Combination of fasn inhibitors and glp-1 agonists for liver disease

Abstract

Combination of a fatty acid synthesis (FASN) inhibitor with a glucagon-like peptide-1 (GLP-1) agonist for the treatment of NAFLD / MAFLD, NASH / MASH, liver fibrosis and / or cirrhosis.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 589,280, filed October 10, 2023, and U.S. Provisional Application No. 63 / 623,511, filed January 22, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to a combination of fatty acid synthase (FASN) modulators and glucagon-like peptide-1 (GLP-1) modulators for the treatment of liver diseases associated with fat accumulation in the liver (fatty liver disease, also known as steatotic liver disease), including non-metabolic fatty liver disease (MAFLD, also known as non-alcoholic fatty liver disease (NAFLD)) and metabolic steatohepatitis (MASH, also known as non-alcoholic steatohepatitis (NASH)), liver fibrosis, and / or cirrhosis. Background Technology

[0004] Increased de novo lipid production (DNL) drives the development of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), and fatty acid synthase (FASN) is the rate-limiting enzyme in the DNL pathway. FASN inhibition not only reduces hepatic steatosis but also acts directly on the immune system 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 / MAFLD and NASH / MASH. The disclosures mentioned above are incorporated herein by reference. One of the compounds described in the aforementioned applications, denifanstat (TVB-2640), is the first-in-class FASN inhibitor, which has been shown to improve hepatic steatosis and biomarkers associated with inflammation and fibrosis in NASH / MASH trials.

[0005] GLP-1 agonist therapy was associated with improved glucose control and weight loss. In patients with MASH, GLP-1 therapy led to impaired glucose tolerance and decreased liver fat fraction. Weight loss may be caused by appetite suppression. For example, in a recent NASH / MASH trial, the GLP-1 agonist semaglutide resulted in weight loss and demonstrated NASH / MASH regression; however, it did not improve fibrosis compared to placebo.

[0006] The industry needs further treatments for NAFLD / MAFLD and NASH / MASH that can improve all symptoms and markers of the disease, including fibrosis, while minimizing toxicity. Summary of the Invention

[0007] In some aspects, a method is provided for treating fatty liver disease / steatohepatitis in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0008] In some aspects, a method for treating liver fibrosis in a subject of need is provided, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0009] In some aspects, a method is provided to reverse a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0010] In some aspects, a method is provided for treating nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0011] In some aspects, a method is provided for reducing the expression of fibrosis genes in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0012] In some aspects, a method for treating cirrhosis in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0013] In some respects, the cirrhosis described is a complication of fatty liver disease / steatohepatitis.

[0014] In some aspects, a method is provided to improve or restore liver function in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

[0015] In some respects, the subjects had been diagnosed with fatty liver disease.

[0016] In some aspects, a method is provided for treating fatty liver disease / steatohepatitis in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0017] Equation (I) is:

[0018] ;

[0019] in:

[0020] L-Ar is or ;

[0021] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

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

[0023] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0024] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0025] R 3 It can be H, -OH or halogen;

[0026] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0027] R 22 It is H, halogen, or C1-C2 alkyl;

[0028] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t-OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0029] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0030] t is 0 or 1;

[0031] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0032] L 1 For CR 23 Or N;

[0033] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0034] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0035] v is 0 or 1;

[0036] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0037] In some aspects, a method is provided for treating liver fibrosis in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0038] Equation (I) is:

[0039] ;

[0040] in:

[0041] L-Ar is or ;

[0042] R 1The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0043] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0044] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0045] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0046] R 3 It can be H, -OH or halogen;

[0047] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0048] R 22 It is H, halogen, or C1-C2 alkyl;

[0049] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0050] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0051] t is 0 or 1;

[0052] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0053] L 1 For CR 23 Or N;

[0054] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl)v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0055] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0056] v is 0 or 1;

[0057] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0058] In some respects, the subjects had been diagnosed with fatty liver disease / steatohepatitis.

[0059] In some aspects, a method is provided for reversing a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0060] Equation (I) is:

[0061] ;

[0062] in:

[0063] L-Ar is or ;

[0064] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0065] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0066] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0067] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0068] R 3 It can be H, -OH or halogen;

[0069] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0070] R22 It is H, halogen, or C1-C2 alkyl;

[0071] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0072] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0073] t is 0 or 1;

[0074] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0075] L 1 For CR 23 Or N;

[0076] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0077] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0078] v is 0 or 1;

[0079] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0080] In some aspects, a method is provided for treating nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0081] Equation (I) is:

[0082] ;

[0083] in:

[0084] L-Ar is or ;

[0085] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0086] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0087] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0088] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0089] R 3 It can be H, -OH or halogen;

[0090] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0091] R 22 It is H, halogen, or C1-C2 alkyl;

[0092] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0093] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0094] t is 0 or 1;

[0095] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0096] L 1 For CR 23 Or N;

[0097] R 23It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0098] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0099] v is 0 or 1;

[0100] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0101] In some aspects, a method is provided for reducing fibrosis gene expression in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0102] Equation (I) is:

[0103] ;

[0104] in:

[0105] L-Ar is or ;

[0106] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0107] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0108] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0109] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0110] R 3 It can be H, -OH or halogen;

[0111] R 21H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0112] R 22 It is H, halogen, or C1-C2 alkyl;

[0113] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0114] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0115] t is 0 or 1;

[0116] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0117] L 1 For CR 23 Or N;

[0118] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0119] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0120] v is 0 or 1;

[0121] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0122] In some aspects, a method for treating cirrhosis in a subject in need is provided, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0123] Equation (I) is:

[0124] ;

[0125] in:

[0126] L-Ar is or ;

[0127] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0128] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0129] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0130] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0131] R 3 It can be H, -OH or halogen;

[0132] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0133] R 22 It is H, halogen, or C1-C2 alkyl;

[0134] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0135] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0136] t is 0 or 1;

[0137] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0138] L 1 For CR 23 Or N;

[0139] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0140] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0141] v is 0 or 1;

[0142] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0143] In some respects, the cirrhosis described is a complication of fatty liver disease / steatohepatitis.

[0144] In some aspects, a method is provided for restoring or improving liver function in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein:

[0145] Equation (I) is:

[0146] ;

[0147] in:

[0148] L-Ar is or ;

[0149] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0150] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0151] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0152] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0153] R 3It can be H, -OH or halogen;

[0154] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0155] R 22 It is H, halogen, or C1-C2 alkyl;

[0156] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0157] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0158] t is 0 or 1;

[0159] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0160] L 1 For CR 23 Or N;

[0161] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0162] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0163] v is 0 or 1;

[0164] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0165] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as denoxinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for treating fatty liver disease / steatohepatitis, said agents being formulated for administration in combination with a GLP-1 agonist. In other aspects, the combination of the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as denoxinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with a GLP-1 agonist can be used to treat fatty liver disease / steatohepatitis.

[0166] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) or symptoms of NASH / MASH, wherein said agents are configured for administration in combination with a GLP-1 agonist. In other aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be combined with a GLP-1 agonist for treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) or symptoms of NASH / MASH.

[0167] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for treating nonalcoholic steatohepatitis / metabolic dysfunction-related fatty liver disease (NAFLD / MAFLD), said agents being formulated for administration in combination with a GLP-1 agonist. In other aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be combined with a GP-1 agonist for treating nonalcoholic steatohepatitis / metabolic dysfunction-related fatty liver disease (NAFLD / MAFLD).

[0168] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for treating liver fibrosis, wherein said agents are configured for administration in combination with a GLP-1 agonist. In other aspects, the combination of the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with a GLP-1 agonist can be used to treat liver fibrosis.

[0169] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for improving liver function (e.g., in subjects diagnosed with a disease associated with fat accumulation in the liver (fatty liver disease / steatohepatitis), subjects diagnosed with NASH / MASH, subjects diagnosed with NAFLD / MAFLD, subjects diagnosed with liver fibrosis, subjects diagnosed with cirrhosis), wherein said agents are configured for administration in combination with a GLP-1 agonist. In other respects, the combination of the FASN inhibitors disclosed herein (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with GLP-1 agonists may be used to improve liver function (e.g., in subjects diagnosed with a disease associated with fat accumulation in the liver (fatty liver disease / steatohepatitis), subjects diagnosed with NASH / MASH, subjects diagnosed with NAFLD / MAFLD, subjects diagnosed with liver fibrosis, and subjects diagnosed with cirrhosis).

[0170] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for treating cirrhosis, said agents being formulated for administration in combination with a GLP-1 agonist. In other aspects, the combination of the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with a GLP-1 agonist can be used to treat cirrhosis.

[0171] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for treating or reversing diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), said agents being formulated for administration in combination with a GLP-1 agonist. In other aspects, the combination of the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with a GLP-1 agonist can be used to treat or reverse diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH).

[0172] In various aspects, the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as denoxinistat or TVB-3664, or pharmaceutically acceptable salts thereof) can be used to manufacture agents for reducing the expression of fibrosis genes, said agents being formulated for administration in combination with a GLP-1 agonist. In other aspects, the combination of the FASN inhibitors of this disclosure (e.g., compounds having formula (I), such as denoxinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with a GLP-1 agonist can be used to reduce the expression of fibrosis genes. Attached Figure Description

[0173] Figure 1 This is a schematic diagram of the study design for Example 1. SC - subcutaneous administration; PO - oral administration; FI - food intake; BW - body weight; QW - once a week.

[0174] Figure 2A Paired plots showing changes in hepatic NAFLD / MAFLD activity scores (NAS) following administration of the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combinations of TVB-3664 and semaglutide. Individual before-and-after scores. For each animal, pre- and post-study biopsy scores are indicated by lines. Score shifts for each score are slight to allow for visual dissociation in the animals.

[0175] Figure 2B This is a summary of changes in NAFLD / MAFLD activity scores induced by administration of the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combinations of TVB-3664 and semaglutide. Before and after scores. The percentage of animals with 1 point of worsening, no change, 1 point of improvement, 2 points of improvement, or 3 points of improvement is indicated by the height of the bar (n = 8–16).

[0176] Figure 3A A graph showing changes in liver fibrosis based on AI-assisted digital imaging (FibroNest) after administration of the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combinations of TVB-3664 and semaglutide. Figure 3B Graphs showing absolute liver fibrosis as determined histologically by PSR after administration of the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination of TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. Dunnett's test was used for a one-way linear model. ***: P < 0.001 compared to the DIO-NASH mediator.

[0177] Figure 4This is a graph showing the changes in liver collagen gene expression after administration of a mediator (control), exemplary FASNi TVB-3364, semaglutide, and a combination of TVB-3664 and semaglutide.

[0178] Figure 5 The graph shows the change in body weight with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide.

[0179] Figure 6 A graph showing the change in plasma alanine aminotransferase (ALT) levels with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator.

[0180] Figure 7 A graph showing the change in plasma aspartate aminotransferase (AST) levels with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. **: P < 0.01, ***: P < 0.001 compared to the DIO-NASH mediator.

[0181] Figure 8A Plots showing the change in relative total liver cholesterol levels with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 7–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator. Figure 8B Graph showing the change in total liver cholesterol levels with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 7–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator.

[0182] Figure 9APlots showing the change in relative hepatic triglyceride levels with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. **: P < 0.01, ***: P < 0.001 compared to the DIO-NASH mediator. Figure 9B Graphs showing the change in hepatic triglyceride levels with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator.

[0183] Figure 10A A graph showing the change in hepatic steatosis (percentage of hepatocytes with hepatic droplets) with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator. Figure 10B A graph showing the change in hepatic steatosis scores with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Before and after scores. The percentage of animals with a score of 1 indicating worsening, no change, 1 indicating improvement, or 2 indicating improvement is indicated by the height of the bar (n = 8–16). Figure 10C Plots showing the change in relative liver lipid content (as determined by histological quantification) with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator. Figure 10D Graph showing the change in absolute liver lipid content, as measured by histological quantification, with treatment with the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. One-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator.

[0184] Figure 11APlots showing the change in liver inflammation (total hepatic galactolectin) with treatment using the mediator (control), exemplary FASNiTVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Values ​​are expressed as mean + SEM for n = 8–16. A one-way linear model was performed using the DIO-NASH mediator. ***: P < 0.001 compared to the DIO-NASH mediator. Figure 11B A graph showing the change in lobular inflammation scores with treatment using the mediator (control), exemplary FASNi TVB-3364, semaglutide, and combination therapy with TVB-3664 and semaglutide. Before and after scores. The percentage of animals with a score of 1 indicating worsening, no change, 1 indicating improvement, or 2 indicating improvement is indicated by the height of the bar (n = 8–16).

[0185] Figure 12 A graph showing the percentage of patients who achieved NASH remission without worsening fibrosis on a stable background of GLP1 agonist semaglutide, and the percentage of patients who achieved at least one stage of improvement in liver fibrosis without worsening NASH after adding dinistat or placebo to their treatment regimen. Detailed Implementation

[0186] In some respects, this disclosure provides a method for treating liver conditions associated with fat accumulation in the liver (fatty liver disease / steatohepatitis), cirrhosis and / or liver fibrosis and / or improving liver function using a combination of a fatty acid synthase (FASN) inhibitor and a glucagon-like peptide-1 (GLP-1) agonist.

[0187] definition

[0188] As those skilled in the art will understand, the chemical moiety referred to as a monovalent chemical moiety (e.g., alkyl, aryl, etc.) also encompasses structurally permissible polyvalent moieties. For example, while the term "alkyl" typically refers to a monovalent group (e.g., CH3CH2-), in appropriate contexts, "alkyl" can also refer to a divalent group (e.g., -CH2CH2-, which is equivalent to "alkylene"). Similarly, where a divalent moiety is required, those skilled in the art will understand that the term "aryl" refers to the corresponding divalent arylene.

[0189] It should be understood that all atoms have their normal valences for bond formation (e.g., carbon is 4, N is 3, O is 2, and S is 2, 4, or 6, depending on the atom's oxidation state). 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.

[0190] If the number of atoms or groups of the same kind in the substituent can vary (e.g., alkyl groups can be C1, C2, C3, etc.), then the number of repeating atoms or groups can be expressed by a range (e.g., C...). l -C6 alkyl), which includes each of the numbers in 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.

[0191] "Alkyl group" refers to a carbonyl group with a lower alkyl group as a substituent.

