0094] Z A It is H or -C≡N;

[0095] R 2A It is a lower alkyl group having 1 to 4 carbon atoms;

[0096] R 3 It is H or a lower alkyl group;

[0097] n is 1 or 2; and

[0098] p is 1 or 2.

[0099] In some implementations, the thyroid hormone receptor agonist is a compound of formula (XXI-1):

[0100] (XXI-1), or a pharmaceutically acceptable salt thereof, wherein:

[0101] R 3A Is it H or CH2R? 3B ;

[0102] R 3B It is a hydroxyl group, an O-linked amino acid, -OP(O)(OH)2 or -OC(O)R 3C , where R 3C It is a lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or -(CH2). n -heteroaryl, where n is 0 or 1;

[0103] R 4A It is H, and R 5A It is CH2COOH, C(O)CO2H or their esters or amides, or R 4A and R 5 Together for -N═C(R) 4B )-C(O)-NH-C(O)-; where R 4B It is an H or cyano group.

[0104] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: (Compound A). Compound A is also known as MGL-3196 or resmetiro, and is marketed as Rezdifra. TM Sold for the treatment of non-cirrhotic NASH.

[0105] In some embodiments of the combinations and methods disclosed herein, the fatty acid synthase inhibitor has the following formula:

[0106] (a) Equation (IX)

[0107] (IX),

[0108] Or its pharmaceutically acceptable salt, wherein:

[0109] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0110] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0111] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0112] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0113] R 3 It is H, -OH or halogen;

[0114] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0115] R 22 It is H, halogen, or C1-C2 alkyl;

[0116] R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH 、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0117] t is 0 or 1;

[0118] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0119] L 1 It is CR 23 Or N;

[0120] L 2 It is CH or N;

[0121] L 1 or L 2 At least one of them is N; and

[0122] R 23 It is an H or C1-C4 straight-chain or branched alkyl group; or

[0123] (b) Equation (X):

[0124] (X),

[0125] Or its pharmaceutically acceptable salt, wherein:

[0126] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0127] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0128] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0129] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0130] R 3 It is H, -OH or halogen;

[0131] L 3 It is C(R) 60 2. O or NR 50 ;

[0132] Each R 60 Independently H, -OH, -CN, -O t -(C3-C5 cycloalkyl), -O-(C1-C4 straight-chain or branched alkyl) or -C(O)-N(R) 601 )2, of which:

[0133] t is 0 or 1, and

[0134] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0135] Each R 50 Independently H, –C(O)-Ot -(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C3-C5 cyclic alkyl), optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R) 501 2. C1-C4 straight-chain or branched alkyl groups, wherein:

[0136] t is 0 or 1, and

[0137] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0138] n is 1, 2, or 3;

[0139] m is 1 or 2;

[0140] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms.

[0141] R 22 It is H, halogen, C1-C2 alkyl;

[0142] Each R 26 Independently, it can be –OH, -CN, halogen, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C1-C4 alkyl) or -C(O)-N(R) 501 )2, of which:

[0143] t is 0 or 1, and

[0144] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0145] s is 0, 1, or 2;

[0146] Each R 601 and R 501 Independently, it is an H or C1-C4 straight-chain or branched alkyl group; and

[0147] Where R 26 R 60 R 50 R 501 and R 601 The two in R are optionally joined to form a loop, where R 26 R 60 R 50 R 501and R 601 The two in can be two R. 26 Two Rs 60 Two Rs 50 Two Rs 501 Or two Rs 601 ;or

[0148] (c) Equation (VI-J)

[0149] (VI-J),

[0150] Or its pharmaceutically acceptable salt, wherein:

[0151] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0152] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0153] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0154] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[0155] R 3 It is H, -OH or halogen;

[0156] R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl;

[0157] R 22 It is H, halogen, or C1-C2 alkyl;

[0158] R 35 It is –C(O)-R 351 -C(O)-NHR 351 -C(O)-OR 351 or S(O)2R 351 ;and

[0159] R 351 It is a C1-C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

[0160] (d) Formula (XII):

[0161] (XII),

[0162] Or its pharmaceutically acceptable salt, wherein:

[0163] L-Ar is , or ;

[0164] Ar is , , , or ;

[0165] Het is a 5- to 6-membered heteroaryl group;

[0166] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0167] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0168] R 3 It is H or F;

[0169] R 11 It is H or -CH3;

[0170] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0171] R 22 It is H, halogen, or C1-C2 alkyl;

[0172] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[0173] t is 0 or 1;

[0174] u is 0 or 1;

[0175] The condition is that when u is 1, t is 1; and

[0176] Each R 241 Independently H or C1-C2 alkyl; and

[0177] R 25 It is a halogen, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, or cyclopropyl; or

[0178] (e) Equation (XIII):

[0179] (XIII),

[0180] Or its pharmaceutically acceptable salt, wherein:

[0181] L-Ar is , or ;

[0182] Ar is , , , or ;

[0183] Het is a 5- to 6-membered heteroaryl group;

[0184] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0185] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0186] R 3 It is H or F;

[0187] R 11 It is H or -CH3;

[0188] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0189] R 22 It is H, halogen, or C1-C2 alkyl; and

[0190] Each R 24 and R 25Independently, it can be H, halogen, -CN, -(C1-C4 alkyl)-CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-N(R). 241 2, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[0191] Each t is independently 0 or 1;

[0192] Each u is independently 0 or 1; and

[0193] Each R 241 Independently H or C1-C2 alkyl; or

[0194] (f) Equation (XIV):

[0195] (XIV),

[0196] Or its pharmaceutically acceptable salt, wherein:

[0197] L-Ar is , or ;

[0198] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[0199] Het is a 5- to 6-membered heteroaryl group;

[0200] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0201] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0202] R 3 It is H or F;

[0203] R 11 It is H or -CH3;

[0204] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0205] R 22 It is H, halogen, or C1-C2 alkyl; and

[0206] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[0207] Each t is independently 0 or 1; and

[0208] Each R 241 Independently H or C1-C2 alkyl; or

[0209] (g) Equation (XV):

[0210] (XV),

[0211] Or its pharmaceutically acceptable salt, wherein:

[0212] L 3 It is -CH2-, -CHR 50 -、-O-、-NR 50 -、-NC(O)R 50 -OR-NC(O)OR 50 -, where R 50 It is a C1-C6 alkyl, C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle;

[0213] n is 1, 2, or 3;

[0214] m can be 1 or 2, provided that n + m ≥ 3;

[0215] L-Ar is , or ;

[0216] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[0217] Het is a 5- to 6-membered heteroaryl group;

[0218] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0219] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0220] R 3 It is H or F;

[0221] R 11 It is H or -CH3;

[0222] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and

[0223] R 22 It is H, halogen, or C1-C2 alkyl; or

[0224] (h) Equation (XVI):

[0225] (XVI),

[0226] Or its pharmaceutically acceptable salt, wherein:

[0227] L-Ar is , or ;

[0228] Ar is , , , or ;

[0229] Het is a 5- to 6-membered heteroaryl group;

[0230] R 1It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0231] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0232] R 3 It is H or F;

[0233] R 11 It is H or -CH3;

[0234] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0235] R 22 It is H, halogen, or C1-C2 alkyl; and

[0236] R 24 and R 25 Each of these is independently H, -C1-C4 alkyl, or halogen; or

[0237] (i) Equation (XVII):

[0238] (XVII),

[0239] Or its pharmaceutically acceptable salt, wherein:

[0240] L-Ar is , or ;

[0241] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[0242] Het is a 5- to 6-membered heteroaryl group;

[0243] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1Optionally replaced by one or more halogens;

[0244] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0245] R 3 It is H or F;

[0246] R 11 It is H or -CH3;

[0247] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0248] R 22 It is H, halogen, or C1-C2 alkyl; and

[0249] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[0250] t is 0 or 1;

[0251] u is 0 or 1;

[0252] The condition is that when u is 1, t is 1; and

[0253] R 241 It is H or C1-C2 alkyl; or

[0254] (j) Equation (XVIII):

[0255] (XVIII),

[0256] Or its pharmaceutically acceptable salt, wherein:

[0257] L-Ar is , or ;

[0258] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[0259] L 2 Yes - NHR 35 or -C(O)NHR 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl;

[0260] Het is a 5- to 6-membered heteroaryl group;

[0261] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0262] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0263] R 3 It is H or F;

[0264] R 11 It is H or -CH3;

[0265] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0266] R 22 It is H, halogen, or C1-C2 alkyl; and

[0267] R 35 It is -C(O)R 351 -C(O)NHR 351 C(O)OR 351 or S(O)2R 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl; or

[0268] (k) Equation (XIX):

[0269] (XIX),

[0270] Or its pharmaceutically acceptable salt, wherein:

[0271] Each W, X, Y, and Z is independently -N- or -CR. 26 -, provided that no more than two of W, X, Y, and Z are -N-;

[0272] Each R 26 Independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), -N(R) 27 2. -S(O)2-(C1-C4 alkyl) or -C(O)-(C1-C4 alkyl);

[0273] Each R 27 Independently H or C1-C4 alkyl, or two R 27 They are C1-C4 alkyl groups and are joined together with the N atoms to which they are attached to form 3- to 6-membered rings, wherein the rings optionally include an oxygen atom as one of the members of the ring;

[0274] Ar is , , , or ;

[0275] Het is a 5- to 6-membered heteroaryl group;

[0276] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0277] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0278] R 3 It is H or F;

[0279] R 11 It is H or -CH3;

[0280] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and

[0281] R 22 It is H, halogen, or C1-C2 alkyl; or

[0282] (l) Equation (XX):

[0283] (XX),

[0284] Or its pharmaceutically acceptable salt, wherein:

[0285] L-Ar is , or ;

[0286] Ar is ;

[0287] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0288] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0289] R 3 It is H or F;

[0290] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0291] R 22 It is H, halogen, or C1-C2 alkyl;

[0292] R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl), -O-(C3-C5 cycloalkyl) or -O-(4- to 6-membered heterocycle), wherein R 24 Optionally substituted with one or more hydroxyl groups or halogens; and

[0293] R 25 It is H, halogen, C1-C4 alkyl or C3-C5 cycloalkyl, wherein R 25 Optionally replaced by one or more halogens; or

[0294] (m) Equation (XI):

[0295] (XI)

[0296] Or its pharmaceutically acceptable salt, wherein:

[0297] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0298] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0299] When R 1When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0300] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[0301] R 3 It is H, -OH or halogen;

[0302] R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl;

[0303] R 22 It is H, halogen, C1-C2 alkyl; and

[0304] R 351 It is a C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

[0305] In various aspects, this disclosure relates to a method of treating fatty liver disease in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating fatty liver disease in a subject of need, 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, this disclosure relates to a method of treating fatty liver disease in a subject of need, 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).

[0306] In various aspects, this disclosure relates to a method of treating a subject in need of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating a subject in need of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), comprising administering to the subject 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, this disclosure relates to a method of treating a subject in need of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (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.

[0307] In various aspects, this disclosure relates to a method of treating a subject with nonalcoholic fatty liver disease / metabolic dysfunction-related fatty liver disease (NAFLD / MASLD) in need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating a subject with nonalcoholic fatty liver disease / metabolic dysfunction-related fatty liver disease (NAFLD / MASLD) in need, 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, this disclosure relates to a method of treating a subject with non-alcoholic fatty liver disease / metabolic dysfunction-associated fatty liver disease (NAFLD / MASLD) in need, 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.

[0308] In various aspects, this disclosure relates to a method of treating metabolic syndrome in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating metabolic syndrome in a subject of need, 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, this disclosure relates to a method of treating metabolic syndrome in a subject of need, 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.

[0309] In various aspects, this disclosure relates to a method of treating type 2 diabetes in a subject of need, comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating type 2 diabetes in a subject of need, comprising administering to the subject 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, this disclosure relates to a method of treating type 2 diabetes in a subject of need, comprising administering to the subject 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.

[0310] In various aspects, this disclosure relates to a method of treating atherosclerosis in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating atherosclerosis in a subject of need, 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, this disclosure relates to a method of treating atherosclerosis in a subject of need, 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.

[0311] In various aspects, this disclosure relates to a method of treating cirrhosis in a subject in need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating cirrhosis in a subject in need, 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, this disclosure relates to a method of treating cirrhosis in a subject in need, 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.

[0312] In various aspects, this disclosure relates to a method of treating liver fibrosis in a subject of need, comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating liver fibrosis in a subject of need, comprising administering to the subject 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, this disclosure relates to a method of treating liver fibrosis in a subject of need, comprising administering to the subject 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.

[0313] In various aspects, this disclosure relates to a method of treating liver cancer in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating liver cancer in a subject of need, 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, this disclosure relates to a method of treating liver cancer in a subject of need, 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.

[0314] In various aspects, this disclosure relates to a method of treating a subject with liver cancer of the formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) (XXI) and a thyroid hormone receptor agonist of the formula (XXI). In some embodiments, this disclosure relates to a method of treating a subject with liver cancer, wherein the liver cancer is developed from NAFLD / MASLD or NASH / MASH, the method comprising administering to the subject 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.

[0315] In various aspects, this disclosure relates to a method of treating hepatocellular carcinoma in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating hepatocellular carcinoma in a subject of need, 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, this disclosure relates to a method of treating hepatocellular carcinoma in a subject of need, 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.

[0316] In various aspects, this disclosure relates to a method of treating a subject with hepatocellular carcinoma of NAFLD / MASLD or NASH / MASH, wherein the method comprises administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating a subject with hepatocellular carcinoma of NAFLD / MASLD or NASH / MASH, wherein the method comprises 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, this disclosure relates to a method of treating a subject with hepatocellular carcinoma, wherein the hepatocellular carcinoma is developed from NAFLD / MASLD or NASH / MASH, the method comprising administering to the subject 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.

[0317] In various aspects, this disclosure relates to a method of treating a subject with cholangiocarcinoma in need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating a subject with cholangiocarcinoma in need, 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, this disclosure relates to a method of treating a subject with cholangiocarcinoma in need, 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.

[0318] In various aspects, this disclosure relates to a method of treating a disease or disorder in which a subject in need has elevated interleukin-1β (IL1β) levels, comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating a disease or disorder in which a subject in need has elevated interleukin-1β (IL1β) levels, comprising administering to the subject 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, this disclosure relates to a method of treating a disease or disorder in which a subject in need has elevated interleukin-1β (IL1β) levels, comprising administering to the subject 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.

[0319] In various aspects, this disclosure relates to a method of treating a disease or disorder regulated by interleukin-1β (IL1β) in a subject of need, comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating a disease or disorder regulated by interleukin-1β (IL1β) in a subject of need, comprising administering to the subject 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, this disclosure relates to a method of treating a disease or disorder regulated by interleukin-1β (IL1β) in a subject of need, comprising administering to the subject 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.

[0320] In various aspects, this disclosure relates to a method of treating a disease or disorder in which a subject in need has elevated levels of t-helper (Th) cells, comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating a disease or disorder in which a subject in need has elevated levels of t-helper (Th) cells, comprising administering to the subject 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, this disclosure relates to a method of treating a disease or disorder in which a subject in need has elevated levels of t-helper (Th) cells, comprising administering to the subject 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.

[0321] In all respects, this disclosure relates to a regulatory T cell (T) for treating subjects in need. reg Methods for reducing or suppressing diseases or disorders, including administering fatty acid synthase inhibitors and thyroid hormone receptor agonists (e.g., thyroid hormone receptor-β agonists) to a subject. For example, in some embodiments, this disclosure relates to a method for treating a subject with regulatory T cells (T cells) in need. reg Methods for reducing or suppressing diseases or disorders, comprising administering to a subject 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, this disclosure relates to a method for treating a subject with regulatory T cells (T cells). reg Methods for reducing or suppressing disease or ailment, comprising administering to a subject 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.

[0322] In various aspects, this disclosure relates to a method for reversing a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method for reversing a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, 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, this disclosure relates to a method for reversing a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, 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.

[0323] In various aspects, this disclosure relates to a method for reducing fibrosis gene expression in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method for reducing fibrosis gene expression in a subject of need, 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, this disclosure relates to a method for reducing fibrosis gene expression in a subject of need, 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.

[0324] In various aspects, this disclosure relates to a method of treating liver fibrosis in a subject of need, comprising administering to the subject a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating liver fibrosis in a subject of need, comprising administering to the subject 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, this disclosure relates to a method of treating liver fibrosis in a subject of need, comprising administering to the subject 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.

[0325] In various aspects, this disclosure relates to a method of treating skin fibrosis in a subject in need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating skin fibrosis in a subject in need, 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, this disclosure relates to a method of treating skin fibrosis in a subject in need, 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.

[0326] In various aspects, this disclosure relates to a method of treating pulmonary fibrosis in a subject of need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist) to the subject. For example, in some embodiments, this disclosure relates to a method of treating pulmonary fibrosis in a subject of need, 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, this disclosure relates to a method of treating pulmonary fibrosis in a subject of need, 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.

[0327] In various aspects, this disclosure relates to a method for lowering triglycerides in a subject of need, including, for example, severe hypertriglyceridemia (sHTG), comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method for lowering triglycerides in a subject of need 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, this disclosure relates to a method for lowering triglycerides in a subject of need 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.

[0328] In various aspects, this disclosure relates to a method for improving or restoring liver function in a subject in need, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method for improving or restoring liver function in a subject in need, 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, this disclosure relates to a method for improving or restoring liver function in a subject in need, 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.

[0329] In various aspects, this disclosure relates to a method of treating a subject with moderate to severe fibrosis of NASH / MASH, comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist). For example, in some embodiments, this disclosure relates to a method of treating a subject with moderate to severe fibrosis of 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, this disclosure relates to a method of treating a subject with moderate to severe fibrosis of 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.

[0330] In all respects, this 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.

[0331] In other respects, this disclosure further relates to pharmaceutical formulation compounds 001-152 or pharmaceutically acceptable salts thereof and compound A or pharmaceutically acceptable salts thereof.

[0332] In various other respects, this disclosure further relates to pharmaceutical formulation compounds 001-152 or pharmaceutically acceptable salts thereof and type A of compound A.

[0333] In various other respects, this disclosure relates to methods of treating the diseases and / or conditions described herein, wherein the treatment methods include administration of compound 001-152 or a pharmaceutically acceptable salt thereof and type A of compound A.

[0334] In various other respects, this disclosure relates to methods of treating the diseases and / or conditions described herein, wherein the treatment methods include administering a pharmaceutical preparation comprising a type A compound containing compound 001-152 or a pharmaceutically acceptable salt thereof and compound A.

[0335] In all respects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for manufacturing an agent for treating fatty liver disease, non-alcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), non-alcoholic fatty liver disease / metabolic dysfunction-associated steatohepatitis (NAFLD / MASLD), cirrhosis, liver fibrosis, liver cancer (e.g., liver cancer developed from NAFLD / MASLD or NASH / MASH), cholangiocarcinoma, or hepatocellular carcinoma (e.g., hepatocellular carcinoma developed from NAFLD / MASLD or NASH / MASH) or for improving or restoring liver function, wherein the agent is used in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist, such as a compound of formula (XXI)).

[0336] In all respects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for the manufacture of a fatty acid synthase inhibitor for the treatment of diseases or disorders with elevated interleukin 1β (IL1β) levels, diseases or disorders regulated by interleukin 1β (IL1β), diseases or disorders with elevated t helper (Th) cell levels, or regulatory t cells (T cells). reg A medicine that reduces or suppresses a disease or ailment, wherein the medicine is to be administered in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist, such as a compound of formula (XXI)).

[0337] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of an agent for reversing a diagnosed nonalcoholic steatohepatitis (NASH / MASH), wherein the agent is used in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist, such as a compound of formula (XXI)).

[0338] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of a medicament for the treatment of metabolic syndrome, wherein the medicament is to be administered in combination with a THR β agonist (e.g., a compound of formula (XXI)).

[0339] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of a medicament for the treatment of type II diabetes, wherein the medicament is to be administered in combination with a THR β agonist (e.g., a compound of formula (XXI)).

[0340] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of a pharmaceutical agent for the treatment of atherosclerosis, wherein the pharmaceutical agent is used in combination with a THR β agonist (e.g., a compound of formula (XXI)).

[0341] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of an agent for reducing the expression of fibrosis genes, wherein the agent is used in combination with a THR β agonist (e.g., a compound of formula (XXI)).

[0342] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of an agent for the treatment of liver fibrosis, wherein the agent is to be administered in combination with a THR β agonist (e.g., a compound of formula (XXI)).

[0343] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for use in the manufacture of a pharmaceutical agent for improving or restoring liver function, wherein the pharmaceutical agent is used in combination with a THR β agonist (e.g., a compound of formula (XXI)).

[0344] In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for the manufacture of an agent for the treatment of NASH / MASH with moderate to severe fibrosis, wherein the agent is to be administered in combination with a THR β agonist (e.g., a compound of formula (XXI)). In various aspects, this disclosure relates to a fatty acid synthase inhibitor of structure (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) for the manufacture of an agent for the treatment of skin fibrosis or pulmonary fibrosis, wherein the agent is to be administered in combination with a thyroid hormone receptor agonist (e.g., a thyroid hormone receptor-β agonist, such as a compound of formula (XXI)).

[0345] In any of the foregoing aspects and embodiments, the fatty acid synthase inhibitors of formula (IX), (X), (VI-J), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or (XI) are compounds selected from Tables C-1 to C-3. Attached Figure Description

[0346] Figure 1AThis is a graph showing the effects of compounds 001-152 and A in a human liver microtissue model under de novo lipogenesis (DNL) conditions, as measured by intratissue triglyceride levels. Single-dose treatment with compound 001-152 (30 nM and 3 μM) reduced cellular triglycerides in vitro in the human liver microtissue model. The combination of compound 001-152 and compound A enhanced the effect of compound A, and the combination had an increased overall efficacy relative to single-dose treatment. This liver microtissue model included hepatocytes, Kupffer cells, and hepatic endothelial cells. Liver microtissue treatment lasted 7 days. To simulate increased lipid accumulation within hepatocytes, the microtissue was treated with glucose and free fatty acids (FFA). The graph depicts the mean ± standard deviation (SD). A two-tailed t-test with Welch's correction (p < 0.05) was used. Figure 1B This is a graph showing the effects of compounds 001-152 and compound A in a human liver microtissue model under NASH conditions, as measured by intratissue triglyceride content. The model includes stellate cells and incorporates pro-inflammatory stimulation with lipopolysaccharide (LPS). This liver microtissue model includes hepatocytes, hepatic endothelial cells, and hepatic stellate cells. Liver microtissue was treated for 10 days. To simulate increased lipid accumulation within hepatocytes and the processes of inflammation and fibrosis, the microtissue was treated with sugars, free fatty acids (FFA), and lipopolysaccharide (LPS). The graph depicts the mean ± standard deviation (SD). A two-tailed t-test with Welch correction *p < 0.05 was used. Figure 1C It is a graph showing the timeline of the research.

