Use of MDM2 inhibitor and method of use

Abstract

Provided is use of an MDM2 inhibitor in weight management by inducing weight loss in a subject, as well as the MDM2 inhibitor in the treatment and / or prevention of obesity, dyslipidemia, a non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes. The present invention further relates to a method for using the MDM2 inhibitor in the use.

Description

Uses and methods of using MDM2 inhibitors Technical Field

[0001] This invention relates to the field of medicine. More specifically, this invention relates to the use of MDM2 inhibitors for weight management to induce weight loss, and the use of MDM2 inhibitors for the treatment and / or prevention of obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes. This invention also relates to methods of using MDM2 inhibitors. Background Technology

[0002] MDM2 is an E3 ubiquitin ligase that is typically amplified in different types of tumors. In tumors, MDM2 binds to the tumor suppressor p53, causing p53 to lose its function.

[0003] MDM2 inhibitors interfere with the binding of the MDM2 protein to the p53 protein, thus acting as a p53 activator in medicine. Emerging evidence suggests that p53 dysfunction also exacerbates inflammation and supports tumor immune evasion; therefore, p53 dysfunction is considered an immunological driver of tumorigenesis (Guo G, Cancer Research, 2017; 77(9):2292).

[0004] MDM2 and p53 are part of a self-regulating feedback loop (Wu et al., Genes Dev. 7:1126 (1993)). MDM2 is transcribedly activated by p53, and in turn, MDM2 inhibits p53 activity through at least three mechanisms (Wu et al., Genes Dev. 7:1126 (1993)). First, the MDM2 protein directly binds to the p53 transactivation domain, thereby inhibiting p53-mediated transactivation. Second, the MDM2 protein contains a nuclear export signal sequence, which, upon binding to p53, induces the nuclear export of p53, thereby preventing p53 from binding to target DNA. Third, the MDM2 protein is an E3 ubiquitin ligase, and upon binding to p53, it promotes p53 degradation.

[0005] The prior art uses MDM2 inhibitors as an anticancer treatment (see, for example, US 9745314, the entire contents of which are incorporated herein by reference).

[0006] Further research is needed in this field to develop new uses and methods of application for MDM2 inhibitors. Summary of the Invention

[0007] Through dedicated research, the inventors have discovered that MDM2 inhibitors can be used to treat or prevent metabolic disorders or diseases associated with GDF15, such as in weight management that causes weight loss, and in the treatment and / or prevention of obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes.

[0008] Therefore, in a first aspect, the present invention relates to methods for treating or preventing GDF15-related metabolic disorders or diseases, for example, selected from overweight, obesity, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and / or type 2 diabetes, the methods comprising administering an effective amount of an MDM2 inhibitor to a subject in need. In one embodiment, the method of the present invention causes weight loss in the subject.

[0009] In a second aspect, the present invention relates to the use of MDM2 inhibitors for the preparation of medicaments for treating or preventing GDF15-related metabolic disorders or diseases by increasing growth differentiation factor 15 (GDF15). In some embodiments, the GDF15-related metabolic disorders or diseases are selected from overweight, obesity, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and / or type 2 diabetes.

[0010] In some embodiments, the MDM2 inhibitors described in the first and second aspects of the present invention are compounds with the following structural formulas or pharmaceutically acceptable salts or solvates thereof:

[0011] in:

[0012] Selected from

[0013] B is C 4-7 Carbon rings;

[0014] R1 is H, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic alkyl, OR a or NR a R b ;

[0015] n is 0, 1, or 2;

[0016] R2, R3, R4, R5, R7, R8, R9 and R 10 It is independently selected from H, F, Cl, CH3 and CF3;

[0017] R6 is

[0018] R a It is hydrogen or substituted or unsubstituted C 1-4 alkyl;

[0019] R b It is hydrogen or substituted or unsubstituted C 1-4 alkyl;

[0020] R c and R d It is a substituent on a carbon atom of ring B, wherein

[0021] R c It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated;

[0022] R d It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated; or

[0023] R c and R d Together with the carbon atoms to which they are attached, they form 4- to 6-membered spirocyclic substituents, which optionally contain oxygen or nitrogen atoms; and

[0024] R e It is -C(=O)OR a -C(=O)NR a R b Or -C(=O)NHSO2CH3. Attached Figure Description

[0025] The preferred embodiments of the invention described in the following detailed description will be better understood when read in conjunction with the accompanying drawings. The drawings show presently preferred embodiments for illustrative purposes. However, it should be understood that the invention is not limited to the precise arrangement and means of the embodiments shown in the drawings.

[0026] Figure 1 shows the fold change from baseline in serum MIC-1 levels of subjects in the 10mg-50mg, 100mg, 200mg, and 300mg groups after administration of compound A in Example 2, at 6 hours and 24 hours after administration on day 1 of cycle 1 (represented as C1D1-6h and C1D1-24h in Figure 1, respectively), and at 6 hours and 24 hours after administration on day 21 of cycle 1 (represented as C1D21-6h and C1D21-24h in Figure 1, respectively).

[0027] Figure 2 shows the mean fold change of serum MIC-1 from baseline at 6 hours and 24 hours after administration of compound A on day 1, and 6 hours and 24 hours after administration on day 21 in Example 2.

[0028] Figure 3 shows the mean fold change in serum MIC-1 from baseline in each dose group 24 hours after administration of compound A on day 1 in Example 2.

[0029] Figure 4 shows the serum MIC-1 concentrations of all subjects in Example 3 before administration of compound A, 6 hours and 24 hours after administration on day 1, and 6 hours and 24 hours after administration on day 21.

[0030] Figure 5 shows the mean fold change in serum MIC-1 from baseline in subjects of each dose group 24 hours after administration of compound A on day 1 in Example 3.

[0031] Figure 6 shows the results of plotting the fold change of serum MIC-1 from baseline to time points at 6 hours and 24 hours after administration of compound A on day 1 and 24 hours after administration on day 21 in Example 3 (small plots A and B in Figure 6); and plotting the fold change of serum MIC-1 from baseline to time points at 6 hours and 24 hours after administration of compound A on day 1 and 24 hours after administration on day 21 in each dose group (small plot C in Figure 6).

[0032] Figure 7 shows the results of plotting the fold change of serum MIC-1 in each dose group of subjects from baseline (before administration on day 1 of cycle 1) against time points in Example 4 (small plot A in Figure 7); and plotting the mean fold change of serum MIC-1 in all subjects from baseline (before administration on day 1 of cycle 1) against time points at 6 hours, 24 hours, and 6 hours and 24 hours after administration of compound A on day 1 and day 7 (small plot B in Figure 7).

