Therapeutic compounds for use in insulin resistance

Abstract

The present invention provides methods for treating, preventing, and / or reducing the risk or severity of insulin resistance. [Solution] Embodiments of the present disclosure encompass a method for treating insulin resistance in an individual in need by administering one or more STAT3 inhibitors to the individual. In certain embodiments, this method makes it possible to reverse insulin resistance in an individual. The STAT3 inhibitors may be one or more specific small molecules as incorporated herein.

Description

[Technical Field]

[0001] (Reference to related applications) This application is based on U.S. Provisional Patent Application No. 62 / 943,053, filed on December 3, 2019. The author asserts the rights of the number, and its entire contents are incorporated herein by reference.

[0002] (Description of federally funded research and development) This invention is based on government support granted by the National Institutes of Health (NIH) under DK37175. The United States government has certain rights in this invention.

[0003] (Technical field) Provided herein are the compounds described herein, or their pharmaceutically effective products. This includes administering a tolerable salt or its pharmaceutical composition to a subject, if necessary. To treat, prevent and / or treat the risk or severity of insulin resistance in subjects. This is a method to reduce it. [Background technology]

[0004] Chronic kidney disease (CKD) 1-3 In patients, the degree of CKD or glomerular filtration rate is at a normal level. Even within the same population, insulin resistance (IR) is common. 4 IR is progressively lower GF It is becoming increasingly common in patients with R levels and in patients with end-stage renal failure (ESKF). It is almost universal among them. 3,5 Unfortunately, infrared radiation in patients with heart disease is acidic. Chemical stress 6 , chronic inflammation 6 , and endothelial dysfunction 7 Including those that contribute to cardiovascular (CV) disease It is closely associated with risk factors. Regarding the involvement of other organs, skeletal muscle is the risk factor for CKD. Represents the primary site of R, and the defect in the intracellular signaling process in muscle is recognized as the main defect underlying IR in CKD Since IR is a modifiable risk factor, its modification may reduce the morbidity and mortality of CV, but the first step in modifying IR is to clarify the molecular mechanisms underlying the etiology of CKD-related IR. Potentially, understanding the mechanisms that cause IR may lead to the identification of new therapeutic targets aimed at reducing the high CV risk of CKD

[0005] According to reports, IR is induced by inflammation, excessive glucocorticoids or myostatin expression 8-11 Activation of IKK-β, TGF-β1 or Smad3 signaling can act as an association between inflammatory disorders and the biological characteristics of IR 12 High glucose or high-fat diet treatment induces myostatin expression in muscle, and this reaction leads to the development of IR through the degradation of IRS1. Alternatively, signal transducer and transcription activator 3 (Stat3) has been reported to be involved in the regulation of insulin signaling in some tissues. For example, Stat3 knockdown prevents IR that occurs in hepatoma cell lines exposed to high levels of amino acids IRS1 10 ; while Stat3 activation in adipocytes is associated with growth hormone-induced IR 13 On the other hand 14 Stat3 is activated by a series of cytokines and growth factors including IL-6, IL-9, and epidermal growth factor. Following its nuclear translocation, it binds to the promoter, regulating inflammation, cell development, and differentiation ​​​​​​​​​​​​​It regulates the expression of genes involved in cell proliferation, survival, and angiogenesis. 15 Stat3 Activation is also due to their ability to downregulate cytokine signaling. It induces the expression of SOCS proteins characterized by [specific characteristics]. 16 The SOCS protein also Because it incorporates cytokine and insulin signaling processes, it is related to the pathogenesis of IR. and play an important role 17 For example, overexpression of SOCS3 is associated with insulin in the myotubes. It inhibits inducible glycogen synthesis activity and suppresses glucose uptake in adipocytes. but 18 Hepatocyte-specific SOCS3 deletion improves insulin sensitivity in the liver. 19 Mechanistically, SOCS protein activity is related to IRS1 20 Ubiquitin binding and decomposition It inhibits lancelin signaling. In the skeletal muscle of patients with type 2 diabetes (T2D), Sta It was found that t3 is constitutively phosphorylated. 21 The main question remaining is, Stat 3. The question is whether inhibiting activation improves insulin signaling in muscles.