[0347] Figure 2A This graph shows NASH-induced intracellular triglyceride levels after administration of compound 001-152 as a single agent and in combination with other agents (including compound A). The graph illustrates that in a human liver microtissue model, compound 001-152 alone reduced cellular triglycerides. Other agents under development for NASH are not effective at reducing triglycerides (see speckled bars). Combinations of compound 001-152 with those agents (gray and black bars) are more effective at reducing triglycerides. Combinations of compound 001-152 with compound A (resmetiro or MGL-3196) reduced TG levels to below baseline. The graph depicts the median and interquartile range. Figure 2B It is a graph showing the timeline of the research.

[0348] Figure 3The figures are depicted in a human liver microtissue model, showing that the combination therapy exhibited improved and / or more consistent decreases in inflammatory markers MIP1a, IL-8, and TNFa (columns 7 and 8) and IP10 (columns 5 and 6) compared to single-agent treatment (compound A, columns 1 and 2, and compound 001-152, columns 3 and 4). Compared to single-agent treatment, the combination therapy also showed improved decreases in the fibrosis marker collagen 1 (columns 7 and 8). These results indicate that the combination of compounds 001-152 and compound A has the potential to improve the inflammatory and fibrotic pathways, exceeding the efficacy observed with single-agent treatment. In the figures, “MGL” represents compound A, “U” indicates a fold increase in the change of NASH inflammatory or fibrotic markers, and “D” indicates a fold decrease in the change of NASH inflammatory or fibrotic markers; the intensity of the effect is reflected in the grayscale hue of the regions, with darker gray indicating a more pronounced effect. Black areas indicate no data collected.

[0349] Figure 4A This is a schematic diagram showing the research design. Figure 4B This is a graph showing the effect of the combination of compound 001-152 and compound A on collagen 1α1 in human liver sections cultured under simulated human NASH conditions. The graph shows that the combination of compound 001-152 and compound A improves the suppression of the fibrosis marker collagen 1α1 compared to single agents (see time points T72 and thereafter).

[0350] Figure 5 This graph shows the effects of compounds 001-152 and compound A on collagen production in human primary hepatic stellate cells stimulated with 10 ng / ml TGF-β during 4 days of treatment. Compound 001-152 directly inhibited collagen production (other cell types were not present in this model). * indicates p < 0.05 compared to the control group.

[0351] Figure 6 This is the X-ray powder diffraction (XRPD) pattern of compound A, type A.

[0352] Figure 7 This is the X-ray powder diffraction (XRPD) pattern of compound A in its amorphous (type A) form.

[0353] Figure 8 This is a differential scanning calorimetry (DSC) chromatogram of the A-type of compound A.

[0354] Figure 9 This is the XRPD diagram of the solvate (G type) of compound A in methyl isobutyl ketone (MIBK).

[0355] Figure 10 This is the XRPD diagram of the dimethylacetamide solvate (K type) of compound A.

[0356] Figure 11A The changes in plasma ALT over time in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH characteristics are shown. Figures represent mean ± SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated mice. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15 (Example 11).

[0357] Figure 11B The changes in plasma ALT on day 28 of treatment in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food diet (FFD) to induce MASH characteristics are shown. Figures represent mean ± SD, *p < 0.05 and ***p < 0.001 compared to FFD-mediated mice. Treatment groups: control (normal food n = 8); mediator, TVB-3664, MGL-3196, combinations n = 14–15 (Example 11).

[0358] Figure 12A The changes in plasma AST over time in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH characteristics are shown. Figures represent mean ± SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated mice. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15 (Example 11).

[0359] Figure 12B The changes in plasma AST on day 28 of treatment in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) feeding to induce MASH characteristics are shown. Figures represent mean ± SD, *p < 0.05 and ***p < 0.001 compared to FFD-mediated mice. Treatment groups: control (normal food n = 8); mediator, TVB-3664, MGL-3196, combinations n = 14–15 (Example 11).

[0360] Figure 13The changes in plasma triglycerides over time in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food diet (FFD) to induce MASH characteristics are shown. Figures represent mean ± SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated mice. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15 (Example 11).

[0361] Figure 14 The changes in plasma cholesterol over time in male LDL receptor knockout (Ldlr- / -) mice fed a fast-food diet (FFD) for 18 weeks to induce MASH characteristics are shown. Figures represent mean + SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated diets. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15 (Example 11).

[0362] Figure 15 The changes in plasma lipoproteins in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH characteristics are shown. Figures represent mean + SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated groups. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15; lipoprotein profiles at the start of treatment in the FFD-mediated group are for reference only (Example 11).

[0363] Figure 16 This paper illustrates changes in liver collagen in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH characteristics. Data shown are from 10 weeks after treatment. Figures represent mean ± SD, *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD-mediated group. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15; Liver collagen profiles at the start of treatment in the FFD-mediated group are for reference only (Example 11).

[0364] Figure 17The changes in total steatosis in the histopathology of male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH features are shown. Data shown are from 10 weeks after treatment. Figures represent data as mean + SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated groups. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combination n=14–15; steatosis profiles at the start of treatment in the FFD-mediated group are for reference only (Example 11). Insets are exemplary sections showing differences between lean controls and MASH sections as visualized in the experiment.

[0365] Figure 18 This paper illustrates the changes in microvesicular and macrovesicular steatosis in the histopathology of male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) feeding to induce MASH features. Data shown are from 10 weeks after treatment. Figures represent data as mean + SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated groups. Treatment groups: Control (normal food n=8); Mediator, TVB-3664, MGL-3196, combinations n=14–15; including the microvesicular and macrovesicular steatosis profiles at the start of treatment in the FFD-mediated group for reference only (Example 11). Insets are exemplary sections showing the differences between lean controls and MASH sections (microvesicular and macrovesicular steatosis) as visualized in the experiment.

[0366] Figure 19 This paper illustrates the changes in inflammation in the histopathology of male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH features. Data shown are from 10 weeks after treatment. Figures represent data as mean + SD, *p<0.05, **p<0.01, and ***p<0.001 compared to FFD-mediated treatment. Treatment groups: control (normal food n=8); mediator, TVB-3664, MGL-3196, combinations n=14–15; the inflammation profile at the start of treatment in the FFD-mediated group is for reference only (Example 11). Insets are exemplary slices showing visualization of inflammation.

[0367] Figure 20This diagram illustrates the changes in abnormally enlarged hepatocytes (hypertrophy expressed as a percentage of surface area) histopathologically in male LDL receptor knockout (Ldlr- / -) mice after 18 weeks of fast food (FFD) diet to induce MASH characteristics. Data shown are from 10 weeks after treatment. Figures represent data as mean + SD, *p<0.05, **p<0.01, and ***p<0.001 compared to the FFD-mediated group. Treatment groups: Control group (normal food, n=8); Mediator, TVB-3664, MGL-3196, combinations, n=14–15; Spectrum at the start of treatment in the FFD-mediated group is for reference only (Example 11).

[0368] Figure 21 The liver lipid content at 6 weeks is shown in the DIO (diet-induced obesity) MASH Gubra mouse model (Example 12). The groups are NC (normal diet control); VEH (MASH mediator control); FASN (TVB-3664, a FASN inhibitor, an alternative to denifastat); RES (resimetirox); and COMBO (a combination of TVB-3664 and resimetirox).

[0369] Figure 22 The changes in NAS scores at 6 weeks are shown in the DIO (diet-induced obesity) MASH Gubra mouse model (Example 12). The groups are NC (normal diet control); VEH (MASH mediator control); FASN (TVB-3664, a FASN inhibitor, an alternative to denifastat); RES (resimetirox); and COMBO (a combination of TVB-3664 and resimetirox). Detailed Implementation

[0370] This disclosure addresses the limitations of treating disorders characterized by FASN dysfunction in subjects (such as liver diseases, liver cancer (e.g., cholangiocarcinoma, hepatocellular carcinoma), and metabolic disorders (e.g., type II diabetes)) by providing novel treatment methods comprising a combination of administration of a fatty acid synthase inhibitor and a thyroid receptor hormone agonist, and / or a pharmaceutical formulation comprising a fatty acid synthase inhibitor and a thyroid receptor hormone agonist.

[0371] definition

[0372] Chemical moieties referred to as monovalent chemical moieties (e.g., alkyl, aryl, etc.) also encompass structurally permissible polyvalent moieties, as understood by those skilled in the art. For example, while the "alkyl" moiety typically refers to a monovalent group (e.g., CH3CH2-), in appropriate contexts, the "alkyl" moiety may also refer to a divalent group (e.g., -CH2CH2-, which is equivalent to an "alkylene" group). Similarly, where a divalent moieties are required, those skilled in the art will understand that the term "aryl" refers to the corresponding divalent arylene group.

[0373] All atoms should be understood as having their normal valence for bond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the atom). Sometimes a part can be defined, for example, (A). a B, where a is 0 or 1. In this case, when a is 0, the part is B, and when a is 1, the part is AB.

[0374] Where the number of substituents can vary in terms of the same type of atoms or groups (e.g., alkyl groups can be C1, C2, C3, etc.), the number of repeating atoms or groups can vary from range (e.g., C... l -C6 alkyl) indicates that the range includes every value within the range and any and all subranges. For example, C1-C3 alkyl includes C l C2, C3, C l-2 C l-3 and C 2-3 alkyl.

[0375] "Alkyl group" refers to a carbonyl group that has a lower alkyl group as a substituent.

[0376] "Alkylamino" refers to an amino group that has been replaced by an alkyl group.

[0377] "Alkoxy" refers to an O-atom substituted with an alkyl group as defined herein, for example, methoxy [–OCH3, C1 alkoxy]. The term "C"... 1-6 "Alkoxy" encompasses C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy, and any of their subranges.

[0378] "Alkoxycarbonyl" refers to a carbonyl group that has an alkoxy group as a substituent.

[0379] “alkyl,” “alkenyl,” and “alkynyl” refer to a straight-chain or branched aliphatic group having 1 to 30 carbon atoms, preferably 1 to 15 carbon atoms, or more preferably 1 to 6 carbon atoms, which may be optionally substituted. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutylenyl, ethynyl, and propynyl. As used herein, the term “heteroalkyl” covers an alkyl group having one or more heteroatoms.

[0380] "alkylene" refers to a divalent group that is optionally substituted, which is a branched or unbranched hydrocarbon segment containing a specific number of carbon atoms and having two attachment points. An example is propylene [–CH2CH2CH2–, C3 alkylene].

[0381] "Amino" refers to the group -NH2.

[0382] "Aryl" refers to an optionally substituted aromatic group having at least one ring with a conjugated π-electron system and includes carbocyclic aryl and biaryl groups, both of which may be optionally substituted. Phenyl and naphthyl groups are preferred carbocyclic aryl groups.

[0383] "Arylalkyl" or "arylalkyl" refers to an alkyl-substituted aryl group. Examples of arylalkyl groups include butylphenyl, propylphenyl, ethylphenyl, methylphenyl, 3,5-dimethylphenyl, and tert-butylphenyl.

[0384] As used in this article, "carbamoyl" encompasses the formula. The group, wherein R N Choose from the following groups: hydrogen, -OH, C1 to C2. 12 Alkyl, C1 to C 12 Heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkylyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

[0385] "Carbonyl" refers to the formula . group.

[0386] "Cycloalkyl" refers to an optionally substituted ring, which can be saturated or unsaturated and monocyclic, bicyclic, or tricyclic, formed entirely of carbon atoms. An example of a cycloalkyl group is the cyclopentenyl group (C5H7–), which is a five-carbon (C5) unsaturated cycloalkyl group.

[0387] "Heterocycle" refers to a 5- to 7-membered cycloalkyl ring system containing one, two, or three heteroatoms selected from N, O, or S, and optionally containing a double bond, wherein the heteroatoms may be the same or different.

[0388] "Halogen" refers to a chlorine, bromine, fluorine, or iodine atom group. The term "halogen" also encompasses the terms "halogen group" or "halogen."

[0389] "Heteroatoms" refers to non-carbon atoms, among which boron, nitrogen, oxygen, sulfur and phosphorus are preferred heteroatoms, and nitrogen, oxygen and sulfur are particularly preferred heteroatoms in the compounds disclosed herein.

[0390] "Heteroaryl" refers to an aryl group having one to nine carbon atoms that are optionally substituted, and the remaining atoms are heteroatoms, including those heterocyclic systems described in "Handbook of Chemistry and Physics," 49th edition, 1968, ed. RC Weast; The Chemical Rubber Co., Cleveland, Ohio. See in particular Part C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryl groups include thiophene, pyrrolyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrololinyl, pyridazinyl, triazolyl, indoleyl, isoindoleyl, indoleazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, inzolyl, benzotriazolyl, tetrazolpyridazinyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, thiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, etc.

[0391] The "optionally substituted" portion may be substituted by one to four, preferably one to three, or more preferably one or two non-hydrogen substituents. Unless otherwise stated, when the substituent is on a carbon atom, it is selected from the group consisting of: -OH, -CN, -NO2, halogens, C1 to C2. 12 Alkyl, C1 to C 12 Heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate, sulfonamide, and amino groups, all of which are not further substituted. Unless otherwise stated, when the substituent is on nitrogen, it is selected from the group consisting of C1 to C2. 12 Alkyl, C1 to C 12 Heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkylyl, carbamoyl, sulfonyl, sulfonate and sulfonamide, none of which are further substituted.

[0392] As used herein, the term "sulfonamide" encompasses products having the following formula: The group, wherein R N Choose from the following groups: hydrogen, -OH, C1 to C2.12 Alkyl, C1 to C 12 Heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkylyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

[0393] As used herein, the term "sulfonate" encompasses esters having the following formula: The group, wherein R s Choose from the following groups: hydrogen, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkyl or C1-C 10 Alkoxycarbonyl group.

[0394] As used alone or as part of another group, "sulfonyl" refers to the SO2 group. The SO2 moiety is optionally substituted.

[0395] The compounds disclosed herein can exist as stereoisomers, wherein an asymmetric or chiral center is present. Stereoisomers are named (R) or (S) according to the configuration of the substituents surrounding the chiral carbon atom. The terms (R) and (S) as used herein refer to configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, PureAppl. Chem., (1976), 45: 13-30, which are hereby incorporated by reference. This disclosure covers a variety of stereoisomers and mixtures thereof and is explicitly included within the scope of this disclosure. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds disclosed herein can be prepared by synthesis from commercially available starting materials containing an asymmetric or chiral center, or by preparing a racemic mixture followed by resolution well known to those skilled in the art. These separation methods are illustrated by the following examples: (1) attaching a mixture of enantiomers to a chiral auxiliaries, separating the resulting diastereomeric mixture by recrystallization or chromatography and releasing the optically pure product from the auxiliaries, or (2) directly separating a mixture of optically enantiomers on a chiral chromatographic column.

[0396] Furthermore, the portion disclosed herein that exists in multiple tautomeric forms includes all such forms covered by the given tautomeric configuration. For example, it should be understood that when compound 001-152 is drawn as: At the same time, it also includes, for example: .

[0397] A tautomer is one of two or more structural isomers that exists in equilibrium and readily transforms from one isomer to another. This transformation results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. A chemical equilibrium of tautomers is achieved in a solution where tautomerization is possible. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers capable of interconverting through tautomerization is called tautomerism. An example of a fraction existing in several tautomer forms is 1,2,4-triazole, which exists in tautomer forms called 1H-1,2,4-triazole, 4H-1,2,4-triazole, and 3H-1,2,4-triazole, and they rapidly interconvert.

[0398] Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, electrons and hydrogen atoms move simultaneously. Ring tautomerism results from the reaction of the aldehyde group (-CHO) in the sugar molecule with a hydroxyl group (-OH) in the same molecule, causing it to adopt the cyclic (ring-like) form exhibited by glucose.

[0399] Common tautomer pairs are: keto-enol, amide-nitrile, lactam-lactamimide, amide-imine tautomerism in heterocycles (e.g., in nucleobases such as guanine, thymine, and cytosine), imine-enamine, and enamine-enamine. An example of a keto-enol equilibrium is between pyridin-2(1H)-one and its corresponding pyridin-2-ol, as shown below.

[0400] .

[0401] In the disclosed compound, a single atom can be any isotope of the element. For example, hydrogen can be in the form of deuterium.

[0402] "Pharmaceutical acceptable" means approved by a federal regulatory agency or state government, or listed in the United States Pharmacopeia (US Pharmacopoeia) or other generally recognized pharmacopoeia, for use in animals and more specifically in humans. It can be a material that is not biologically or otherwise undesirable; that is, the material can be administered to an individual without causing any undesirable biological effects or interacting in a harmful manner with any component of the composition it contains.

[0403] The term "pharmaceutically acceptable salt" for a compound means a salt that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Such salts include, for example, acid addition salts and base addition salts.

[0404] According to this disclosure, the "acid addition salt" is 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, It is formed from 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4′-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, hexadienoic acid, etc.

[0405] A "base addition salt" according to this disclosure is 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 metal ion, or an aluminum ion; or when it coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. It should be understood that the pharmaceutically acceptable salts mentioned include solvation forms or their crystalline forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during the crystallization process. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. Polymorphs include different crystalline arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Various factors such as recrystallization solvents, crystallization rates, and storage temperatures can cause the single-crystal form to dominate.

[0406] The term "treatment" includes administering the compounds or agents of the present invention to a subject to prevent or delay, alleviate, stop, or inhibit the development of symptoms or disorders associated with fatty acid synthase-related conditions (e.g., tumor growth associated with cancer). Skilled physicians know how to use standard methods to determine whether a patient has a disease associated with fatty acid synthase activity, for example, by examining the patient and determining whether the patient has a known disease associated with fatty acid synthase activity, or by measuring the level of fatty acid synthase in the plasma or tissues of an individual suspected of having a fatty acid synthase-related disease and comparing the level of fatty acid synthase in the plasma or tissues of an individual suspected of having a fatty acid synthase-related disease with the level of fatty acid synthase in the plasma or tissues of a healthy individual. Increased serum levels indicate disease. Therefore, the present invention particularly provides a method for administering the compounds of the present invention to a subject and determining the subject's fatty acid synthase activity. The subject's fatty acid synthase activity can be determined before and / or after administration of the compound.

[0407] "Therapeutic effective amount" or "pharmaceutical effective amount" means the amount that, when administered to a subject, produces the desired effect. For example, when administered to a subject to inhibit fatty acid synthase activity, a "therapeutic effective amount" is sufficient to inhibit fatty acid synthase activity. When administered to a subject to treat a disease, a "therapeutic effective amount" is sufficient to treat the disease.

[0408] In some implementations, the term "therapeutic effective dose" refers to a synergistic effective dose or a synergistic therapeutic dose.

[0409] "Synergy" means that when a FASN inhibitor is administered in combination with a THR agonist (e.g., a THR-β agonist) as described herein, its therapeutic effect is greater than the predicted additive therapeutic effect when the FASN inhibitor and the THR agonist (e.g., a THR-β agonist) are administered alone. The terms "synergistic therapeutic dose" or "synergistic effective dose" refer to a dose of one or both drugs below the standard therapeutic dose, meaning that the amount required to achieve the desired effect is less than the amount required when the drugs are used alone. Synergistic therapeutic doses also include situations where one drug is administered at a standard therapeutic dose while another drug is administered at a sub-standard therapeutic dose. For example, a FASN inhibitor may be administered at a therapeutic dose, and a THR agonist (e.g., a THR-β agonist) may be administered at a standard or sub-standard therapeutic dose to provide a synergistic outcome, or vice versa.

[0410] The term "treatment combination" is intended to cover the sequential administration of two or more therapeutic agents (e.g., the fatty acid synthase inhibitor and the THR-β agonist of this disclosure), wherein each therapeutic agent is administered at different times, and the therapeutic agents or at least two of the therapeutic agents are administered simultaneously or substantially simultaneously. Simultaneous administration can be achieved, for example, by administering to a subject a single capsule of each therapeutic agent (e.g., the fatty acid synthase inhibitor and the THR-β agonist of this disclosure) in a fixed ratio, or by administering multiple single capsules for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent (e.g., the fatty acid synthase inhibitor and the THR-β agonist of this disclosure) can be achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption via mucosal tissue. The therapeutic agents can be administered via the same or different routes. For example, the first therapeutic agent of a selected combination can be administered intravenously, while the other therapeutic agents in the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally, or all therapeutic agents can be administered intravenously. The therapeutic agents can also be administered alternately.

[0411] Unless otherwise specified, the terms “subject” or “patient” are used interchangeably and refer to mammals (such as human patients and non-human primates), 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 may be administered. In an exemplary aspect of the invention, in order to identify a subject patient to be treated according to the methods of the present invention, acceptable screening methods are employed to determine risk factors associated with the target or suspected disease or condition, or to determine the state of the disease or condition present in the subject. These screening methods include, for example, routine work-ups to determine risk factors associated with the target or suspected disease or condition. These and other routine methods allow physicians to select patients in need of therapy using the methods and formulations of the present invention.

[0412] FASN pathway modifier

[0413] In some implementations, the fatty acid synthase inhibitor is a compound of formula (I):

[0414] (I), or a pharmaceutically acceptable salt thereof, wherein:

[0415] X, Y, and Z are each independently CR or NR′, where R is hydrogen or C. 1-6 Alkyl group, and R′ is hydrogen, C 1-6 Alkyl groups may not be present;

[0416] A is CH or N;

[0417] R1 is hydrogen, cyano, halogen, or C.1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0418] q can be 0, 1, 2, 3, or 4;

[0419] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0420] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0421] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0422] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group, –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0423] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0424] R 12 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0425] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0426] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino;

[0427] R 17 and R 18 Each is independently hydrogen or alkyl, or optionally bonded together to form a bond;

[0428] n is 1 or 2; and

[0429] m is 0 or 1.

[0430] In some implementations of formula (I), R3 is F.

[0431] In some implementations of formula (I), A is CH.

[0432] In some implementations of formula (I), A is N.

[0433] In some implementations of formula (I), X, Y, and Z are NR′.

[0434] In some embodiments of formula (I), R4 is a heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), or -N(R7)C(=O)R8. 10 C 1-6 Alkyl, C 1-6 Alkoxy, or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups.

[0435] In some embodiments of formula (I), R5 is hydrogen and R6 is aryl or heteroaryl.

[0436] In some embodiments, the fatty acid synthase inhibitor of formula (I) has one of the following formulas (IA) or (IB):

[0437] (IA)or (IB), or their pharmaceutically acceptable salts, wherein:

[0438] X, Y, and Z are each independently CR or NR′, where R is hydrogen or C. 1-6 Alkyl group, and R′ is hydrogen, C 1-6 Alkyl groups may not be present;

[0439] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0440] q can be 0, 1, 2, 3, or 4;

[0441] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0442] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy, C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0443] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0444] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group, –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0445] R 11It is hydrogen, halogen, 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 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0446] R 12 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3, –S(=O)2R 20 , or R 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0447] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0448] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino; and

[0449] R 17 and R 18 Each is independently hydrogen or alkyl, or optionally bonded together to form a bond.