[0033] Figure 8 shows the body weight (kg) of subjects in each dose group during the first cycle of compound A administration (day 1 (C1D1), day 13 (C1D13), and the second cycle (day 1 (C2D1), day 13 (C2D13)) in Example 5.

[0034] Figure 9 shows the percentage change in body weight from baseline for each dose group during the first cycle of compound A administration (days 1 (C1D1), 13 (C1D13), and the second cycle (days 1 (C2D1), 13 (C2D13)); and the percentage change in body weight from baseline for all subjects during the first cycle of compound A administration (days 1 (C1D1), 13 (C1D13), and the second cycle (days 1 (C2D1), 13 (C2D13)) (inside figure B). Detailed Implementation

[0035] Before describing the invention in detail, it should be understood that the invention is not limited to the specific methods and experimental conditions described herein, as these methods and conditions can be modified. Furthermore, the terminology used herein is for illustrative purposes only and is not intended to be restrictive.

[0036] I. Definition

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of this invention, the following terms are defined.

[0038] The term “about” when used in conjunction with a numeric value means to cover a range of numeric values ​​that have a lower limit of 10% less than the specified numeric value and an upper limit of 10% greater than the specified numeric value.

[0039] When the term “and / or” is used to connect two or more options, it should be understood to mean any one of the options or any two or more of the options.

[0040] As used herein, the terms “comprising” or “including” mean to include the stated elements, integers, or steps, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover situations consisting of the mentioned elements, integers, or steps. For example, when referring to an antibody variable region “comprising” a specific sequence, it is also intended to cover the antibody variable region consisting of that specific sequence.

[0041] The terms "pharmaceutically acceptable salt" and "medicinal salt" are used interchangeably and refer to salts that retain the biological effects and properties of the compounds of the present invention, and which are not biologically or otherwise undesirable. The compounds of the present invention can exist in their pharmaceutically acceptable salt forms, including acid addition salts and base addition salts. In the present invention, a pharmaceutically acceptable, non-toxic acid addition salt refers to a salt formed by the compounds of the present invention with an organic or inorganic acid, including but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. Pharmaceutically acceptable non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and organic base salts, such as ammonium salts formed by reacting with an organic base containing an N group.

[0042] The term "solvent" refers to an association formed by one or more solvent molecules with the compound of the present invention. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc.

[0043] The terms “application” and “administration” are used interchangeably to refer to the physical introduction of the active ingredient of the compound of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art.

[0044] Term "C" 1-4 "Alkyl" refers to any straight-chain or branched group containing 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.

[0045] Term "C" 1-3 "Alkyl" refers to any straight-chain or branched group containing 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, etc.

[0046] The alkyl group is optionally selected independently as one or more of, for example, halogenated, trifluoromethyl, trifluoromethoxy, hydroxyl, alkoxy, nitro, cyano, alkylamino, or amino, and is generally substituted with one to three. In one embodiment, the optionally substituted alkyl group is substituted with two substituents. In another embodiment, the optionally substituted alkyl group is substituted with one substituent. In yet another embodiment, the optionally substituted alkyl group is unsubstituted.

[0047] Term "C" 1-3 "alkylene" refers to the above "C 1-3 An alkyl group is a group obtained by removing a hydrogen atom.

[0048] As used herein, the term "heterocyclic" refers to heteroaryl ring systems and heterocyclic alkyl rings.

[0049] Term "C" 3-8 "Cycloalkyl" means a monocyclic or bicyclic, saturated or partially unsaturated cyclic system containing three to eight carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, wherein the cyclic system is optionally independently selected from one or more of, for example, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, or amino, and is usually substituted with one to three.

[0050] The term "heterocyclic alkyl" refers to a monocyclic or bicyclic, saturated or partially unsaturated cyclic system containing a total of 4 to 12 atoms, wherein one to five of the atoms are independently selected from nitrogen, oxygen, and sulfur, and the remaining atoms are carbon. Non-limiting examples of heterocyclic alkyl groups are azirrobutyl, pyrrolidinyl, piperidinyl, piperazine, dihydropyrrolidinyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxoheptanyl, dioxoheptanyl, thioheptanyl, and diazaheptanyl, each optionally with an independently selected halogenated or carbon-containing atom on the ring. 1-6 Alkyl, C 1-6 Alkoxy, cyano, amino, carbamoyl, nitro, carboxyl, C 2-7 alkenyl, C 2-7 One or more of the alkynyl group, and usually one to three substitutions.

[0051] The term "halogen" or "halogenated" refers to the elements and atoms of Group VIIA of the periodic table, including fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0052] The terms "heterocyclic", "heterocyclic alkyl", and "C" used in this article 3-8 "Cycloalkyl" and "halogen" have their common meanings in the art, and their meanings can be understood by those skilled in the art through general knowledge or by reference to the prior art (e.g., WO2015 / 161032, which is incorporated herein by reference in its entirety).

[0053] The term "prevention" refers to the ability of an MDM2 inhibitor, when used for a disease or condition, to reduce the frequency of symptoms of the disease or delay its onset in an individual compared to an individual who has not received an MDM2 inhibitor.

[0054] The term "treatment" refers to the reduction, relief, or improvement of symptoms of a disease or condition, improvement of underlying metabolic symptoms, inhibition of a disease or condition, such as preventing the development of a disease or condition, relieving a disease or condition, causing the remission of a disease or condition, alleviating the condition caused by a disease or condition, or preventing the symptoms of a disease or condition.

[0055] The term "GDF15-related metabolic disorders or diseases" refers to metabolic disorders or diseases caused by decreased serum levels of mature GDF15 compared to healthy subjects, including but not limited to overweight, obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D).

[0056] In this article, "subject" and "individual" refer to animals that need to lose weight, preferably mammals, and more preferably humans. Mammals also include, but are not limited to, farm animals, racing animals, pets, primates, horses, dogs, cats, mice, and rats.

[0057] The terms “effective amount” or “effective amount for prevention and / or treatment” are used interchangeably to refer to an amount (e.g., dose) of an administered compound that is effective in achieving a specific biological outcome, by alleviating one or more symptoms of the disease or condition being treated. These outcomes may include, but are not limited to, weight loss, treatment or prevention of obesity, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and / or type 2 diabetes. Unless otherwise stated, “effective amount” refers to the amount of the drug in its free form. If the drug is in a pharmaceutically acceptable salt form, the amount of the drug is increased proportionally to the amount of the drug in its free form.