[0192] "Alkylamino" refers to an amino group that has been replaced by an alkyl group.

[0193] "Alkoxy" refers to an O atom substituted with an alkyl group as defined herein, such as a methoxy group [-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 its subranges.

[0194] "Alkoxycarbonyl" refers to a carbonyl group that has an alkoxy group as a substituent.

[0195] "alkyl," "alkenyl," and "ynyl" refer to a straight-chain or branched aliphatic group having 1 to 30 carbon atoms, or preferably 1 to 15 carbon atoms, or more preferably 1 to 6 carbon atoms, and 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 alkyl groups having one or more heteroatoms.

[0196] "alkylene" refers to a divalent group that is optionally substituted, which is a branched or unbranched hydrocarbon segment containing a specified number of carbon atoms and having two connection points. An example is propylene [-CH2CH2CH2-, C3 alkylene].

[0197] "Amino" refers to the group -NH2.

[0198] "Aryl" refers to an aromatic group having at least one ring with a conjugated π-electron system that is optionally substituted, and includes carbocyclic aryl and biaryl groups, all of which may optionally be substituted. Phenyl and naphthyl are preferred carbocyclic aryl groups.

[0199] "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.

[0200] As used in this article, "carbamoyl" encompasses the following structures. 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.

[0201] "Carbonyl" refers to the structure . group.

[0202] "Cycloalkyl" refers to a ring that is optionally substituted, which may be saturated or unsaturated and is a monocyclic, bicyclic, or tricyclic ring formed entirely of carbon atoms. An example of a cycloalkyl group is cyclopentenyl (C5H7-), which is a five-carbon (C5) unsaturated cycloalkyl group. In some embodiments, the cycloalkyl group is described as optionally including heteroatoms (e.g., oxygen or nitrogen atoms), thereby forming a heterocycle.

[0203] "Heterocycle" refers to a 5- to 7-membered cycloalkyl ring system that is optionally substituted, containing 1, 2 or 3 heteroatoms selected from N, O or S, which may be the same or different, and optionally contains a double bond.

[0204] "Halogen" refers to a chlorine, bromine, fluorine, or iodine atom group. The term "halogen" also encompasses the terms "halogen group" or "halogen."

[0205] "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.

[0206] "Heteroaryl" refers to an aryl group having 1 to 9 carbon atoms, with the remaining atoms being heteroatoms, and includes those heterocyclic systems described in "Handbook of Chemistry and Physics," 49th edition, 1968, RC Weast (ed.); The Chemical Rubber Co., Cleveland, Ohio. See, for details, Part C, Rules for Naming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitable heteroaryl groups include thiophene, pyrrolyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazoleyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrololinyl, pyridazinyl, triazolyl, indolyl, isoindolyl, inazinyl, benzimidazolyl, quinolinyl, isoquinazolyl, inazolyl, benzotriazolyl, tetrazolpyridazinyl, oxadiazolyl, benzooxazolyl, benzooxadiazolyl, thiazolyl, benzothiazolyl, benzothiazolyl, benzothiazolyl, etc.

[0207] The "optionally substituted" portion may be substituted by one to four, or preferably one to three, or more preferably one or two non-hydrogen substituents. Unless otherwise specified, when the substituent is located on a carbon atom, it is selected from the group consisting of: -OH, -CN, -NO2, halogen, 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, none of which are further substituted. Unless otherwise specified, when the substituent is on nitrogen, it is selected from the group consisting of C1 to C1. 12 Alkyl, C1 to C 12 Heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide, none of which are further substituted.

[0208] As used herein, the term "sulfonamide" encompasses structures with 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, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

[0209] As used herein, the term "sulfonate" encompasses substances with a structure The group, wherein R s Choose from the following groups: hydrogen, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl or C1-C 10 Alkoxycarbonyl group.

[0210] As used herein, “sulfonyl” alone or as part of another group refers to the SO2 group. The SO2 moiety may optionally be substituted.

[0211] The compounds disclosed herein may exist in stereoisomeric forms, 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 are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, PureAppl. Chem., (1976), 45: 13-30, which is hereby incorporated by reference. This disclosure covers a variety of stereoisomers and mixtures thereof, and is expressly included within the scope of this disclosure. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds disclosed may be prepared synthetically from commercially available starting materials containing asymmetric or chiral neutrality, or by preparing racemic mixtures followed by resolution as well known to those skilled in the art. These separation methods are exemplified by: (1) linking a mixture of enantiomers to a chiral auxiliaries, separating the resulting diastereomer mixture and the optically pure product from the auxiliaries by recrystallization or chromatography, or (2) directly separating a mixture of optically enantiomers on a chiral chromatographic column.

[0212] Furthermore, the portions disclosed herein that exist in multiple tautomer forms include all such forms covered by a given tautomer structure.

[0213] Individual atoms in the disclosed compounds may be any isotopes of the element. For example, hydrogen may be in the form of deuterium.

[0214] "Pharmaceutical acceptable" means that it has been approved or is likely to be approved by a federal or state regulatory agency or is listed in the United States Pharmacopeia or other recognized pharmacopoeia for use in animals, and more specifically in humans. It can be a material that is not biologically or otherwise undesirable, meaning that the material can be administered to an individual without causing any undesirable biological effects or interacting in a harmful manner with any component of a composition containing it.

[0215] The term "pharmaceutically acceptable salt" of a compound refers to 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.

[0216] According to this disclosure, the "acid addition salt" forms with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or with organic acids (e.g., 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, etc.). It is formed from 1,2-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, mucoconic acid, etc.

[0217] When an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or coordinated with an organic base, a "base addition salt" according to this disclosure is formed. 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 references to pharmaceutically acceptable salts include their solvation or crystalline forms, specifically solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are typically formed during crystallization. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. Polymorphs comprise 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 forms, optical and electrical properties, stability, and solubility. For example, factors such as recrystallization solvent, crystallization rate, and storage temperature can lead to the dominance of the single crystal form.

[0218] The term "treatment" includes administering to a subject a compound or agent, as provided herein, to prevent or delay, mitigate, stop, or inhibit the development of a disease or condition, including diseases or conditions associated with fat accumulation in the liver (fatty liver disease or condition), such as NAFLD / MAFLD and NASH / MASH, liver fibrosis, and cirrhosis. As used herein, the term "treatment" includes achieving a therapeutic benefit and / or a preventive benefit. A therapeutic benefit means the eradication / normalization or improvement / reversal / regression or stabilization / progression-free status of one or more physiological symptoms associated with the underlying liver disease.

[0219] As used herein and unless otherwise specified, a "therapeuticly effective amount" of a compound is an amount sufficient, alone or in combination with other therapies, to provide therapeutic benefit in the therapeutic treatment of a disease, condition, or disorder, or to delay or minimize one or more symptoms associated with said disease, condition, or disorder. The term "therapeuticly effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent. In some embodiments, the term "therapeuticly effective amount" refers to a synergistic effective amount or a synergistic therapeutic amount.

[0220] "Synergy" means that the therapeutic effect of a FASN inhibitor when combined with a GLP-1 agonist, as described herein, is greater than the predicted additive therapeutic effect of either the FASN inhibitor or the GLP-1 agonist when 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 the amount required for 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 and the other at a sub-standard therapeutic dose. For example, a FASN inhibitor may be administered at a therapeutic dose and a GLP-1 agonist may be administered at a standard or sub-standard therapeutic dose to provide a synergistic outcome, or vice versa.

[0221] Unless otherwise noted, the terms “subject” or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as laboratory animals such as rabbits, rats, and mice, and other animals. Therefore, as used herein, the terms “subject” or “patient” mean any mammalian patient or subject to whom the compounds provided herein may be administered. In one aspect, the subject is a human subject. In some embodiments, methods are provided to identify subject patients treated according to the methods provided herein, employing recognized screening methods to determine risk factors associated with a target or suspected disease or condition, or to determine the subject’s existing disease or condition status. These screening methods include, for example, routine examinations to determine risk factors associated with a target or suspected disease or condition. These and other methods allow clinicians to select patients in need of therapy using the methods, compounds, compositions, and formulations provided herein.

[0222] FASN pathway modulators

[0223] One aspect of this disclosure includes a method for treating diseases associated with fat accumulation in the liver (fatty liver disease / steatohepatitis) (e.g., NAFLD / MAFLD, NASH / MASH), cirrhosis, and / or liver fibrosis using a combination of a FASN pathway modulator and a GLP-1 agonist. In one aspect, the FASN pathway modulator may be an inhibitor of the fatty acid synthesis pathway.

[0224] Examples of fatty acid synthesis pathway inhibitors that can be used in the methods and compositions of this disclosure are described below.

[0225] Compound of formula (I)

[0226] Compounds of formula (I) are provided in various respects:

[0227] Equation (I) is:

[0228] ;

[0229] in:

[0230] L-Ar is or ;

[0231] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0232] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0233] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0234] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0235] R 3 It can be H, -OH or halogen;

[0236] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0237] R 22 It is H, halogen, or C1-C2 alkyl;

[0238] R24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0239] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0240] t is 0 or 1;

[0241] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0242] L 1 For CR 23 Or N;

[0243] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0244] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0245] v is 0 or 1;

[0246] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0247] In some aspects of equation (I), L-Ar is .

[0248] In some aspects of equation (I), L-Ar is .

[0249] In some aspects of equation (I), R 24 It is a C1-C4 straight-chain or branched alkyl group, which is optionally substituted with one, two, or three halogens. In some aspects of formula (I), R 24 For -Me or -CF3. In some aspects of equation (I), R 24 For -Me. In some aspects of equation (I), R 24 It is -CF3.

[0250] In some aspects of equation (I), 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; -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. In some aspects of formula (I), R 21 It is a C1-C4 straight-chain or branched alkyl group or a C3-C5 cycloalkyl group. In some aspects of formula (I), R 21 It is either Me or cyclobutyl. In some aspects of formula (I), R 21 It is cyclobutyl. In some aspects of formula (I), R 21 For -Me.

[0251] In some aspects of equation (I), R 3 It is H or a halogen. In some aspects of formula (I), R 3 For H.

[0252] In some aspects of equation (I), R 1 It is a halogen, -CN, or C1-C2 haloalkyl. In some aspects of formula (I), R 1 For CN.

[0253] In some aspects of equation (I), L 1 For N. In some aspects of equation (I), L 1 For CR 23 .

[0254] In some aspects of equation (I), R 22 It is a C1-C2 alkyl group. In some aspects of formula (I), R 22 For Me.

[0255] In some aspects of equation (I), R 21 It is a C1-C2 alkyl or C3-C5 cycloalkyl, and R 22 It is a C1-C2 alkyl group. In some aspects of formula (I), R 21 It is -Me or cyclobutyl, and R 22 For -Me.

[0256] In some aspects of equation (I), R 21 It is a C3-C5 cycloalkyl group, and R 22 It is a C1-C2 alkyl group. In some aspects of formula (I), R 21 It is cyclobutyl, and R 22 For Me.

[0257] In some aspects of equation (I), R 21 It is a C1-C2 alkyl group, and R 22 It is a C1-C2 alkyl group. In some aspects of formula (I), R 21 For -Me, and R 22 For -Me.

[0258] In some aspects of equation (I), R 23 -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), where v is 0 or 1. In some respects, v is 1. In some respects of formula (I), R 23 It is CH2-O-CH3.

[0259] In some aspects of equation (I), R 1 For -CN, each R 2 For H, R 3 For H or F, R 21 It is a C1-C4 straight-chain or branched alkyl or a C3-C4 cycloalkyl, R 22 For methyl, R 24 It is a C1-C4 straight-chain or branched alkyl group, optionally substituted with one, two or three halogens, L 1 For N or CR 23 R 23 It is a methoxymethyl group.

[0260] In some aspects of equation (I), R 1 For -CN, each R 2 For H, R 3 For H, R 21 It is a C1-C4 straight-chain or branched alkyl or a C3-C4 cycloalkyl, R 22 For methyl, R 24 It is a C1-C4 straight-chain or branched alkyl group, optionally substituted with one, two or three halogens, L 1 For N or CR 23 R 23 It is a methoxymethyl group.

[0261] All aspects of equation (I) presented in this paper are intended to be combinable with each other.

[0262] When L 1 When N is used, references to equation (I) are intended to cover all possible triazole tautomers selected from the following:

[0263] and

[0264] In some aspects of formula (I), the compound has a structure selected from the group consisting of:

[0265] (Denista) and (TVB-3664)

[0266] Throughout the claims and specification, the use of dinista or the structure The reference is intended to cover all possible triazole tautomers, including those illustrated and those selected from [other sources]. and Any possible alternative triazole tautomers.

[0267] Fatty acid synthesis pathway

[0268] Various aspects of this disclosure relate to compositions and methods for modulating the activity of fatty acid synthesis pathways to treat diseases associated with fat accumulation in the liver (fatty liver disease / steatohepatitis) and / or liver fibrosis. The fatty acid synthesis pathway in humans 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 diseases associated with fat accumulation in the liver (fatty liver disease, including NASH / MASH, NAFLD / MAFLD), cirrhosis, and / or liver fibrosis.

[0269] The final products of fatty acid synthase are free fatty acids, which can be 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 mammary glands, where C... 10 -C 14 Fatty acids (Thompson et al., (1985) Pediatr. Res., 19:139-143).

[0270] Fatty acids can be synthesized from acetyl-CoA in the cytoplasm. Acetyl-CoA is generated from pyruvate via pyruvate dehydrogenase (PDH) and through β-oxidation of fatty acids in the mitochondria. The “citate shuttle” transports acetyl-CoA from the mitochondria to the cytoplasm. Acetyl-CoA reacts with oxaloacetate to produce citrate, and a tricarboxylate transloase transports citrate from the mitochondria to the cytoplasm. In the cytoplasm, citrate can be cleaved back to oxaloacetate and acetyl-CoA, a reaction catalyzed by ATP-citate lyase. Oxaloacetate can be converted back to pyruvate for re-entry into the mitochondria.

[0271] 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 performs three functions: a biotin carboxyl carrier protein, a biotin carboxylase, and a carboxyltransferase. Following ATP-dependent carboxylation of the biotin prosthetic group (cofactor), the carboxyl group is then transferred to acetyl-CoA.