[0450] In some embodiments, the fatty acid synthase inhibitor of formula (I) has one of the following formulas (IC) or (ID):

[0451] (IC) or (ID)

[0452] Or their pharmaceutically acceptable salts, wherein:

[0453] X, Y, and Z are each independently CR or NR′, where R is hydrogen or C.1-6 Alkyl group, and R′ is hydrogen, C 1-6 Alkyl groups may not be present;

[0454] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0455] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0456] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0457] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0458] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0459] R5, R6, R7, R8, R9 and R 10 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0460] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0461] In some embodiments, the fatty acid synthase inhibitor of formula (I) has one of the following formulas: (IE), (IF), (IG), and (IH):

[0462] (IE) (IF),

[0463] (IG) and (IH), or their pharmaceutically acceptable salts, wherein:

[0464] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0465] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0466] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0467] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0468] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0469] R 12 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0470] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0471] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0472] In some embodiments, the fatty acid synthase inhibitor of formula (I) has one of the following formulas (II), (IJ), and (IK):

[0473] (II) (IJ) and

[0474] (IK), or their pharmaceutically acceptable salts, wherein:

[0475] X and Y are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0476] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0477] q can be 0, 1, 2, 3, or 4;

[0478] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R)13 (R) 14 );

[0479] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy, C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0480] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0481] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0482] R5, R6, R7, R8, R9 and R 10 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0483] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0484] In some embodiments, the fatty acid synthase inhibitor of formula (I) has the following formula (IL) or (IM):

[0485] (IL) or (IM), or their pharmaceutically acceptable salts, wherein:

[0486] X and Y are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0487] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0488] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0489] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0490] R5, R6, R7, R8, R9 and R 10 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0491] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0492] In some embodiments, the fatty acid synthase inhibitor is compound 001-346 or 001-495 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0493] Or their pharmaceutically acceptable salts.

[0494] In some embodiments, the fatty acid synthase inhibitor of formula (I) has the following formula (IP):

[0495] (IP)

[0496] Or its pharmaceutically acceptable salt, wherein:

[0497] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0498] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0499] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0500] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0501] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0502] R 12 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3, –S(=O)2R 20 , or R 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0503] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0504] R 15 and R 16 Each independently represents H and C. 1-6Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0505] In some 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.

[0506] In some embodiments, the fatty acid synthase inhibitor of formula (I) has the following formula (IT):

[0507] (IT), or a pharmaceutically acceptable salt thereof, wherein:

[0508] X, Y, and Z are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0509] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0510] q can be 0, 1, 2, 3, or 4;

[0511] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0512] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy, C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0513] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0514] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group, –S(=O)2R20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0515] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0516] R 12 It is hydrogen, halogen, 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 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0517] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0518] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0519] In some embodiments, the fatty acid synthase inhibitor is compound 001-118 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0520] In some embodiments, the fatty acid synthase inhibitor of formula (I) has the following formula (IV):

[0521] (IV), or a pharmaceutically acceptable salt thereof, wherein:

[0522] X, Y, and Z are each independently CR or NR′, where R is H or C. 1-6Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0523] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0524] q can be 0, 1, 2, 3, or 4;

[0525] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0526] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy, C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0527] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0528] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0529] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0530] R 12 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3, –S(=O)2R 20 , or R 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0531] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0532] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0533] In some embodiments, the fatty acid synthase inhibitor is compound 001-40 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0534] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: 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 pharmaceutically acceptable salts thereof.

[0535] In some implementations, the fatty acid synthase inhibitor is a compound of formula (II):

[0536] (II), or a pharmaceutically acceptable salt thereof, wherein:

[0537] X, Y, and Z are each independently CR or NR′, where R is hydrogen or C. 1-6 Alkyl group, and R′ is hydrogen, C 1-6 Alkyl groups may not be present;

[0538] L and D are each independently C or N;

[0539] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0540] q can be 0, 1, 2, 3, or 4;

[0541] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0542] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy, C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0543] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0544] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0545] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0546] R 12 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R14 ), CF3, –OCF3 or –S(=O)2R 20 , or R 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0547] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0548] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino;

[0549] R 17 and R 18 Each is independently hydrogen or alkyl, or optionally bonded together to form a bond;

[0550] n is 1 or 2; and

[0551] m is 0 or 1.

[0552] In some embodiments, the fatty acid synthase inhibitor of formula (II) has the following formula (II-A):

[0553] (II-A), or a pharmaceutically acceptable salt thereof, wherein:

[0554] X, Y, and Z are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0555] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy, C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0556] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0557] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0558] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0559] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0560] R 12 It is hydrogen, halogen, 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 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0561] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0562] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0563] In some embodiments, the fatty acid synthase inhibitor of formula (II) has the following formula (II-B):

[0564] (II-B), or a pharmaceutically acceptable salt thereof, wherein:

[0565] X and Y are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0566] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0567] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0568] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0569] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0570] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0571] R5, R6, R7, R8, R9 and R 10 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0572] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0573] In some embodiments, the fatty acid synthase inhibitor of formula (II) has one of the following formulas (II-C), (II-D), and (II-E):

[0574] (II-C) (II-D) and (II-E), or their pharmaceutically acceptable salts, wherein:

[0575] X and Y are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0576] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 Alkyl groups, or R2 and R3 together with the atoms to which they are attached, form 5-membered heterocyclic groups;

[0577] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy groups, or R2 and R3, together with the atoms to which they are attached, form a 5-membered heterocyclic group;

[0578] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0579] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0580] R5, R6, R7, R8, R9 and R 10 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0581] R 15 and R16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0582] In some embodiments, the fatty acid synthase inhibitor is compound 001-347 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0583] In some implementations, the fatty acid synthase inhibitor is a compound of formula (III):

[0584] (III), or a pharmaceutically acceptable salt thereof, wherein:

[0585] X, Y, and Z are each independently CR or NR′, where R is hydrogen or C. 1-6 Alkyl group, and R′ is hydrogen, C 1-6 Alkyl groups may not be present;

[0586] Q is either C or N;

[0587] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl, C 1-6 Alkoxy group, or if Q is N, then R3 is not present;

[0588] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0589] R 11 It is hydrogen, halogen, 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 They combine with the atoms to which they are attached to form heteroaryl groups, or R... 11 and R 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0590] R 12 It is hydrogen, halogen, 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 12 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0591] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0592] R5, R6, R7, R8, R9, R 10 R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0593] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino;

[0594] R 17 and R 18 Each is independently hydrogen or alkyl, or optionally bonded together to form a bond;

[0595] R 19 It is aryl, heteroaryl, cycloalkyl, or heterocyclic;

[0596] n is 0, 1, or 2; and

[0597] m is 0 or 1.

[0598] In some embodiments, the fatty acid synthase inhibitor of formula (III) has one of the following formulas (III-A), (III-B), and (III-C):

[0599] (III-A) (III-B) and (III-C), or their pharmaceutically acceptable salts, wherein:

[0600] X and Y are each independently CR or NR′, where R is H or C. 1-6 Alkyl group, and R′ is H or C. 1-6 Alkyl groups may not be present;

[0601] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[0602] R4 represents hydrogen, heteroaryl, heterocyclic, -C(=O)N(R5R6), -N(R7)C(=O)R8, -N(R9R6), etc. 10 C 1-6 Alkyl, C 1-6 Alkyl group or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0603] R 11 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 13 R 14 ), CF3, –OCF3 or –S(=O)2R 20 , or R4 and R 11 They combine with the atoms to which they are attached to to form heteroaryl groups;

[0604] R5, R6, R7, R8, R9 and R 10 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, alkylamino, or -N(R) 15 R 16 );and

[0605] R 15 and R 16 Each independently represents H and C. 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, or alkylamino.

[0606] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-50, 001-51 and 001-326 of Table C-1, or pharmaceutically acceptable salts thereof.

[0607] In some implementations, the fatty acid synthase inhibitor is a compound of formula (IV-A), (IV-B), or (IV-C):

[0608] (IV-A) (IV-B) or (IV-C).

[0609] Or their pharmaceutically acceptable salts, wherein:

[0610] L1, L2, L3, L4 and A are each independently CH or N;

[0611] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0612] q can be 0, 1, 2, 3, or 4;

[0613] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0614] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0615] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[0616] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, CF3,

[0617] –OCF3 or –S(=O)2R 20 ;

[0618] R 23 It is hydrogen, –N(R) 13 (R) 14 C 1-6 Alkyl, C 1-6 Alkoxy group, not present if L1 is N, or R 23 and R 24 They combine with the atoms to which they are attached to form heterocyclic groups, heteroaryl groups, or cycloalkyl groups;

[0619] R 24 It is hydrogen, –N(R) 13 (R) 14 C 1-6 Alkyl, C 1-6 Alkoxy, –(C 1-6 alkoxy (heterocyclic group), heterocyclic group, or R 23 and R24 They combine with the atoms to which they are attached to form heterocyclic groups, heteroaryl groups, or cycloalkyl groups;

[0620] R 26 It is hydrogen, heteroaryl, heterocyclic, –N(R) 13 (R) 14 ) or –S(=O)2R 20 ;

[0621] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0622] R 25 It is hydrogen, C 1-6 Alkyl or C 1-6 alkoxy groups; and

[0623] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

[0624] In some embodiments, the fatty acid synthase inhibitor of formula (IV) has one of the following formulas (IV-D) and (IV-E):

[0625] (IV-D) (IV-E), or their pharmaceutically acceptable salts.

[0626] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0627] q can be 0, 1, 2, 3, or 4;

[0628] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R)14 );

[0629] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0630] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[0631] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, CF3,

[0632] –OCF3 or –S(=O)2R 20 ;

[0633] R 26 It is hydrogen, heteroaryl, heterocyclic, –N(R) 13 (R) 14 ) or –S(=O)2R 20 ;

[0634] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0635] R 25 It is hydrogen, C 1-6 Alkyl or C 1-6 alkoxy groups; and

[0636] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

[0637] In some embodiments, the fatty acid synthase inhibitor of formula (IV) has one of the following formulas (IV-F) and (IV-G):

[0638] (IV-F) or (IV-G), or their pharmaceutically acceptable salts, wherein:

[0639] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0640] q can be 0, 1, 2, 3, or 4;

[0641] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0642] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0643] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[0644] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkoxy, CF3,

[0645] –OCF3 or –S(=O)2R 20 ;

[0646] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0647] R 25 It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0648] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino;

[0649] s is 0, 1, or 2;

[0650] L5 is CH2, NH, S, or O;

[0651] L6 is CH or N;

[0652] R 27 is hydrogen, –C(=O)R′′, –S(=O)2R 20 ;

[0653] R 28 is hydrogen, –C(=O)R′′, –S(=O)2R 20 Or, if L6 is 0, then it does not exist; and

[0654] R′′ is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ) or –N(R 13 (R) 14 ).

[0655] In some embodiments of formula (IV), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group or –C(=O)N(R) 13 (R) 14 ).

[0656] In some embodiments of formula (IV), R1 is a cyano group.

[0657] In some embodiments of formula (IV), R2 is hydrogen or a halogen group; R2 is hydrogen.

[0658] In some embodiments of formula (IV), R3 is hydrogen.

[0659] In some implementations of formula (IV), R 21 and R 22 Each is independently hydrogen or C 1-6 alkyl.

[0660] In some implementations of formula (IV), R 21 and R 22 Each independently is C 1-6 alkyl.

[0661] In some implementations of formula (IV), R 25 It is hydrogen.

[0662] In some implementations of formula (IV), L2 is N.

[0663] In some implementations of formula (IV), L1 is CH.

[0664] In some implementations of formula (IV), L3 is CH.

[0665] In some implementations of formula (IV), L4 is CH.

[0666] In some implementations of formula (IV), A is N.

[0667] In some implementations of formula (IV), A is CH.

[0668] In some implementations of formula (IV), R 26 It is a heterocyclic group.

[0669] In some implementations of formula (IV), R 24 It is –N(R) 13 (R) 14 ).

[0670] In some embodiments of formula (IV), L5 and L6 are each independently N. In some embodiments of formula (IV), s is 1.

[0671] In some implementations of formula (IV), s is 0.

[0672] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-1, 001-3, 001-4, 001-14, 001-20, 001-27, 001-31 and 001-36 of Table C-1, or pharmaceutically acceptable salts thereof.

[0673] In some implementations, the fatty acid synthase inhibitor is a compound of formula (V):

[0674] (V)

[0675] Or its pharmaceutically acceptable salt, wherein:

[0676] L7 is N or O, where if L7 is O, then R 30 It does not exist;

[0677] A is CH or N;

[0678] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0679] q can be 0, 1, 2, 3, or 4;

[0680] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0681] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0682] R3 is a halogen group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0683] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[0684] R 29 and R 30 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, –N(R) 15 R 16 ), –C(=O)R 46 Or –R 48 C(=O)R 47 , or R 29 and R 30 They combine with the atoms to which they are attached to form heteroaryl or heterocyclic groups, where if L7 is O, then R 30 It does not exist;

[0685] R 46 and R 47 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0686] R 48 It is an alkyl group or does not exist;

[0687] R 31 It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0688] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0689] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

[0690] v is 0 or 1.

[0691] In some embodiments, the fatty acid synthase inhibitor of formula (V) has one of the following formulas: (VA), (VB), (VC), and (VD):

[0692] (VA), (VB)

[0693] (VC) and (VD), or their pharmaceutically acceptable salts, wherein:

[0694] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0695] q can be 0, 1, 2, 3, or 4;

[0696] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0697] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0698] R3 is a halogen group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0699] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[0700] R 30 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, –N(R) 15 R 16 ), –C(=O)R 46 Or –R 48 C(=O)R 47 Where L7 is O, then R 30 It does not exist;

[0701] R 46 and R 47 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0702] R 48 It is an alkyl group or does not exist;

[0703] R 31 It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0704] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0705] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino;

[0706] L8, L9 and L 10 Each can be independently CH2, NH or O;

[0707] L 11 and L12 Each can be independently CH or N;

[0708] R 32 and R 33 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl group, –S(=O)2R 20 –C(=O)R 46 , hydroxyalkyl, hydroxyl or absent;

[0709] u is 0, 1, or 2; and

[0710] t can be 0, 1, or 2.

[0711] In some implementations of formula (V), L7 is N.

[0712] In some implementations of formula (V), L7 is O.

[0713] In some implementations of formula (V), A is N.

[0714] In some implementations of formula (V), A is CH.

[0715] In some embodiments of formula (V), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group or –C(=O)N(R) 13 (R) 14 ).

[0716] In some embodiments of formula (V), R1 is a cyano group.

[0717] In some embodiments of formula (V), R2 is hydrogen or a halogen group.

[0718] In some embodiments of formula (V), R2 is hydrogen.

[0719] In some embodiments of formula (V), R3 is fluorine.

[0720] In some implementations of formula (V), R 21 and R 22 Each is independently hydrogen or C 1-6 alkyl.

[0721] In some implementations of formula (V), R 21 and R 22 Each independently is C 1-6 alkyl.

[0722] In some implementations of formula (V), R 31 It is hydrogen.

[0723] In some implementations of formula (V), R 30 It is hydrogen.

[0724] In some implementations of formula (V), L8 is O.

[0725] In some implementations of formula (V), L9 is O.

[0726] In some implementations of formula (V), L 10 It is O, and L 11 It is N.

[0727] In some implementations of formula (V), L 12 It is N.

[0728] In some implementations of formula (V), R 32 and R 33 Each is independently hydrogen.

[0729] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-64, 001-65, 001-70, 001-78, 001-498, 001-336 and 001-338 of Table C-1, or pharmaceutically acceptable salts thereof.

[0730] In some implementations, the fatty acid synthase inhibitor is a compound of formula (VI-A) or (VI-B):

[0731] (VI-A) or (VI-B), or their pharmaceutically acceptable salts, wherein:

[0732] L 13 L 14 L 15 A and C are independently CH or N;

[0733] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0734] q can be 0, 1, 2, 3, or 4;

[0735] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6Alkyl or –N(R) 13 (R) 14 );

[0736] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0737] R3 is a halogen group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0738] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[0739] R 34 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, hydroxy, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, CF3, –OCF3, –S(=O)2R 20 or –N(R) 15 R 16 );

[0740] R 35 It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0741] R 36 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 15 R 16 ), heterocyclic group or heteroaryl group;

[0742] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;and

[0743] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

[0744] In some embodiments, the fatty acid synthase inhibitor of formula (VI) has one of the following formulas (VI-C) or (VI-D):

[0745] (VI-C) or (VI-D), or their pharmaceutically acceptable salts, wherein:

[0746] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0747] q can be 0, 1, 2, 3, or 4;

[0748] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0749] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0750] R3 is a halogen group, C 1-6 Alkyl or C 1-6 Alkoxy;

[0751] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[0752] R 35 It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0753] R 36 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, –N(R) 15 R 16 ), heterocyclic group or heteroaryl group;

[0754] R 13 and R14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0755] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

[0756] R 37 and R 38 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, or R 37 and R 38 They combine with the atoms to which they are attached to form heteroaryl or heterocyclic groups.

[0757] In some embodiments of formula (VI), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group or –C(=O)N(R) 13 (R) 14 ).

[0758] In some embodiments of formula (VI), R1 is a cyano group.

[0759] In some embodiments of formula (VI), R2 is hydrogen or a halogen group.

[0760] In some embodiments of formula (VI), R2 is hydrogen.

[0761] In some embodiments of formula (VI), R3 is fluorine.

[0762] In some implementations of formula (VI), R 21 and R 22 Each is independently hydrogen or C 1-6 alkyl.

[0763] In some implementations of formula (VI), R 21 and R 22 Each independently is C 1-6 alkyl.

[0764] In some implementations of formula (VI), R 35 It is hydrogen.

[0765] In some implementations of formula (VI), R 34 It is a heteroaryl group;

[0766] In some implementations of formula (VI), R 34 It is thiophene, pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazoleyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrololinyl, pyridazinyl, triazolyl, indoleyl, isoindoleyl, indoleazinyl, benzimidazolyl, quinolinyl, isoquinolinyl, inzolyl, benzotriazolyl, tetrazolpyridazinyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, thiazolyl, benzothiazolyl, or benzothiazolyl.

[0767] In some implementations of formula (VI), L 13 It is N.

[0768] In some implementations of formula (VI), L 14 and L 15 Each is independently represented by CH.

[0769] In some implementations of formula (VI), A is N.

[0770] In some implementations of formula (VI), A is CH.

[0771] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-42, 001-43, 001-48, 001-62 and 001-322 of Table C-1, or pharmaceutically acceptable salts thereof.

[0772] In some implementations, the fatty acid synthase inhibitor is a compound of formula (VI-J):

[0773] (VI-J), or a pharmaceutically acceptable salt thereof, wherein:

[0774] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl) or -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0775] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0776] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0777] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[0778] R3 It is H, -OH or halogen;

[0779] R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl;

[0780] R 22 It is H, halogen, or C1-C2 alkyl;

[0781] R 35 It is –C(O)-R 351 -C(O)-NHR 351 -C(O)-OR 351 or S(O)2R 351 ;and

[0782] R 351 It is a C1-C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group.

[0783] In some implementations of formula (VI-J), R 3 It is H or halogen.

[0784] In some implementations of formula (VI-J), R 1 It is a halogen, –CN, or C1-C2 haloalkyl.

[0785] In some implementations of formula (VI-J), R 22 It is a C1-C2 alkyl group.

[0786] In some implementations of formula (VI-J), R 21 It is cyclobutyl, and R 22 It is a C1-C2 alkyl group.

[0787] In some implementations of formula (VI-J), R 21 It is cyclobutyl.

[0788] In some implementations of formula (VI-J), R 3 It is H or F.

[0789] In some implementations of formula (VI-J), R 1 Yes –CN.

[0790] In some implementations of formula (VI-J), R 1 Yes –CF3.

[0791] In some implementations of formula (VI-J), R 22 It is H, methyl, or ethyl.

[0792] In some implementations of formula (VI-J), R 22 It is H.

[0793] In some implementations of formula (VI-J), R 22 It is a methyl group.

[0794] In some implementations of formula (VI-J), R 35 It is -C(O)-NHR 351 .

[0795] In some implementations of formula (VI-J), R 351 It is 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.

[0796] In some implementations of formula (VI-J), R 351 It is (R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

[0797] In some implementations of formula (VI-J), R 1 It is –CN, for each R 2 It is hydrogen, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is H, R 35 It is -C(O)-NHR 351 , where R 351 It is 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.

[0798] In some implementations of formula (VI-J), R 35 It is -C(O)-O- R 351 .

[0799] In some implementations of formula (VI-J), R 351 It is 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.

[0800] In some implementations of formula (VI-J), R 1 It is –CN, for each R2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is H, R 35 It is -C(O)-OR 351 , where R 351 It is 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.

[0801] In some implementations of formula (VI-J), R 351 It is (R)-3-tetrahydrofuranyl or (S)-3-tetrahydrofuranyl.

[0802] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-443, 001-444, 001-490, 001-491, 001-492 and 001-493 of Table C-1, or pharmaceutically acceptable salts thereof.

[0803] In some implementations, the fatty acid synthase inhibitor is a compound of formula (VII-A) or (VII-B):

[0804] (VII-A) or (VII-B), or their pharmaceutically acceptable salts, wherein:

[0805] L 16 It is C or N, where if L 16 If it is N, then R 41 It does not exist;

[0806] L 17 L 18 A and C are independently CH or N;

[0807] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0808] q can be 0, 1, 2, 3, or 4;

[0809] R20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0810] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0811] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[0812] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[0813] R 40 R 42 and R 43 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl group, –S(=O)2R 20 –C(=O)R, hydroxyalkyl, hydroxyl or –N(R) 13 R 14 ), or R 41 and R 42 They combine with the atoms to which they are attached to form heteroaryl or heterocyclic groups;

[0814] R 41 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkyl group, –S(=O)2R 20 –C(=O)R, hydroxyalkyl, hydroxyl or –N(R) 13 R 14 ), or if L 16 If it is N, then R 41 Does not exist, or R 41 and R 42 They combine with the atoms to which they are attached to form heteroaryl or heterocyclic groups;

[0815] R is hydrogen, C is... 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[0816] R 39It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0817] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;and

[0818] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

[0819] In some embodiments of formula (VII), R1 is hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkyl group or –C(=O)N(R) 13 (R) 14 ).

[0820] In some embodiments of formula (VII), R1 is a cyano group.

[0821] In some embodiments of formula (VII), R2 is hydrogen or a halogen group.

[0822] In some embodiments of formula (VII), R2 is hydrogen.