[0058] The term "pharmaceutical-grade" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0059] Undefined technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0060] II. The MDM2 inhibitor used in this invention

[0061] "MDM2 inhibitor" refers to a substance that inhibits the activity of MDM2. "MDM2" is an abbreviation for Murine Double Minute 2. The term MDM2 encompasses both the MDM2 gene and its products (e.g., mRNA, protein). Exemplary sequences of human MDM2 are available from NCBI under accession numbers ABT17086, ABT17084.1, ABT17085.1, or ABT17083.1.

[0062] The MDM2 inhibitor applicable to this invention is the MDM2 inhibitor disclosed in Chinese Patent Application Publication No. CN 112294965A, the entire contents of which are incorporated herein by reference.

[0063] In some implementations, the MDM2 inhibitor is a compound of formula I or a pharmaceutically acceptable salt or solvate thereof:

[0064] in:

[0065] Selected from

[0066] B is C 4-7 Carbon rings;

[0067] R1 is H, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic alkyl, OR a or NR a R b ;

[0068] n is 0, 1, or 2;

[0069] R2, R3, R4, R5, R7, R8, R9 and R 10 It is independently selected from H, F, Cl, CH3 and CF3;

[0070] R6 is

[0071] R a It is hydrogen or substituted or unsubstituted C 1-4 alkyl;

[0072] R b It is hydrogen or substituted or unsubstituted C 1-4 alkyl;

[0073] R c and R d It is a substituent on a carbon atom of ring B, wherein

[0074] R c It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated;

[0075] R d It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated; or

[0076] R c and R dTogether with the carbon atoms to which they are attached, they form 4- to 6-membered spirocyclic substituents, which optionally contain oxygen or nitrogen atoms; and

[0077] R e It is -C(=O)OR a -C(=O)NR a R b Or -C(=O)NHSO2CH3.

[0078] In some implementations, the compound of formula I yes

[0079] B is

[0080] R c and R d It is F and F, H and H, OH and CH3, CH3 and CH3, CH3 and OH, H and OH, CH2CH3 and CH2CH3, and CH2OH and CH2OH.

[0081] In some implementations, the -(CH2) in the compound of formula I n R1 is H, CH3, or CH2CH3.

[0082] In some embodiments, R2 in the compound of formula I is H; R3 is halogenated; and R4 and R5 are both H.

[0083] In some embodiments, R7 in the compound of formula I is halogenated; R8, R9, and R 10 Each of them is H; R e It is -C(=O)OH, -C(=O)NH2 or -C(=O)NHSO2CH3.

[0084] In some implementations, the MDM2 inhibitor is selected from the following compounds or their pharmaceutically acceptable salts or solvates:

[0085] In some implementations, the MDM2 inhibitor is compound A and its pharmaceutically acceptable salt or solvate:

[0086] The IUPAC / chemical name of compound A is 4-((3'R,4'S,5'R)-6”-chloro-4'-(3-chloro-2-fluorophenyl)-1'-ethyl-2”-oxo-bispiro-[cyclohexane-1,2'-pyrrolidine-3',3”-indoline]-5'-carboxamide)bicyclo[2.2.2]octane-1-carboxylic acid.

[0087] In some implementations, the MDM2 inhibitor is compound B and its pharmaceutically acceptable salt or solvate:

[0088] III. Uses of MDM2 Inhibitors

[0089] The MDM2 inhibitor of the present invention can be used to treat or prevent GDF15-related metabolic disorders or diseases by increasing growth differentiation factor 15 (GDF15), for example, to induce weight loss in subjects; and to treat or prevent obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and / or type 2 diabetes (T2D).

[0090] GDF15, also known as MIC-1 (macrophage inhibitory cytokine-1), prostate-derived factor (PDF), placental bone morphogenetic factor (PLAB), nonsteroidal anti-inflammatory drug-activated gene (NAG-1), and placental transforming growth factor β (PTGFB), is a member of the transforming growth factor β (TGF-β) superfamily. The human GDF15 gene is located on chromosome 19p 13.2-13.1.

[0091] Mature human GDF15 is a peptide of 112 amino acids. Circulating GDF15 forms a homodimer (25 kDa) via interchain disulfide bonds between Cys residues at position 77 on each GDF15 chain. Homodimer formation is required for the biological activity of GDF15 (see International Patent Application Publication No. WO 2017 / 147742).

[0092] The MDM2 inhibitor of the present invention increases the level of mature GDF15 in serum, thereby causing weight loss in subjects; and exerts therapeutic or preventive effects on obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D).

[0093] Without being bound by any specific theory, it is believed that the MDM2 inhibitor of this invention increases serum levels of mature GDF15, which leads to reduced food intake, possibly related to changes in food preferences, delayed gastric emptying, and CTA; GDF15 may counteract inflammation-induced insulin resistance or protect β-cells from apoptosis; GDF15 may promote lipolysis through brain somatic tissue circuits. GDF15 induces weight loss through its ability to reduce food intake and increase energy expenditure, and also has the ability to improve glucose tolerance.

[0094] The glial cell-derived neurotrophic factor (GDNF) receptor α-like (GFRAL) has been identified as a receptor that binds to GDF15. GDF15 specifically binds to GFRAL, and this complex induces activation and phosphorylation of the signal co-receptor Ret to activate signaling molecules Akt, Erk, and PLCγ, and provides beneficial properties such as inducing weight loss, and treating or preventing obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D).

[0095] The uses of the MDM2 inhibitor of the present invention will be described below.

[0096] weight loss

[0097] As used in this article, the term "weight loss" can refer to things such as weight (e.g., in kilograms), body mass index (kg / m²), etc. 2 A reduction in parameters such as waist-to-hip ratio (e.g., in centimeters), body fat mass (e.g., in kilograms), hip circumference (e.g., in centimeters), or waist circumference (e.g., in centimeters).

[0098] Weight loss can be calculated by subtracting the value of one or more of the above parameters from the value of the parameter at the start of the intervention by the value of one or more of the parameters at the end of the intervention (e.g., administration of the MDM2 inhibitor of the present invention).

[0099] The degree of weight loss can be expressed as a percentage change in one of the aforementioned weight phenotypic parameters (e.g., subject weight (in kilograms) or body mass index (kg / m²)). 2 (Percentage change). For example, a subject may lose at least 10% of their initial weight, at least 8% of their initial weight, or at least 5% of their initial weight. By way of example only, a subject may lose between 5% and 10% of their initial weight.

[0100] In one implementation, a weight loss of at least 10% of initial body weight can lead to a significant reduction in the risk of obesity-related comorbidities.