[0006] In skeletal muscle, atrogin-1 acts as a muscle-specific E3 ubiquitin rigor. It has been identified as a marker of the degree of muscle protein degradation that occurs in skeletal muscle atrophy models. It is used as such. Atrogin-1 is also a muscle-specific F-box protein (Fbxo32). That is 22,23 The F-box protein is SCF(Skp1-Cullin1-Fb F-box proteins are important components of complexes. Interact with Skp1 using the main 24It becomes a ubiquitin-binding protein. Specifically It contains more than 70 genes that code for proteins including F-box, and the cell cycle and It exhibits E3 ubiquitin ligase activity, which is involved in regulating signal transduction function. 25 . recent years Fbxo40 is another muscle-specific F-box protein. 26 It has been identified as, but the muscle mechanism Its role in brain function has not been clarified. Fbxo40 expression is muscle-specific, and There are a few reports indicating that its expression is upregulated during differentiation. Therefore, muscle Knockdown of Fbxo40 in this case induces dramatic hypertrophy of muscle fibers. 25 Fbxo 40 expression was also found to be upregulated in skeletal muscle after denervation. 2 6 On the other hand, mice that were null for Fbxo40 showed elevated serum IGF1 levels during the proliferative phase. During this period, he showed increased body and muscle size. 25 In summary, these reports are Fbx This suggests that o40 may play an important role when muscle atrophy occurs, but F Since the factors or mechanisms that regulate bxo40 expression are unknown, this remains speculative. .

[0007] Insulin receptor substrate (IRS) proteins are insulin receptor tyrosine kinase signaling proteins. It mediates IRS1 transmission. Decreased IRS1 expression and protein levels are associated with IR transmission in humans. It is related to the occurrence of both T2D. 27 In mice, IRS1 genetic disruption This involves insulin-stimulated glucose discarding in vivo and glucose transport in vitro. Disability-related 28-30 These responses are important because IRS proteins Does activating PI3K lead to the recruitment of Akt to the cell membrane, causing phosphorylation and activation? Furthermore, the involvement of p-Akt in metabolic regulation is multiplicative: downstream substrates are 160kD IR / IGF containing Akt substrate (AS160), FOXO transcription factor, and mTORC1 It can play an important role in the cellular response to -1R signaling. Akt activation is triggered by the translocation of the glucose transporter GLUT4 to the cell membrane, which leads to glucose It is necessary for the protein to migrate into muscle cells or fat cells (Figure 5).

[0008] This disclosure addresses a long-standing need in the IR and related health technology fields. We provide solutions for sexual issues. [Overview of the Initiative]

[0009] (overview) This disclosure addresses the risk or severity of insulin resistance (IR) in individuals who require it. Compounds, compositions, and methods related to treating, preventing, and / or reducing severity In certain embodiments, IR is related to CKD, but in other embodiments, IR is C Not related to KD, and / or the individual does not have CKD.

[0010] In some embodiments, this disclosure directly or indirectly results in IR including CKD. This disclosure relates to the inhibition of the mechanism. For example, this disclosure inhibits Stat3 and therefore IR The present invention provides compounds and compositions useful for treatment. In some embodiments, Stat Inhibition of 3 results in improvement of IRs, including IRs associated with CKD. In some embodiments, Stat3 inhibitor (for example, this item) The Stat3 inhibitor described in the book is used to reverse IR in patients with IR. It is useful, and in certain embodiments, the Stat3 inhibitor directly inhibits Stat3. This can lead to a reversal of fortune.