[0823] In some embodiments of formula (VII), R3 is hydrogen.

[0824] In some implementations of formula (VII), R 21 and R 22 Each is independently hydrogen or C 1-6 alkyl.

[0825] In some implementations of formula (VII), R 21 and R 22 Each independently is C 1-6 alkyl.

[0826] In some implementations of formula (VII), R 39 It is hydrogen.

[0827] In some implementations of formula (VII), R 40 It is hydrogen.

[0828] In some implementations of formula (VII), L 16 It is N.

[0829] In some implementations of formula (VII), L 17 It is N.

[0830] In some implementations of formula (VII), L 18 It is CH.

[0831] In some implementations of formula (VII), L 18 It is N.

[0832] In some implementations of equation (VII), A is N.

[0833] In some embodiments of formula (VII), A is CH.

[0834] In some implementations of formula (VII), R 42 It is C 1-6 alkyl.

[0835] In some implementations of formula (VII), R 41 It is C 1-6 alkyl.

[0836] In some embodiments, the fatty acid synthase inhibitor is compound 001-161 or 001-499 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0837] In some embodiments, the fatty acid synthase inhibitor is a compound of any one of formulas (VIII-A), (VIII-B), and (VIII-C):

[0838] (VIII-A) (VIII-B) and (VIII-C), or their pharmaceutically acceptable salts, wherein:

[0839] L 19 A and C are independently CH or N;

[0840] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[0841] q can be 0, 1, 2, 3, or 4;

[0842] R20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[0843] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[0844] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[0845] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[0846] R 39 It is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0847] R 44 and R 45 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, –S(=O)2R 20 –C(=O)R or –N(R) 13 R 14 );and

[0848] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;and

[0849] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino.

[0850] In some embodiments of formula (VIII), R1 is a cyano group.

[0851] In some embodiments of formula (VIII), R2 is hydrogen or a halogen.

[0852] In some embodiments of formula (VIII), R2 is hydrogen.

[0853] In some embodiments of formula (VIII), R3 is hydrogen.

[0854] In some implementations of formula (VIII), R 21 and R 22 Each is independently hydrogen or C 1-6 alkyl.

[0855] In some implementations of formula (VIII), R 21 and R 22 Each independently is C 1-6 alkyl.

[0856] In some implementations of formula (VIII), R 39 It is hydrogen.

[0857] In some implementations of formula (VIII), L 19 It is N.

[0858] In some implementations of formula (VIII), A is N.

[0859] In some implementations of formula (VIII), A is CH.

[0860] In some embodiments, the fatty acid synthase inhibitor is compound 001-498 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0861] In some implementations, the fatty acid synthase inhibitor is a compound of formula (IX):

[0862] (IX), or a pharmaceutically acceptable salt thereof, wherein:

[0863] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl) or -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0864] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0865] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0866] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0867] R 3It is H, -OH or halogen;

[0868] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0869] R 22 It is H, halogen, or C1-C2 alkyl;

[0870] R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH 、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0871] t is 0 or 1;

[0872] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0873] L 1 It is CR 23 Or N;

[0874] L 2 It is CH or N;

[0875] L 1 or L 2 At least one of them is N; and

[0876] R 23 It is an H or C1-C4 straight-chain or branched alkyl group.

[0877] In some implementations of formula (IX), R 24 It is a C1-C4 straight-chain or branched alkyl group or -(C1-C4 alkyl group). t -O-(C1-C4 straight-chain or branched alkyl), where t is 0 or 1.

[0878] In some implementations of formula (IX), R 21 It is a halogen, a C1-C4 straight-chain or branched alkyl group, a C3-C5 cycloalkyl group (wherein the C3-C5 cycloalkyl group optionally includes an oxygen or nitrogen heteroatom), or –S(O). u -(C1-C4 straight-chain or branched alkyl) (where u is 0 or 2) or –S(O) u -(C3-C5 cycloalkyl) (where u is 0 or 2);

[0879] In some implementations of formula (IX), R3 It is H or halogen.

[0880] In some implementations of formula (IX), R 1 It is a halogen, –CN, or C1-C2 haloalkyl.

[0881] In some implementations of formula (IX), L 1 and L 2 All are N.

[0882] In some implementations of formula (IX), R 21 It is a C1-C2 alkyl or C3-C5 cycloalkyl, and R 22 It is a C1-C2 alkyl group.

[0883] In some implementations of formula (IX), R 21 It is a C3-C5 cycloalkyl group, and R 22 It is a C1-C2 alkyl group.

[0884] In some implementations of formula (IX), R 24 It is -(C1-C2 alkyl) t -O-(C1-C2 alkyl), where t is 0 or 1.

[0885] In some implementations of formula (IX), R 21 It is a C3-C5 cycloalkyl group, R 22 It is a C1-C2 alkyl group, and R 24 It is a C1-C2 alkyl group.

[0886] In some implementations of formula (IX), R 21 It is cyclobutyl, R 22 It is a C1-C2 alkyl group, and R 24 It is a C1-C2 alkyl group.

[0887] In some implementations of formula (IX), R 21 It is cyclobutyl.

[0888] In some implementations of formula (IX), R 3 It is H or F.

[0889] In some implementations of formula (IX), R 1 Yes –CN.

[0890] In some implementations of formula (IX), R 1 Yes –CF3.

[0891] In some implementations of formula (IX), R 22 It is H, methyl, or ethyl.

[0892] In some implementations of formula (IX), R 22 It is H.

[0893] In some implementations of formula (IX), R 22 It is a methyl group.

[0894] In some implementations of formula (IX), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is methyl, L 1 and L 2 It is N, and R 24 It is methyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

[0895] In some implementations of formula (IX), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is methyl, L 1 and L 2 It is N, and R 24 It is methoxy or ethoxy.

[0896] In some implementations of formula (IX), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is methyl, L 1 It is CH, L 2 It is N, and R 24 It is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

[0897] In some implementations of formula (IX), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is methyl, L 1 It is N, L 2 It is CH, and R 24 It is methyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

[0898] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-152, 001-154, 001-156 and 001-246 of Table C-1, or pharmaceutically acceptable salts thereof.

[0899] In some implementations, the fatty acid synthase inhibitor is a compound of formula (IX-1):

[0900] (IX-1), or a pharmaceutically acceptable salt thereof, wherein:

[0901] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (4- to 6-membered heterocycle), or -O- (C1-C4 straight-chain or branched alkyl), wherein when R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0902] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[0903] R 3 It is H, -OH or halogen;

[0904] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0905] R 22 It is H, halogen, or C1-C2 alkyl;

[0906] R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH 、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0907] t is 0 or 1;

[0908] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0909] L 1 It is N; and

[0910] L 2 It is N.

[0911] In some implementations of formula (IX-1), R 1 It is H, -CN, halogen, or C1-C4 straight-chain or branched alkyl; each R 2 Independently for H; R 3 It is H or halogen; R 21 It is a C1-C4 straight-chain or branched alkyl group or a C3-C5 cycloalkyl group; R 22 It is H or C1-C2 alkyl; and R 24 It is an H or C1-C4 straight-chain or branched alkyl group.

[0912] In some implementations of formula (IX-1), R 1 It is -CN; each R 2 Independently for H; R 3 It is H; R 21 It is a C3-C5 cycloalkyl group; R 22 It is H or C1-C2 alkyl; and R 24 It is a C1-C4 straight-chain or branched alkyl group.

[0913] In some embodiments, the fatty acid synthase inhibitor of formula (IX-1) has the following structure: (Compound 001-152).

[0914] In some implementations, the fatty acid synthase inhibitor is a compound of formula (X):

[0915] (X), or a pharmaceutically acceptable salt thereof, wherein:

[0916] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl) or -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0917] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0918] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0919] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0920] R 3 It is H, -OH or halogen;

[0921] L 3 It is C(R) 60 2. O or NR 50 ;

[0922] Each R60 Independently H, -OH, -CN, -O t -(C3-C5 cycloalkyl), -O-(C1-C4 straight-chain or branched alkyl) or -C(O)-N(R) 601 )2, of which:

[0923] t is 0 or 1, and

[0924] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0925] Each R 50 Independently H, –C(O)-O t -(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C3-C5 cyclic alkyl), optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R) 501 )2 or C1-C4 straight-chain or branched alkyl groups, wherein:

[0926] t is 0 or 1, and

[0927] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0928] n is 1, 2, or 3;

[0929] m is 1 or 2;

[0930] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms.

[0931] R 22 It is H, halogen, or C1-C2 alkyl;

[0932] Each R 26 Independently, it can be –OH, -CN, halogen, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C1-C4 alkyl) or -C(O)-N(R) 501 )2, of which:

[0933] t is 0 or 1, and

[0934] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[0935] s is 0, 1, or 2; and

[0936] Each R 601 and R 501 Independently, it is an H or C1-C4 straight-chain or branched alkyl group; and

[0937] Where R 26 R 60 R 50 R 501 and R 601 The two in R are optionally joined to form a loop, where R 26 R 60 R 50 R 501 and R 601 The two in can be two R. 26 Two Rs 60 Two Rs 50 Two Rs 501 Or two Rs 601 .

[0938] In some implementations of formula (X), R 21 It is a halogen, a C1-C4 straight-chain or branched alkyl group, or a C3-C5 cycloalkyl group.

[0939] In some implementations of formula (X), R 3 It is H or halogen.

[0940] In some implementations of formula (X), R 1 It is a –CN or C1-C2 haloalkyl group.

[0941] In some implementations of formula (X), R 3 It is H or F.

[0942] In some implementations of formula (X), R 1 Yes –CN.

[0943] In some implementations of formula (X), R 1 Yes –CF3.

[0944] In some implementations of equation (X), n is 1.

[0945] In some implementations of equation (X), n is 2.

[0946] In some implementations of equation (X), m is 1.

[0947] In some implementations of equation (X), m is 2.

[0948] In some implementations of formula (X), R 21 It is a C1-C2 alkyl or C3-C5 cycloalkyl, and R 22It is a C1-C2 alkyl group.

[0949] In some implementations of formula (X), R 21 It is a C3-C5 cycloalkyl group, and R 22 It is a C1-C2 alkyl group.

[0950] In some implementations of equation (X), n is 2, m is 1, and L 3 It is -N–C(O)-O-(C1-C2 alkyl).

[0951] In some implementations of formula (X), L 3 It is NR 50 ;R 50 It is a C1-C2 alkyl group; R 21 It is cyclobutyl; R 22 It is H or methyl; R 3 It is H; R 1 It is -CN; m is 2, and n is 1 or 2.

[0952] In some implementations of equation (X), n is 2, m is 1, and L 3 It is O, and s is 0.

[0953] In some implementations of formula (X), R 22 It is H, methyl, or ethyl.

[0954] In some implementations of formula (X), R 22 It is a methyl group.

[0955] In some implementations of formula (X), R 22 It is H.

[0956] In some implementations of formula (X), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is a methyl group, n is 2, and L 3 It is NR 50 , where R 50 It is methyl or ethyl.

[0957] In some implementations of formula (X), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is a C3-C4 cycloalkyl group, R 22 It is a methyl group, n is 2, and L 3 It is O.

[0958] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compounds 001-406, 001-440 and 001-439 of Table C-1, or pharmaceutically acceptable salts thereof.

[0959] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XI):

[0960] (XI), or a pharmaceutically acceptable salt thereof, wherein:

[0961] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl) or -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0962] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0963] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[0964] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[0965] R 3 It is H, -OH or halogen;

[0966] R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl;

[0967] R 22 It is H, halogen, C1-C2 alkyl; and

[0968] R 351 It is a C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

[0969] In some implementations of formula (XI), R 3 It is H or halogen.

[0970] In some implementations of formula (XI), R 1 It is a halogen, –CN, or C1-C2 haloalkyl.

[0971] In some implementations of formula (XI), R 21 It is a C3-C4 cycloalkyl group, and R 22 It is a C1-C2 alkyl group.

[0972] In some implementations of formula (XI), R 21 It is cyclobutyl, and R 22 It is a C1-C2 alkyl group.

[0973] In some implementations of formula (XI), R 21 It is cyclobutyl.

[0974] In some implementations of formula (XI), R 3 It is H or F.

[0975] In some implementations of formula (XI), R 1 Yes –CN.

[0976] In some implementations of formula (XI), R 1 Yes –CF3.

[0977] In some implementations of formula (XI), R 22 It is H, methyl, or ethyl.

[0978] In some implementations of formula (XI), R 22 It is H.

[0979] In some implementations of formula (XI), R 22 It is a methyl group.

[0980] In some implementations of formula (XI), R 1 It is –CN, for each R 2 It is H, R 3 Is it H or F, R? 21 It is cyclobutyl, R 22 It is methyl, and R 351 It is methyl or ethyl.

[0981] In some embodiments, the fatty acid synthase inhibitor is compound 001-254 or 001-256 of Table C-1 or a pharmaceutically acceptable salt thereof.

[0982] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XII):

[0983] (XII), or a pharmaceutically acceptable salt thereof, wherein:

[0984] L-Ar is , or ;

[0985] Ar is , , , or ;

[0986] Het is a 5- to 6-membered heteroaryl group;

[0987] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[0988] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[0989] R 3 It is H or F;

[0990] R 11 It is H or -CH3;

[0991] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[0992] R 22 It is H, halogen, or C1-C2 alkyl;

[0993] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[0994] t is 0 or 1;

[0995] u is 0 or 1;

[0996] The condition is that when u is 1, t is 1; and

[0997] Each R 241 Independently H or C1-C2 alkyl; and

[0998] R 25 It is a halogen, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, C1-C4 haloalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl) or cyclopropyl.

[0999] In some implementations of formula (XII), L-Ar is Ar is not .

[1000] In some implementations of formula (XII), L-Ar is or And Ar is , , , or .

[1001] In some implementations of formula (XII), L-Ar is And Ar is , , , or .

[1002] In some implementations of formula (XII), Ar is .

[1003] In some implementations of formula (XII), R 1 It is a halogen, -CN, or C1-C2 haloalkyl.

[1004] In some implementations of formula (XII), R 1 Yes - CN.

[1005] In some implementations of formula (XII), R 2 It is H.

[1006] In some implementations of formula (XII), R 21 It is a halogen, a C1-C4 alkyl or a C3-C5 cycloalkyl.

[1007] In some implementations of formula (XII), R 21 It is a C1-C4 alkyl or a C3-C5 cycloalkyl.

[1008] In some implementations of formula (XII), R 21 It is a C1-C2 alkyl or a C3-C5 cycloalkyl.

[1009] In some implementations of formula (XII), R 21 It is a C1-C2 alkyl group.

[1010] In some implementations of formula (XII), R 21 It is -CH3.

[1011] In some implementations of formula (XII), R 22 It is H or C1-C2 alkyl.

[1012] In some implementations of formula (XII), R 22 It is H or -CH3.

[1013] In some implementations of formula (XII), R 22 It is -CH3.

[1014] In some implementations of formula (XII), R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1015] In some implementations of formula (XII), R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1016] In some implementations of formula (XII), R 24 It is a C1-C4 alkyl or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1017] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XII), wherein R 24 It is -(C1-C2 alkyl)-O-(C1-C2 alkyl).

[1018] In some implementations of formula (XII), R 24 It is -CH2-O-CH3.

[1019] In some implementations of formula (XII), R 24 It is a C1-C2 alkyl group.

[1020] In some implementations of formula (XII), R 24 It is -CH3.

[1021] In some implementations of formula (XII), R 24 It is a C3-C6 cycloalkyl group.

[1022] In some implementations of formula (XII), R 24 It is -CN or -(C1-C2 alkyl)-CN.

[1023] In some implementations of formula (XII), R 24 Yes - CN.

[1024] In some implementations of formula (XII), R 24 It is -(C1-C2 alkyl)-CN.

[1025] In some implementations of formula (XII), R 24 It is H, -CH3, -CH2OH, -CH2OCH3, -(CH2)2OH, -(CH2)2OCH3 or -(CH2)2N(CH3)2.

[1026] In some implementations of formula (XII), R 24 It is methyl, isopropyl, cyclopropyl, -CN, or -(C1-C2 alkyl)-CN.

[1027] In some implementations of formula (XII), R 24 It is substituted by one or more substituents selected from C1-C2 alkyl, oxo, -CN, halogen, alkyl acyl, alkoxy carbonyl, -OH and C1-C2 alkoxy.

[1028] In some implementations of formula (XII), R 24 It is substituted by one or more substituents selected from methyl, -F, methoxy, -C(=O)CH3 and -C(=O)-OCH3.

[1029] In some implementations of formula (XII), R 24 It is substituted by two identical or different substituents.

[1030] In some implementations of formula (XII), R 24 It is substituted by three identical or different substituents.

[1031] In some implementations of formula (XII), R 25 It is a halogen, -CN, C1-C2 alkyl, or cyclopropyl.

[1032] In some implementations of formula (XII), R 25 It is halogen, C1-C2 alkyl, or cyclopropyl.

[1033] In some implementations of formula (XII), R 25 It is -CN, -Cl, or -CH3.

[1034] In some implementations of formula (XII), R 25 It is -Cl.

[1035] In some implementations of formula (XII), R 25 It is -CH3.

[1036] In some implementations of formula (XII), R 25 It is substituted by one or more substituents selected from -OH, halogen, C1-C2 alkyl and alkyl carbonyloxy groups.

[1037] In some implementations of formula (XII), R 25 It is substituted by one or more substituents selected from -F, methyl and -OC(=O)-CH3.

[1038] In some implementations of formula (XII), R 25 It is substituted by two identical or different substituents.

[1039] In some implementations of formula (XII), R 25 It is substituted by three identical or different substituents.

[1040] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XII-1):

[1041] (XII-1), or a pharmaceutically acceptable salt thereof, wherein:

[1042] L-Ar is , or ;

[1043] Ar is , , , or ;

[1044] Het is a 5- to 6-membered heteroaryl group;

[1045] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1046] Each R2 Independently, it is H, halogen, or C1-C4 alkyl;

[1047] R 3 It is H or F;

[1048] R 11 It is H or -CH3;

[1049] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1050] R 22 It is H, halogen, or C1-C2 alkyl;

[1051] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[1052] t is 0 or 1;

[1053] u is 0 or 1;

[1054] Each R 241 Independently H or C1-C2 alkyl; and

[1055] R 25 It is a halogen, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, C1-C4 haloalkyl, -(C1-C4 alkyl)-O-(C1-C4 alkyl) or cyclopropyl.

[1056] In some implementations of formula (XII-1), L-Ar is Ar is R 1 It is H, -CN, halogen, or C1-C4 alkyl; each R 2 Independently for H; R 3 It is H or F; R 21 It is H, halogen, or C1-C4 alkyl; R 22 It is H, halogen, or C1-C2 alkyl; R 24 It is a C1-C4 alkyl, a C1-C4 haloalkyl, or -(C1-C4 alkyl). t-O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl); R 25 It is a C1-C2 alkyl, a C1-C4 haloalkyl, or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1057] In some implementations of formula (XII-1), L-Ar is Ar is R 1 It is -CN; each R 2 Independently for H; R 3 It is H; R 21 It is a C1-C4 alkyl group; R 22 It is H or C1-C2 alkyl; R 24 It is a C1-C4 haloalkyl or -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings), and R 25 It is -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1058] In some embodiments, the compound of formula (XII-1) has the following structure: (Compound 002-386).

[1059] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XIII):

[1060] (XIII), or a pharmaceutically acceptable salt thereof, wherein:

[1061] L-Ar is , or ;

[1062] Ar is , , , or ;

[1063] Het is a 5- to 6-membered heteroaryl group;

[1064] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1065] Each R2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1066] R 3 It is H or F;

[1067] R 11 It is H or -CH3;

[1068] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1069] R 22 It is H, halogen, or C1-C2 alkyl; and

[1070] Each R 24 and R 25 Independently, it can be H, halogen, -CN, -(C1-C4 alkyl)-CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-N(R). 241 2, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[1071] Each t is independently 0 or 1;

[1072] Each u is independently 0 or 1; and

[1073] Each R 241 It is independently H or C1-C2 alkyl.

[1074] In some implementations of formula (XIII), when L-Ar is At that time, Ar was not .

[1075] In some implementations of formula (XIII), L-Ar is or And Ar is , , , or .

[1076] In some implementations of formula (XIII), L-Ar is And Ar is , , , or .

[1077] In some implementations of formula (XIII), Ar is .

[1078] In some implementations of formula (XIII), R 1 It is a halogen, -CN, or C1-C2 haloalkyl.

[1079] In some implementations of formula (XIII), R 1 Yes - CN.

[1080] In some implementations of formula (XIII), R 2 It is H.

[1081] In some implementations of formula (XIII), R 21 It is a halogen, a C1-C4 alkyl, a C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle.

[1082] In some implementations of formula (XIII), R 21 It is a C1-C4 alkyl, C3-C5 cycloalkyl, or a 4- to 6-membered heterocyclic ring.

[1083] In some implementations of formula (XIII), R 21 It is a C1-C2 alkyl or a C3-C5 cycloalkyl.

[1084] In some implementations of formula (XIII), R 21 It is a C1-C2 alkyl group.

[1085] In some implementations of formula (XIII), R 21 It is -CH3.

[1086] In some implementations of formula (XIII), R 22 It is H or C1-C2 alkyl.

[1087] In some implementations of formula (XIII), R 22 It is H or -CH3.

[1088] In some implementations of formula (XIII), R 22 It is -CH3.

[1089] In some implementations of formula (XIII), each R 24 and R 25 Independently H, -CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH 、 -(C1-C4 alkyl)-N(R) 2412, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1090] In some implementations of formula (XIII), each R 24 and R 25 Independently H, C1-C4 alkyl, -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1091] In some implementations of formula (XIII), R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1092] In some implementations of formula (XIII), R 24 It is -CN, -Cl, C1-C4 alkyl or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1093] In some implementations of formula (XIII), R 24 It is a C1-C4 alkyl or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1094] In some implementations of formula (XIII), R 24 It is -(C1-C2 alkyl)-O-(C1-C2 alkyl).

[1095] In some implementations of formula (XIII), R 24 It is a C1-C4 alkyl group.

[1096] In some implementations of formula (XIII), R 24 It is -CH3.

[1097] In some implementations of formula (XIII), R 24 It is hydrogen.

[1098] In some implementations of formula (XIII), R 24 It is substituted by one or more substituents selected from halogens, C3-C5 cycloalkyl groups and C1-C2 alkoxy groups.

[1099] In some implementations of formula (XIII), R 24 It is substituted by one or more substituents selected from -F, cyclopropyl and -OCH3.

[1100] In some implementations of formula (XIII), R 24 It is substituted by two identical or different substituents.

[1101] In some implementations of formula (XIII), R 24 It is substituted by three identical or different substituents.

[1102] In some implementations of formula (XIII), R 25 It is halogen, methyl, ethyl or cyclopropyl.