[0101] Application of the MDM2 inhibitor of the present invention can cause a reduction of at least 10%, at least 8%, at least 5%, or at least 3% of one or more of the above parameters over a period of time.

[0102] In one aspect, the present invention provides the non-therapeutic use of the MDM2 inhibitor of the present invention to induce weight loss and thereby maintain a healthy body composition.

[0103] obesity

[0104] As used herein, the term “obesity” refers to a condition in which the natural energy reserves stored in the adipose tissue of animals (particularly humans and other mammals) increase to a degree associated with certain health conditions or increased mortality. As used herein, the term “obesity” is defined as a body mass index (BMI) greater than 30 in adults.

[0105] As used in this article, the term "body mass index" refers to the ratio of weight (in kilograms) to the square of height (in meters).

[0106] For adults, the term “normal weight” is defined as having a BMI of 18.5 to 25, while “underweight” can be defined as having a BMI of less than 18.5.

[0107] The term “overweight” is defined as a body mass index (BMI) between 25 and 30.

[0108] Obesity is a chronic metabolic disorder that has reached epidemic levels in many parts of the world.

[0109] Administration of the MDM2 inhibitor of the present invention can reduce the subject's BMI, preferably to a BMI of 18.5 to 25.

[0110] dyslipidemia

[0111] The term "dyslipidemia" refers to a disorder of lipoprotein metabolism, including excessive or insufficient production of lipoproteins. Dyslipidemia may manifest as elevated total cholesterol, elevated levels of low-density lipoprotein (LDL) cholesterol and triglycerides, and decreased levels of high-density lipoprotein (HDL) cholesterol in the blood.

[0112] For triglycerides, serum triglyceride levels in the range of 150 to 199 mg / dL [1.70 mmol / L to 2.25 mmol / L] are generally considered borderline high; serum triglyceride levels in the range of 200 to 499 mg / dL [2.26 mmol / L to 5.64 mmol / L] are considered high; and serum triglyceride levels in the range of 500 mg / dL [5.65 mmol / L] or higher are considered very high.

[0113] Administration of the MDM2 inhibitor of the present invention can reduce elevated total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations in subjects.

[0114] Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)

[0115] Nonalcoholic fatty liver disease (NAFLD) refers to an excessive accumulation of fat in the liver of people who do not drink alcohol or drink very little alcohol. The most common form of NAFLD is a non-serious condition called hepatic steatosis (fatty liver), in which fat accumulates in liver cells; although the accumulation of fat in the liver is not a physiologically normal state, it in itself rarely causes harm or permanent damage.

[0116] Obesity is considered the most common cause of NAFLD, and some experts estimate that about two-thirds of obese adults and half of obese children may have hepatic steatosis. Most individuals with NAFLD are asymptomatic and present with a normal physical examination (although the liver may be slightly enlarged). The diagnosis of NAFLD usually begins in overweight or obese individuals with a slight elevation in their liver blood tests during routine examinations; NAFLD can be present in normal liver blood tests, but may also be detected incidentally on imaging examinations such as abdominal ultrasound or CT scans. It is confirmed by imaging studies, most commonly liver ultrasound or magnetic resonance imaging (MRI), after ruling out other causes.

[0117] Some people with NAFLD may develop a more serious condition called nonalcoholic steatohepatitis (NASH). NASH is a condition in which benign lipid accumulation (steatodegeneration) in the liver progresses to steatosis accompanied by inflammation. In NASH, fat accumulation in the liver is associated with inflammation and varying degrees of scarring. Steatodegeneration alone is considered a relatively benign condition of the liver itself and is also a reversible condition. However, the transition to NASH represents a key step in the pathogenesis as it sets the stage for further liver damage, such as fibrosis, cirrhosis, and hepatocellular carcinoma. While the mechanisms leading to steatosis are well described, little is known about the actual risk factors driving liver inflammation during the progression to NASH. Consequently, treatment options are difficult to determine. NASH is a potentially serious disease with a substantial risk of progressing to end-stage liver disease, cirrhosis, and hepatocellular carcinoma. In cirrhosis caused by NASH, the liver is permanently damaged and scarred, and can no longer function properly. Some patients who develop cirrhosis are at risk of developing liver failure and may eventually require a liver transplant.

[0118] NAFLD can be differentiated from NASH using the NAFLD Activity Score (NAS), which is the sum of histopathological scores from liver biopsies for hepatic steatosis (0 to 3), lobular inflammation (0 to 2), and hepatocellular glomerulonephrosis (0 to 2). NAS < 3 is equivalent to NAFLD, 3-4 is equivalent to borderline NASH, and > 5 is equivalent to NASH. The biopsy also scores for fibrosis (0 to 4).

[0119] NASH is usually first detected in individuals with elevated levels of, for example, alanine aminotransferase (ALT) or aspartate aminotransferase (AST), in liver tests included in routine blood tests. NASH is suspected when further evaluation reveals no obvious cause of liver disease (such as medication, viral hepatitis, or excessive alcohol use), and when X-rays or imaging of the liver show fat. NASH is diagnosed and differentiated from NAFLD by liver biopsy. For a liver biopsy, a needle is inserted through the skin to remove a small piece of liver. If microscopic examination of the tissue reveals fat, inflammation, and damaged hepatocytes, a diagnosis of NASH is made. If the tissue shows fat without inflammation and damage, a diagnosis of NAFLD is made. An important piece of information from the biopsy is whether scar tissue has developed in the liver.

[0120] NASH can slowly worsen, leading to scarring or fibrosis that accumulates in the liver. As fibrosis progresses, cirrhosis develops; the liver becomes severely scarred, hardened, and unable to function properly. Most people with NASH feel well and are unaware they have a liver problem. NASH is a common, often "silent," liver disease. Once severe scarring or cirrhosis develops, there are few treatments that can stop its progression. Patients with cirrhosis experience fluid retention, muscle atrophy, intestinal bleeding, and liver failure. Liver transplantation is the only treatment for advanced cirrhosis with liver failure, and its use is gradually increasing among patients with NASH.

[0121] The administration of the MDM2 inhibitor of the present invention can reduce hepatic steatosis and liver fibrosis, thereby treating or preventing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

[0122] Type 2 diabetes

[0123] The prevalence of diabetes has been steadily rising over the past few decades. Type 2 diabetes is the most common form of diabetes, accounting for 90% of all cases.