[0272] HCO3 - + ATP + Acetyl-CoA -> ADP + P i +malonyl-CoA

[0273] 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 lipid-producing tissues. Several alternative splice transcript variants of this gene have been identified, which are sequence-different and encode different isoforms. ACC-β (also known as ACC2, ACCB, HACC275, and ACACB) encodes a protein believed to control fatty acid oxidation by means of malonyl-CoA's ability to inhibit carnitine-palmitoyl-CoA transferase I (the rate-limiting step in mitochondrial uptake and oxidation of fatty acids). ACC-β is involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis. There is evidence of two ACC-β isoforms.

[0274] ACC can be regulated by phosphorylation / dephosphorylation of targeted 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. Acta1123:231-8). In addition, cAMP-dependent protein kinases (protein kinase A or PKA) can phosphorylate ACC.

[0275] ACC can be regulated by allotropic conversion of citrate or palmitoyl-CoA. For example, citrate can be a positive effector (i.e., citrate can allotropically activate ACC). Citrate concentrations can be high when sufficient acetyl-CoA enters the Krebs cycle. Excess acetyl-CoA can then be converted to fatty acids via malonyl-CoA. Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA is a product of fatty acid synthase (FASN) and promotes the inactive conformation of ACC, reducing malonyl-CoA production (a feedback inhibition process). AMP can regulate fatty acid synthesis by modulating malonyl-CoA availability. Insulin-binding receptors can activate phosphatases to dephosphorylate ACC, thus removing the inhibitory effect.

[0276] 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 that can function in fatty acid biosynthesis. FASN catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids in the presence of NADPH. 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 fused within the C-terminal frame of ER-α.

[0277] FASN proteins exist as dimers of the same subunits in the cytoplasm. FASN consists of three catalytic domains (-ketoacyl synthase (KS), malonyl / acetyltransferase (MAT), and dehydratase (DH)) in the N-terminal region. The N-terminal region is separated from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase (TE)) by a core of approximately 600 amino acids. The crystal structures of mammalian fatty acid synthases have been reported (Maier T. et al. (2008) Science 321: 1315-1322).

[0278] Enzymatic steps in fatty acid synthesis can involve decarboxylation condensation, reduction, dehydration, and another reduction, and can produce saturated acyl moieties. NADPH can serve as an electron donor in reduction reactions.

[0279] GLP-1 agonists

[0280] One aspect of this disclosure includes a method for treating diseases associated with fat accumulation in the liver (fatty liver disease / steatohepatitis) (e.g., NAFLD / MAFLD, NASH / MASH), cirrhosis, and / or liver fibrosis using a combination of a FASN pathway modulator and a GLP-1 agonist. The GLP-1 agonist can be a compound whose therapeutic activity is solely or primarily related to its GLP-1 agonist activity, or a compound that also has multiple mechanisms of action in addition to GLP-1 agonist activity. GLP-1 agonists include pharmaceutical compositions and dosage forms in which a compound having GLP-1 agonist activity is co-formulated with other therapeutic agents.

[0281] In some respects, GLP-1 agonists include (but are not limited to) agents selected from the following: single-agent GLP-1 receptor agonists, dual GIP / GLP-1 receptor agonists, dual GIP receptor antagonists / GLP-1 receptor agonists, dual amylin / GLP-1 receptor agonists, dual glucagon / GLP-1 receptor agonists, and triple glucagon / GIP / GLP-1 receptor agonists.

[0282] In some respects, GLP-1 receptor agonists are single-agent GLP-1 receptor agonists. In some respects, single-agent GLP-1 receptor agonists are selected from the group consisting of: semaglutide, liraglutide, LY3502970, and danuglipron.

[0283] In some respects, GLP-1 receptor agonists are dual GIP / GLP-1 receptor agonists. In some respects, dual GIP / GLP-1 receptor agonists are selected from tirzepatide, CT388, and dapiglutide.

[0284] In some respects, GLP-1 receptor agonists are dual GIP receptor antagonists / GLP-1 receptor agonists. In some respects, dual GIP receptor antagonists / GLP-1 receptor agonists are AMG133.

[0285] In some respects, GLP-1 receptor agonists are dual amylin / GLP-1 receptor agonists. In other respects, dual amylin / GLP-1 receptor agonists are Cagri-Sema.

[0286] In some respects, GLP-1 receptor agonists are dual glucagon / GLP-1 receptor agonists. In some respects, dual glucagon / GLP-1 receptor agonists are selected from the group consisting of: BI456906, NN9277, cotadutide, and pemvidutide.

[0287] In some respects, GLP-1 receptor agonists are triple glucagon / GIP / GLP-1 receptor agonists. In other respects, triple glucagon / GIP / GLP-1 receptor agonists are retatrutide.

[0288] In some respects, GLP-1 receptor agonists include (but are not limited to) GLP-1 agonists selected from the group consisting of: semaglutide, liraglutide, daglitron, LY3502970, AMG-133, CT388, daviglutide, tesipatide, cotadulide, pegutide, BI456906, NN9277, Cagri-Sema, and retaglutide.

[0289] In some respects, the GLP-1 agonist is semaglutide. In some respects, the GLP-1 receptor agonist is liraglutide. In some respects, the GLP-1 receptor agonist is daglione. In some respects, the GLP-1 receptor agonist is LY3502970. In some respects, the GLP-1 receptor agonist is AMG-133. In some respects, the GLP-1 receptor agonist is CT388. In some respects, the GLP-1 receptor agonist is daviglutide. In some respects, the GLP-1 receptor agonist is tesipatide. In some respects, the GLP-1 receptor agonist is cotadole. In some respects, the GLP-1 receptor agonist is perivutide. In some respects, the GLP-1 receptor agonist is BI456906. In some respects, the GLP-1 receptor agonist is NN9277. In some respects, the GLP-1 receptor agonist is Cagri-Sema. In some respects, the GLP-1 receptor agonist is retaloglutide.

[0290] The GLP-1 agonists considered in the methods described herein may be administered orally or parenterally (e.g., subcutaneously). For GLP-1 agonists approved by the Food and Drug Administration (FDA) for at least one indication, the route of administration may be as stated on their FDA-approved label. In some respects, GLP-1 agonists are administered orally. In other respects, GLP-1 agonists are administered subcutaneously.

[0291] GLP-1 agonists are currently in use, including the GLP-1 agonists considered in the methods described herein, and in some cases have been approved by the Food and Drug Administration for the treatment of two main indications: type 2 diabetes (T2D) and weight loss.

[0292] In some aspects of the methods described herein, the dose of the GLP-1 agonist administered is equal to the dose indicated on its label as a maintenance dose for the treatment of type 2 diabetes in adult patients. In some aspects of the methods described herein, the dose of the GLP-1 agonist administered is lower than the dose indicated on its label as a maintenance dose for the treatment of type 2 diabetes (i.e., a certain percentage of the dose indicated on its label as a maintenance dose for the treatment of type 2 diabetes in adult patients). In some aspects of the methods described herein, the dose of the GLP-1 agonist administered is 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%, 60% to 80%, 70% to 80%, 80% to 80%, 20% to 80%, 30% to 80%, 40% to 80%, 50% to 80%, 60% to 80%, 70% to 80%, 8 ... 0%, 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%.

[0293] In some aspects, the dosage of the GLP-1 agonist is 10% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 20% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 30% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 40% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 50% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 60% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 70% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 80% to 90% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 10% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 20% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 30% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 40% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 50% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 60% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dosage of the GLP-1 agonist is 70% to 80% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dosage of the GLP-1 agonist is 10% to 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dosage of the GLP-1 agonist is 20% to 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dosage of the GLP-1 agonist is 30% to 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dosage of the GLP-1 agonist is 40% to 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dosage of the GLP-1 agonist is 50% to 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients.In some aspects, the dosage of the GLP-1 agonist is 60% to 70% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 10% to 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 20% to 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 30% to 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 40% to 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 50% to 60% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 10% to 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 20% to 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 30% to 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 40% to 50% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 10% to 40% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 20% to 40% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 30% to 40% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some aspects, the dosage of the GLP-1 agonist is 10% to 30% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dose of the GLP-1 agonist administered is 20% to 30% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects, the dose of the GLP-1 agonist administered is 10% to 20% of the maintenance dose indicated for the treatment of type 2 diabetes in adult patients. In some respects of the methods described herein, the dose of the GLP-1 agonist administered is equal to the dose indicated on its label as the maintenance dose for weight loss in adult patients. In some respects of the methods described herein, the dose of the GLP-1 agonist administered is lower than the dose indicated on its label as the maintenance dose for weight loss in adult patients (i.e., a percentage of the dose indicated on its label as the maintenance dose for weight loss in adult patients).

[0294] In some respects, the dosage of GLP-1 agonists is 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 80% of the indicated maintenance dose for weight loss in adult patients. 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%.

[0295] In some aspects, the dosage of the GLP-1 agonist is 10% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dosage of the GLP-1 agonist is 20% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dosage of the GLP-1 agonist is 30% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dosage of the GLP-1 agonist is 40% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dosage of the GLP-1 agonist is 50% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dosage of the GLP-1 agonist is 60% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dosage of the GLP-1 agonist is 70% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 80% to 90% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 10% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 20% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 30% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 40% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 50% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 60% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 70% to 80% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 10% to 70% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 20% to 70% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 30% to 70% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 40% to 70% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 50% to 70% of the indicated maintenance dose for weight loss in adult patients.In some aspects, the dose of the GLP-1 agonist is 60% to 70% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 10% to 60% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 20% to 60% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 30% to 60% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 40% to 60% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 50% to 60% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 10% to 50% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 20% to 50% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 30% to 50% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 40% to 50% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 10% to 40% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 20% to 40% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 30% to 40% of the indicated maintenance dose for weight loss in adult patients. In some aspects, the dose of the GLP-1 agonist is 10% to 30% of the indicated maintenance dose for weight loss in adult patients. In some respects, the dose of the GLP-1 agonist is 20% to 30% of the indicated maintenance dose for weight loss in adult patients. In other respects, the dose of the GLP-1 agonist is 10% to 20% of the indicated maintenance dose for weight loss in adult patients.

[0296] As part of the methods described herein, GLP-1 agonists may be administered at various frequencies. In some respects, GLP-1 agonists are administered at the frequency indicated on their label for the treatment of one of their approved indications. In some respects, GLP-1 agonists are administered at the frequency indicated on their label as a maintenance regimen for the treatment of type 2 diabetes in adult patients. In some respects, GLP-1 agonists are administered at the frequency indicated on their label as a maintenance regimen for weight loss in adult patients. In some respects, GLP-1 agonists are administered daily (e.g., once or twice daily) or intermittently (e.g., every other day, according to a men / women / fever schedule, weekly, bi-weekly, monthly, bi-monthly, etc.).

[0297] Its efficacy in metabolic disorders

[0298] In all respects, the compounds disclosed herein can be used to treat metabolic diseases. FASN has been shown to be involved in the regulation of glucose, lipid, and cholesterol metabolism. Mice with liver-specific FASN inactivation exhibit normal physiological function unless fed a zero-fat diet, in which case the mice develop hypoglycemia and fatty liver, both of which can be reversed by dietary fat (Chakravarthy, MV et al. (2005) Cell Metabolism 1:309-322). Db / + mice fed a high-fructose diet showed reduced hepatic triglyceride levels and improved insulin sensitivity after 28 days of treatment with the FASN covalent inhibitor platensimycin (Wu, M. et al. (2011) PNAS 108(13):5378-5383). Environmental glucose levels were also reduced in db / db mice after treatment with platensimycin. These results provide evidence that inhibition of FASN can produce therapeutic benefits in animal models of diabetes and related metabolic disorders. Therefore, the disclosed FASN inhibitors can be used to treat conditions characterized by these systemic disorders. Examples include (but are not limited to) fatty degeneration and diabetes.

[0299] Nonalcoholic steatohepatitis / metabolic dysfunction-associated fatty liver disease (NAFLD / MAFLD) is a condition in which the liver contains more than 5% fat and is not caused by alcohol consumption. This disease currently affects approximately 20-30% of the general population in the United States and the Western world and is associated with a significantly increased risk of cardiovascular disease, chronic kidney disease, and malignancies extending beyond the liver. Obesity and metabolic syndrome are two key risk factors for NAFLD / MAFLD, characterized by an imbalance between energy utilization and storage. This imbalance leads to dysregulation of metabolic pathways and inflammatory responses, driving further changes that result in liver damage and comorbidities. As metabolic syndrome progresses, NAFLD / MAFLD leads to more advanced liver disease, beginning with nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH) and can then progress to major liver diseases, including cirrhosis and hepatocellular carcinoma.

[0300] In subjects with metabolic syndrome and NAFLD / MAFLD, fatty acid synthesis in the liver (a pathway known as de novo lipogenesis (DNL)) is increased. The DNL pathway not only produces fatty acids that increase hepatic triglyceride storage, but also produces saturated fatty acids, primarily palmitate (C16:0), which facilitate signaling events that increase liver inflammation. Free palmitate fatty acids are also involved in liver inflammatory processes, such as macrophage recruitment and activation of endoplasmic reticulum stress responses.

[0301] In various implementation schemes, the combination of FASN inhibitors and GLP-1 agonists can act preventively to prevent the progression of NASH / MASH symptoms, such as elevated AST and ALT, elevated levels of hepatic triglycerides and cholesterol, hepatic steatosis, liver inflammation, hepatocyte (hepatocyte) swelling, liver fibrosis, and NAFLD / MAFLD activity scores.

[0302] Furthermore, the combination of a FASN inhibitor and a GLP-1 agonist can reverse the symptoms of NASH / MASH in a confirmed NASH / MASH disease model. For example, Example 1 demonstrated that in mice diagnosed with NASH / MASH after 44 weeks on a high-fat, fructose, and cholesterol diet, the combination of a FASN inhibitor and a GLP-1 agonist reduced levels of AST, ALT, hepatic triglycerides, and cholesterol, as well as symptoms such as hepatic steatosis, liver inflammation, hepatocyte (hepatocyte) swelling, liver fibrosis, and NAFLD / MAFLD activity scores. In Example 1, NASH / MASH disease progression had progressed to a stage showing fibrosis before the mice were administered the drug combination. Data showed a response to all major indicators of disease progression.