[1103] In some implementations of formula (XIII), R 25 It is -CN, -Cl, C1-C4 alkyl, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 alkyl).

[1104] In some implementations of formula (XIII), R 25 It is -CN, -Cl, -CH3, -O-(C3-C5 cycloalkyl) or -O-(C1-C2 alkyl).

[1105] In some implementations of formula (XIII), R 25 It is -CN, -Cl, or C1-C4 alkyl.

[1106] In some implementations of formula (XIII), R 25 It is -CH3.

[1107] In some implementations of formula (XIII), R 25 It is -Cl 。

[1108] In some implementations of formula (XIII), R 25 It is replaced by one or more halogens.

[1109] In some implementations of formula (XIII), R 25 Replaced by one or more -F.

[1110] In some implementations of formula (XIII), R 25 It is replaced by two substituents.

[1111] In some implementations of formula (XIII), R 25 It is replaced by three substituents.

[1112] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XIII-1):

[1113] (XIII-1), or a pharmaceutically acceptable salt thereof, wherein:

[1114] L-Ar is , or ;

[1115] Ar is , , , or ;

[1116] Het is a 5- to 6-membered heteroaryl group;

[1117] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1118] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1119] R 3 It is H or F;

[1120] R 11 It is H or -CH3;

[1121] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1122] R 22 It is H, halogen, or C1-C2 alkyl; and

[1123] Each R 24 and R 25 Independently, it can be H, halogen, -CN, -(C1-C4 alkyl)-CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-N(R). 2412, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[1124] Each t is independently 0 or 1;

[1125] Each u is independently 0 or 1; and

[1126] Each R 241 It is independently H or C1-C2 alkyl.

[1127] In some implementations of formula (XIII-1), L-Ar is Ar is R 1 It is H, -CN, halogen, or C1-C4 alkyl; each R 2 Independently for H; R 3 It is H or F; R 21 It is H, halogen, or C1-C4 alkyl; R 22 It is H, halogen, or C1-C2 alkyl; and each R 24 and R 25 It can be independently halogenated, C1-C4 alkyl, or -(C1-C4 alkyl). t -O-(C1-C4 alkyl).

[1128] In some implementations of formula (XIII-1), L-Ar is Ar is R 1 It is -CN; each R 2 Independently for H; R 3 It is H; R 21 It is a C1-C4 alkyl group; R 22 It is H or C1-C2 alkyl; and each R 24 and R 25 It can be independently halogenated, C1-C4 alkyl, or -(C1-C4 alkyl). t -O-(C1-C4 alkyl).

[1129] In some embodiments, the fatty acid synthase inhibitor of formula (XIII-1) has the following structure: (Compound 002-242).

[1130] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XIV):

[1131] (XIV), or a pharmaceutically acceptable salt thereof, wherein:

[1132] L-Ar is , or ;

[1133] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1134] Het is a 5- to 6-membered heteroaryl group;

[1135] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1136] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1137] R 3 It is H or F;

[1138] R 11 It is H or -CH3;

[1139] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1140] R 22 It is H, halogen, or C1-C2 alkyl; and

[1141] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[1142] Each t is independently 0 or 1; and

[1143] Each R 241 It is independently H or C1-C2 alkyl.

[1144] In some implementations of formula (XIV), L-Ar is or And Ar is , , , or .

[1145] In some implementations of formula (XIV), L-Ar is And Ar is , , , or .

[1146] In some implementations of formula (XIV), Ar is .

[1147] In some implementations of formula (XIV), R 1 It is a halogen, -CN, or C1-C2 haloalkyl.

[1148] In some implementations of formula (XIV), R 1 Yes - CN.

[1149] In some implementations of formula (XIV), R 2 It is H.

[1150] In some implementations of formula (XIV), R 21 It is a halogen, a C1-C4 alkyl, a C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle.

[1151] In some implementations of formula (XIV), R 21 It is H, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocyclic rings.

[1152] In some implementations of formula (XIV), R 21 It is a C1-C2 alkyl or a C3-C5 cycloalkyl.

[1153] In some implementations of formula (XIV), R 21 It is a C1-C2 alkyl group.

[1154] In some implementations of formula (XIV), R 21It is a C3-C5 cycloalkyl group.

[1155] In some implementations of formula (XIV), R 22 It is H or C1-C2 alkyl.

[1156] In some implementations of formula (XIV), R 22 It is H.

[1157] In some implementations of formula (XIV), R 22 It is a C1-C2 alkyl group.

[1158] In some implementations of formula (XIV), R 22 It is -CH3.

[1159] In some implementations of formula (XIV), R 24 It is a C1-C4 alkyl or -(C1-C4 alkyl) t -O-(C1-C4 alkyl).

[1160] In some implementations of formula (XIV), R 24 It is -(C1-C2 alkyl) t -O-(C1-C2 alkyl).

[1161] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XV):

[1162] (XV), or a pharmaceutically acceptable salt thereof, wherein:

[1163] L 3 It is -CH2-, -CHR 50 -、-O-、-NR 50 -、-NC(O)R 50 -OR-NC(O)OR 50 -, where R 50 It is a C1-C6 alkyl, C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle;

[1164] n is 1, 2, or 3;

[1165] m can be 1 or 2, provided that n + m ≥ 3;

[1166] L-Ar is , or ;

[1167] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1168] Het is a 5- to 6-membered heteroaryl group;

[1169] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1170] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1171] R 3 It is H or F;

[1172] R 11 It is H or -CH3;

[1173] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and

[1174] R 22 It is H, halogen, or C1-C2 alkyl.

[1175] In some implementations of formula (XV), L-Ar is or And Ar is , , , or .

[1176] In some implementations of formula (XV), L-Ar is And Ar is , , , or .

[1177] In some implementations of formula (XV), R 1 It is H, -CN, -C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocyclic) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H or -CN, R 1 It may be optionally replaced by one or more halogens.

[1178] In some implementations of formula (XV), R1 It is a halogen, -CN, or C1-C2 haloalkyl.

[1179] In some implementations of formula (XV), R 1 It is a -CN or C1-C2 haloalkyl group.

[1180] In some implementations of formula (XV), R 1 Yes - CN.

[1181] In some implementations of formula (XV), R 1 It is -Cl.

[1182] In some implementations of formula (XV), R 2 It is H.

[1183] In some implementations of formula (XV), R 21 It is a halogen, a C1-C4 alkyl, a C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle.

[1184] In some implementations of formula (XV), R 21 It is a C1-C2 alkyl or a C3-C5 cycloalkyl.

[1185] In some implementations of formula (XV), R 21 It is a C3-C5 cycloalkyl group.

[1186] In some implementations of formula (XV), R 22 It is H or C1-C2 alkyl.

[1187] In some implementations of formula (XV), R 22 It is H.

[1188] In some implementations of formula (XV), R 22 It is a C1-C2 alkyl group.

[1189] In some implementations of formula (XV), R 22 It is -CH3.

[1190] In some implementations of formula (XV), L 3 It is -N(CH3)-.

[1191] In some implementations of equation (XV), n is 2 and m is 2.

[1192] In some implementations of formula (XV), n is 1 or 2.

[1193] In some implementations of equation (XV), n is 1 and m is 2.

[1194] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XVI):

[1195] (XVI), or a pharmaceutically acceptable salt thereof, wherein:

[1196] L-Ar is , or ;

[1197] Ar is , , , or ;

[1198] Het is a 5- to 6-membered heteroaryl group;

[1199] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1200] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1201] R 3 It is H or F;

[1202] R 11 It is H or -CH3;

[1203] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1204] R 22 It is H, halogen, or C1-C2 alkyl; and

[1205] Each R 24 and R 25 It can be H, -C1-C4 alkyl, or halogen independently.

[1206] In some implementations of formula (XVI), L-Ar is or And Ar is , , , or .

[1207] In some implementations of formula (XVI), L-Ar is And Ar is , , , or .

[1208] In some implementations of formula (XVI), R 1 It is a halogen, -CN, or C1-C2 haloalkyl.

[1209] In some implementations of formula (XVI), R 21 It is a halogen, a C1-C4 alkyl, a C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle.

[1210] In some implementations of formula (XVI), R 21 It is -CH3.

[1211] In some implementations of formula (XVI), R 22 It is H.

[1212] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XVII):

[1213] (XVII), or a pharmaceutically acceptable salt thereof, wherein:

[1214] L-Ar is , or ;

[1215] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1216] Het is a 5- to 6-membered heteroaryl group;

[1217] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1218] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1219] R3 It is H or F;

[1220] R 11 It is H or -CH3;

[1221] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1222] R 22 It is H, halogen, or C1-C2 alkyl; and

[1223] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[1224] t is 0 or 1;

[1225] u is 0 or 1;

[1226] The condition is that when u is 1, t is 1; and

[1227] R 241 It is H or C1-C2 alkyl.

[1228] In some implementations of formula (XVII), L-Ar is or And Ar is , , , or .

[1229] In some implementations of formula (XVII), R 1 It is a halogen, -CN, or C1-C2 haloalkyl.

[1230] In some implementations of formula (XVII), R 1 Yes - CN.

[1231] In some implementations of formula (XVII), R 2 It is H.

[1232] In some implementations of formula (XVII), R 21 It is a halogen, a C1-C4 alkyl, a C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle.

[1233] In some implementations of formula (XVII), R 21 It is a C1-C2 alkyl or a C3-C5 cycloalkyl.

[1234] In some implementations of formula (XVII), R 21 It is a C1-C2 alkyl group.

[1235] In some implementations of formula (XVII), R 21 It is a C3-C5 cycloalkyl group.

[1236] In some implementations of formula (XVII), R 22 It is H or C1-C2 alkyl.

[1237] In some implementations of formula (XVII), R 22 It is H.

[1238] In some implementations of formula (XVII), R 22 It is a C1-C2 alkyl group.

[1239] In some implementations of formula (XVII), R 22 It is -CH3.

[1240] In some implementations of formula (XVII), R 24 It is a C1-C4 alkyl or -(C1-C4 alkyl)-O-(C1-C4 alkyl).

[1241] In some implementations of formula (XVII), R 24 It is -(C1-C2 alkyl)-O-(C1-C2 alkyl).

[1242] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XVIII):

[1243] (XVIII), or a pharmaceutically acceptable salt thereof, wherein:

[1244] L-Ar is , or ;

[1245] Ar is , , , or

[1246] The condition is that L-Ar is At that time, Ar was not ;

[1247] L 2 Yes - NHR 35 or -C(O)NHR 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl;

[1248] Het is a 5- to 6-membered heteroaryl group;

[1249] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1250] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1251] R 3 It is H or F;

[1252] R 11 It is H or -CH3;

[1253] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1254] R 22 It is H, halogen, or C1-C2 alkyl; and

[1255] R 35 It is -C(O)R 351 -C(O)NHR 351 C(O)OR 351 or S(O)2R 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl.

[1256] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XVIII), wherein L-Ar is... Ar is not .

[1257] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XVIII), wherein L 2 Yes - NHR 35 .

[1258] In some embodiments, the fatty acid synthase inhibitor is a compound of formula (XVIII), wherein L 2 It is -C(O)NHR 351 .

[1259] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XIX): (XIX), or a pharmaceutically acceptable salt thereof, wherein:

[1260] Each W, X, Y, and Z is independently -N- or -CR. 26 -, provided that no more than two of W, X, Y, and Z are -N-;

[1261] Each R 26 Independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), -N(R) 27 2. -S(O)2-(C1-C4 alkyl) or -C(O)-(C1-C4 alkyl);

[1262] Each R 27 Independently H or C1-C4 alkyl, or two R 27 They are C1-C4 alkyl groups and are joined together with the N atoms to which they are attached to form 3- to 6-membered rings, wherein the rings optionally include an oxygen atom as one of the members of the ring;

[1263] Ar is , , , or ;

[1264] Het is a 5- to 6-membered heteroaryl group;

[1265] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1266] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1267] R 3 It is H or F;

[1268] R 11 It is H or -CH3;

[1269] R 21It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and

[1270] R 22 It is H, halogen, or C1-C2 alkyl.

[1271] In some implementations of formula (XIX), Ar is .

[1272] In some implementations of formula (XIX), Y is -CR 26 -, where R 26 It is -N(R) 27 )2.

[1273] In some implementations of formula (XIX), X is -N-.

[1274] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XX):

[1275] (XX), or a pharmaceutically acceptable salt thereof, wherein:

[1276] L-Ar is , or ;

[1277] Ar is ;

[1278] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1279] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1280] R 3 It is H or F;

[1281] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1282] R 22 It is H, halogen, or C1-C2 alkyl;

[1283] R 24It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl), -O-(C3-C5 cycloalkyl) or -O-(4- to 6-membered heterocycle), wherein R 24 Optionally substituted with one or more hydroxyl groups or halogens; and

[1284] R 25 It is H, halogen, C1-C4 alkyl or C3-C5 cycloalkyl, wherein R 25 It may be optionally replaced by one or more halogens.

[1285] In some implementations of formula (XX), L-Ar is .

[1286] In some implementations of formula (XX), L-Ar is .

[1287] In some implementations of formula (XX), L-Ar is .

[1288] In some implementations of formula (XX), R 3 It is H.

[1289] In some implementations of formula (XX), R 1 It is -CN or -O-(C1-C4 alkyl), wherein when R 1 When it is not -CN, R 1 It may be optionally replaced by one or more halogens.

[1290] In some implementations of formula (XX), R 1 Yes - CN.

[1291] In some implementations of formula (XX), R 1 It is an -O-(C1-C4 alkyl) optionally substituted with one or more halogens.

[1292] In some implementations of formula (XX), each R 2 It is hydrogen.

[1293] In some implementations of formula (XX), R 21 It is a C1-C4 alkyl group.

[1294] In some implementations of formula (XX), R 22 It is H or C1-C2 alkyl.

[1295] In some implementations of formula (XX), R 24 It is an -O-(C1-C4 alkyl) optionally substituted with one or more hydroxyl groups or halogens.

[1296] In some implementations of formula (XX), R 24 It is an -O-(C1-C4 alkyl) optionally substituted with one or more hydroxyl groups.

[1297] In some implementations of formula (XX), R 25 It is -CH3.

[1298] In some implementations, the fatty acid synthase inhibitor is a compound of formula (XX-1):

[1299] (XX-1),

[1300] Or its pharmaceutically acceptable salt, wherein:

[1301] L-Ar is , or ;

[1302] Ar is ;

[1303] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1304] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1305] R 3 It is H or F;

[1306] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1307] R 22 It is H, halogen, or C1-C2 alkyl;

[1308] R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl), -O-(C3-C5 cycloalkyl) or -O-(4- to 6-membered heterocycle), wherein R 24 Optionally substituted with one or more hydroxyl groups or halogens; and

[1309] R 25 It is H, halogen, C1-C4 alkyl or C3-C5 cycloalkyl, wherein R 25 It may be optionally replaced by one or more halogens.

[1310] In some implementations of formula (XX-1), L-Ar is Ar is R 1 It is -CN or -O-(C1-C4 alkyl) optionally substituted with one or more halogens; each R 2 Independently for H; R 3 It is H or F; R 21 It is H or C1-C4 alkyl; R 22 It is H or C1-C2 alkyl; R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl) or -O-(4- to 6-membered heterocycle), where R 24 Optionally substituted with one or more hydroxyl groups or halogens; and R 25 It is H, halogen, or C1-C4 alkyl.

[1311] In some implementations of formula (XX-1), L-Ar is Ar is R 1 It is -CN or -O-(C1-C4 alkyl) optionally substituted with one or more halogens; each R 2 Independently for H; R 3 It is H or F; R 21 It is H or C1-C4 alkyl; R 22 It is H or C1-C2 alkyl; R 24 It is an -O-(C1-C4 alkyl) substituted with one or more hydroxyl groups or halogens; and R 25 It is a C1-C4 alkyl group.

[1312] In some embodiments, the compound of formula (XX-1) has one of the following structures:

[1313] (Compound 005-2)

[1314] (Compound 005-5).

[1315] In some embodiments, this disclosure provides pharmaceutical compositions comprising any one of 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.

[1316] In some embodiments, the fatty acid synthase inhibitor is a compound selected from the following: compound 001-152, compound 002-386, compound 002-242, compound 005-2 and compound 005-5, or a pharmaceutically acceptable salt thereof.

[1317] In some embodiments, the fatty acid synthase inhibitor is a compound selected from compounds 001-152 and 005-2, or their pharmaceutically acceptable salts.

[1318] In some implementations, the fatty acid synthase inhibitor is a compound selected from Table C-1 or a pharmaceutically acceptable salt thereof.

[1319] In some implementations, the fatty acid synthase inhibitor is a compound selected from Table C-2 or a pharmaceutically acceptable salt thereof.

[1320] In some implementations, the fatty acid synthase inhibitor is a compound selected from Table C-3 or a pharmaceutically acceptable salt thereof.

[1321] Table C-1: Fatty acid synthase inhibitors

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340]

[1341]

[1342]

[1343]

[1344]

[1345]

[1346]

[1347]

[1348]

[1349]

[1350]

[1351] Table C-2: Fatty acid synthase inhibitors

[1352]

[1353]

[1354]

[1355]

[1356]

[1357]

[1358]

[1359]

[1360]

[1361]

[1362]

[1363]

[1364]

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387] Table C-3: Fatty acid synthase inhibitors

[1388]

[1389]

[1390] thyroid hormone receptor agonists

[1391] The following describes examples of thyroid hormone receptor agonists that can be used in the methods and compositions of this disclosure.

[1392] In some implementations, the thyroid hormone receptor (THR) agonist (e.g., a THHβ agonist) is selected from:

[1393] VK2809;

[1394] TERN-501; and

[1395] ALG-055009.

[1396] In some implementations, the thyroid hormone receptor agonist is a compound of formula (XXI):

[1397] (XXI), or a pharmaceutically acceptable salt thereof, wherein:

[1398] A A It is O, CH2, S, SO or SO2;

[1399] X A and Y A Each group is independently selected from the groups composed of Br, Cl, and CH3;

[1400] R 1A Choose from the following groups: -(CH2) n COOH, -OCH2COOH, -NHC(═O)COOH, -NHCH2COOH, and ;

[1401] Z A It is H or -C≡N;

[1402] R 2A It is a lower alkyl group having 1 to 4 carbon atoms;

[1403] R 3 It is H or a lower alkyl group;

[1404] n is 1 or 2; and

[1405] p is 1 or 2.

[1406] In some implementations, the thyroid hormone receptor agonist is a compound of formula (XXI-1):

[1407] (XXI-1), or a pharmaceutically acceptable salt thereof, wherein:

[1408] R 3A Is it H or CH2R? 3B ;

[1409] R 3B It is a hydroxyl group, an O-linked amino acid, -OP(O)(OH)2 or -OC(O)R 3C , where R 3C It is a lower alkyl, alkoxy, alkyl acid, cycloalkyl, aryl, heteroaryl, or -(CH2). n -heteroaryl, where n is 0 or 1;

[1410] R 4A It is H, and R 5A It is CH2COOH, C(O)CO2H or their esters or amides, or R 4A and R 5 Together for -N═C(R) 4B )-C(O)-NH-C(O)-; where R 4B It is an H or cyano group.

[1411] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: (Compound A).

[1412] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1413] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1414] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1415] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1416] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1417] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1418] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1419] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1420] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1421] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1422] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1423] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1424] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1425] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1426] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1427] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1428] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1429] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1430] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1431] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1432] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1433] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1434] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1435] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1436] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1437] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1438] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1439] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1440] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1441] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1442] In some implementations, the thyroid hormone receptor agonist of formula (XXI) has the following structure: .

[1443] In some embodiments, the morphology of compound A (type 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, wherein the X-ray powder diffraction pattern is 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 type A may further include one or more peaks from Table P-1. In some embodiments, the X-ray diffraction pattern of type A is consistent with... Figure 6 The X-ray diffraction patterns shown are essentially similar. In some embodiments, the X-ray diffraction pattern of type A is similar to... Figure 7 The X-ray diffraction patterns shown are substantially similar. In this embodiment, type A is characterized by an initial melting temperature of approximately 321°C, and the differential scanning calorimetry (DSC) pattern includes an endothermic peak at approximately 329°C. In this embodiment, the DSC pattern is similar to... Figure 8 The DSC diagrams shown are basically the same.

[1444] In some embodiments, compound A is in the form of a hydrate. In some embodiments, the hydrate is a monohydrate. In some embodiments, the hydrate is a dihydrate.

[1445] In some embodiments, the morphology (G-type) of compound A is characterized by an X-ray powder diffraction pattern including peaks at approximately 9.50, 12.9, 16.7, 17.3, 19.5, 20.2, 25.6, and 28.3 degrees 2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Ka radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of the G-type may further include one or more peaks from Table P-2. In some embodiments, the X-ray powder diffraction pattern of the G-type is consistent with... Figure 9 The X-ray diffraction patterns shown are basically similar.

[1446] In some embodiments, the morphology (K-type) of compound A is characterized by an X-ray powder diffraction pattern including peaks at approximately 8.42, 11.4, 14.5, 18.9, 21.1, and 21.6 degrees 2θ, wherein the X-ray powder diffraction pattern is obtained using a Cu Ka radiation source (1.54 Å). In some embodiments, the X-ray powder diffraction pattern of the K-type may further include one or more peaks from Table 3. In some embodiments, the X-ray diffraction pattern of the K-type is related to... Figure 10 The X-ray diffraction patterns shown are basically similar.

[1447] Table P-1: XRPD Peak Positions of Type A

[1448]

[1449] Table P-2: Peak positions of G-type XRPD

[1450]

[1451] Table P-3: Peak positions of K-type XRPD

[1452]

[1453] Dosage and administration of thyroid hormone receptor agonists

[1454] The thyroid hormone receptor beta agonists covered in this article can be administered orally or parenterally (e.g., subcutaneously). For thyroid hormone receptor beta agonists approved by the U.S. Food and Drug Administration (FDA) for at least one indication, the route of administration may be as described on the FDA-approved label. In some respects, thyroid hormone receptor beta agonists are administered orally.

[1455] Thyroid hormone receptor beta agonists, including those covered by the methods described herein, are currently in use and, in some cases, have been approved by the U.S. Food and Drug Administration for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).