[0124] The terms "type 2 diabetes" or "T2D" or "T2DM" refer to a metabolic disease that causes glucose to accumulate in the bloodstream and is characterized by high blood sugar levels caused by a lack of insulin or the body's inability to use insulin effectively, primarily related to insulin resistance. Blood glucose levels are measured in milligrams per deciliter (mg / dL) or mmol / L. The desired treatment for people with diabetes is to lower blood glucose and HbA1c (glycated hemoglobin).

[0125] Administration of the MDM2 inhibitor of the present invention can reduce blood glucose and HbA1c in subjects.

[0126] IV. Pharmaceutical Compositions

[0127] This invention also relates to pharmaceutical compositions comprising an MDM2 inhibitor as described herein. Such pharmaceutical compositions may comprise an effective amount of the MDM2 inhibitor of this invention and a pharmaceutically or physiologically acceptable carrier. The carrier is generally selected to suit the intended administration mode and may include features for altering, maintaining, or protecting, for example, the composition's pH, molar osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, dissolution or release rate, absorption, or permeability. Typically, these carriers comprise aqueous solutions or alcohol / water solutions, emulsions, or suspensions, including saline and / or buffer media.

[0128] Suitable agents included in pharmaceutical compositions include, but are not limited to, antimicrobial agents, antioxidants (e.g., ascorbic acid, sodium sulfite, or sodium bisulfite), buffers (e.g., borates, bicarbonates, Tris-HCl, citrates, phosphates, or other organic acids), fillers (e.g., mannitol or glycine), chelating agents (e.g., ethylenediaminetetraacetic acid (EDTA)), complexing agents (e.g., caffeine, polyvinylpyrrolidone, β-cyclodextrin, or hydroxypropyl-β-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (e.g., glucose, mannose, or dextrin), proteins (e.g., free serum albumin, gelatin, or immunoglobulins), colorants, flavorings, and diluents, emulsifiers, hydrophilic polymers (e.g., polyvinylpyrrolidone), low molecular weight peptides, and salt-forming agents. Ions (e.g., sodium), preservatives (e.g., benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenylethanol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (e.g., glycerol, propylene glycol, or polyethylene glycol), sugar alcohols (e.g., mannitol or sorbitol), suspending agents, surfactants or wetting agents (e.g., protonide derivatives; PEG; sorbitol esters; polysorbates, such as polysorbate 20 or polysorbate 80; Triton; tromethamine; lecithin; cholesterol or tyloxapal), stabilizing agents (e.g., sucrose or sorbitol), tension enhancers (e.g., alkali metal halides, such as sodium chloride or potassium chloride or mannitol and sorbitol), delivery carriers, diluents, excipients, and / or pharmaceutical adjuvants. Pharmaceutical compositions can be prepared using conventional excipients known in the art for pharmaceutical products, through any of a variety of techniques (Remington's Pharmaceutical Sciences, 21st edition, University of the Sciences in Philadelphia, Philadelphia, PA, USA (2006)).

[0129] In some embodiments, pharmaceutical compositions comprising the MDM2 inhibitor described herein may be administered orally to a subject patient in need. When the pharmaceutical compositions are administered orally, they may be formulated as tablets, capsules, granules, powders, or syrups.

[0130] In some embodiments, pharmaceutical compositions comprising the MDM2 inhibitor described herein can be administered parenterally to a subject patient in need. When the pharmaceutical compositions are administered parenterally, they can be formulated as intravenous, intramuscular, subcutaneous, or intrathecal injections, or infusions. Parenterial administration can be performed via subcutaneous, intramuscular, or intravenous injection using a syringe, optionally a pen syringe, or a mechanically driven syringe. Alternatively, parenterial administration can be performed using an infusion pump.

[0131] When considering parenteral administration, pharmaceutical compositions are typically in the form of sterile, pyrogen-free, and parenteral-acceptable compositions. Particularly suitable solvents for parenteral injection are properly preserved sterile isotonic solutions.

[0132] The pharmaceutical composition may be in lyophilized form, such as lyophilized cake.

[0133] Oral or parenteral formulations can be prepared by conventional methods. The MDM2 inhibitors described herein can be mixed with any conventional additives or excipients, such as binders, disintegrants, lubricants, corrosives, solubilizers, suspending agents, emulsifiers, coating agents, cyclodextrins, and / or buffers, as needed.

[0134] In some embodiments, the present invention provides a kit or article for carrying out methods of inducing weight loss in a subject; or methods of treating or preventing obesity, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and / or type 2 diabetes, comprising: (a) a container including the MDM2 inhibitor described herein; and (b) a packaging insert having instructions for administering an effective amount of the MDM2 inhibitor described herein to induce weight loss in a subject; or for treating or preventing obesity, dyslipidemia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and / or type 2 diabetes. In some embodiments, the packaging insert includes instructions for a dosing regimen for oral administration of the MDM2 inhibitor described herein. In some embodiments, the packaging insert includes instructions for a dosing regimen for parenteral administration of the MDM2 inhibitor described herein.

[0135] V. Dosing regimen

[0136] In the methods and uses of the present invention, the MDM2 inhibitor (e.g., compound A) may be administered in the form of a pharmaceutical composition comprising an MDM2 inhibitor as a single therapeutic ingredient or a pharmaceutical composition further comprising at least one other therapeutic agent.

[0137] Those skilled in the art can determine, through routine experiments, the effective and non-toxic dosage of an MDM2 inhibitor (e.g., compound A) for inducing weight loss in subjects and for treating or preventing obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D). For example, the therapeutically effective dose of an MDM2 inhibitor (e.g., compound A) can vary depending on factors such as the subject's disease stage, age, sex, and overall health. Dosing regimens can be adjusted to provide an optimal therapeutic response.

[0138] MDM2 inhibitors (e.g., compound A) can be administered in any suitable manner, such as parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular, intrathecal injection or infusion), oral, topical, intranasal, or inhalation. Oral administration is generally preferred.

[0139] In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered orally daily (QD) or every other day (QOD). In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered orally daily or every other day in an amount from about 10 mg to about 300 mg. In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered orally daily or every other day in an amount from about 50 mg to about 250 mg. In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered orally daily or every other day in an amount of about 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg.

[0140] In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered over at least one 21-day or 28-day treatment cycle. In some embodiments, the MDM2 inhibitor is administered over approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more treatment cycles.

[0141] In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered over at least a 28-day treatment cycle, wherein the MDM2 inhibitor is administered orally daily in an effective amount on certain days (e.g., the first 5, 6, or 7 consecutive days of the treatment cycle), the effective amount of which is about 50 mg to about 250 mg (e.g., about 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg).