[0303] Therefore, in various aspects, this disclosure provides methods for treating NASH / MASH or NASH / MASH symptoms in a subject, the methods comprising administering to a subject requiring such treatment an effective amount of a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) and a GLP-1 agonist. In other aspects, the FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) can be used to manufacture an agent for treating NASH / MASH or NASH / MASH symptoms, said agent being configured for administration in combination with a GLP-1 agonist. In other aspects, the combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) and a GLP-1 agonist can be used to treat NASH / MASH or NASH / MASH symptoms. In some implementations, subjects are diagnosed with NASH / MASH, and treatment with a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) and a GLP-1 agonist can reduce 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 implementations, prophylactic treatment is used to prevent the onset of nonalcoholic steatohepatitis / metabolic dysfunction-related fatty liver disease (NAFLD / MAFLD), the onset of NASH / MASH, the progression of NAFLD / MAFLD to NASH / MASH, or to halt the progression of NASH / MASH disease. Regardless of whether prophylactic treatment is used or NAFLD / MAFLD or NASH / MASH disease is diagnosed, treatment of fatty liver disease / steatohepatitis reduces risk factors associated with diagnosed or progressed diabetes, liver cancer, cardiovascular disease, hypertriglyceridemia, kidney disease, and metabolic syndrome.

[0304] Therefore, in some embodiments, this disclosure provides a method for treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), the method comprising administering to a subject in need a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) and a GLP-1 agonist, wherein the method comprises improving or reversing at least one symptom of a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH). In some embodiments, the method comprises preventing the progression of at least one symptom of nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH). In some embodiments, the symptom is selected from elevated AST levels; elevated ALT levels; elevated hepatic triglyceride levels; elevated cholesterol levels; hepatic steatosis; hepatic inflammation; hepatocyte (hepatocyte) swelling; hepatic fibrosis; and NAFLD / MAFLD activity score.

[0305] Furthermore, as stated in Example 1, it has been found that the combination of a FASN inhibitor (e.g., a compound of formula (I)) with a GLP-1 agonist reduces the expression of fibrosis genes in human hepatocytes. Therefore, in some embodiments, the combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) with a GLP-1 agonist 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 recover upon withdrawal of the compound. Therefore, it is not desirable to be bound by theory, and the downregulation of fibrosis genes is not a toxic effect of the FASN inhibitor.

[0306] Therefore, in various aspects, this disclosure provides a method for reducing the expression of fibrosis genes in a subject (e.g., liver cells of a subject), said method comprising administering to a subject requiring such treatment an effective amount of a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) and a GLP-1 agonist. In other aspects, the FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) can be used to manufacture an agent for reducing the expression of fibrosis genes (e.g., in liver cells), said agent being configured for administration in conjunction with a GLP-1 agonist. In other aspects, the combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664) and a GLP-1 agonist can be used to reduce the expression of fibrosis genes (e.g., in liver cells).

[0307] Cardiovascular disease is closely associated with the progression of metabolic syndrome. However, NAFLD / MAFLD is also a strong predictor of cardiovascular disease, such as an increased risk of carotid atherosclerotic plaques and endothelial dysfunction, which is not associated with the presence of metabolic syndrome (Francis WB et al., “De novo lipogenesis in the liver inhealth and disease: more than just a shunting yard for glucose.” Biol. Rev. (2016), 91, pp. 452-468). NAFLD / MAFLD is also considered an independent factor contributing to the development of type 2 diabetes. Individuals with NAFLD / MAFLD have a 2.6-fold higher incidence of prediabetes or type 2 diabetes, suggesting 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 nonalcoholic fatty liver disease and impaired fasting glucose on the development of type 2 diabetes.” Diabetes Care, 2011, 34, 727-729). Therefore, DNL is an important avenue for therapeutic intervention to reduce the consequences associated with metabolic syndrome and NAFLD / MAFLD (Bae, JC, Diabetes Care, 2011, 727-729).

[0308] NAFLD / MAFLD and NASH / MASH are associated with obesity and diabetes in humans on high-fat and high-calorie diets. In subjects with metabolic syndrome and NAFLD / MAFLD, fatty acid synthesis in the liver (i.e., via the hepatic de novo lipogenesis (DNL) pathway) is increased. One of the key enzymes in DNL is fatty acid synthase (FASN). Despite the promising association between FASN, DNL, ​​and NAFLD / MAFLD, there is very little evidence that direct inhibition of FASN is a competent mechanism for treating NAFLD / MAFLD or controlling the progression of hepatic steatosis. Some literature reports of direct intervention in FASN through gene knockout or small molecule inhibitors have yielded results suggesting worsening of hepatic steatosis; this is the exact opposite of the effect required for treating NAFLD / MAFLD or NASH / MASH. These results teach that FASN inhibition is not expected to reduce hepatic steatosis, nor is it a suitable mechanism for controlling underlying metabolic disorders or inflammatory signaling that drive the progression of fatty liver disease / steatohepatic liver disease.

[0309] For example, liver-specific FASN knockout mice have been shown to have normal livers when maintained on a standard diet. Unexpectedly, when fed a zero-fat / high-carbohydrate diet, the mice developed fatty liver (hepatic steatosis) and hypoglycemia, indicating that complete inhibition of FASN in the liver of mammals on a fat-restricted diet leads to NAFLD / MAFLD, a precursor form of NASH / MASH (Chakravarthy, MV et al., “New hepatic fat activates PPAR alphato maintain glucose, lipid, and cholesterol homeostasis”, Cell Metabol. 1(5), 2005, 309-322). When the knockout mice were fed a normal diet, no effect on metabolism or hepatic steatosis caused by the complete inhibition of FASN by knockout was observed, suggesting that FASN inhibition in the liver has no effect on mammals on a fat-containing diet, or will induce a fatty liver state (leading to NAFLD / MAFLD and NASH / MASH) in mammals on a low-fat / high-carbohydrate diet, which provides the opposite effect required to treat NASH / MASH.

[0310] Small molecule inhibitors of FASN have been used to evaluate insulin resistance and hepatic steatosis. In a recent study on obese, insulin-resistant Zucker rats (a type 2 diabetes model), 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). It has also been shown that FASN inhibitors inhibit hepatic de novo lipogenesis but lead to hepatic steatosis or increased fat deposition in the liver (“A Novel FattyAcid 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 Meeting, June 6-10, 2008, San Francisco, CA, Poster 58LB; WO2008059214). These studies show that direct inhibition of FASN reduces fat synthesis in the liver, but leads to an accelerated development of NAFLD / MAFLD and NASH / MASH in obese diabetic mammals. Therefore, FASN inhibition is not expected to have a therapeutic effect on fatty liver disease / steatohepatopathy in obese and diabetic individuals at the highest risk of developing NAFLD / MAFLD and NASH / MASH.

[0311] The combination of the FASN inhibitor and GLP-1 agonist described in this application can be used to treat various aspects of metabolic syndrome, including non-alcoholic liver disease (NAFLD / MAFLD) and more advanced non-alcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH). Without treatment, these liver dysfunction states can progress to major liver diseases, including cirrhosis, a condition in which the liver exhibits steatosis, inflammation, fibrosis, steatohepatitis, and can progress to hepatocellular carcinoma (HCC). Cirrhosis can have direct health consequences due to liver dysfunction, including spider angiomas or spider nevi, palmar erythema, gynecomastia, hypogonadism, ascites, hepatic foul odor, jaundice, portal hypertension leading to splenomegaly, esophageal varices, caput medusa, hepatic encephalopathy, and acute kidney injury (particularly hepatorenal syndrome). In some embodiments, the combination of the FASN inhibitor and GLP-1 agonist disclosed herein may be used to treat metabolic syndrome, non-alcoholic liver disease (NAFLD / MAFLD), non-alcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis (NASH / MASH), cirrhosis, liver fibrosis, and / or hepatocellular carcinoma.

[0312] In another embodiment, this disclosure relates to a method of treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis nonalcoholic fatty acid disease (NAFLD / MAFLD) using a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664, or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0313] In various aspects, the combination of a FASN inhibitor (e.g., a compound of formula (I), such as denosumatine or TVB-3664, or a pharmaceutically acceptable salt thereof) with a GLP-1 agonist can be used to treat metabolic syndrome. In one embodiment, this disclosure relates to a method of treating metabolic syndrome using a combination of a FASN inhibitor (e.g., a compound of formula (I), such as denosumatine or TVB-3664, or a pharmaceutically acceptable salt thereof) with a GLP-1 agonist.

[0314] In various aspects, combinations of FASN inhibitors (e.g., compounds of formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with GLP-1 agonists can be used to treat liver fibrosis. In one embodiment, this disclosure relates to a method of treating liver fibrosis using a combination of FASN inhibitors (e.g., compounds of formula (I), such as dinistat or TVB-3664, or pharmaceutically acceptable salts thereof) with GLP-1 agonists.

[0315] In some embodiments, the disclosed FASN inhibitors (i.e., compounds of formula (I), such as denosinetamine or TVB-3664) and GLP-1 agonists may also be combined with one or more antifibrotic agents for the treatment of conditions associated with fatty liver or metabolic syndrome. Such antifibrotic agents include (but are not limited to) (1) inhibitors of CC chemokine receptors or dual inhibitors of the type 2 CC chemokine receptor (CCR2) and type 5 CC chemokine receptor (CCR5) pathways, such as cenivirocin; (2) galactolectin antagonists or galactolectin-3 antagonists, such as GR-MD-02; (3) angiotensin receptor blockers (ARBs) that disrupt the renin-angiotensin system, such as losartan; (4) lysyl oxidase-like 2 (LOXL2) inhibitors, such as sutuzumab; and (5) fibrosis mediators, such as vitamin A, vitamin C, and vitamin D.

[0316] Treatment

[0317] In some respects, the embodiments provided herein relate to a method of treating a subject with fatty liver disease / steatohepatitis, the method comprising administering to the subject a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664, or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0318] In some respects, the embodiments provided herein relate to a method for treating nonalcoholic steatohepatitis / metabolic dysfunction-associated steatohepatitis nonalcoholic fatty acid disease (NAFLD / MAFLD) in a subject of need, the method comprising administering to the subject a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664, or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0319] In some respects, 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 (e.g., a compound of formula (I), such as dinistat or TVB-3664, or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0320] In some respects, 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 (e.g., a compound of formula (I), such as dinistat or TVB-3664, or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0321] In some respects, the embodiments provided herein relate to a method for treating liver fibrosis in a subject in need, the method comprising administering to the subject a combination of a FASN inhibitor (e.g., a compound of formula (I), such as dinistat or TVB-3664, or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0322] In some respects, the embodiments provided herein relate to a method of treating a subject with liver cancer (e.g., hepatocellular carcinoma) in need, the method comprising administering to the subject a combination of a FASN inhibitor (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a GLP-1 agonist.

[0323] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein:

[0324] Equation (I) is:

[0325] ;

[0326] in:

[0327] L-Ar is or ;

[0328] R 1 The following are possible values: H, -CN, halogen, C1-C4 straight-chain or branched alkyl, -O- (C3-C5 cycloalkyl), -O- (C1-C4 straight-chain or branched alkyl), wherein:

[0329] C3-C5 cycloalkyl groups optionally include oxygen or nitrogen heteroatoms; and

[0330] When R 1 When it is not H, -CN or a halogen, it may be optionally replaced by one, two or three halogens;

[0331] Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl;

[0332] R 3 It can be H, -OH or halogen;

[0333] R 21 H, halogen, C1-C4 straight-chain or branched alkyl, C3-C5 cycloalkyl, wherein the C3-C5 cycloalkyl optionally includes oxygen or nitrogen heteroatoms;

[0334] R 22 It is H, halogen, or C1-C2 alkyl;

[0335] R 24 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein

[0336] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0337] t is 0 or 1;

[0338] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms;

[0339] L 1 For CR 23 Or N;

[0340] R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein:

[0341] The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens;

[0342] v is 0 or 1;

[0343] The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

[0344] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein L-Ar is .

[0345] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein L-Ar is .

[0346] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R24 It is a C1-C4 straight-chain or branched alkyl group, optionally substituted with one, two, or three halogens. In some embodiments of the methods provided herein (e.g., those described above (or below)), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 24 For -Me or -CF3. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 24 For -Me. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 24 It is -CF3.

[0347] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein 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; -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. In some embodiments of the methods provided herein (e.g., those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is a C1-C4 straight-chain or branched alkyl group or a C3-C5 cycloalkyl group. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is Me or cyclobutyl. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is cyclobutyl. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 For -Me.

[0348] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 3 It is H or halogen. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 3 For H.

[0349] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 1 It is a halogen, -CN, or C1-C2 haloalkyl group. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 1 For CN.

[0350] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein L 1 For N. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein L 1 For CR 23 .

[0351] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 22 It is a C1-C2 alkyl group. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 22 For Me.

[0352] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is a C1-C2 alkyl or C3-C5 cycloalkyl, and R 22 It is a C1-C2 alkyl group. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is -Me or cyclobutyl, and R 22 For -Me.

[0353] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is a C3-C5 cycloalkyl group, and R 22 It is a C1-C2 alkyl group. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is cyclobutyl, and R 22 For Me.

[0354] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 It is a C1-C2 alkyl group, and R 22 It is a C1-C2 alkyl group. In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 21 For -Me, and R 22 For -Me.

[0355] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 23 -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), where v is 0 or 1. In some aspects, v is 1. In some embodiments of the methods provided herein (e.g., those set forth above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 23 It is CH2-O-CH3.

[0356] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 1 For -CN, each R 2 For H, R 3 For H or F, R 21 It is a C1-C4 straight-chain or branched alkyl or a C3-C4 cycloalkyl, R 22 For methyl, R 24 It is a C1-C4 straight-chain or branched alkyl group, which is optionally substituted with one, two or three halogens, L 1 For N or CR 23 R 23 It is a methoxymethyl group.

[0357] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein R 1 For -CN, each R 2 For H, R 3 For H, R 21 It is a C1-C4 straight-chain or branched alkyl or a C3-C4 cycloalkyl, R 22 For methyl, R 24 It is a C1-C4 straight-chain or branched alkyl group, which is optionally substituted with one, two or three halogens, L 1For N or CR 23 R 23 It is a methoxymethyl group.