[1456] In some aspects of the methods described herein, the dose of the thyroid hormone receptor beta agonist administered is equivalent to the dose indicated on its label 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, the dose of the thyroid hormone receptor beta agonist administered is lower than the dose indicated on its label as the recommended dose for the treatment of non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH) (i.e., the dose represents a percentage of the dose indicated on its label 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, the dose of the thyroid hormone receptor beta agonist administered is the indicated dose for the treatment of non-alcoholic steatohepatitis (NASH). (For example, non-cirrhotic NASH) doses of 10% to 90%, 20% to 90%, 30% to 90%, 40% to 90%, 50% to 90%, 60% to 90%, 70% to 90%, 80% to 90%, 10% to 80%, 20% to 80%, 30% to 80%, 40% to 80%, 50% to 80%, 60% to 80%, 70% to 80%, 10% to 70%, 20% to 70%. 30% to 70%, 40% to 70%, 50% to 70%, 60% to 70%, 10% to 60%, 20% to 60%, 30% to 60%, 40% to 60%, 50% to 60%, 10% to 50%, 20% to 50%, 30% to 50%, 40% to 50%, 10% to 40%, 20% to 40%, 30% to 40%, 10% to 30%, 20% to 30%, and 10% to 20%.

[1457] In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 30% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 40% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 50% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 60% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 70% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 80% to 90% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 30% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 40% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 50% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 60% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 70% to 80% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 70% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 70% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 30% to 70% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 40% to 70% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 50% to 70% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 60% to 70% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 60% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 60% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 30% to 60% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 40% to 60% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 50% to 60% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 50% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 50% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 30% to 50% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 40% to 50% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 40% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 40% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 30% to 40% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 30% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 20% to 30% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH). In some aspects, the dose of the thyroid hormone receptor beta agonist administered is 10% to 20% of the indicated dose for treating non-alcoholic steatohepatitis (NASH) (e.g., non-cirrhotic NASH).

[1458] As part of the methods described herein, thyroid hormone receptor beta agonists may be administered at various frequencies. In some aspects, thyroid hormone receptor beta agonists are administered at the frequency indicated on their label for the treatment of one of their approved indications. In some aspects, thyroid hormone receptor beta agonists are administered at the frequency indicated on their label as a maintenance treatment regimen for the treatment of non-alcoholic fatty liver disease (NASH) (e.g., non-cirrhotic NASH). In some aspects, thyroid hormone receptor beta agonists are administered daily (e.g., once or twice daily) or intermittently (e.g., every other day, according to a M / W / F schedule, weekly, every two weeks, monthly, every two months, etc.). In some aspects, thyroid hormone receptor beta agonists are administered daily (e.g., once or twice daily). In some aspects, thyroid hormone receptor beta agonists are administered intermittently (e.g., every other day, according to a M / W / F schedule, weekly, every two weeks, monthly, every two months, etc.).

[1459] In some implementations, the thyroid hormone receptor beta agonist is resmetiro, and the indicated dose for treating NASH (e.g., non-cirrhotic NASH) is 80 mg once daily for patients weighing ≤100 kg and 100 mg once daily for patients weighing ≥100 kg.

[1460] Treatment

[1461] In some aspects, the embodiments provided herein relate to a method of treating a subject with fatty liver disease / fatty liver syndrome, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1462] In some aspects, the embodiments provided herein relate to a method of treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject 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. In some embodiments, NASH / MASH is NASH / MASH accompanied by moderate to severe fibrosis (e.g., a fibrosis score of 2 or 3). In some embodiments, treatment of nonalcoholic steatohepatitis includes preventing the progression of at least one symptom of nonalcoholic 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; hepatic steatosis; liver inflammation; liver ballooning; liver fibrosis; and NAFLD activity score. In some embodiments, treatment of NASH / MASH includes improvement of liver fibrosis in the subject by ≥ 1 stage without worsening of NASH / MASH.

[1463] In some implementations, treatment for NASH / MASH includes the regression of NASH / MASH in the subject without worsening of fibrosis.

[1464] In some aspects, the embodiments provided herein relate to a method for treating a subject in need of non-alcoholic fatty liver disease / metabolic dysfunction-associated fatty liver disease (NAFLD / MASLD), the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1465] In some aspects, the embodiments provided herein relate to a method for treating metabolic syndrome in a subject of need, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1466] In some aspects, the embodiments provided herein relate to a method of treating a subject with type 2 diabetes in need, the method comprising administering to the subject 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.

[1467] In some aspects, the embodiments provided herein relate to a method of treating atherosclerosis in a subject of need, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1468] In some aspects, the embodiments provided herein relate to a method for treating cirrhosis in a subject in need, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1469] In some aspects, the embodiments provided herein relate to a method of treating a subject with liver cancer (e.g., hepatocellular carcinoma), said method comprising administering to the subject 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. 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.

[1470] In some aspects, the embodiments provided herein relate to a method for treating a disease or disorder with elevated interleukin 1β (IL1β) levels in a subject of need, said method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein. In some embodiments, the disease or disorder is selected from familial Mediterranean fever (FMF), pyogenic arthritis, pyoderma gangrenosa, acne acne (PAPA), cold pyridine-associated periodic syndrome (CAPS), high IgD syndrome (HIDS), adult and adolescent Still's disease, Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS), Blau syndrome; Sweet syndrome, IL-1 receptor antagonist deficiency (DIRA), recurrent idiopathic pericarditis, macrophage activation syndrome (MAS), urticarial vasculitis, antisynthetic enzyme syndrome, recurrent chondritis, Behçet's disease, and Erdheim-Chester syndrome. Histiocytosis, synovitis, acne, impetigo, osteophyte formation, osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, polydactyly syndrome (PFAPA), urate crystal arthritis (gout), type 2 diabetes, smoldering multiple myeloma, heart failure after myocardial infarction, osteoarthritis, transfusion-related acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. In some implementations, the disease or ailment is acne.

[1471] In some respects, the implementation methods provided herein relate to a regulatory T cell (T cell) for treating subjects in need. reg Methods for reducing or suppressing disease or ailment, the methods comprising administering to a subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein. In some embodiments, T reg The cells are suppressed.

[1472] In some respects, the implementation schemes provided herein relate to a t-adjuvant (T) therapy for subjects in need of treatment. h A method for treating diseases or disorders with elevated t helper cells, the method comprising administering to a subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein. In some embodiments, the elevated t helper cells are T cells.h 1. T h 2. T h 9 or T h 17. In some implementations, elevated T helper cells are T cells. 17 In some implementation schemes, the disease or ailment is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and transplant rejection.

[1473] In some aspects, the embodiments provided herein relate to a method for reversing a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject 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.

[1474] In some aspects, the embodiments provided herein relate to a method for treating liver fibrosis in a subject of need, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1475] In some aspects, the embodiments provided herein relate to a method for reducing fibrosis gene expression in a subject in need, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1476] In some aspects, the embodiments provided herein relate to a method for lowering triglycerides in a subject in need, the method comprising administering to the subject a combination of a FASN inhibitor as defined in any of the embodiments described herein and a thyroid hormone receptor β agonist as defined in any of the embodiments described herein.

[1477] In some implementations, the combination of FASN inhibitors and thyroid hormone receptor-β agonists is synergistic.

[1478] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor has the following formula:

[1479] (a) Equation (IX)

[1480] (IX),

[1481] Or its pharmaceutically acceptable salt, wherein:

[1482] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[1483] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[1484] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[1485] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[1486] R 3 It is H, -OH or halogen;

[1487] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[1488] R 22 It is H, halogen, or C1-C2 alkyl;

[1489] R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH 、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein:

[1490] t is 0 or 1;

[1491] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[1492] L 1 It is CR 23 Or N;

[1493] L 2 It is CH or N;

[1494] L 1 or L 2 At least one of them is N; and

[1495] R 23 It is an H or C1-C4 straight-chain or branched alkyl group; or

[1496] (b) Equation (X):

[1497] (X),

[1498] Or its pharmaceutically acceptable salt, wherein:

[1499] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[1500] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[1501] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[1502] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[1503] R 3 It is H, -OH or halogen;

[1504] L 3 It is C(R) 60 2. O or NR 50 ;

[1505] Each R 60 Independently H, -OH, -CN, -O t -(C3-C5 cycloalkyl), -O-(C1-C4 straight-chain or branched alkyl) or -C(O)-N(R) 601 )2, of which:

[1506] t is 0 or 1, and

[1507] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[1508] Each R 50 Independently H, –C(O)-O t -(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C3-C5 cyclic alkyl), optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R) 501 2. C1-C4 straight-chain or branched alkyl groups, wherein:

[1509] t is 0 or 1, and

[1510] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[1511] n is 1, 2, or 3;

[1512] m is 1 or 2;

[1513] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms.

[1514] R 22 It is H, halogen, C1-C2 alkyl;

[1515] Each R 26 Independently, it can be –OH, -CN, halogen, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C1-C4 alkyl) or -C(O)-N(R) 501 )2, of which:

[1516] t is 0 or 1, and

[1517] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms;

[1518] s is 0, 1, or 2;

[1519] Each R 601 and R 501 Independently, it is an H or C1-C4 straight-chain or branched alkyl group; and

[1520] Where R 26 R 60 R 50 R 501 and R 601 The two in R are optionally joined to form a loop, where R 26 R 60 R 50 R 501 and R 601 The two in can be two R. 26 Two Rs 60 Two Rs 50 Two Rs 501 Or two Rs 601 ;or

[1521] (c) Equation (VI-J)

[1522] (VI-J),

[1523] Or its pharmaceutically acceptable salt, wherein:

[1524] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[1525] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[1526] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[1527] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[1528] R 3 It is H, -OH or halogen;

[1529] R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl;

[1530] R 22 It is H, halogen, or C1-C2 alkyl;

[1531] R 35 It is –C(O)-R 351 -C(O)-NHR 351 -C(O)-OR 351 or S(O)2R 351 ;and

[1532] R 351 It is a C1-C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or

[1533] (d) Formula (XII):

[1534] (XII),

[1535] Or its pharmaceutically acceptable salt, wherein:

[1536] L-Ar is , or ;

[1537] Ar is , , , or ;

[1538] Het is a 5- to 6-membered heteroaryl group;

[1539] R 1It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1540] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1541] R 3 It is H or F;

[1542] R 11 It is H or -CH3;

[1543] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1544] R 22 It is H, halogen, or C1-C2 alkyl;

[1545] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[1546] t is 0 or 1;

[1547] u is 0 or 1;

[1548] The condition is that when u is 1, t is 1; and

[1549] Each R 241 Independently H or C1-C2 alkyl; and

[1550] R 25 It is a halogen, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, or cyclopropyl; or

[1551] (e) Equation (XIII):

[1552] (XIII),

[1553] Or its pharmaceutically acceptable salt, wherein:

[1554] L-Ar is , or ;

[1555] Ar is , , , or ;

[1556] Het is a 5- to 6-membered heteroaryl group;

[1557] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1558] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1559] R 3 It is H or F;

[1560] R 11 It is H or -CH3;

[1561] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1562] R 22 It is H, halogen, or C1-C2 alkyl; and

[1563] Each R 24 and R 25 Independently, it can be H, halogen, -CN, -(C1-C4 alkyl)-CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-N(R). 241 2, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[1564] Each t is independently 0 or 1;

[1565] Each u is independently 0 or 1; and

[1566] Each R 241 Independently H or C1-C2 alkyl; or

[1567] (f) Equation (XIV):

[1568] (XIV),

[1569] Or its pharmaceutically acceptable salt, wherein:

[1570] L-Ar is , or ;

[1571] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1572] Het is a 5- to 6-membered heteroaryl group;

[1573] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1574] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1575] R 3 It is H or F;

[1576] R 11 It is H or -CH3;

[1577] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1578] R 22 It is H, halogen, or C1-C2 alkyl; and

[1579] R 24 It is H, C1-C4 alkyl, -(C1-C4 alkyl)-OH 、 -(C1-C4 alkyl) t -N(R 2412, -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O t -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein:

[1580] Each t is independently 0 or 1; and

[1581] Each R 241 Independently H or C1-C2 alkyl; or

[1582] (g) Equation (XV):

[1583] (XV),

[1584] Or its pharmaceutically acceptable salt, wherein:

[1585] L 3 It is -CH2-, -CHR 50 -、-O-、-NR 50 -、-NC(O)R 50 -OR-NC(O)OR 50 -, where R 50 It is a C1-C6 alkyl, C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle;

[1586] n is 1, 2, or 3;

[1587] m can be 1 or 2, provided that n + m ≥ 3;

[1588] L-Ar is , or ;

[1589] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1590] Het is a 5- to 6-membered heteroaryl group;

[1591] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1Optionally replaced by one or more halogens;

[1592] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1593] R 3 It is H or F;

[1594] R 11 It is H or -CH3;

[1595] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and

[1596] R 22 It is H, halogen, or C1-C2 alkyl; or

[1597] (h) Equation (XVI):

[1598] (XVI),

[1599] Or its pharmaceutically acceptable salt, wherein:

[1600] L-Ar is , or ;

[1601] Ar is , , , or ;

[1602] Het is a 5- to 6-membered heteroaryl group;

[1603] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1604] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1605] R 3 It is H or F;

[1606] R 11 It is H or -CH3;

[1607] R 21It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1608] R 22 It is H, halogen, or C1-C2 alkyl; and

[1609] R 24 and R 25 Each of these is independently H, -C1-C4 alkyl, or halogen; or

[1610] (i) Equation (XVII):

[1611] (XVII),

[1612] Or its pharmaceutically acceptable salt, wherein:

[1613] L-Ar is , or ;

[1614] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1615] Het is a 5- to 6-membered heteroaryl group;

[1616] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1617] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1618] R 3 It is H or F;

[1619] R 11 It is H or -CH3;

[1620] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1621] R 22 It is H, halogen, or C1-C2 alkyl; and

[1622] R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein:

[1623] t is 0 or 1;

[1624] u is 0 or 1;

[1625] The condition is that when u is 1, t is 1; and

[1626] R 241 It is H or C1-C2 alkyl; or

[1627] (j) Equation (XVIII):

[1628] (XVIII),

[1629] Or its pharmaceutically acceptable salt, wherein:

[1630] L-Ar is , or ;

[1631] Ar is , , , or The condition is that L-Ar is At that time, Ar was not ;

[1632] L 2 Yes - NHR 35 or -C(O)NHR 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl;

[1633] Het is a 5- to 6-membered heteroaryl group;

[1634] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1Optionally replaced by one or more halogens;

[1635] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1636] R 3 It is H or F;

[1637] R 11 It is H or -CH3;

[1638] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1639] R 22 It is H, halogen, or C1-C2 alkyl; and

[1640] R 35 It is -C(O)R 351 -C(O)NHR 351 C(O)OR 351 or S(O)2R 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl; or

[1641] (k) Equation (XIX):

[1642] (XIX),

[1643] Or its pharmaceutically acceptable salt, wherein:

[1644] Each W, X, Y, and Z is independently -N- or -CR. 26 -, provided that no more than two of W, X, Y, and Z are -N-;

[1645] Each R 26 Independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), -N(R) 27 2. -S(O)2-(C1-C4 alkyl) or -C(O)-(C1-C4 alkyl);

[1646] Each R 27 Independently H or C1-C4 alkyl, or two R 27 They are C1-C4 alkyl groups and are joined together with the N atoms to which they are attached to form 3- to 6-membered rings, wherein the rings optionally include an oxygen atom as one of the members of the ring;

[1647] Ar is , , , or ;

[1648] Het is a 5- to 6-membered heteroaryl group;

[1649] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1650] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1651] R 3 It is H or F;

[1652] R 11 It is H or -CH3;

[1653] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and

[1654] R 22 It is H, halogen, or C1-C2 alkyl; or

[1655] (l) Equation (XX):

[1656] (XX),

[1657] Or its pharmaceutically acceptable salt, wherein:

[1658] L-Ar is , or ;

[1659] Ar is ;

[1660] R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens;

[1661] Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently;

[1662] R 3 It is H or F;

[1663] R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle;

[1664] R 22 It is H, halogen, or C1-C2 alkyl;

[1665] R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl), -O-(C3-C5 cycloalkyl) or -O-(4- to 6-membered heterocycle), wherein R 24 Optionally substituted with one or more hydroxyl groups or halogens; and

[1666] R 25 It is H, halogen, C1-C4 alkyl or C3-C5 cycloalkyl, wherein R 25 Optionally replaced by one or more halogens; or

[1667] (m) Equation (XI):

[1668] (XI)

[1669] Or its pharmaceutically acceptable salt, wherein:

[1670] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[1671] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[1672] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[1673] Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl;

[1674] R 3 It is H, -OH or halogen;

[1675] R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl;

[1676] R 22 It is H, halogen, C1-C2 alkyl; and

[1677] R 351 It is a C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

[1678] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound selected from the group consisting of:

[1679] (Denifacrol);

[1680] (TVB-3664);

[1681] (Compound 005-2).

[1682] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is a compound selected from the group consisting of:

[1683] (Denifacrol);

[1684] and

[1685] (Compound 005-2).

[1686] In some embodiments of the methods provided herein, such as those described above (or below), fatty acid synthase inhibitors are (Denifacrol);

[1687] In some embodiments of the methods provided herein, such as those described above (or below), fatty acid synthase inhibitors are (Compound 005-2).

[1688] In some embodiments of the methods provided herein, such as those described above (or below), the fatty acid synthase inhibitor is denifasstat or a pharmaceutically acceptable salt thereof, including all possible tautomers of denifasstat.

[1689] 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.

[1690] In some embodiments of the methods provided herein, such as those described above (or below), the thyroid hormone receptor-β agonist is selected from:

[1691] VK2809;

[1692] TERN-501; and

[1693] ALG-055009.

[1694] In some embodiments of the methods provided herein, such as those described above (or below), the thyroid hormone receptor-β agonist is a compound of formula (XXI):

[1695] (XXI),

[1696] Or its pharmaceutically acceptable salt, wherein:

[1697] A A It is O, CH2, S, SO or SO2;

[1698] X A and Y A Each group is independently selected from the groups composed of Br, Cl, and CH3;

[1699] R 1A Choose from the following groups: -(CH2) n COOH, -OCH2COOH, -NHC(═O)COOH, -NHCH2COOH, and ;

[1700] Z A It is H or -C≡N;

[1701] R 2A It is a lower alkyl group having 1 to 4 carbon atoms;

[1702] R 3A It is H or a lower alkyl group;

[1703] n is 1 or 2;

[1704] p is 1 or 2.

[1705] In some embodiments of the methods provided herein, such as those described above (or below), the thyroid hormone receptor-β agonist is resmetiro (also known as MGL-3196):

[1706] .

[1707] Throughout this disclosure, references to “treatment methods” are intended to encompass the use of compounds, compositions, and combinations thereof in the treatment methods described herein, compounds, compositions, and combinations thereof for treating the diseases described herein, and the use of compounds, compositions, and combinations thereof described herein in the manufacture of pharmaceutical agents for treating the diseases described herein.

[1708] Compound Synthesis

[1709] This document also describes a method for synthesizing the fatty acid synthase inhibitors disclosed herein. The fatty acid synthase inhibitors of this disclosure can be synthesized as indicated in the following synthetic schemes 1-13.

[1710] Option 1

[1711]

[1712] in:

[1713] R′′ is hydrogen or alkyl;

[1714] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[1715] q can be 0, 1, 2, 3, or 4;

[1716] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[1717] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[1718] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[1719] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[1720] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[1721] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

[1722] R 17 It is hydrogen or alkyl.

[1723] Option 2

[1724]

[1725] in:

[1726] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[1727] q can be 0, 1, 2, 3, or 4;

[1728] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[1729] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[1730] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[1731] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[1732] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R)15 R 16 ) or –S(=O)2R 20 ;

[1733] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino;

[1734] R 23 It is hydrogen, –N(R) 13 (R) 14 C 1-6 Alkyl, C 1-6 Alkoxy group, not present if L1 is N, or R 23 and R 24 They combine with the atoms to which they are attached to form heterocyclic groups, heteroaryl groups, or cycloalkyl groups; and

[1735] R 24 It is hydrogen, –N(R) 13 (R) 14 C 1-6 Alkyl, C 1-6 Alkoxy, –(C 1-6 alkoxy (heterocyclic group), heterocyclic group, or R 23 and R 24 They combine with the atoms to which they are attached to form heterocyclic groups, heteroaryl groups, or cycloalkyl groups.

[1736] Option 3

[1737]

[1738] in:

[1739] LG is a leaving group;

[1740] Nu is a nucleophile;

[1741] L2, L3, L4 and L 4′ Each can be independently CH or N;

[1742] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[1743] q can be 0, 1, 2, 3, or 4;

[1744] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[1745] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[1746] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[1747] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[1748] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[1749] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino; and

[1750] R 17 It is hydrogen or alkyl.

[1751] Option 4

[1752]

[1753] in:

[1754] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14), CF3, –OCF3 or –S(=O)2R 20 ;

[1755] q can be 0, 1, 2, 3, or 4;

[1756] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[1757] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[1758] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[1759] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[1760] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[1761] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino;

[1762] R 17 It is hydrogen or alkyl; and

[1763] R 24 It is hydrogen, –N(R) 13 (R) 14 C 1-6 Alkyl, C 1-6 Alkoxy, –(C 1-6 Alkoxy (heterocyclic group) or heterocyclic group.

[1764] Option 5

[1765]

[1766] in:

[1767] R1 is hydrogen, cyano, halogen, or C. 1-6 Alkyl, C 1-6 Alkyl group, –C(=O)N(R) 13 (R) 14 ), –(CH2) q C(=O)N(R 13 (R) 14 ), CF3, –OCF3 or –S(=O)2R 20 ;

[1768] q can be 0, 1, 2, 3, or 4;

[1769] R 20 Is it hydrogen or C? 1-6 Alkyl, C 1-6 Alkyl or –N(R) 13 (R) 14 );

[1770] R2 is hydrogen, a halogen group, or C. 1-6 Alkoxy or C 1-6 alkyl;

[1771] R3 represents hydrogen, hydroxyl, halogen, or C. 1-6 Alkyl or C 1-6 Alkoxy;

[1772] R 21 and R 22 Each is independently hydrogen, halo group, cyano group, C 1-6 Alkyl, C 1-6 Alkyl, CF3, –OCF3 or –S(=O)2R 20 ;

[1773] R 13 and R 14 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, alkylamino, –N(R) 15 R 16 ) or –S(=O)2R 20 ;

[1774] R 15 and R 16 Each independently is hydrogen, C 1-6 Alkyl, cycloalkyl, aryl, heterocyclic, heteroaryl, hydroxyalkyl, or alkylamino;

[1775] R 17 It is hydrogen or alkyl;

[1776] R24 It is hydrogen, –N(R) 13 (R) 14 C 1-6 Alkyl, C 1-6 Alkoxy, –(C 1-6 Alkoxy (heterocyclic group) or heterocyclic group.

[1777] R 29 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyalkyl, heteroaryl, heterocyclic, –N(R) 15 R 16 ), –C(=O)R 46 Or –R 48 C(=O)R 47 ;

[1778] R 34 It is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, cycloalkyl, hydroxy, hydroxyalkyl, aryl, heterocyclic, heteroaryl, alkylamino, CF3, –OCF3, –S(=O)2R 20 or –N(R) 15 R 16 );and

[1779] m can be 0, 1, or 2.