[0142] In some embodiments, an MDM2 inhibitor, such as compound A or a pharmaceutically acceptable salt thereof, is administered over at least one 21-day or 28-day treatment cycle, wherein the MDM2 inhibitor is administered orally every other day in an effective amount for two consecutive weeks prior to the 21-day or 28-day treatment cycle, or for three consecutive weeks prior to the 28-day treatment cycle, wherein the effective amount of the MDM2 inhibitor is about 50 mg to about 250 mg (e.g., about 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg).

[0143] In some implementations, a method is provided to induce weight loss in subjects in need; and to treat or prevent obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D) in subjects, wherein the method comprises orally administering to the subject approximately 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of an MDM2 inhibitor (e.g., compound A) daily on days 1 to 7 of a 28-day treatment cycle.

[0144] The present invention also provides for administering the MDM2 inhibitor of the present invention in combination with one or more other pharmaceutical agents to a subject in need. When the MDM2 inhibitor (e.g., compound A) is administered in combination with another pharmaceutical agent, the agent may be administered simultaneously or sequentially to provide an additive or synergistic therapeutic effect of the individual drugs. Examples of other pharmaceutical agents that can be combined with the MDM2 inhibitor of the present invention include:

[0145] - Weight loss drugs, such as those selected from orlistat, rimonaban, phentermine, and topiramate;

[0146] - Lipid-lowering drugs, such as those selected from lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, davastatin, atorvastatin; squalene synthase inhibitors; bile acid sequestrants such as cholestyramine and cholesvelam; fibrates; niacin and aspirin;

[0147] - Antidiabetic drugs, such as those selected from insulin, insulin derivatives, and mimics; insulin secretagogues such as sulfonylureas (e.g., chlorpropamide, tolazoline, acesulfame potassium, tolbutamide, glibenclamide, glimepiride, glipizide); glibenclamide and amaryl; insulinotropic sulfonylurea receptor ligands such as chloropicrin, e.g., nateglinide and repaglinide; thiazolidinediones (e.g., rosiglitazone, troglitazone, pioglitazone, baglitazone, linaglitazone, naproxen, troglitazone, empaglitazone, cycloglitazone, dapaglitazone); biguanides, e.g. Examples of drugs that work by promoting glucose utilization, reducing hepatic glucose production, and / or reducing intestinal glucose output include metformin and others; alpha-glucosidase inhibitors, such as acarbose and migiitoi, and others that slow carbohydrate digestion, thereby slowing intestinal absorption and reducing postprandial hyperglycemia; GLP-1 (glucagon-like peptide-1), GLP-1 analogs, such as exendin-4 and GLP-1 mimics; and DPPIV (dipeptidyl peptidase IV) inhibitors, such as vildagliptin.

[0148] In some implementations, the MDM2 inhibitor may be administered before, simultaneously or substantially simultaneously, after, intermittently or in any order of the other agent.

[0149] Example

[0150] The invention generally described herein will be more readily understood by referring to the following embodiments, which are provided by way of example and are not intended to limit the scope of the invention. These embodiments are not intended to represent all or only the experiments performed below.

[0151] Example 1. Preparation of compound A

[0152] MDM2 inhibitor compound A was prepared according to US Patent No. 9745314, International Publication No. WO2015 / 161032 and Aguilar et al., J. Med. Chem., 2017(60)2819-2839.

[0153] Example 2. One of the Phase I clinical studies on compound A increasing serum MIC-1 levels

[0154] A multicenter, open-label phase I clinical trial was conducted in the United States to evaluate changes in serum MIC-1 levels in subjects treated with compound A as monotherapy for advanced solid tumors or lymphoma. The dosing regimen for compound A ranged from 10 mg to 300 mg per dose, starting on day 1 (D1) and administered orally every other day for 21 consecutive days, followed by a one-week break, constituting cycle 1. Each dosing cycle lasted 28 days.

[0155] Twenty-nine subjects were recruited. One subject was enrolled in each of the 10mg, 20mg, and 50mg dosage groups of compound A; 15 subjects were enrolled in the 100mg, 200mg, and 300mg dosage groups; and 6 subjects were enrolled in the 300mg dosage groups. Among the 29 subjects, there were 4 cases of lung cancer, 4 cases of ovarian cancer, 3 cases of colon cancer, 2 cases each of breast cancer, pancreatic cancer, prostate cancer, liposarcoma, and oral adenoid cystadenocarcinoma, and 1 case each of esophageal squamous cell carcinoma, leiomyosarcoma, ampullary carcinoma, gastrointestinal stromal tumor, intrahepatic bile duct carcinoma, pulmonary adenoid cystadenocarcinoma, osteosarcoma, and rectal cancer.

[0156] Figure 1 shows the fold change in serum MIC-1 from baseline in subjects in the 10mg-50mg, 100mg, 200mg, and 300mg groups after administration of compound A at 6 hours and 24 hours after administration on day 1 and 6 hours and 24 hours after administration on day 21. The baseline is the C1D1-0h MIC-1 detection value.

[0157] After administration of compound A, the mean fold change of serum MIC-1 from baseline (C1D1-0h) in all subjects was plotted against time points. The mean fold change of serum MIC-1 from baseline at each time point (6 hours and 24 hours after administration of compound A on day 1, and 6 hours and 24 hours after administration on day 21) is shown in Figure 2.

[0158] Figures 1 and 2 show that an increase in serum MIC-1 can be observed as early as 6 hours on day 1 of the first cycle of compound A administration; as can be seen from the comparison of the median values ​​in the box plot of Figure 2, the increase in serum MIC-1 is most significant at 24 hours on day 21 of the first cycle of compound A administration.

[0159] Figure 3 shows the mean fold change in serum MIC-1 from baseline for each dose group 24 hours after administration of compound A on day 1.

[0160] As shown in Figure 3, on day 2 of the first cycle of compound A administration, low-dose (10mg-50mg) compound A induced an average increase of 1.3-2.7 times in serum MIC-1; while higher-dose (100mg-300mg) compound A induced an average increase of 3.38-5.75 times in serum MIC-1 from baseline.

[0161] The above results indicate that the serum MIC-1 level in subjects was significantly increased relative to baseline after treatment with compound A, and this increase was time- and dose-dependent.

[0162] Example 3. Phase I clinical study of compound A to increase serum MIC-1 levels (Part II)

[0163] An open-label, dose-escalation phase I clinical trial was conducted in China to evaluate changes in serum MIC-1 levels in subjects with advanced solid tumors when compound A was used as monotherapy. The dosing regimen for compound A was 100 mg to ~200 mg per dose, starting on day 1 (D1), administered orally every other day for 21 consecutive days, followed by a one-week break, constituting cycle 1. Each dosing cycle lasted 28 days.