[0358] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is a compound of formula (I), wherein the compound has a structure selected from the group consisting of:

[0359] (Denista) and (TVB-3664)

[0360] In some embodiments of the methods provided herein (such as those described above (or below), the fatty acid synthase inhibitor is dinistat or a pharmaceutically acceptable salt thereof, including all possible tautomers of dinistat.

[0361] In some embodiments of the methods provided herein (e.g., those described above (or below), the fatty acid synthase inhibitor is TVB-3664 or a pharmaceutically acceptable salt thereof. Reducing the activity of fatty acid synthesis pathways (e.g., FASN gene expression or FASN protein activity) is also referred to as “inhibiting” fatty acid synthesis pathways (e.g., FASN gene expression or FASN protein activity). The term “inhibit” and its grammatical variations (e.g., “inhibitory”) do not require complete inhibition, but refer to a reduction in fatty acid synthesis activity (e.g., FASN gene expression or FASN protein activity). On the other hand, 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 the 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. In addition, the phrase “basically not inhibited” and its grammatical inflection form refer to situations where enzyme activity is reduced by less than 30%, less than 20%, and in some respects less than 10% in the presence of an agent.

[0362] Increasing the activity of fatty acid synthesis pathways (e.g., FASN gene expression or FASN protein activity) is also referred to as “activating” fatty acid synthesis pathways (e.g., FASN gene expression or FASN protein activity). The term “activated” and its grammatical variations (e.g., “activating”) do not require complete activation, but refer to an increase in the activity of fatty acid synthesis pathways (e.g., FASN gene expression or FASN protein activity). On the other hand, in the absence of an activating effect, such an increase is at least 50%, at least 75%, at least 90%, and may be at least 95% of the enzyme activity in the absence of an activating agent. 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 activating agent. Furthermore, the phrase “substantially inactive” and its grammatical variations refer to an increase in enzyme activity of less than 30%, less than 20%, and on the other hand, less than 10% in the presence of an activating agent.

[0363] The ability to reduce enzyme activity is a measure of the potency or activity of an agent or combination of agents against or against an enzyme. Potency can be measured in terms of IC50, K+, etc., by cell-free, whole-cell, and / or in vivo assays. i The IC50 value is measured using the IC50 value. The IC50 value represents the concentration of the agent required to inhibit enzyme activity by half (50%) under a given set of conditions. i The value represents the equilibrium affinity constant for the binding of the inhibitor to the enzyme. The ED50 value represents the dose of agent required to achieve the half-maximal reaction in a bioassay. Further details of these measurements will be appreciated by those skilled in the art and can be found in standard textbooks on biochemistry, enzymology, etc.

[0364] This article also provides kits for the treatment of diseases associated with fat accumulation in the liver (fatty liver disease / steatohepatitis). These kits contain an agent or combination of agents that inhibit fatty acid synthesis pathways (e.g., FASN gene expression or FASN protein activity), and optionally instructions for use of the kit according to the various methods and pathways described herein. Such kits may also include information indicating or establishing the activity and / or benefits of the agent, such as scientific literature references, packaging inserts, clinical trial results, and / or summaries of these. This information may be based on the results of various studies, such as studies using laboratory animals involving in vivo models and studies based on human clinical trials. The kits described herein are available, sold, and / or marketed to healthcare providers, including physicians, nurses, pharmacists, and formaly officials.

[0365] Formulation, route of administration and effective dosage

[0366] In some embodiments, embodiments are provided relating to formulations, routes of administration, and effective doses of pharmaceutical compositions comprising agents or combinations thereof as provided herein. Such pharmaceutical compositions may be used in the methods provided herein.

[0367] The compounds and compositions described herein are applicable as pharmaceutical preparations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal patch, pulmonary, vaginal, suppository, or parenteral (including intramuscular, intra-arterial, intrathecal, intradermal, intraperitoneal, subcutaneous, and intravenous) administration, or in forms suitable for aerosolization, inhalation, or inhalation. 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)).

[0368] In various aspects, pharmaceutical compositions include carriers and excipients (including, but not limited to, buffers, carbohydrates, mannitol, proteins, peptides or amino acids (e.g., glycine), antioxidants, antibacterial agents, chelating agents, suspending agents, thickeners and / or preservatives), water, oils (including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.), saline solutions, dextran and glycerol solutions, flavoring agents, coloring agents, anti-sticking agents and other acceptable additives, adjuvants or binders, and other pharmaceutically acceptable excipients required to approximate physiological conditions, such as pH buffers, tension regulators, emulsifiers, wetting agents, 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 another aspect, pharmaceutical preparations may contain at least one preservative. For general methods regarding drug dosage forms, see Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It should be understood that while any suitable carrier known to those skilled in the art may be used to administer the compositions and compounds provided herein, the type of carrier will vary depending on the mode of administration.

[0369] Compounds can also be encapsulated in liposomes using well-known techniques. Biodegradable microspheres can also be used as carriers for pharmaceutical compositions as provided herein. 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.

[0370] The compound can be administered in liposomes or microspheres (or particles). Methods for preparing liposomes and microspheres for administration to patients 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, with the addition of appropriate phospholipids and lipids, as well as surfactants (if necessary), and the material is dialyzed or sonicated if necessary. G. Gregoriadis, Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp. 2, Supplement 87-341 (Academic Press, 1979), provides a review of known methods.

[0371] Microspheres formed from polymers or proteins are well known to those skilled in the art and can be adapted to pass through the gastrointestinal tract and enter the bloodstream directly. Alternatively, compounds can be incorporated and implanted into microspheres or microsphere complexes for slow release over a period ranging from days to months. See, for example, U.S. Patents 4,906,474, 4,925,673, and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contents of which are hereby incorporated by reference.

[0372] As is well known in the art, the concentration of the drug, the pH of the buffer solution, and the isotonicity can be adjusted to make it compatible with intravenous injection.

[0373] The compounds described herein can be formulated as sterile solutions or suspensions in suitable media, as is well known in the art. Pharmaceutical compositions can be sterilized using conventional, well-known sterilization techniques, or by sterile filtration. The resulting aqueous solutions can be packaged as is for use, or lyophilized, with the lyophilized formulation combined with the sterile solution prior to administration. Suitable formulations and additional carriers are described in Remington's "The Science and Practice of Pharmacy" (20th edition, Lippincott Williams & Wilkins, Baltimore MD), the teachings of which are incorporated herein by reference in their entirety.

[0374] In some respects, each of the agents described herein (e.g., FASN inhibitors of formula (I), such as dinistat or TVB-3664 or their pharmaceutically acceptable salts, GLP-1 agonists) may be provided alone or in combination with one or more other agents. In some aspects, the FASN inhibitor and one or more GLP-1 agonists are provided as a fixed-dose combination (i.e., a combination comprising a fixed dose of the FASN inhibitor and a fixed dose of one or more GLP-1 agonists, formulated together in the same dosage unit, for example, in a cream, suppository, tablet, capsule, aerosol spray, solution for parenteral administration, or powder packet to be dissolved in a beverage or carrier medium for parenteral administration). In some aspects, the FASN inhibitor and one or more GLP-1 agonists are provided as separate dosage units (e.g., two creams, two suppositories, two tablets, two solutions or suspensions for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration), two powder packets to be dissolved in a beverage or carrier medium for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration, one tablet, and one for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration. A solution or suspension, a tablet, and a powder packet to be dissolved in a beverage or carrier medium for parenteral (e.g., intramuscular, intravenous, subcutaneous) administration, wherein the two dosing units may be administered simultaneously or separately. In some respects, the dosing units are administered simultaneously. In some respects, the dosing units are administered sequentially. In some respects, the dosing units are administered according to the same dosing schedule. In some respects, the dosing units are administered according to different dosing schedules (e.g., FASN inhibitors may be administered on a daily dosing schedule, and GLP-1 agonists may be administered on a weekly dosing schedule). The term “pharmaceuticalally acceptable salt” means those salts that retain the bioavailability and properties of the agents used as provided herein and are not biologically or otherwise undesirable. For example, pharmaceutically acceptable salts will not interfere with the beneficial effects of agents as provided herein, such as inhibition of fatty acid synthesis pathways, such as inhibition of FASN gene expression or FASN protein activity.

[0375] Typical salts are those containing inorganic ions, such as sodium, potassium, calcium, and magnesium ions. These salts include those with inorganic or organic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid, or maleic acid). Additionally, if the agent contains a carboxyl group or other acidic group, it can be converted into a pharmaceutically acceptable addition salt with an inorganic or organic base. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, and triethanolamine.

[0376] Pharmaceutically acceptable esters or amides are those that retain the bioavailability and properties of the agents provided herein and are not biologically or otherwise undesirable. For example, said esters or amides do not interfere with the beneficial effects of agents such as those provided herein, such as inhibition of fatty acid synthesis pathways, such as inhibition of FASN gene expression or FASN protein activity. Typical esters include ethyl, methyl, isobutyl, ethylene glycol, etc. Typical amides include unsubstituted amides, alkylamides, dialkylamides, etc.

[0377] On the other hand, the agent may be administered in combination with one or more other compounds, forms, and / or agents, such as those described above. Pharmaceutical compositions comprising a combination of a fatty acid synthesis pathway inhibitor (e.g., an inhibitor of FASN gene expression or FASN protein activity) and one or more other active agents may be formulated to contain certain molar ratios. For example, a molar ratio of about 99:1 to about 1:99 of the fatty acid synthesis pathway inhibitor (e.g., an inhibitor of FASN gene expression or FASN protein activity) to other active agents may be used. In some subsets of this aspect, the molar ratio of the fatty acid synthesis pathway inhibitor (e.g., an inhibitor of FASN gene expression or FASN protein activity): other active agent ranges from about 80:20 to about 20:80; about 75:25 to about 25:75; about 70:30 to about 30:70; about 66:33 to about 33:66; about 60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. Inhibitors of fatty acid synthesis pathways (e.g., inhibitors of FASN gene expression or FASN protein activity): The molar ratio of other active agents may be approximately 1:9, and in another respect, approximately 1:1. The two agents, forms, and / or compounds may be formulated together in the same dosage unit, for example, in a cream, suppository, tablet, capsule, or powder packet to be dissolved in a beverage; or each agent, form, and / or compound may be formulated in a separate unit, for example, two creams, suppositories, tablets, two capsules, tablets and a liquid for dissolving the tablets, an aerosol spray, a powder packet and a liquid for dissolving the powder, etc.

[0378] When necessary or required, the agent and / or combination of agents may be administered together with other agents. The selection of agents that may be co-administered with the agents and / or combinations of agents as provided herein may depend at least in part on the disease being treated. As provided herein, these may be GLP-regulating compounds, some of which are described herein. In some respects, the FASN inhibitors and GLP-1 compounds of this disclosure may be administered in combination with known cancer therapeutic agents, for example as part of a method for treating liver cancer (e.g., hepatocellular carcinoma). For example, the compounds may be administered in combination with: paclitaxel (available at Taxol, Bristol-Myers Squibb), doxorubicin (also known under the trade name Adriamycin), vincristine (known under the trade names Oncovin, Vincasar PES, and Vincrex), and actinomycin D. D) Hexamethylmelamine, asparaginase, bleomycin, busulphan, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin The list includes cin), ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine, steroids, streptozocin, taxotere, tamozolomide, thioguanine, thiotepa, tomudex, topotecan, treosulfan, UFT (urea-tegafur), vinblastine, and vindesine, among others.

[0379] Pharmaceutical agents (or their pharmaceutically acceptable salts, esters, or amides) may be administered alone or as pharmaceutical compositions in which the active agent is blended or mixed with one or more pharmaceutically acceptable carriers. Pharmaceutical compositions as used herein may be any composition prepared for administration to a subject. Pharmaceutical compositions used according to the methods provided herein or other compounds may be formulated in a conventional manner using one or more physiologically acceptable carriers (containing excipients, diluents, and / or adjuvants, such as those that facilitate the formulation of the active agent into an administerable formulation). Appropriate formulations may depend at least in part on the chosen route of administration. Pharmaceutical agents (compounds) as provided herein, or their pharmaceutically acceptable salts, esters, or amides, may be delivered to patients via a variety of routes or modalities of administration, including oral, buccal, topical, rectal, transdermal, transmucosal, subcutaneous, intravenous, and intramuscular administration, as well as inhalation. In some embodiments, the route of administration is oral.

[0380] For oral administration, pharmaceutical preparations can be readily formulated by combining the active agent with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the formulation of the preparation as tablets (including chewable tablets), pills, sugar-coated pills, capsules, sugar tablets, hard candies, liquids, gels, syrups, liquids, powders, suspensions, elixirs, rice paper capsules, etc., for oral ingestion by a patient to be treated. Such preparations may contain pharmaceutically acceptable carriers, including solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents. Solid carriers may be one or more substances and may also be used as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulating materials. In powders, the carrier is typically a finely powdered solid, a mixture with the finely powdered active ingredient. In tablets, the active ingredient is typically mixed with a carrier having the necessary binding capacity in a suitable proportion and compressed into the desired shape and size. Powders and tablets preferably contain about one (1)% to about seventy (70)% of the active compound. Suitable carriers include (but are not limited to) magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, cocoa butter, etc. In some embodiments, the pharmaceutical agent will be included at concentration levels ranging from about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80%, or about 90% of the total composition of the oral dosage form, in an amount sufficient to provide the desired dose unit.

[0381] Aqueous suspensions intended for oral use may contain pharmaceutical agents and pharmaceutically acceptable excipients as described herein, such as suspending agents (e.g., methylcellulose), wetting agents (e.g., lecithin, lysophosphatidylcholine, and / or long-chain fatty alcohols), as well as coloring agents, preservatives, flavoring agents, etc.

[0382] On the other hand, due to the presence, for example, a large lipophilic portion, oil or non-aqueous solvents may be required to carry the agent into the solution. Alternatively, emulsions, suspensions, or other formulations, such as liposome formulations, may be used. Regarding liposome formulations, any known method for preparing liposomes for treating diseases may be used. For example, see Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), which are incorporated herein by reference. Ligands may also be attached to liposomes to direct these compositions to specific sites of action. Agents as described herein may also be incorporated into foods, such as cheese, butter, salad dressings, or ice cream, to facilitate dissolution, administration, and / or compliance in certain patient populations.