[1780] Scheme 6-13 provides the synthesis of exemplary compounds of formula IX, wherein:

[1781] R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[1782] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[1783] When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens;

[1784] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[1785] R 3 It is H, -OH or halogen;

[1786] R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[1787] R22 It is H, halogen, or C1-C2 alkyl;

[1788] R 23 It is an H or C1-C4 straight-chain or branched alkyl group; and

[1789] R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH 、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein:

[1790] t is 0 or 1; and

[1791] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms.

[1792] Option 6

[1793]

[1794] Option 7

[1795]

[1796] Option 8

[1797]

[1798] Option 9

[1799]

[1800] Option 10

[1801]

[1802] Option 11

[1803]

[1804] Option 12

[1805]

[1806]

[1807] Option 13

[1808]

[1809] Additional methods for generating specific compounds according to this disclosure are provided in the examples. Those skilled in the art will recognize that compounds with other structures can be prepared by modifying the specific disclosed schemes using methods known to them. Additional examples can be found in Tables C-1, C-2, and C-3.

[1810] Many such techniques are well known in the art. However, many known techniques are described in the Compendium of Organic Synthetic Methods (Volume 1, 1971; Volume 2, 1974; Volume 3, 1977; Volume 4, 1980; Volume 5, 1984; and Volume 6) and in March in Advanced Organic Chemistry (1985); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. 9 Volumes (1993); Advanced Organic Chemistry Part B: Reactions and Synthesis, 2nd Edition (1983); Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 2nd Edition (1977); Protecting Groups in Organic Synthesis, 2nd Edition; and Comprehensive Organic Transformations (1999).

[1811] Fatty acid synthesis pathway

[1812] Various aspects of this disclosure relate to compositions and methods for modulating the activity of fatty acid synthesis pathways to treat viral infections or cancer. The fatty acid synthesis pathway in the human body utilizes four enzymes: 1) acetyl-CoA carboxylase (ACC), which synthesizes malonyl-CoA; 2) malic acidase, which produces NADPH; 3) citrate lyase, which synthesizes acetyl-CoA; and 4) fatty acid synthase, which catalyzes the NADPH-dependent synthesis of fatty acids from acetyl-CoA and malonyl-CoA. In various aspects, this disclosure relates to treating viral infections and cancer by modulating the activity of fatty acid synthase proteins.

[1813] The final products of fatty acid synthase are free fatty acids, which can be enzymatically derivatized with coenzyme A alone to be incorporated into other products. In humans, fatty acid synthesis can occur in two sites: the liver, where palmitic acid is produced (Roncari, (1974) Can. J. Biochem., 52:221-230) and the lactating mammary gland, where C... 10 -C 14 Fatty acids (Thompson et al., (1985) Pediatr. Res., 19:139-143).

[1814] Fatty acids can be synthesized in the cytoplasm from acetyl-CoA. Acetyl-CoA is produced from pyruvate via pyruvate dehydrogenase (PDH) and fatty acid β-oxidation in the mitochondria. The "citrate shuttle" transports acetyl-CoA from the mitochondria to the cytoplasm. Acetyl-CoA reacts with oxaloacetate to produce citrate, and tricarboxylic acid translocase transports citrate from the mitochondria to the cytoplasm. In the cytoplasm, citrate can be cleaved back into oxaloacetate and acetyl-CoA, a reaction catalyzed by ATP-citrate lyase. Oxaloacetate can be converted back into pyruvate for re-entry into the mitochondria.

[1815] Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxylase (ACC) is a complex, multifunctional, biotin-containing enzyme system that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. This conversion is an irreversible rate-limiting step in fatty acid synthesis. ACC functions in three ways: as a biotin carboxyl carrier protein, a biotin carboxylase, and a carboxyltransferase. ATP-dependent carboxylation of biotin (the cofactor) subsequently transfers the carboxyl group to acetyl-CoA.

[1816] HCO3 - + ATP + Acetyl-CoA -> ADP + P i +malonyl-CoA

[1817] There are two forms of ACC, α and β, encoded by two different genes. ACC-α (also known as ACC, ACAC, ACC1, ACCA, and ACACA) encodes a protein highly enriched in adipogenic tissues. Multiple alternatively spliced ​​transcriptomorphs of this gene have been identified, differing in sequence and encoding different isoforms. ACC-β (also known as ACC2, ACCB, HACC275, and ACACB) encodes a protein believed to control fatty acid oxidation by inhibiting carnitine-palmitoyl-CoA transferase I, the rate-limiting step in mitochondrial uptake and oxidation of fatty acids. ACC-β may be involved in regulating fatty acid oxidation, rather than fatty acid biosynthesis. There is evidence of two ACC-β isoforms.

[1818] ACC can be regulated by phosphorylation / dephosphorylation of target serine residues. For example, AMP-activated kinase (AMPK) phosphorylates ACC, and this phosphorylation inhibits ACC's ability to produce malonyl-CoA. On ACACA, AMPK phosphorylates Ser79, Ser1200, and Ser1215 (Park SH et al. (2002) J. Appl. Physiol. 92:2475-82). AMPK phosphorylates Ser218 on ACACB (Hardie DG (1992) Biochim. Biophys. Acta 1123:231-8). Furthermore, cAMP-dependent protein kinases (protein kinase A or PKA) phosphorylate ACC.

[1819] ACC can be regulated by allosteric conversion of 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. As a product of fatty acid synthase (FASN), palmitoyl-CoA promotes an inactive conformation of ACC, thereby reducing malonyl-CoA production (a feedback inhibition process). AMP can regulate fatty acid synthesis by modulating the availability of malonyl-CoA. Insulin-binding receptors can activate phosphatases, dephosphorylating ACC and thus removing the inhibitory effect.

[1820] The fatty acid synthase gene (also known as FAS, OA-519, SDR27X1; MGC14367; MGC15706; FASN) is involved in fatty acid synthesis. This gene encodes an enzyme that is a multifunctional protein of approximately 272 kDa with multiple domains, each possessing different enzymatic activities, which play a role in fatty acid biosynthesis. FASN catalyzes the synthesis of palmitic acid from acetyl-CoA and malonyl-CoA in the presence of NADPH, forming a long-chain saturated fatty acid. In some cancer cell lines, the FASN protein has been found to fuse with estrogen receptor-α (ER-α), with the N-terminus of FASN in-frame with the C-terminus of ER-α.

[1821] FASN proteins exist as dimers of identical subunits in the cytoplasm. FASN consists of three catalytic domains (-ketoacyl synthase (KS), malonyl / acetyltransferase (MAT), and dehydratase (DH)) in its N-terminal region. The N-terminal region is separated from the N-terminal region by a core region of approximately 600 amino acids by four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE)). The crystal structures of mammalian fatty acid synthases have been reported (Maier T. et al. (2008) Science 321: 1315-1322). The method for treating viral infections provided by this invention targets each catalytic domain of FASN.

[1822] Enzymatic steps in fatty acid synthesis can involve decarboxylation condensation, reduction, dehydration, and another reduction, and can produce a saturated acyl moiety. NADPH can serve as an electron donor in the reduction reaction.

[1823] efficacy in metabolic disorders

[1824] In all respects, the therapeutic combination disclosed herein is effective in the treatment of metabolic diseases. FASN has been shown to be involved in the regulation of glucose, lipid, and cholesterol metabolism. Mice with liver-specific FASN inactivation, unless fed a fat-free diet, exhibit normal physiological function, under which they develop hypoglycemia and fatty liver, both of which are reversed by dietary fat (Chakravarthy, MV et al. (2005) Cell Metabolism 1:309-322). When treated for 28 days with platensimycin, a covalent inhibitor of FASN, Db / + mice fed a high-fructose diet showed reduced hepatic triglyceride levels and improved insulin sensitivity (Wu, M. et al. (2011) PNAS 108(13):5378-5383). Environmental glucose levels were also reduced in db / db mice after platensimycin treatment. These results provide evidence that inhibition of FASN can produce therapeutically relevant benefits in animal models of diabetes and related metabolic disorders. Therefore, the disclosed FASN inhibitors can be used to treat conditions characterized by dysregulation in these systems. Examples, without limitation, include steatosis and diabetes.

[1825] Nonalcoholic fatty liver disease / metabolic steatohepatitis-associated fatty liver disease (NAFLD / MASLD), a condition in which the liver contains more than 5% fat and is not caused by alcohol consumption, currently affects approximately 20-30% of the population in the United States and throughout the Western world. It is associated with a significantly increased risk of cardiovascular disease, chronic kidney disease, and malignancies outside the liver. 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 metabolic pathway dysregulation and inflammatory responses, which further drive changes leading to liver damage and comorbidities. As metabolic syndrome progresses, NAFLD / MASLD can lead to more severe liver disease, initially nonalcoholic steatohepatitis / metabolic steatohepatitis-associated fatty liver disease (NASH / MASH), and may then progress to serious liver diseases, including cirrhosis and hepatocellular carcinoma.

[1826] Subjects with metabolic syndrome and NAFLD / MASLD exhibit increased hepatic fatty acid synthesis, a pathway known as de novo lipogenesis (DNL). The DNL pathway not only produces fatty acids that contribute to elevated hepatic triglyceride storage, but also produces saturated fatty acids, primarily palmitic acid (C16:0), which contributes to increased liver inflammatory signaling events. Free palmitic acid is also associated with liver inflammatory processes such as macrophage recruitment and activation of endoplasmic reticulum stress responses.

[1827] Thyroid hormones play a central role in liver function by activating beta receptors in hepatocytes, influencing a range of health parameters from serum cholesterol and triglyceride levels to pathological fat accumulation in the liver. THR-β action is crucial for normal liver function, including regulating mitochondrial activity (such as hepatic lipolysis) and controlling the levels of normal, healthy mitochondria. Patients with NASH / MASH have reduced levels of THR-β receptor activity in their livers.

[1828] Therefore, in various aspects, this disclosure provides a method for treating a subject with NASH / MASH or NASH / MASH symptoms, the method comprising administering to a subject requiring such treatment an effective amount of a combination of a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a THR-β agonist), wherein the thyroid hormone receptor agonist has the formula (XXI), and the fatty acid synthase inhibitor has the formulas (I), (II), (III), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or as provided in Tables C-1, C-2, or C-3. In a further aspect, the treatment combination can be used to manufacture a pharmaceutical agent for treating NASH / MASH or NASH / MASH symptoms. In a further aspect, the treatment combination can be used to treat NASH / MASH or NASH / MASH symptoms. In some embodiments, the subject has been diagnosed with NASH / MASH, and treatment with the compounds disclosed herein can alleviate or eliminate the symptoms and causes of NASH / MASH, such as systemic steatosis, hepatic steatosis, steatohepatitis, inflammation, liver inflammation, lysosomal acid lipase deficiency, and cirrhosis. In other embodiments, the treatment is used to prevent the development of nonalcoholic fatty liver disease / metabolic dysfunction-associated fatty liver disease (NAFLD / MASLD), the development of NASH / MASH, the progression of NAFLD / MASLD to NASH / MASH, or to halt the progression of NASH / MASH disease. Whether for preventative treatment or for a confirmed diagnosis of NAFLD / MASLD or NASH / MASH disease, treatment of fatty liver disease reduces risk factors associated with the diagnosis or progression of diabetes, liver cancer, cardiovascular disease, hypertriglyceridemia, kidney disease, and metabolic syndrome.

[1829] Therefore, in some embodiments, this disclosure provides a method for treating non-alcoholic steatohepatitis (NAHH) comprising administering to a subject in need a combination of a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a THR-β agonist), wherein the thyroid hormone receptor agonist has the formula (XXI), and the fatty acid synthase inhibitor has the formulas (I), (II), (III), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or as provided in Tables C-1, C-2, or C-3, wherein the method comprises reversing at least one symptom of a diagnosed NHAH. In some embodiments, the method comprises preventing the progression of at least one symptom of NHAH. In some implementations, symptoms are selected from elevated AST levels; elevated ALT levels; elevated GGT levels; elevated liver triglyceride levels; elevated cholesterol levels; hepatic steatosis; liver inflammation; hepatic ballooning degeneration; liver fibrosis; and NAFLD activity score.

[1830] Furthermore, as shown in Example 6, the compounds of this disclosure (e.g., compound 002-386) were found to reduce the expression of fibrosis genes in human hepatocytes. Therefore, in some embodiments, the treatment combination of this disclosure can reduce the expression of fibrosis genes (e.g., Col 1a1, αSMA, βPDGFR, TGFbR1, TIMP1, TIMP2, and / or MMP2). In some embodiments, gene expression can be restored upon discontinuation of the compound (e.g., compound 002-386). Therefore, it is not intended to be theoretically correct that the downregulation of fibrosis genes is not a toxic effect of the compounds of this disclosure.

[1831] Therefore, in various aspects, this disclosure provides a method for reducing the expression of fibrosis genes in a subject (e.g., in the subject's hepatocytes), the method comprising administering to a subject requiring such treatment an effective amount of a combination of a fatty acid synthase inhibitor and a thyroid hormone receptor agonist (e.g., a THR-β agonist), wherein the thyroid hormone receptor agonist has the formula (XXI), and the fatty acid synthase inhibitor has the formulas (I), (II), (III), (IV), (V), (VI), (VI-J), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), (XX), or as provided in Tables C-1, C-2, or C-3. In a further aspect, the treatment combination can be used to manufacture an agent for reducing the expression of fibrosis genes (e.g., in hepatocytes). In a further aspect, the treatment combination can be used to reduce the expression of fibrosis genes (e.g., in hepatocytes).

[1832] Cardiovascular disease is closely associated with the progression of metabolic syndrome. However, NAFLD / MASLD is also a strong predictor of cardiovascular disease, such as an increased risk of carotid atherosclerotic plaques and endothelial dysfunction, independent of the presence of metabolic syndrome (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 is also considered an independent factor contributing to the development of type 2 diabetes. Individuals with NAFLD / MASLD have a 2.6 times higher incidence of prediabetes or type 2 diabetes, suggesting that it plays an independent role in the pathogenesis of type 2 diabetes beyond initial insulin resistance (Francis WB, Biol. Rev. (2016), pp. 452–468; Bae, JC et al., “Combined effect of nonalcoholicfatty 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 intervention to reduce the consequences associated with metabolic syndrome and NAFLD / MASLD (Bae, JC, Diabetes Care, 2011, 727–729).

[1833] NAFLD / MASLD and NASH / MASH are associated with obesity and diabetes in people on high-fat and high-calorie diets. Subjects with metabolic syndrome and NAFLD / MASLD have increased hepatic fatty acid synthesis (i.e., synthesis via the hepatic de novo lipogenesis (DNL) pathway). A key enzyme in DNL is fatty acid synthase (FASN). While there is a promising association 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 hepatic steatosis. Some literature reports that direct intervention with FASN through gene knockout or small molecule inhibitors exacerbates hepatic steatosis; this is the opposite of the effect required for treating NAFLD / MASLD or NASH / MASH. These results suggest that FASN inhibition is not expected to alleviate hepatic steatosis or be a suitable mechanism for controlling underlying metabolic dysregulations or inflammatory signaling that drive the progression of fatty liver disease.

[1834] For example, studies have shown that liver-specific FASN knockout mice have normal livers when maintained on a standard diet. Unexpectedly, when mice are fed a zero-fat / high-carbohydrate diet, they develop fatty liver (hepatic steatosis) and hypoglycemia, suggesting that complete inhibition of FASN in the liver of fat-restricted mammals 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 are fed a normal diet, no effect on metabolism or the development of hepatic steatosis was observed due to the complete inhibition of FASN by knockout, indicating that FASN inhibition in the liver either has no effect on mammals fed a fat-containing diet or induces a fatty liver state (leading to NAFLD / MASLD and NASH / MASH) in mammals fed a low-fat / high-carbohydrate diet, thus providing the opposite effect required to treat NASH / MASH.

[1835] Small molecule inhibitors of FASN have been used to evaluate insulin resistance and hepatic steatosis. In a recent study in obese Zucker rats (a type 2 diabetes model) with insulin resistance, inhibition of de novo lipogenesis with small molecule FASN inhibitors did not improve insulin sensitivity and actually increased fat levels in the liver (i.e., hepatic steatosis). FASN inhibitors have also been shown to inhibit de novo lipogenesis in the liver, but lead to hepatic steatosis 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 indicate that directly inhibiting FASN reduces hepatic fat synthesis but leads to accelerated 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 at the highest risk of developing NAFLD / MASLD and NASH / MASH.

[1836] The therapeutic methods and combinations described in this application can be used to control NAFLD / MASLD in rodents, reduce pro-inflammatory cytokines (such as IL-1β), and regulate T cell activity from pro-inflammatory cells (such as Th). 17 Cells differentiate into anti-inflammatory T cells regCells. The FASN inhibitors of this application can be used to treat various aspects of metabolic syndrome, including non-alcoholic liver disease (NAFLD / MASLD) and the more advanced disease non-alcoholic steatohepatitis (NASH / MASH). Without treatment, these liver dysfunction states can progress to serious liver diseases, including cirrhosis, liver showing steatosis, inflammation, fibrosis, steatohepatitis, and potentially hepatocellular carcinoma (HCC). Cirrhosis can have direct health consequences due to liver dysfunction, including spider angiomas or spider nevi, palmar erythema, gynecomastia, hypogonadism, ascites, fetor hepatis, jaundice, portal hypertension leading to splenomegaly, esophageal varices, serpentine head, hepatic encephalopathy, and acute kidney injury (particularly hepatorenal syndrome). In some embodiments, the therapeutic combinations of this disclosure can be used to treat metabolic syndrome, non-alcoholic liver disease (NAFLD / MASLD), non-alcoholic steatohepatitis (NASH / MASH), cirrhosis, liver fibrosis, and / or hepatocellular carcinoma (HCC, cholangiocarcinoma). In some embodiments, the treatment combinations of this disclosure can be used to treat type 2 diabetes. In some embodiments, the treatment combinations of this disclosure can be used to treat atherosclerosis.

[1837] The treatment methods and combinations of this application can also be used to treat inflammatory diseases by inducing changes in inflammation-induced cytokines. Examples of inflammatory diseases that can be treated with the treatment combinations of this application include, but are not limited to, inflammatory diseases involving IL-1β, such as diseases that respond to IL-1β blockade or are associated with increased IL-1β expression. In some embodiments, the diseases or disorders in which IL-1β is elevated or regulated by IL-1β are selected from familial Mediterranean fever (FMF); pyogenic arthritis, pyoderma gangrenosa, acne acne (PAPA); cold pyridine-associated periodic syndrome (CAPS); high IgD syndrome (HIDS); adult and adolescent Still's disease; Schnitzler syndrome; TNF receptor-associated periodic syndrome (TRAPS); Blau syndrome; Sweet's syndrome; IL-1 receptor antagonist deficiency (DIRA); recurrent idiopathic pericarditis; macrophage activation syndrome (MAS); urticarial erythematosus Bronchitis; antisynergistic enzyme syndrome; relapsing chondritis; Behcet's disease; Eldheim-Chester syndrome (histiocytosis); synovitis, acne, impetigo, osteoproliferative disease, osteitis (SAPHO); rheumatoid arthritis; periodic fever, aphthous stomatitis, pharyngitis, lymphadenitis syndrome (PFAPA); urate crystal arthritis (gout); type 2 diabetes; smoldering multiple myeloma; heart failure after myocardial infarction; osteoarthritis; transfusion-related acute lung injury; ventilator-induced lung injury; pulmonary fibrosis including idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease (COPD); and asthma. In some implementations, the disease or disorder characterized by elevated or regulated IL-1β is acne.

[1838] The treatment methods and combinations described in this application can also be used to treat diseases or disorders associated with elevated levels of inflammatory T cells and / or decreased or insufficient levels of anti-inflammatory T cells, or to treat the regulation of leukocyte (i.e., T cells) differentiation away from T helper cells and the increase of anti-inflammatory T regulatory activity (T T cells). reg Cells can cause beneficial diseases or disorders. (T) reg Cells are crucial for immune tolerance and play a significant role in limiting T helper cells (i.e., Th1, Th2, Th9, Th2, Th3, Th4, Th5, Th6, Th7, Th8, Th9, Th8 ... 17 T helper cells (T cells) play a crucial role in excessive immune and inflammatory responses. Therefore, inhibiting T helper cell differentiation into regulatory T cells through FASN suppression could be used to treat inflammatory diseases.

[1839] The treatment methods or combinations thereof described in this application can inhibit the maturation of T cells into T helper inflammatory cells (the inhibitable T helper cells include, but are not limited to, Th1, Th2, Th9, Th...). 17 ), and promote its differentiation into T regCells. Naïve CD4+ cells differentiate into T helper cells and regulatory T cells to perform their immune functions. Differentiation depends on the presence of cytokines. Although T helper cells such as Th... 17 Cells play a crucial role in protective immune responses against intracellular pathogens, but excessive immune responses generated by these T helper cells can also lead to autoimmune and inflammatory diseases. Examples of immune-mediated diseases treatable 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 transplant 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., 34Suppl 1, 2014, S56–60)

[1840] In various aspects, the disclosed treatment methods and combinations can be used to treat nonalcoholic fatty acid disease (NAFLD / MASLD), nonalcoholic steatohepatitis (NASH / MASH), steatosis, and diabetes. In one embodiment, this disclosure relates to a method of treating nonalcoholic steatohepatitis (NASH / MASH) using a combination of the FASN inhibitor compound of this 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)) and a thyroid receptor hormone agonist (i.e., a thyroid receptor hormone agonist of formula (XXI)).

[1841] In another embodiment, this disclosure relates to a method of treating non-alcoholic steatohepatitis (NASH / MASH) using a combination of the FASN inhibitor compound of this 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)) and a thyroid receptor hormone agonist (i.e., a thyroid receptor hormone agonist of formula (XXI)).

[1842] In another embodiment, this disclosure relates to a method for treating metabolic syndrome. In one embodiment, this disclosure relates to a method for treating metabolic syndrome using a combination of compounds of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)).

[1843] In another embodiment, this disclosure relates to a method of treating type 2 diabetes. In one embodiment, this disclosure relates to a method of treating type 2 diabetes using a combination of compounds of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)).

[1844] In another embodiment, this disclosure relates to a method for treating atherosclerosis. In one embodiment, this disclosure relates to a method for treating atherosclerosis using a combination of compounds of the disclosed (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)) and a thyroid receptor hormone agonist (i.e., a thyroid receptor hormone agonist of formula (XXI)).

[1845] In another embodiment, this disclosure relates to a method of treating cirrhosis. In one embodiment, this disclosure relates to a method of treating cirrhosis using a combination of compounds of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)).

[1846] In another embodiment, this disclosure relates to a method for treating liver fibrosis. In one embodiment, this disclosure relates to a method for treating liver fibrosis using a combination of compounds of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)).