[0011] Embodiments of the disclosure also involve mice with CKD or those fed a high-fat diet (HFD). This provides a mouse model of insulin resistance in mice. Such a model is activated Level of Stat3 (Stat3 phosphorylated on tyrosine 705, p-Stat3) This is useful because it increases in the skeletal muscle of CKD or HFD mice. Such models are This was useful in characterizing a new approach to the long-standing problem of IR in CKD. Ta.

[0012] In certain embodiments, the Stat3 inhibitor used in the manner disclosed herein - in individuals (e.g., mice or humans) with or without CKD or HFD It is a small molecule inhibitor of Stat3 that improves insulin signaling. 3. Inhibitors can be prescribed in any form that allows for therapeutically effective treatment. Individuals receiving treatment for phosphate resistance or CKD should be aware of their respective insulin resistance or In some cases, patients may or may not be receiving additional treatment for CKD. In certain embodiments, The Stat3 inhibitor compounds and compositions included herein are for type II diabetes. Used to treat obesity and / or cardiovascular diseases. In some embodiments, IR This includes inflammation, acute and chronic renal failure (e.g., type 2 diabetes, obesity and / or cardiovascular disease). It develops as a complication of several diseases characterized by the presence of (in)

[0013] Embodiments of this disclosure involve administering a therapeutically effective dose of one or more inhibitors of STAT3 to an individual. A method for treating insulin resistance in individuals that require it, which includes doing so. This includes embodiments of the present disclosure relating to insulin resistance in individuals who require insulin. For those who treat, prevent, or reduce the risk or severity of conditions associated with insulin resistance. This includes the use of one or more signal transducers in an individual in a therapeutically effective amount and Transcription activator 3 The present disclosure includes the step of administering an inhibitor of STAT 3. The method of administration addresses, prevents, and treats the risk or severity of diabetes in individuals who require it. or a method of reducing, which includes one or more signal transducers in a therapeutically effective amount and inhibitors of transcription activator 3 (STAT3) in organisms This includes administering it to individuals that require it. Embodiments of this disclosure describe metabolic This includes methods for treating, preventing, or reducing the risk or severity of yck syndrome. This involves a therapeutically effective amount of one or more signal transducers and transcription factor 3 (transcriptional activator). This includes administering an inhibitor of activator 3) (STAT3) to an individual. The IR may be associated with inflammation. The patient may have chronic kidney disease. Specific implementation Morphologically, the individual does not have cachexia or muscle wasting. In certain embodiments, the individual is human These are mammals such as dogs, cats, horses, cows, pigs, sheep, or goats. STAT The inhibitor 3 may be a small molecule in certain cases, and in some embodiments S If the inhibitors in TAT3 are one or more inhibitors from any one of Tables 1-7, It is its pharmaceutically acceptable salt. The method involves administering it to an individual in the presence of IR or related medical conditions. This further includes administering an effective dose of additional treatment for the condition.

[0014] The above is intended to help you better understand the features and technical advantages of this disclosure, as described in the following detailed explanation. The points have been outlined quite broadly. Additional features and claims that form the subject matter of the claims herein The advantages are described below. The disclosed concepts and specific embodiments perform the same purpose of this design. It can be easily used as a basis for modifying or designing other structures, This should be understood by those skilled in the art. Furthermore, such equivalent configurations are described in the attached claims. It should be understood by those skilled in the art that this does not deviate from the spirit and scope described within the scope. Novel features that are considered to be features of the designs disclosed herein are further objectives. And along with its advantages, both the configuration and method of operation should be considered in relation to the attached drawings. If so, it will be better understood from the following explanation. However, each figure is an illustration and explanation. Provided solely for an explicit purpose and not intended as a definition of the limitations of this disclosure It should be explained. [Brief explanation of the drawing]

[0015] To fully understand this disclosure, please refer to the following description in conjunction with the attached drawings:

[0016] [Figure 1A] Figure 1A shows the percentage change in body weight in mice with CKD from day 1 to day 12 after injection of TTI-101 or D5W diluent. (*, p<0.05 vs CKD-D5W, n=10 mice).