[0383] Pharmaceutical formulations for oral use can be obtained as solid excipients, optionally by grinding the resulting mixture and then processing the granular mixture after adding suitable adjuvants (if necessary) to obtain a tablet or sugar-coated tablet core. Suitable excipients are particularly fillers, such as sugars including lactose, sucrose, mannitol, or sorbitol; flavoring elements; cellulose formulations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). Disintegrants, such as croscarmellose, agar, or alginate or its salts such as sodium alginate, may be added if necessary. The formulation can also be formulated as a sustained-release formulation.

[0384] The core of the sugar-coated tablet may have a suitable coating. For this purpose, a concentrated sugar solution may be used, optionally containing gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, varnish solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the coating of the tablet or sugar-coated tablet for the identification or characterization of different combinations of active agents.

[0385] Orally administered pharmaceutical formulations include pushfit capsules made from gelatin and soft-sealable capsules made from gelatin and plasticizers (such as glycerin or sorbitol). Pushfit capsules may contain an active ingredient blended with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate) and optionally a stabilizer. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. The dosage of all formulations intended for oral administration should be appropriate for the administration.

[0386] Other forms suitable for oral administration include liquid formulations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid formulations intended to be converted into a liquid form just before use. Emulsions can be prepared in solution, such as in an aqueous solution of propylene glycol, or may contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavoring agents, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing a finely powdered active ingredient in water containing a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents. Suitable fillers or carriers that can be applied with the composition include agar, alcohols, fats, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrrolidone, silica, sterile saline, etc., or mixtures thereof used in suitable amounts. Solid formulations include solutions, suspensions, and emulsions, and may contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc., in addition to the active ingredient.

[0387] Syrups or suspensions can be prepared by adding an active compound to a concentrated aqueous solution of sugar (e.g., sucrose), or by adding any auxiliary ingredients. Such auxiliary ingredients may include flavoring agents, agents that delay sugar crystallization, or agents that increase the solubility of any other ingredient, such as polyols, like glycerol or sorbitol.

[0388] When formulating compounds for oral administration as provided herein, it is desirable to utilize gastric retention formulations to enhance absorption in the gastrointestinal (GI) tract. Formulations retained in the stomach for several hours can slowly release one or more compounds and provide sustained release that can be used in methods as provided herein. For disclosures on such gastroretentive formulations, see Klausner, EA; Lavy, E.; Barta, M.; Cserepes, E.; Friedman, M.; D.;Lavy, E.; Eyal, S. Klausner, E.; Friedman, M. 2004 “Pharmacokinetic and pharmacodynamic aspects of gastroretentive dosage forms” Int. J. Pharm. 11,141-53, Streubel, A.; Drug Deliver. 3, 217-3, and Chavanpatil, MD; Jain, P.; Chaudhari, S.; Shear, R.; Vavia, PR, “Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for olfoxacin” Int. J. Pharm. March 24, 2006 (electronic version). Expandable, swellable, and bioadhesive technologies can be used to maximize the absorption of the compounds and compositions presented herein.

[0389] The compounds and compositions provided herein can be formulated for parenteral administration (e.g., by injection, such as concentrated injection or continuous infusion) and can be presented in unit dose form in ampoules, pre-filled syringes, small-volume infusions, or multi-dose containers with added preservatives. The compositions can be in the form of suspensions, solutions, or emulsions, for example, in oily or aqueous media, such as solutions in aqueous polyethylene glycol solutions.

[0390] For injectable formulations, the carrier may be selected from those known to be suitable in the art, including aqueous solutions, oil suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar drug carriers. Formulations may also contain biocompatible, biodegradable polymer compositions, such as poly(lactic acid-co-glycolic acid). These materials can be formed into micro or nanospheres, loaded with the drug, and further coated or derivatized to provide excellent sustained release properties. Carriers suitable for periocular or intraocular injection include, for example, suspensions of therapeutic agents in injection-grade water, liposomes, and carriers suitable for lipophilic substances. Other carriers for periocular or intraocular injection are well known in the art.

[0391] In a preferred aspect, the composition is formulated according to conventional procedures as a modified pharmaceutical composition for intravenous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic buffer solution. If necessary, the composition may also include a solubilizer and a local anesthetic (e.g., lidocaine) to relieve pain at the injection site. Typically, the components are supplied separately or mixed together in unit dosage forms, such as as dried lyophilized powders or anhydrous concentrates in airtight containers (e.g., ampoules or capsules) indicating the amount of active agent. In cases where the composition is to be administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical-grade water or saline. In cases where the composition is to be administered by injection, ampoules containing sterile water or saline for injection can be provided, allowing the components to be mixed prior to administration.

[0392] When administered by injection, the active compound may be formulated in an aqueous solution, specifically in a physiologically compatible buffer such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain formulations such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active compound may be in powder form to be prepared with a suitable medium (e.g., sterile, pyrogen-free water) prior to use. On the other hand, the pharmaceutical composition does not contain adjuvants or any other substances added to enhance the immune response stimulated by the peptide. On the other hand, the pharmaceutical composition contains a substance that inhibits the immune response to said peptide. Formulation methods are known in the art, for example, as disclosed in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton P.

[0393] In addition to the formulations described above, pharmaceutical preparations may also be formulated as long-acting formulations. Such long-acting formulations can be administered via implantation or transdermal delivery (e.g., subcutaneous or intramuscular), intramuscular injection, or the use of transdermal patches. Thus, for example, pharmaceutical preparations may be formulated with suitable polymeric or hydrophobic materials (e.g., as emulsions in acceptable oils) or with ion exchange resins, or as poorly soluble derivatives, such as poorly soluble salts.

[0394] Lubricants that can be used to form pharmaceutical compositions and dosage forms comprising the compounds and compositions provided herein include (but are not limited to) calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Other lubricants include, for example, syloid silica gel, condensed aerosols of synthetic silica, or mixtures thereof. Lubricants may optionally be added in an amount less than about 1% by weight of the pharmaceutical composition.

[0395] In some cases, FASN inhibitors are administered at doses of 10-100 mg. In some cases, FASN inhibitors are administered at doses of 10-90 mg. In some cases, FASN inhibitors are administered at doses of 10-80 mg. In some cases, FASN inhibitors are administered at doses of 10-70 mg. In some cases, FASN inhibitors are administered at doses of 10-60 mg. In some cases, FASN inhibitors are administered at doses of 10-50 mg. In some cases, FASN inhibitors are administered at doses of 10-40 mg. In some cases, FASN inhibitors are administered at doses of 10-30 mg. In some cases, FASN inhibitors are administered at doses of 10-20 mg. In some cases, FASN inhibitors are administered at doses of 20-100 mg. In some cases, FASN inhibitors are administered at doses of 20-90 mg. In some cases, FASN inhibitors are administered at doses of 20-80 mg. In some cases, FASN inhibitors are administered at doses of 20-70 mg. In some cases, FASN inhibitors are administered at a dose of 20-60 mg. In some cases, FASN inhibitors are administered at a dose of 20-50 mg. In some cases, FASN inhibitors are administered at a dose of 20-40 mg. In some cases, FASN inhibitors are administered at a dose of 20-30 mg. In some cases, FASN inhibitors are administered at a dose of 30-100 mg. In some cases, FASN inhibitors are administered at a dose of 30-90 mg. In some cases, FASN inhibitors are administered at a dose of 30-80 mg. In some cases, FASN inhibitors are administered at a dose of 30-70 mg. In some cases, FASN inhibitors are administered at a dose of 30-60 mg. In some cases, FASN inhibitors are administered at a dose of 30-50 mg. In some cases, FASN inhibitors are administered at a dose of 30-40 mg. In some cases, FASN inhibitors are administered at a dose of 40-100 mg. In some cases, FASN inhibitors are administered at a dose of 40-90 mg. In some cases, FASN inhibitors are administered at a dose of 40-80 mg. In some cases, FASN inhibitors are administered at a dose of 40-70 mg. In some cases, FASN inhibitors are administered at a dose of 40-60 mg. In some cases, FASN inhibitors are administered at a dose of 40-50 mg. In some cases, FASN inhibitors are administered at a dose of 50-100 mg. In some cases, FASN inhibitors are administered at a dose of 50-90 mg. In some cases, FASN inhibitors are administered at a dose of 50-80 mg. In some cases, FASN inhibitors are administered at a dose of 50-70 mg. In some cases, FASN inhibitors are administered at a dose of 50-60 mg.In some cases, FASN inhibitors are administered at the following doses: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

[0396] In some cases, FASN inhibitors are administered at the following doses: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.

[0397] In some cases, FASN inhibitors are administered at the following doses: 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.

[0398] In some cases, FASN inhibitors are administered at a dose of 10 mg. In some cases, FASN inhibitors are administered at a dose of 15 mg. In some cases, FASN inhibitors are administered at a dose of 20 mg. In some cases, FASN inhibitors are administered at a dose of 25 mg. In some cases, FASN inhibitors are administered at a dose of 30 mg. In some cases, FASN inhibitors are administered at a dose of 35 mg. In some cases, FASN inhibitors are administered at a dose of 40 mg. In some cases, FASN inhibitors are administered at a dose of 45 mg. In some cases, FASN inhibitors are administered at a dose of 50 mg. In some cases, FASN inhibitors are administered at a dose of 55 mg. In some cases, FASN inhibitors are administered at a dose of 60 mg. In some cases, FASN inhibitors are administered at a dose of 65 mg. In some cases, FASN inhibitors are administered at a dose of 70 mg. In some cases, FASN inhibitors are administered at a dose of 75 mg. In some cases, FASN inhibitors are administered at a dose of 80 mg. In some cases, FASN inhibitors are administered at a dose of 85 mg. In some cases, FASN inhibitors are administered at a dose of 90 mg. In some cases, FASN inhibitors are administered at a dose of 95 mg. In some cases, FASN inhibitors are administered at a dose of 100 mg.

[0399] In some cases, FASN inhibitors are administered once or twice daily. In some cases, FASN inhibitors are administered once daily. In some cases, FASN inhibitors are administered twice daily. In some cases, FASN inhibitors are administered intermittently, such as every two days, every three days, every five days, once a week, once or twice a month, etc. In some cases, FASN inhibitors are administered three times a week. In some cases, FASN inhibitors are administered according to a do-and-stop schedule (e.g., Monday, Wednesday, Friday schedule). In some cases, FASN inhibitors are administered twice a week. In some cases, FASN inhibitors are administered once a week. In some cases, FASN inhibitors are administered orally.

[0400] In some respects, FASN inhibitors and GLP-1 agonists are administered as a fixed-dose combination. In some respects, FASN inhibitors and GLP-1 agonists are administered as a single dose unit. In some respects, FASN inhibitors and GLP-1 agonists are administered simultaneously. In some respects, FASN inhibitors and GLP-1 agonists are administered sequentially. In some respects, FASN inhibitors and GLP-1 agonists are administered according to the same dosing schedule. In some respects, FASN inhibitors and GLP-1 agonists are administered according to different dosing schedules. In another respect, the amount, form, and / or dosage of different agents and / or forms may vary at different times of administration.

[0401] The following examples are illustrative of the compounds, compositions, and methods described herein and are not intended to be limiting. Other suitable modifications and adjustments known to those skilled in the art are within the scope of the following embodiments.

[0402] Example

[0403] Example 1: The combination of FASN inhibitor and GLP-1 agonist in diet-induced obese NASH (DIO-NASH) mice

[0404] This study was designed to evaluate the effects of FASN inhibitors alone and in combination with semaglutide on liver pathology in diet-induced obese (DIO) NASH mice, including NAFLD / MAFLD activity score (NAS) and fibrosis. Body weight, lipid levels, and liver enzymes were also included as endpoints.

[0405] method:

[0406] DIO mice (C57BI / 6J) with histologically confirmed NASH / MASH (hepatic steatosis score = 3, inflammation score ≥ 2, and fibrosis stage = F2 or F3) were randomly assigned to groups and treated for 12 weeks with TVB-3664 (an alternative FASN inhibitor to dinistat, 10 mg / kg, PO, QD) or semaglutide (30 nmol / kg, SC, QD), alone or in combination (Gubra, Denmark). The treatment groups are shown in Table 1.

[0407] Table 1: Treatment Group

[0408]

[0409] The research overview is shown in Figure 1 In the study, mice included in the DIO-NASH model group were fed a GAN diet inducing NASH / MASH for 38 weeks prior to administration. The control group was fed a LEAN CHOW diet. Pre-biopsy and histological analysis were performed four weeks prior to administration. One week prior to administration, mice with a steatosis score of 3, an inflammation score ≥2, and a fibrosis stage (PSR) of F2–F3 were randomized to the balanced intervention group. The same diet was maintained throughout the 12-week administration period. As shown in Table 1, mice were administered the mediator, semaglutide, TVB-3664, or a combination of TVB-3664 and semaglutide for 12 weeks. At the end of the study, plasma samples were collected, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, and total cholesterol were measured. Changes in ALT and AST are shown in Table 1. Figure 6 and Figure 7 Mice were sacrificed, and livers were collected for analysis of end-biochemical (cholesterol and triglycerides) and histological changes. Total liver cholesterol (TC) results are shown in [Figure number missing]. Figure 8A (relative) and Figure 8B (Total) is shown in the results. Triglyceride results are presented in... Figure 9A (relative) and Figure 9B (Total)

[0410] Changes in NAFLD / MAFLD activity score (using hematoxylin and eosin staining) (HE) Figure 2A The image shows the matched pairs of each individual animal before and after treatment, and... Figure 2B The change in score is shown as a percentage change compared to the baseline before treatment.

[0411] The stage of fibrosis was determined by Sirius red (PSR) staining (before and after), and the results are shown in... Figure 3B (Absolutely) in.

[0412] Figure 10AThe study showed the level of steatosis measured by histological quantification of hepatocytes with lipid droplets. Figure 10B The results show changes in the steatosis score before and after treatment. Figure 10C and Figure 10D The figures show the relative and total liver lipids measured by histological quantitative assessment, respectively.

[0413] Inflammation level (Gal-3) (IHC) is shown in Figure 11A In the middle, and the changes in lobular inflammation before and after treatment are shown in Figure 11B middle.

[0414] For example, the level of type I collagen α1 as measured by immunohistochemistry (IHC) is shown in... Figure 4 middle.