[1847] In another embodiment, this disclosure relates to a method of treating inflammation. In one embodiment, this disclosure relates to a method of treating inflammation using a combination of compounds of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)).

[1848] In another embodiment, this disclosure relates to a method for treating a disease or condition with elevated interleukin-1β (IL1β) levels. In one embodiment, this disclosure relates to a method for treating a disease or condition with elevated interleukin-1β (IL1β) levels using a compound of the disclosed invention (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., a thyroid receptor hormone agonist of formula (XXI)). In some embodiments, interleukin-1β... Diseases or disorders with elevated (IL1β) levels include familial Mediterranean fever (FMF), septic arthritis, pyoderma gangrenosa, acne var. acnes (PAPA), cold pyridine-associated periodic syndrome (CAPS), high IgD syndrome (HIDS), adult-onset Still's disease, Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS), Blau syndrome, Sweet's syndrome, IL-1 receptor antagonist deficiency (DIRA), recurrent idiopathic pericarditis, macrophage activation syndrome (MAS), urticarial vasculitis, and anti-syndrome Enzyme-forming syndrome, recurrent chondritis, Behcet's disease, Eldheim-Chester syndrome (histiocytosis), synovitis, acne, impetigo, osteoproliferation, osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, polydactyly syndrome (PFAPA), urate crystal arthritis (gout), type 2 diabetes, smoldering multiple myeloma, heart failure after myocardial infarction, osteoarthritis, transfusion-related acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

[1849] In another embodiment, this disclosure relates to a therapeutic t-adjuvant (T) h Methods for treating diseases or disorders with elevated cellular levels. In one embodiment, this disclosure relates to a method for treating adjuvant thyroiditis (Tt) using a compound of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)). h Methods for treating diseases or disorders with elevated cellular levels. In some implementations, t-adjuvant (T)h Diseases or disorders with elevated cellular levels include psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and transplant rejection.

[1850] In another embodiment, this disclosure relates to a therapeutic regulatory T cell (T) reg Methods for reducing or suppressing diseases or disorders. In one embodiment, this disclosure relates to a method for treating regulatory T cells (T cells) using a compound of the disclosed (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., a thyroid receptor hormone agonist of formula (XXI)). reg Methods to reduce or suppress diseases or disorders. In some implementations, regulatory T cells (T cells) are used. reg Diseases or ailments that are reduced or suppressed include psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and transplant rejection.

[1851] Anticancer activity

[1852] In various aspects, the disclosed treatment combinations can be used to treat liver cancer. In one embodiment, this disclosure relates to a method of treating liver cancer using a combination of a fatty acid synthase inhibitor of the disclosed formula (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)) and 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.

[1853] Rapidly proliferating cancer cells activate fatty acid synthesis pathways to replenish high levels of lipids required for membrane components and oxidative metabolism. (Flavin, R. et al. (2010) Future Oncology. 6(4):551-562) Inhibitors of fatty acid synthesis have demonstrated 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 supports angiogenesis, and inhibitors of this pathway are active in in vitro models of angiogenesis. (Browne, CD et al. (2006) The FASEB Journal, 20(12):2027-2035). The compounds disclosed in this invention exhibit the ability to selectively induce cell cycle arrest in HUVEC cells without causing generalized cell death due to apoptosis. See Examples.

[1854] The cancer treatment of the present invention includes an antitumor effect, which can be assessed by conventional means, such as response rate, time to disease progression, and / or survival. The antitumor effect of the present invention includes, but is not limited to, inhibiting tumor growth, delaying tumor growth, causing tumor regression, shrinking tumors, increasing the time for tumor regeneration after treatment cessation, and slowing disease progression. For example, when the combinations of the present invention are administered to warm-blooded animals (such as humans) requiring treatment for cancers involving solid tumors, such treatment is expected to produce an effect, as measured, for example, by one or more of the following: the extent of the antitumor effect, response rate, time to disease progression, and survival.

[1855] In all respects, the disclosed treatment combinations can be used to lower triglycerides in subjects in need. In one embodiment, this disclosure relates to a method of lowering triglycerides using a combination of the disclosed fatty acid synthase inhibitor (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)) and a thyroid receptor hormone agonist (e.g., a compound of formula (XXI)).

[1856] Inhibition of fatty acid synthesis

[1857] Reducing the activity of fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity, is also called “inhibiting” fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity. The term “inhibits” and its grammatical variations, such as “inhibitory,” do not require complete inhibition, but rather refer to a reduction in fatty acid synthesis activity, such as FASN gene expression or FASN protein activity. Alternatively, in the absence of an inhibitory effect, such a reduction is at least 50%, at least 75%, at least 90%, and may be at least 95% of enzyme activity. Conversely, the phrase “not inhibiting” and its grammatical variations refer to a reduction in enzyme activity of less than 20%, less than 10%, and may be less than 5% in the presence of an inhibitor. Further, the phrase “not substantially inhibiting” and its grammatical variations refer to a reduction in enzyme activity of less than 30%, less than 20%, and in some respects less than 10% in the presence of an inhibitor.

[1858] Increasing the activity of fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity, is also referred to as “activating” fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity. The term “activated” and its grammatical variations, such as “activating,” do not require complete activation, but rather refer to an increase in the activity of fatty acid synthesis pathways, such as FASN gene expression or FASN protein activity. Alternatively, in the absence of an activating effect, such as in the absence of an activating agent, this increase is at least 50%, at least 75%, at least 90%, and may be at least 95% of enzyme activity. Conversely, the phrase “inactive” and its grammatical variations refer to an increase in enzyme activity of less than 20%, less than 10%, and may be less than 5% in the presence of an activator. Further, the phrase “not substantially activated” and its grammatical variations refer to an increase in enzyme activity of less than 30%, less than 20%, and in another respect, less than 10% in the presence of an activator.

[1859] The ability to reduce enzyme activity is a measure of the potency or activity of an agent or combination of agents against an enzyme. It can be measured by cell-free, whole-cell, and / or in vivo assays using IC50, K... i Potency is measured using IC50 values ​​and / or ED50 values. The IC50 value represents the concentration of the agent required to inhibit half (50%) of the enzyme activity 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 agent required to achieve the half-maximal reaction in a bioassay. Further details of these measures will be apparent to those skilled in the art and can be found in standard texts in biochemistry, enzymology, etc.

[1860] Formulation, route of administration and effective dosage

[1861] Another aspect of the invention relates to formulations, routes of administration, and effective dosages of the compounds of the invention.

[1862] In some embodiments of the methods disclosed herein, a fatty acid synthase inhibitor and a thyroid receptor hormone agonist (e.g., a thyroid receptor hormone-β agonist; e.g., a compound of formula (XXI)) are administered sequentially.

[1863] In some embodiments of the methods disclosed herein, a fatty acid synthase inhibitor and a thyroid receptor hormone agonist (e.g., a thyroid receptor hormone-β agonist; e.g., a compound of formula (XXI)) are administered simultaneously.

[1864] In some embodiments of the methods disclosed herein, fatty acid synthase inhibitors and thyroid receptor hormone agonists (e.g., thyroid receptor hormone-β agonists; e.g., compounds of formula (XXI)) are formulated in separate dosage forms.

[1865] In some embodiments of the methods disclosed herein, fatty acid synthase inhibitors and thyroid receptor hormone agonists (e.g., thyroid receptor hormone-β agonists; e.g., compounds of formula (XXI)) are formulated in the same dosage form.

[1866] The dosage forms covered herein may contain any dosage and combination of dosages described herein.

[1867] The compounds of the present invention may be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, external, transdermal patch, pulmonary, vaginal, suppository, or parenteral (including intramuscular, intra-arterial, intrathecal, intradermal, intraperitoneal, subcutaneous, and intravenous) administration, or in the form suitable for aerosolization, inhalation, or inhalation administration. General information on drug delivery systems can be found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)).

[1868] In various aspects, pharmaceutical compositions include carriers and excipients (including, but not limited to, buffers, carbohydrates, mannitol, proteins, peptides or amino acids such as glycine, antioxidants, antibacterial agents, chelating agents, suspending agents, thickeners and / or preservatives), water, oils (including petroleum, animal-derived, plant-derived or synthetic oils such as peanut oil, soybean oil, mineral oil, sesame oil, etc.), saline solutions, glucose solutions and glycerol solutions, flavoring agents, coloring agents, anti-sticking agents and other acceptable additives, adjuvants or binders, and, where necessary, other pharmaceutically acceptable excipients that approximate physiological conditions, such as pH buffers, tension regulators, emulsifiers, humectants, etc. Examples of excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc. In another aspect, pharmaceutical preparations are substantially free of preservatives. In yet another aspect, pharmaceutical preparations may contain at least one preservative. General methods for drug formulations are described in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It will be appreciated that while any suitable carrier known to those skilled in the art may be used to administer the compositions of the present invention, the type of carrier will vary depending on the mode of administration.

[1869] The compounds can also be encapsulated in liposomes using well-known techniques. Biodegradable microspheres can also be used as carriers for the pharmaceutical compositions of the present invention. Suitable biodegradable microspheres are disclosed, for example, in U.S. Patent Nos. 4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883; 5,853,763; 5,814,344 and 5,942,252.

[1870] Compounds can be administered via liposomes or microspheres (or particles). Methods for preparing liposomes and microspheres for patient administration are well known to those skilled in the art. U.S. Patent No. 4,789,734 describes a method for encapsulating biomaterials in liposomes, the contents of which are hereby incorporated by reference. Essentially, the material is dissolved in an aqueous solution, appropriate phospholipi...

Claims

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

2. A method for treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

3. The method of claim 2, wherein treating the nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) includes preventing the progression of at least one symptom of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH).

4. The method of 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; hepatic steatosis; liver inflammation; hepatic ballooning degeneration; liver fibrosis; and NAFLD activity score.

5. A method for treating nonalcoholic fatty liver disease / metabolic dysfunction-associated fatty liver disease (NAFLD / MASLD) in a subject of need, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

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

7. A method for treating type 2 diabetes in a subject in need, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

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

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

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

11. The method of claim 10, wherein the liver cancer develops from NAFLD / MASLD or NASH / MASH.

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

13. The method of claim 12, wherein the hepatocellular carcinoma develops from NAFLD / MASLD or NASH / MASH.

14. The method of claim 11, wherein the liver cancer is cholangiocarcinoma.

15. A method for treating a disease or disorder in a subject with elevated interleukin-1β (IL1β) levels, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

16. The method of claim 15, wherein the disease or disorder is selected from familial Mediterranean fever (FMF), suppurative arthritis, pyoderma gangrenosa, acne var. acne (PAPA), cold pyridine-associated periodic syndrome (CAPS), high IgD syndrome (HIDS), adult and adolescent Still's disease, Schnitzler syndrome, TNF receptor-associated periodic syndrome (TRAPS), Blau syndrome, Sweet's syndrome, IL-1 receptor antagonist deficiency (DIRA), recurrent idiopathic pericarditis, macrophage activation syndrome (MAS), urticarial erythematosus Bronchitis, antisynergistic syndrome, recurrent chondritis, Behcet's disease, Eldheim-Chester syndrome (histiocytosis), synovitis, acne, impetigo, osteoproliferation, osteitis (SAPHO), rheumatoid arthritis, periodic fever, aphthous stomatitis, pharyngitis, polydactyly syndrome (PFAPA), urate crystal arthritis (gout), type 2 diabetes, smoldering multiple myeloma, heart failure after myocardial infarction, osteoarthritis, transfusion-related acute lung injury, ventilator-induced lung injury, pulmonary fibrosis including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma.

17. A regulatory T cell (T) for treating subjects in need. reg Methods for reducing or suppressing diseases or disorders, the methods comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

18. The method of claim 17, wherein T reg The cells are suppressed.

19. A t-adjuvant (T) for treating subjects in need of treatment h A method for treating diseases or disorders with elevated cellular levels, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

20. The method of claim 19, wherein the elevated t helper cells are T cells. h 1. T h 2. T h 9 or T h 17.

21. The method of claim 20, wherein the elevated t helper cells are T cells. 17 .

22. The method of any one of claims 17 to 21, wherein the disease or ailment is selected from psoriasis, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, asthma, tumorigenesis, and transplant rejection.

23. A method for reversing a confirmed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

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

25. A method for reducing fibrosis gene expression in a subject in need, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

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

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

28. A method for treating a subject with moderate to severe fibrosis of NASH / MASH, the method comprising administering a fatty acid synthase inhibitor and a thyroid hormone receptor-β agonist to the subject.

29. The method of claim 28, wherein the subject's liver fibrosis improves by ≥ 1 stage without worsening NASH / MASH.

30. The method of claim 28, wherein the subject's NASH / MASH subsides without fibrosis worsening.

31. The method of any one of claims 1 to 30, wherein the thyroid hormone receptor-β agonist has the formula (XXI): (XXI), Or its pharmaceutically acceptable salt, wherein: A A It is O, CH2, S, SO or SO2; X A and Y A Each group is independently selected from the groups composed of Br, Cl, and CH3; R 1A Choose from the following groups: -(CH2) n COOH, -OCH2COOH, -NHC(═O)COOH, -NHCH2COOH, and ; Z A It is H or -C≡N; R 2A It is a lower alkyl group having 1 to 4 carbon atoms; R 3A It is H or a lower alkyl group; n is 1 or 2; p is 1 or 2.

32. The method according to any one of claims 1 to 31, wherein the fatty acid synthase inhibitor has the following formula: (a) Equation (IX) (IX), Or its pharmaceutically acceptable salt, wherein: R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein: C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It is H, -OH or halogen; R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms; R 22 It is H, halogen, or C1-C2 alkyl; R 24 It is H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH 、 -(C1-C4 alkyl) t -O t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein: t is 0 or 1; C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; L 1 It is CR 23 Or N; L 2 It is CH or N; L 1 or L 2 At least one of them is N; and R 23 It is an H or C1-C4 straight-chain or branched alkyl group; or (b) Equation (X): (X)， Or its pharmaceutically acceptable salt, wherein: R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein: C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It is H, -OH or halogen; L 3 It is C(R) 60 2. O or NR 50 ; Each R 60 Independently H, -OH, -CN, -O t -(C3-C5 cycloalkyl), -O-(C1-C4 straight-chain or branched alkyl) or -C(O)-N(R) 601 )2, of which: t is 0 or 1, and C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; Each R 50 Independently H, –C(O)-O t -(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C3-C5 cyclic alkyl), optionally containing oxygen or nitrogen heteroatoms, -C(O)-N(R) 501 2. C1-C4 straight-chain or branched alkyl groups, wherein: t is 0 or 1, and C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; n is 1, 2, or 3; m is 1 or 2; R 21 It is H, halogen, C1-C4 straight-chain or branched alkyl, or C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms. R 22 It is H, halogen, C1-C2 alkyl; Each R 26 Independently, it can be –OH, -CN, halogen, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -O t -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl group), –C(O)-O t -(C1-C4 alkyl) or -C(O)-N(R) 501 )2, of which: t is 0 or 1, and C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; s is 0, 1, or 2; Each R 601 and R 501 Independently, it is an H or C1-C4 straight-chain or branched alkyl group; and Where R 26 R 60 R 50 R 501 and R 601 The two in R are optionally joined to form a loop, where R 26 R 60 R 50 R 501 and R 601 The two in can be two R. 26 Two Rs 60 Two Rs 50 Two Rs 501 Or two Rs 601 ;or (c) Equation (VI-J) (VI-J), Or its pharmaceutically acceptable salt, wherein: R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein: C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It is H, -OH or halogen; R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl; R 22 It is H, halogen, or C1-C2 alkyl; R 35 It is –C(O)-R 351 -C(O)-NHR 351 -C(O)-OR 351 or S(O)2R 351 ;and R 351 It is a C1-C6 straight-chain or branched alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group; or (d) Formula (XII): (XII), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is , , , or ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It is H, halogen, or C1-C2 alkyl; R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The condition is that when u is 1, t is 1; and Each R 241 Independently H or C1-C2 alkyl; and R 25 It is a halogen, -CN, -(C1-C4 alkyl)-CN, C1-C2 alkyl, or cyclopropyl; or (e) Equation (XIII): (XIII), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is , , , or ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It is H, halogen, or C1-C2 alkyl; and Each R 24 and R 25 Independently, it can be H, halogen, -CN, -(C1-C4 alkyl)-CN, C1-C4 alkyl, -(C1-C4 alkyl)-OH, or -(C1-C4 alkyl)-N(R). 241 2, -(C1-C4 alkyl) t -O u -(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -O u -(4- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein: Each t is independently 0 or 1; Each u is independently 0 or 1; and Each R 241 Independently H or C1-C2 alkyl; or (f) Equation (XIV): (XIV), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is , , , or The condition is that L-Ar is At that time, Ar was not ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It is H, halogen, or C1-C2 alkyl; and R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl rings) t -O-(C1-C4 alkyl), wherein: Each t is independently 0 or 1; and Each R 241 Independently H or C1-C2 alkyl; or (g) Equation (XV): (XV), Or its pharmaceutically acceptable salt, wherein: L 3 It is -CH2-, -CHR 50 -、-O-、-NR 50 -、-NC(O)R 50 -OR-NC(O)OR 50 -, where R 50 It is a C1-C6 alkyl, C3-C5 cycloalkyl, or a 4- to 6-membered heterocycle; n is 1, 2, or 3; m can be 1 or 2, provided that n + m ≥ 3; L-Ar is , or ; Ar is , , , or The condition is that L-Ar is At that time, Ar was not ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and R 22 It is H, halogen, or C1-C2 alkyl; or (h) Equation (XVI): (XVI), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is , , , or ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It 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) Equation (XVII): (XVII), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is , , , or The condition is that L-Ar is At that time, Ar was not ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It is H, halogen, or C1-C2 alkyl; and R 24 It is 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- to 6-membered heterocyclic rings) or -(C1-C4 alkyl)-O-(C1-C4 alkyl), wherein: t is 0 or 1; u is 0 or 1; The condition is that when u is 1, t is 1; and R 241 It is H or C1-C2 alkyl; or (j) Equation (XVIII): (XVIII), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is , , , or The condition is that L-Ar is At that time, Ar was not ; L 2 Yes - NHR 35 or -C(O)NHR 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It is H, halogen, or C1-C2 alkyl; and R 35 It is -C(O)R 351 -C(O)NHR 351 C(O)OR 351 or S(O)2R 351 , where R 351 It is a C1-C6 alkyl, C3-C5 cycloalkyl, 4- to 6-membered heterocyclic, aryl or heteroaryl; or (k) Equation (XIX): (XIX), Or its pharmaceutically acceptable salt, wherein: Each W, X, Y, and Z is independently -N- or -CR. 26 -, provided that no more than two of W, X, Y, and Z are -N-; Each R 26 Independently H, C1-C4 alkyl, -O-(C1-C4 alkyl), -N(R) 27 2. -S(O)2-(C1-C4 alkyl) or -C(O)-(C1-C4 alkyl); Each R 27 Independently H or C1-C4 alkyl, or two R 27 They are C1-C4 alkyl groups and are joined together with the N atoms to which they are attached to form 3- to 6-membered rings, wherein the rings optionally include an oxygen atom as one of the members of the ring; Ar is , , , or ; Het is a 5- to 6-membered heteroaryl group; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle), -O-(C1-C4 alkyl), where R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 11 It is H or -CH3; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycle; and R 22 It is H, halogen, or C1-C2 alkyl; or (l) Equation (XX): (XX), Or its pharmaceutically acceptable salt, wherein: L-Ar is , or ; Ar is ; R 1 It is H, -CN, halogen, C1-C4 alkyl, -O-(C3-C5 cycloalkyl), -O-(4- to 6-membered heterocycle) or -O-(C1-C4 alkyl), wherein when R 1 When it is not H, -CN or halogen, R 1 Optionally replaced by one or more halogens; Each R 2 It can be hydrogen, halogen, or C1-C4 alkyl independently; R 3 It is H or F; R 21 It is H, halogen, C1-C4 alkyl, C3-C5 cycloalkyl or 4- to 6-membered heterocycle; R 22 It is H, halogen, or C1-C2 alkyl; R 24 It is -O-(C1-C4 alkyl), -O-(C1-C4 alkyl)-O-(C1-C4 alkyl), -O-(C3-C5 cycloalkyl) or -O-(4- to 6-membered heterocycle), wherein R 24 Optionally substituted with one or more hydroxyl groups or halogens; and R 25 It is H, halogen, C1-C4 alkyl or C3-C5 cycloalkyl, wherein R 25 Optionally replaced by one or more halogens; or (m) Equation (XI): (XI) Or its pharmaceutically acceptable salt, wherein: R 1 It is H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein: C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and When R 1 When it is not H, -CN or a halogen, it may be optionally substituted with one or more halogens; Each R 2 Independently, it is H, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It is H, -OH or halogen; R 21 It is cyclobutyl, azircyclobutyl-1-yl, or cyclopropyl; R 22 It is H, halogen, C1-C2 alkyl; and R 351 It is a C1-C2 alkyl or C2-O-(C1 or C2 alkyl).

33. The method according to any one of claims 1 to 32, wherein the fatty acid synthase inhibitor is: 。 34. The method according to any one of claims 1 to 32, wherein the fatty acid synthase inhibitor is: (Compound 005-2).

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

36. The method of any one of claims 1 to 34, wherein the thyroid hormone receptor-β agonist is resmetiro, having the formula: 。 37. The method of any one of claims 1 to 36, wherein the fatty acid synthase inhibitor and the thyroid hormone receptor-β agonist are administered sequentially.

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

39. The method of claim 38, wherein the FASN inhibitor and the thyroid hormone receptor-β agonist are administered according to the same dosing schedule.

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

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

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

43. The method of any one of claims 1 to 39, wherein the resimetiro is a polymorph of type A.

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

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

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

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

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

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

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

52. The method of any one of claims 1 to 51, wherein the dose of the thyroid hormone receptor β agonist administered is equivalent to the indicated single dose for the treatment of NASH / MASH.

53. The method of any one of claims 1 to 51, wherein the dose of the thyroid hormone receptor β agonist administered is 10% to 90% of the indicated single dose for the treatment of NASH / MASH.

54. The method of any one of claims 1 to 51, wherein the dose of the thyroid hormone receptor β agonist is 80 mg once daily for patients weighing ≤100 kg and 100 mg once daily for patients weighing ≥100 kg.

55. The method of any one of claims 1 to 54, wherein the subject has been diagnosed with comorbidities.

56. The method of claim 55, wherein the comorbidity is obesity, type 2 diabetes, or a combination of both.

57. The method of claim 55, wherein the comorbidity is obesity.

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

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

60. A pharmaceutical preparation comprising compound 001-152 (denifastat) or a pharmaceutically acceptable salt thereof and compound A (resimeltiro) or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical formulation comprising compound 001-152 (denifastat) or a pharmaceutically acceptable salt thereof and a polymorph of compound A (resimeltiro) of type A.

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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