[0164] This study was conducted at the Sun Yat-sen University Prevention and Treatment Center, and a total of 21 subjects were enrolled. Seventeen subjects (81.0%) had soft tissue sarcomas, including 14 cases of liposarcoma, 2 cases of synovial sarcoma, 1 case of rhabdomyosarcoma, 2 cases of adenoid cystadenocarcinoma, 1 case of dedifferentiated chondrosarcoma, and 1 case of osteosarcoma. They received three different treatment doses: 100 mg (n=11), 150 mg (n=8), and 200 mg (n=2).

[0165] After administration of compound A, serum MIC-1 concentrations of all subjects were plotted against time points. Figure 4 shows the serum MIC-1 concentrations of all subjects before administration of compound A, at 6 hours and 24 hours after administration on day 1, and at 6 hours and 24 hours after administration on day 21. An increase in serum MIC-1 was observed as early as 6 hours on day 1 of the first cycle after administration of compound A, and the increase in serum MIC-1 was most significant on day 21 of the first cycle after treatment with compound A (Figure 4).

[0166] Figure 5 shows the mean fold change in serum MIC-1 from baseline for each dose group 24 hours after administration of compound A on day 1.

[0167] As shown in Figure 5, on day 2 of the first cycle of compound A administration, 100 mg of compound A induced a 2.1-15.5-fold increase in serum MIC-1; 150 mg and 200 mg of compound A induced serum MIC-1 increases as high as 39.4-fold and 26.3-fold, respectively.

[0168] For all subjects, the fold change in serum MIC-1 from baseline was plotted against time points at 6 hours and 24 hours after administration of compound A on day 1, and at 6 hours and 24 hours after administration on day 21. The results are shown in subplots A and B in Figure 6. For each dose group, the fold change in serum MIC-1 from baseline was plotted against time points at 6 hours and 24 hours after administration of compound A on day 1, and at 6 hours and 24 hours after administration on day 21. The results are shown in subplot C in Figure 6.

[0169] As shown in Figure 6, starting from a compound A dose >100 mg, serum MIC-1 levels increased after administration compared to pre-administration levels. Within the tested dose range, the increase in MIC-1 was dose-dependent.

[0170] Example 4. Phase I clinical study of compound A increasing serum MIC-1 levels (Part III)

[0171] A multicenter, open-label phase I clinical trial was conducted in China to evaluate the changes in serum MIC-1 levels in patients with relapsed or refractory acute myeloid leukemia and relapsed or progressive high-risk / very high-risk myelodysplastic syndromes, as a monotherapy. The dosing regimen for compound A was 100 mg to 250 mg once daily for 7 days, followed by a 21-day break, with each 28-day period constituting one dosing cycle.

[0172] Serum MIC-1 levels were assessed in 11 subjects in the compound A monotherapy group, including four dose groups: 100 mg (n=3), 150 mg (n=3), 200 mg (n=2), and 250 mg (n=3).

[0173] The fold change in serum MIC-1 levels from baseline (before administration on day 1 of cycle 1) for each dose group was plotted against time points at 6 hours, 24 hours after administration of compound A on day 1, and 6 hours and 24 hours after administration on day 7. The results are shown in subplot A in Figure 7. The mean fold change in serum MIC-1 levels from baseline (before administration on day 1 of cycle 1) for all subjects was plotted against time points at 6 hours, 24 hours after administration of compound A on day 1, and 6 hours and 24 hours after administration on day 7. The results are shown in subplot B in Figure 7.

[0174] As shown in Figure 7, the serum MIC-1 level induced by compound A increased in a dose- and time-dependent manner. At 6 hours on day 7 after treatment with compound A, low and medium doses (100, 150, and 200 mg) of compound A induced a 4.5–32.4-fold increase in serum MIC-1; the highest dose of 250 mg of compound A induced a 20.5–66.4-fold increase in serum MIC-1 (Figure 7, inset B).

[0175] Example 5. Effects of compound A on subject weight and incidence of gastrointestinal adverse events

[0176] This is a multicenter, open-label phase I clinical trial evaluating the changes in body weight and the incidence of gastrointestinal adverse events in subjects when compound A is used in combination with toripalimab (an anti-PD-1 monoclonal antibody) to treat liposarcoma or other solid tumors.

[0177] Twenty-seven subjects were recruited. Compound A was administered at doses of 50, 100, and 150 mg, orally every other day for two weeks followed by a one-week break, with each cycle lasting 21 days. Toripalimab was administered intravenously at a dose of 240 mg every three weeks on day 1 of each cycle. Three subjects received 50 mg of compound A and toripalimab; three subjects received 100 mg of compound A and toripalimab; and 21 subjects received 150 mg of compound A and toripalimab. Subjects were visited and their weight was measured on days 1 and 13 of cycle 1, and on days 1 and 13 of cycle 2. The incidence of gastrointestinal adverse events was recorded.

[0178] Figure 8 shows the body weight (kg) of subjects in each dosage group during days 1 and 13 of the first cycle of compound A administration, and days 1 and 13 of the second cycle. As shown in Figure 8, in the 50 mg compound A dosage group, all three subjects who underwent follow-up experienced weight loss; in the 100 mg compound A dosage group, all three subjects who underwent follow-up experienced weight loss. In the 150 mg compound A dosage group, 12 out of 17 subjects who underwent follow-up experienced weight loss.

[0179] Figure 9 shows the percentage change in body weight from baseline (C1D1) for each dose group on days 1 and 13 of the first cycle of compound A administration, and days 1 and 13 of the second cycle (inset A in Figure 9); and the percentage change in body weight from baseline (C1D1) for all subjects on days 1 and 13 of the first cycle of compound A administration, and days 1 and 13 of the second cycle (inset B in Figure 9). As can be seen from Figure 9, the body weight of subjects in each dose group showed a continuous decreasing trend with prolonged treatment. By day 13 of the second cycle, the average body weight loss was approximately 2.5-5%.

[0180] The incidence of gastrointestinal adverse events in the subjects is shown in Table 1 below.

[0181] Table 1. Incidence of gastrointestinal adverse events Note: TEAE refers to Treatment Emergent Adverse Event.

[0182] As shown in Table 1, adverse reactions such as nausea and vomiting were observed in subjects who used compound A at various doses in combination with toripalimab. These adverse reactions were grade 1-2 and were generally tolerable.