[0415] FibroNest analysis (PharmaNest, NJ) was used to evaluate changes in fibrosis. FibroNest is a quantitative imaging analysis (QIA) test for digital pathology designed to detect changes in the degree of fibrosis, steatosis, inflammation, and edema from histopathologically stained sections of liver biopsies. The computational methods used in FibroNest eliminate inter-reader and intra-reader variability. Furthermore, the continuous scoring provided by FibroNest can identify treatment effects within classification grades / stages, allowing for more refined and quantitative analysis of the results. Changes in fibrosis before and after treatment as measured by FibroNest are shown below. Figure 2A middle.

[0416] result:

[0417] Semaglutide, alone or in combination with TVB-3664, significantly reduced body weight. TVB-3664 and the TVB-3664 / semaglutide combination improved plasma ALT and AST, reduced total hepatic triglycerides and cholesterol, and decreased hepatocytes with lipid droplets and galactolectin-3 staining areas. TVB-3664 and semaglutide significantly improved NAS (NAS ≥1 point, 47% and 56%, respectively), with the combination showing further improvement (94%). The TVB-3664 / semaglutide combination reduced total liver area, collagen 1a1 and smooth muscle actin staining, and collagen 1a1 gene expression in Sirius red (PSR). Digital AI algorithm assessment of PSR staining after treatment (FibroNest) showed that, compared with the mediator, TVB-3664 alone and the TVB-3664 / semaglutide combination significantly reduced the overall phenotypic fibrosis score (p<0.05) and the steatosis area ratio (p<0.01).

[0418] in conclusion:

[0419] In the NASH / MASH mouse model, combination therapy with a FASN inhibitor and semaglutide showed further histological improvement in NAS and fibrosis compared to single-dose treatment. These results support future clinical evaluation of the dinistat / GLP-1 combination therapy.

[0420] Example 2: In a clinical trial of 168 NASH patients with F2 or F3 fibrosis, denosumab achieved statistically significant results at week 52 on the primary endpoint and multiple secondary endpoints.

[0421] The Phase 2b FASCINATE-2 clinical trial was a 52-week randomized, double-blind, placebo-controlled trial evaluating the safety and histological effects of dinistat compared to placebo in 168 biopsy-confirmed NASH patients with moderate to severe fibrosis (F2 or F3 stage) and NAS ≥4. Patients were randomized 2:1 to receive 50 mg dinistat or placebo orally once daily. Histological endpoints at the end of the trial were assessed by a central pathologist. AI-based digital pathology was also used to analyze liver biopsies.

[0422] No treatment-related serious adverse events (SAEs) were observed, and most adverse events (AEs) were mild to moderate in nature (Grade 1 and 2). No treatment-related AEs of grade ≥3 were observed. By systemic organ class, the most common treatment-related AEs (observed in ≥5% of patients in the study) were ocular conditions (15.2% with dinistat, 16.1% with placebo), gastrointestinal conditions (11.6% with dinistat, 8.9% with placebo), and skin and subcutaneous tissue conditions (22.3% with dinistat, 7.1% with placebo). The incidence of treatment-interventional adverse events (TEAEs) leading to treatment discontinuation was 19.6% in the dinistat group, compared to 5.4% in the placebo group.

[0423] In this trial, dinistat (an oral selective FASN inhibitor) demonstrated statistically significant improvement over placebo in both primary endpoints of NASH regression: no worsening of fibrosis and a ≥2-point reduction in NAS score, and a ≥2-point reduction in NAS score and no worsening of fibrosis. Patients treated with dinistat also showed statistically significant improvement in fibrosis at ≥1 stage, with no worsening of NASH, and a greater proportion of responders with a ≥30% proton density fat fraction (MRI-PDFF).

[0424] At week 52 of dinistat treatment, the primary endpoint was statistically significant and secondary endpoints improved. Specifically, the primary endpoints achieved were: a) NASH remission without worsening of fibrosis and a ≥2-point reduction in NAS (NAFLD activity score) in 36% of patients treated with dinistat, compared to 13% in placebo (p=0.002); b) a ≥2-point reduction in NAS and no worsening of fibrosis in 52% of patients treated with dinistat, compared to 20% in placebo (p=0.0001). Several secondary endpoints were also met, including: a) ≥1 stage improvement in fibrosis and no worsening of NASH in 41% of patients treated with dinistat, compared to 18% in placebo (p=0.005); b) NASH regression and no worsening of fibrosis in 38% of patients treated with dinistat, compared to 16% in placebo (p=0.002); and ≥30% decrease in MRI-PDFF from baseline in 65% of patients treated with dinistat (responders), compared to 21% in placebo (p<0.0001). Statistically significant improvements were also observed in other biomarkers of liver health, including improvements in fibrosis assessment, FAST score, and ALT based on artificial intelligence (AI) digital pathology, as well as numerical improvements in LDL.

[0425] The results are summarized in the table below.

[0426]

[0427] The modified intention-to-treat (mITT) group includes all patients with paired biopsies.

[0428] * Artificial Intelligence (AI) Digital Pathology Assessing via Second Harmonic Generation (SHG, HistoIndex)

[0429] **MRI-PDFF responders are patients who have a relative reduction of ≥30% in liver fat at the end of treatment.

[0430] ***Baseline LDL-C greater than 100 mg / dL

[0431] These results demonstrate the effective use of denilastine in treating patients with NASH (those with F2 or F3 fibrosis and NAS of at least 4).

[0432] Example 3: A subset of patients using a stable GLP1-receptor agonist (GLP1-RA) at baseline: liver biopsy with dinistat improved NASH regression and fibrosis.

[0433] Patients from the trial described in Example 2 were analyzed to determine the effect (if any) of the combination of GLP-1 RA and dinistat on NASH regression and fibrosis. Liver biopsies were analyzed at week 52 of treatment to compare with pre-treatment levels of dinistat or placebo. Data analyzed were from patients receiving stable GLP-1 therapy at study entry. In patients receiving placebo (without dinistat) and GLP-1 therapy, there was no evidence of NASH regression or improvement in fibrosis. In patients receiving dinistat and GLP-1 therapy, the fibrotic response was statistically significantly improved. Specifically, 42% of patients receiving the combination of GLP-1 therapy and dinistat (n=12) experienced NASH regression and no worsening of fibrosis, compared to 0% in those receiving placebo and GLP-1 therapy (n=4). In addition, liver fibrosis improved by ≥ 1 stage and NASH did not worsen in 42% of patients using the combination of GLP-1 therapy and dinistat (n=12), compared to 0% in those using placebo and GLP-1 therapy (n=4). Figure 12 The diagram below illustrates this data.

[0434] This data demonstrates that the combination of a GLP-1 receptor agonist and dinistat resulted in NASH remission and fibrosis improvement in patients receiving both treatments, and based on this subset of patients in this clinical trial, the combination showed a synergistic effect that was not predictable by these secondary endpoints.

[0435] This specification contains numerous references to patents, patent applications, and publications. Each of these is hereby incorporated by reference for all purposes.

Claims

1. A method for treating fatty liver disease / steatohepatitis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

2. A method for treating liver fibrosis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

3. The method of claim 2, wherein the subject has been diagnosed with fatty liver disease / steatohepatitis.

4. A method for reversing a confirmed nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

5. A method for treating nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

6. A method for reducing fibrosis gene expression in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

7. A method for treating cirrhosis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

8. The method of claim 7, wherein the cirrhosis is a complication of fatty liver disease / steatohepatitis.

9. A method for improving or restoring liver function in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase (FASN) inhibitor and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist.

10. The method of claim 9, wherein the subject has been diagnosed with fatty liver disease.

11. A method of treating a subject with fatty liver disease / steatohepatitis, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

12. A method of treating liver fibrosis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

13. The method of claim 12, wherein the subject has been diagnosed with fatty liver disease / steatohepatitis.

14. A method for reversing a diagnosed nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

15. A method for treating nonalcoholic steatohepatitis / metabolic dysfunction-related steatohepatitis (NASH / MASH) in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

16. A method for reducing fibrosis gene expression in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

17. A method of treating cirrhosis in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

18. The method of claim 17, wherein the cirrhosis is a complication of fatty liver disease / steatohepatitis.

19. A method for restoring or improving liver function in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

20. The method of claim 19, wherein the patient has been diagnosed with fatty liver disease / steatohepatitis.

21. The method of any one of claims 1, 3, 8, 10, 11, 13, 18 and 20, wherein the fatty liver disease / steatohepatitis is selected from nonalcoholic steatohepatitis / metabolic dysfunction-associated fatty liver disease (NAFLD / MAFLD) and nonalcoholic steatohepatitis / metabolic dysfunction-associated fatty liver disease (NASH / MASH).

22. The method of any one of claims 1, 3, 8, 10, 11, 13, 18 and 20, wherein the fatty liver disease / steatohepatitis is nonalcoholic steatohepatitis / metabolic steatohepatitis (NASH / MASH).

23. The method of any one of claims 1, 3, 8, 10, 11, 13, 18 and 20, wherein the fatty liver disease / steatohepatitis is nonalcoholic steatohepatitis / metabolic dysfunction-related fatty liver disease (NAFLD / MAFLD).

24. The method of any one of claims 5, 15, 21, and 22, wherein treating the non-alcoholic steatohepatitis / metabolic steatohepatitis includes improving or eliminating at least one symptom of non-alcoholic steatohepatitis / metabolic steatohepatitis.

25. The method of any one of claims 4 or 14, wherein reversing a diagnosed nonalcoholic steatohepatitis / metabolic steatohepatitis comprises improving or eliminating at least one symptom of nonalcoholic steatohepatitis / metabolic steatohepatitis.

26. The method of any one of claims 5, 15, 21, and 22, wherein treating the non-alcoholic steatohepatitis / metabolic steatohepatitis includes preventing the progression of at least one symptom of non-alcoholic steatohepatitis / metabolic steatohepatitis.

27. The method of any one of claims 2, 3, 12 and 13, wherein treating the liver fibrosis includes improving or reversing the liver fibrosis.

28. The method of any one of claims 2, 3, 12 and 13, wherein treating the liver fibrosis includes preventing the progression of the liver fibrosis.

29. The method of any one of claims 24-26, wherein the symptoms are selected from elevated AST levels; elevated ALT levels; elevated liver triglyceride levels; elevated liver cholesterol levels; hepatic steatosis; liver inflammation; hepatocyte (hepatocyte) swelling; liver fibrosis; impaired liver function; and NAFLD / MAFLD activity score.

30. The method of any one of claims 24-26, wherein the symptom is elevated AST levels.

31. The method of claim 30, wherein improvement in AST level elevation means normalization of AST levels in the subject.

32. The method of claim 30, wherein improvement in AST level elevation is defined as a reduction in AST level in the subject by at least 10%.

33. The method of claim 30, wherein improvement in AST level elevation is defined as a reduction of at least 20% in AST level in the subject.

34. The method of claim 30, wherein improvement in AST level elevation is defined as a reduction of at least 30% in AST level in the subject.

35. The method of claim 30, wherein improvement in AST level elevation is defined as a reduction of at least 40% in AST level in the subject.

36. The method of claim 30, wherein improvement in AST level elevation is defined as a reduction of at least 50% in AST level in the subject.

37. The method of any one of claims 24-26, wherein the symptom is elevated ALT levels.

38. The method of claim 37, wherein improvement in elevated ALT levels means normalization of ALT levels in the subject.

39. The method of claim 37, wherein improvement in ALT level elevation is defined as a decrease in ALT level in the subject by at least 10%.

40. The method of claim 37, wherein improvement in ALT level elevation is defined as a reduction of at least 20% in ALT level in the subject.

41. The method of claim 37, wherein improvement in ALT level elevation is defined as a reduction in ALT level in the subject by at least 30%.

42. The method of claim 37, wherein improvement in ALT level elevation is defined as a reduction of at least 40% in ALT level in the subject.

43. The method of claim 37, wherein improvement in ALT level elevation is defined as a reduction of at least 50% in ALT level in the subject.

44. The method of any one of claims 24-26, wherein the symptom is elevated liver triglyceride levels.

45. The method of claim 44, wherein improvement in elevated liver triglyceride levels means normalization of liver triglyceride levels in the subject.

46. ​​The method of claim 44, wherein improvement in elevated liver triglyceride levels is defined as a reduction of at least 10% in liver triglyceride levels in the subject.

47. The method of claim 44, wherein improvement in elevated liver triglyceride levels is defined as a reduction of at least 20% in liver triglyceride levels in the subject.

48. The method of claim 44, wherein improvement in elevated liver triglyceride levels is defined as a reduction of at least 30% in liver triglyceride levels in the subject.

49. The method of claim 44, wherein improvement in elevated liver triglyceride levels is defined as a reduction of at least 40% in liver triglyceride levels in the subject.

50. The method of claim 44, wherein improvement in elevated liver triglyceride levels is defined as a reduction of at least 50% in liver triglyceride levels in the subject.

51. The method of any one of claims 24-26, wherein the symptom is elevated liver cholesterol levels.

52. The method of claim 51, wherein improvement in elevated liver cholesterol levels means normalization of liver cholesterol levels in the subject.

53. The method of claim 51, wherein improvement in elevated liver cholesterol levels is defined as a reduction of at least 10% in liver cholesterol levels in the subject.

54. The method of claim 51, wherein improvement in elevated liver cholesterol levels is defined as a reduction of at least 20% in liver cholesterol levels in the subject.

55. The method of claim 51, wherein improvement in elevated liver cholesterol levels is defined as a reduction of at least 30% in liver cholesterol levels in the subject.

56. The method of claim 51, wherein improvement in elevated liver cholesterol levels is defined as a reduction of at least 40% in liver cholesterol levels in the subject.

57. The method of claim 51, wherein improvement in elevated liver cholesterol levels is defined as a reduction of at least 50% in liver cholesterol levels in the subject.

58. The method of any one of claims 24-26, wherein the symptom is hepatic steatosis.

59. The method of claim 58, wherein improvement in hepatic steatosis is defined as a reduction in steatosis score of at least 1 point.

60. The method of any one of claims 24-26, wherein the symptom is liver inflammation.

61. The method of claim 60, wherein improvement in liver inflammation is defined as a reduction in liver inflammation of at least 1 point.

62. The method of any one of claims 24-26, wherein the symptom is swollen liver cells (hepatocytes).

63. The method of claim 55, wherein improvement in liver distension is defined as a reduction in hepatocyte (hepatocyte) distension of at least 1 point.

64. The method of any one of claims 24-26, wherein the symptom is liver fibrosis.

65. The method of claim 27 or 64, wherein improvement or regression of liver fibrosis is defined as a reduction of at least one fibrosis stage on the Metavir, Ishak, Brunt, SAF, FLIP SAF, or NASH / MASH CRN scale by histological analysis.

66. The method of claim 27 or 64, wherein improvement in liver fibrosis is defined as a reduction of at least 1 point in the comprehensive phenotypic fibrosis score as measured by an artificial intelligence (AI) pathology platform.

67. The method of claim 27 or 64, wherein improvement in liver fibrosis is defined as a reduction of at least 20% in fibrosis as measured by an artificial intelligence (AI) pathology platform.

68. The method of claim 66 or 67, wherein the AI ​​pathology platform measures fibrosis using second harmonic generation imaging analysis of unstained biopsy or quantification of fibrotic histological phenotypes based on collagen-stained biopsy.

69. The method of any one of claims 24-26, wherein the symptom is an NAFLD / MAFLD activity score.

70. The method of claim 69, wherein improvement in NAFLD / MAFLD activity score is defined as a decrease in NAFLD / MAFLD activity score of at least 1 point.

71. The method of any one of claims 24-26, wherein the symptom is impaired liver function.

72. The method according to any one of claims 1-10 and 21-71, wherein the FASN inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

73. The method of any one of claims 1 to 71, wherein the fatty acid synthase inhibitor is selected from: (Denista) and (TVB-3664) or its pharmaceutically acceptable salt.

74. The method of any one of claims 1 to 71, wherein the fatty acid synthase (FASN) inhibitor is dinistat or a pharmaceutically acceptable salt thereof.

75. The method of any one of claims 1 to 74, wherein the GLP-1 agonist is selected from the group consisting of: single-agent GLP-1 receptor agonists, dual GIP / GLP-1 receptor agonists, dual GIP receptor antagonists / GLP-1 receptor agonists, dual amylin / GLP-1 receptor agonists, dual glucagon / GLP-1 receptor agonists, and triple glucagon / GIP / GLP-1 receptor agonists.

76. The method of any one of claims 1-75, wherein the GLP-1 receptor agonist is a subcutaneously administered GLP-1 agonist or an orally administered GLP-1 agonist.

77. The method of any one of claims 1-75, wherein the GLP-1 receptor agonist is a subcutaneously administered GLP-1 agonist.

78. The method of any one of claims 1-75, wherein the GLP-1 receptor agonist is an orally administered GLP-1 agonist.

79. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is a single-dose GLP-1 receptor agonist.

80. The method of any one of claims 1-78, wherein the single-agent GLP-1 receptor agonist is selected from the group consisting of semaglutide, liraglutide, LY3502970, and daglione.

81. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is a dual GIP / GLP-1 receptor agonist.

82. The method of any one of claims 1-78 and 81, wherein the dual GIP / GLP-1 receptor agonist is selected from tesipatide, CT388 and dapoxetine.

83. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is a dual GLP receptor antagonist / GLP-1 receptor agonist.

84. The method of any one of claims 1-78 and 83, wherein the dual GIP receptor antagonist / GLP-1 receptor agonist is AMG133.

85. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is a dual amyloid / GLP-1 receptor agonist.

86. The method of any one of claims 1-78 and 85, wherein the dual amyloidin / GLP-1 receptor agonist is Cagri-Sema.

87. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is a dual glucagon / GLP-1 receptor agonist.

88. The method of any one of claims 1-78 and 87, wherein the dual glucagon / GLP-1 receptor agonist is selected from the group consisting of: BI456906, NN9277, cotadole peptide, and pegvista peptide.

89. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is a triple glucagon / GIP / GLP-1 receptor agonist.

90. The method of any one of claims 1-78 and 89, wherein the triple glucagon / GIP / GLP-1 receptor agonist is retaloglutide.

91. The method of any one of claims 1-78, wherein the GLP-1 receptor agonist is selected from the group consisting of: semaglutide, liraglutide, daglitron, LY3502970, AMG-133, CT388, dapoxetine, texipatide, cotadolide, pegutide, BI456906, NN9277, Cagri-Sema, and retaglutide.

92. The method of any one of claims 1-78, wherein the GLP-1 agonist is semaglutide.

93. The method of any one of claims 1-92, wherein the FASN inhibitor and the GLP-1 agonist are administered in synergistically effective amounts.

94. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-100 mg.

95. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-90 mg.

96. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-80 mg.

97. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-70 mg.

98. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-60 mg.

99. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-50 mg.

100. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-40 mg.

101. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-30 mg.

102. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10-20 mg.

103. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-100 mg.

104. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-90 mg.

105. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-80 mg.

106. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-70 mg.

107. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-60 mg.

108. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-50 mg.

109. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-40 mg.

110. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20-30 mg.

111. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-100 mg.

112. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-90 mg.

113. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-80 mg.

114. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-70 mg.

115. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-60 mg.

116. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-50 mg.

117. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30-40 mg.

118. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40-100 mg.

119. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40-90 mg.

120. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40-80 mg.

121. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40-70 mg.

122. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40-60 mg.

123. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40-50 mg.

124. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 50-100 mg.

125. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 50-90 mg.

126. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 50-80 mg.

127. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 50-70 mg.

128. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 50-60 mg.

129. The method of any one of claims 1-93, wherein the FASN inhibitor is administered in doses of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg.

130. The method of any one of claims 1-93, wherein the FASN inhibitor is administered in doses of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.

131. The method of any one of claims 1-93, wherein the FASN inhibitor is administered in doses of 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.

132. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 10 mg.

133. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 15 mg.

134. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 20 mg.

135. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 25 mg.

136. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 30 mg.

137. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 35 mg.

138. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 40 mg.

139. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 45 mg.

140. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 50 mg.

141. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 55 mg.

142. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 60 mg.

143. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 65 mg.

144. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 70 mg.

145. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 75 mg.

146. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 80 mg.

147. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 85 mg.

148. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 90 mg.

149. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 95 mg.

150. The method of any one of claims 1-93, wherein the FASN inhibitor is administered at a dose of 100 mg.

151. The method of any one of claims 94-150, wherein the FASN inhibitor is administered once or twice daily.

152. The method of any one of claims 94-150, wherein the FASN inhibitor is administered once daily.

153. The method of any one of claims 94-150, wherein the FASN inhibitor is administered twice daily.

154. The method of any one of claims 94-150, wherein the FASN inhibitor is administered intermittently.

155. The method of any one of claims 94-150, wherein the FASN inhibitor is administered three times a week.

156. The method of any one of claims 94-150, wherein the FASN inhibitor is administered according to a dosing / stopping / dosing / stopping / dosing / stopping / stopping schedule (e.g., Monday, Wednesday, Friday schedule).

157. The method of any one of claims 94-150, wherein the FASN inhibitor is administered twice weekly.

158. The method of any one of claims 94-150, wherein the FASN inhibitor is administered once weekly.

159. The method of any one of claims 1-158, wherein the FASN inhibitor is administered orally.

160. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is equal to the indicated maintenance dose for weight loss in adult patients.

161. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 90% of the indicated maintenance dose for weight loss in adult patients.

162. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 90% of the indicated maintenance dose for weight loss in adult patients.

163. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 90% of the indicated maintenance dose for weight loss in adult patients.

164. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 90% of the indicated maintenance dose for weight loss in adult patients.

165. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 90% of the indicated maintenance dose for weight loss in adult patients.

166. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 60% to 90% of the indicated maintenance dose for weight loss in adult patients.

167. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 70% to 90% of the indicated maintenance dose for weight loss in adult patients.

168. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 80% to 90% of the indicated maintenance dose for weight loss in adult patients.

169. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 80% of the indicated maintenance dose for weight loss in adult patients.

170. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 80% of the indicated maintenance dose for weight loss in adult patients.

171. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 80% of the indicated maintenance dose for weight loss in adult patients.

172. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 80% of the indicated maintenance dose for weight loss in adult patients.

173. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 80% of the indicated maintenance dose for weight loss in adult patients.

174. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 60% to 80% of the indicated maintenance dose for weight loss in adult patients.

175. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 70% to 80% of the indicated maintenance dose for weight loss in adult patients.

176. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 70% of the indicated maintenance dose for weight loss in adult patients.

177. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 70% of the indicated maintenance dose for weight loss in adult patients.

178. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 70% of the indicated maintenance dose for weight loss in adult patients.

179. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 70% of the indicated maintenance dose for weight loss in adult patients.

180. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 70% of the indicated maintenance dose for weight loss in adult patients.

181. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 60% to 70% of the indicated maintenance dose for weight loss in adult patients.

182. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 60% of the indicated maintenance dose for weight loss in adult patients.

183. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 60% of the indicated maintenance dose for weight loss in adult patients.

184. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 60% of the indicated maintenance dose for weight loss in adult patients.

185. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 60% of the indicated maintenance dose for weight loss in adult patients.

186. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 60% of the indicated maintenance dose for weight loss in adult patients.

187. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 50% of the indicated maintenance dose for weight loss in adult patients.

188. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 50% of the indicated maintenance dose for weight loss in adult patients.

189. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 50% of the indicated maintenance dose for weight loss in adult patients.

190. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 50% of the indicated maintenance dose for weight loss in adult patients.

191. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 40% of the indicated maintenance dose for weight loss in adult patients.

192. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 40% of the indicated maintenance dose for weight loss in adult patients.

193. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 40% of the indicated maintenance dose for weight loss in adult patients.

194. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 30% of the indicated maintenance dose for weight loss in adult patients.

195. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 30% of the indicated maintenance dose for weight loss in adult patients.

196. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 20% of the indicated maintenance dose for weight loss in adult patients.

197. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is equal to the indicated maintenance dose for treating type 2 diabetes in adult patients.

198. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

199. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

200. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

201. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

202. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

203. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 60% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

204. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 70% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

205. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 80% to 90% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

206. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

207. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

208. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

209. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

210. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

211. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 60% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

212. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 70% to 80% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

213. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 70% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

214. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 70% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

215. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 70% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

216. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 70% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

217. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 70% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

218. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 60% to 70% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

219. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 60% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

220. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 60% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

221. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 60% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

222. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 60% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

223. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 50% to 60% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

224. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 50% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

225. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 50% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

226. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 50% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

227. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 40% to 50% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

228. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 40% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

229. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 40% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

230. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 30% to 40% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

231. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 30% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

232. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 20% to 30% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

233. The method of any one of claims 1-159, wherein the dose of the GLP-1 agonist administered is 10% to 20% of the indicated maintenance dose for treating type 2 diabetes in adult patients.

234. The method of any one of claims 1-233, wherein the subject has been diagnosed with a comorbidity.

235. The method of claim 234, wherein the comorbidity is obesity, type 2 diabetes, or a combination of both.

236. The method of claim 234, wherein the comorbidity is obesity.

237. The method of claim 234, wherein the comorbidity is type 2 diabetes.

238. The method of claim 234, wherein the comorbidity is a combination of obesity and type 2 diabetes.

239. The method of any one of claims 1-238, wherein the FASN inhibitor and the GLP-1 agonist are administered as a fixed-dose combination.

240. The method of any one of claims 1-238, wherein the FASN inhibitor and the GLP-1 agonist are administered as separate dose units.

241. The method of claim 240, wherein the FASN inhibitor and the GLP-1 agonist are administered simultaneously.

242. The method of claim 240, wherein the FASN inhibitor and the GLP-1 agonist are administered sequentially.

243. The method of claim 242, wherein the FASN inhibitor and the GLP-1 agonist are administered according to the same dosing schedule.

244. The method of claim 242, wherein the FASN inhibitor and the GLP-1 agonist are administered according to different dosing schedules.

245. A method of treating a subject with NASH and moderate to severe fibrosis, the method comprising administering to the subject a therapeutically effective amount of a fatty acid synthase inhibitor of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a glucagon-like peptide-1 (GLP-1) agonist, wherein: Equation (I) is: ； in: L-Ar is or ; R 1 The following are possible values: 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 replaced by one, two or three halogens; Each R 2 It is independently hydrogen, halogen, or C1-C4 straight-chain or branched alkyl; R 3 It can be H, -OH or halogen; R 21 H, halogen, C1-C4 straight-chain or branched alkyl, 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 can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) t -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) t -O-(C1-C4 straight-chain or branched alkyl), wherein The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; t is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms; L 1 For CR 23 Or N; R 23 It can be H, C1-C4 straight-chain or branched alkyl, or -(C1-C4 alkyl). t -OH, -(C1-C4 alkyl) v -O-(C3-C5 cycloalkyl), -(C1-C4 alkyl) t -(C3-C5 cycloalkyl) or -(C1-C4 alkyl) v -O-(C1-C4 straight-chain or branched alkyl), wherein: The C1-C4 straight-chain or branched alkyl group is optionally substituted with one, two or three halogens; v is 0 or 1; The C3-C5 cycloalkyl group optionally includes oxygen or nitrogen heteroatoms.

246. The method of claim 245, wherein the subject's liver fibrosis improves by ≥ 1 stage, while NASH does not worsen.

247. The method of claim 245, wherein the subject's NASH subsides and fibrosis does not worsen.

248. The method of any one of claims 245-247, wherein the pharmaceutical composition comprises about 25 mg to about 100 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, or about 50 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

249. The method of any one of claims 245-248, wherein the subject suffering from NASH with moderate to severe fibrosis is classified as stage F2 or stage F3 fibrosis.

250. The method of any one of claims 245-249, wherein the subject's NAFLD activity score (NAS) is equal to or greater than 4 prior to administration of the pharmaceutical composition.

251. The method of any one of claims 245-250, wherein the pharmaceutical composition is administered to the subject once daily.

252. The method of any one of claims 245-251, wherein the compound is dinistat or a pharmaceutically acceptable salt thereof.

253. The method of any one of claims 245-252, wherein the GLP-1 agonist is semaglutide, liraglutide, daglitron, LY3502970, AMG-133, CT388, dapoxetine, tesipatide, cotadolide, pegutide, BI456906, NN9277, Cagri-Sema, or retaglutide, or other GLP-1 agonists as provided herein.

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