[0183] The foregoing describes exemplary embodiments of the present invention. Those skilled in the art should understand that these disclosures are merely exemplary, and various other substitutions, adaptations, and modifications can be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. Use of MDM2 inhibitors: to prepare drugs for the treatment or prevention of metabolic disorders or diseases related to GDF15 by increasing growth differentiation factor 15 (GDF15).

2. The use according to claim 1, wherein the metabolic disorder or disease associated with GDF15 is selected from overweight, obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D).

3. The use according to claim 1 or 2, wherein the drug comprises: about 10 mg to about 300 mg of an MDM2 inhibitor, for example, about 50 mg to about 250 mg of an MDM2 inhibitor, and instructions for use, wherein the instructions for use instructs a regimen for administering the drug to a subject.

4. The use according to claim 3, wherein the drug is an oral or parenteral formulation of an MDM2 inhibitor, and the instructions for use instruct the patient to administer the following: The MDM2 inhibitor is administered in cycles of approximately 50 mg to approximately 100 mg, approximately 100 mg to approximately 150 mg, approximately 150 mg to approximately 200 mg, or approximately 200 mg to approximately 250 mg, for example, the cycle length is 21 or 28 days, with approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles.

5. The use according to claim 4, wherein the MDM2 inhibitor is administered in the following cycle: Administer every other day for 21 days, then stop for 7 days, for a total cycle length of 28 days; or Administer every other day for 14 days, then stop for 7 days, for a total cycle length of 21 days; or The medication is administered daily for 7 days, followed by a 21-day break, for a total cycle length of 28 days.

6. The use according to any one of claims 1 to 5, wherein the MDM2 inhibitor is a compound with the following structural formula or a pharmaceutically acceptable salt or solvate thereof: in: Selected from B is C 4-7 Carbon rings; R1 is H, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic alkyl, OR a or NR a R b ; n is 0, 1, or 2; R2, R3, R4, R5, R7, R8, R9 and R 10 It is independently selected from H, F, Cl, CH3 and CF3; R6 is R a It is hydrogen or substituted or unsubstituted C 1-4 alkyl; R b It is hydrogen or substituted or unsubstituted C 1-4 alkyl; R c and R d It is a substituent on a carbon atom of ring B, wherein R c It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated; R d It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated; or R c and R d Together with the carbon atoms to which they are attached, they form 4- to 6-membered spirocyclic substituents, which optionally contain oxygen or nitrogen atoms; and R e It is -C(=O)OR a -C(=O)NR a R b Or -C(=O)NHSO2CH3.

7. The use according to claim 6, wherein yes B is R c and R d It is F and F, H and H, OH and CH3, CH3 and CH3, CH3 and OH, H and OH, CH2CH3 and CH2CH3, and CH2OH and CH2OH.

8. The use according to claim 6 or 7, wherein -(CH2) n R1 is H, CH3, or CH2CH3.

9. The use according to any one of claims 6 to 8, wherein R2 is H; R3 is halogenated; and R4 and R5 are both H.

10. The use according to any one of claims 6 to 9, wherein R7 is halogenated; R8, R9 and R 10 Each of them is H; R e It is -C(=O)OH, -C(=O)NH2 or -C(=O)NHSO2CH3.

11. The use according to any one of claims 1 to 10, wherein the MDM2 inhibitor is selected from the following compounds or pharmaceutically acceptable salts or solvates thereof: Preferably, 12. A method for treating or preventing metabolic disorders or diseases associated with GDF15, for example, the GDF15-associated metabolic disorders or diseases selected from overweight, obesity, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and / or type 2 diabetes (T2D), the method comprising administering an effective amount of an MDM2 inhibitor to a subject in need, for example, about 10 mg to about 300 mg of an MDM2 inhibitor, preferably about 50 mg to about 250 mg of an MDM2 inhibitor.

13. The method of claim 12, wherein the MDM2 inhibitor is formulated as an oral or parenteral formulation, the method comprising administering, in cycles, about 50 mg to about 100 mg, about 100 mg to about 150 mg, about 150 mg to about 200 mg, or about 200 mg to about 250 mg of the MDM2 inhibitor to a subject in need, for example, the cycle length being 21 or 28 days, administered for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more cycles.

14. The method of claim 13, wherein the MDM2 inhibitor is administered periodically as follows: Administer every other day for 21 days, then stop for 7 days, for a total cycle length of 28 days; or Administer every other day for 14 days, then stop for 7 days, for a total cycle length of 21 days; or The medication is administered daily for 7 days, followed by a 21-day break, for a total cycle length of 28 days.

15. The method according to any one of claims 12 to 14, wherein the MDM2 inhibitor is a compound with the following structural formula or a pharmaceutically acceptable salt or solvate thereof: in: Selected from B is C 4-7 Carbon rings; R1 is H, substituted or unsubstituted C. 1-4 Alkyl, substituted or unsubstituted C 3-8 Cycloalkyl, substituted or unsubstituted heterocyclic alkyl, OR a or NR a R b ; n is 0, 1, or 2; R2, R3, R4, R5, R7, R8, R9 and R 10 It is independently selected from H, F, Cl, CH3 and CF3; R6 is R a It is hydrogen or substituted or unsubstituted C 1-4 alkyl; R b It is hydrogen or substituted or unsubstituted C 1-4 alkyl; R c and R d It is a substituent on a carbon atom of ring B, wherein R c It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated; R d It is H, C 1-3 Alkyl, C 1-3 Alkylene-OR a OR a Or halogenated; or R c and R d Together with the carbon atoms to which they are attached, they form 4- to 6-membered spirocyclic substituents, which optionally contain oxygen or nitrogen atoms; and R e It is -C(=O)OR a -C(=O)NR a R b Or -C(=O)NHSO2CH3.

16. The method of claim 15, wherein yes B is R c and R d It is F and F, H and H, OH and CH3, CH3 and CH3, CH3 and OH, H and OH, CH2CH3 and CH2CH3, and CH2OH and CH2OH.

17. The method according to claim 15 or 16, wherein -(CH2) n R1 is H, CH3, or CH2CH3.

18. The method according to any one of claims 15 to 17, wherein R2 is H; R3 is halogenated; and R4 and R5 are both H.

19. The method according to any one of claims 15 to 18, wherein R7 is halogenated; R8, R9 and R 10 Each of them is H; R e It is -C(=O)OH, -C(=O)NH2 or -C(=O)NHSO2CH3.

20. The method according to any one of claims 15 to 19, wherein the MDM2 inhibitor is selected from the group consisting of compounds or pharmaceutically acceptable salts or solvates thereof: Preferably,

Images