[0017] [Figure 1B] Figure 1B shows fasting blood glucose (16-hour fasting) in mice with CKD (*, p<0.05 vs. Sham-D5W, #p<0.05 vs. CKD-D5W n=10 mice).

[0018] [Figure 1C] Figure 1C shows the evaluation of glucose tolerance in mice with CKD (*, p<0.05 vs. CKD-D5W, n=10 mice).

[0019] [Figure 1D] Figure 1D shows gastric muscle lysates from mice with chronic kidney disease (CKD) subjected to Western blotting. Image quantification is shown in the right panel (*, p<0.05 vs CKD-D5W, n=10 mice).

[0020] [Figure 2A] Figure 2A shows the Stat3 binding site in the promoter region of mouse Fbxo40.

[0021] [Figure 2B] Figure 2B shows that the CHIP assay enriched uncoated Stat3 compared to IgG in the Fbxo40 promoter in C2C12 myotubes expressing GFP (control) or overexpressing Stat3C (*, p<0.05 vs. GFP, n=3 repeats).

[0022] [Figure 2C] Figure 2C shows that Stat3C stimulates Fbxo40 promoter activity (*, p<0.05 vs cDNA3, n=3 repeats).

[0023] [Figure 2D] Figure 2D shows that C2C12 cells transfected with Stat3C increased Fbxo40 protein levels.

[0024] [Figure 2E]Figure 2E shows Western blotting of cell lysates of C2C12 myotubes treated with 100 ng / ml IL-6 for 24 hours.

[0025] [Figure 2F] Figure 2F shows that C2C12 cells were transfected with control or Fbxo40 siRNA (24 hours), differentiated into myotubes (48 hours), and then treated with 100 ng / ml IL-6 for 24 hours. Cell lysates were subjected to Western blotting.

[0026] [Figure 2G] Figure 2G shows the mRNA of Fbxo40 evaluated in mouse TA muscle (*, p<0.05 vs. Sham-D5W, #p<0.05 vs. CKD-D5W, n=10 mice).

[0027] [Figure 2H] Figure 2H shows IRS1 mRNA evaluated in mouse TA muscle (*, p<0.05 vs. Sham-D5W, #p<0.05 vs. CKD-D5W, n=10 mice).

[0028] [Figure 2I] Figure 2I shows that muscle lysates from CKD mice treated with or without TTI-101 were subjected to Western blotting to evaluate Fbxo40 protein levels.

[0029] [Figure 2J] Figure 2J. Quantification of images in Figure 2I (*, p<0.05 vs. CKD-D5W, n=10 mice).

[0030] [Figure 3A] Figure 3A shows the results of Western blotting for p-Stat3 in myolysates from mice given HFD for two weeks. Quantification of the images is shown in the right panel (*, p<0.05 vs RD, n=10 mice).

[0031] [Figure 3B] Figure 3B shows the mRNA of Fbxo40 derived from the tibialis anterior muscle obtained after mice were given HFD for two weeks (*, p<0.05 vs RD, n=10 mice).

[0032] [Figure 3C] Figure 3C shows mRNA of Fbxo32 derived from the tibialis anterior muscle obtained after mice were given HFD for two weeks (*, p<0.05 vs RD, n=10 mice).

[0033] [Figure 3D] Figure 3D shows the mRNA of MuRF-1 derived from the tibialis anterior muscle obtained after mice were given HFD for two weeks (*, p<0.05 vs RD, n=10 mice).

[0034] [Figure 3E] Figure 3E shows 12 weeks of HFD feeding-induced obesity in mice (*, p<0.05 vs. RD, n=10 mice).

[0035] [Figure 3F] Figure 3F shows 12 weeks of HFD-induced glucose intolerance (3F) in mice (*, p<0.05 vs RD, n=10 mice).

[0036] [Figure 3G] Figure 3G shows that TTI-101 treatment in HFD mice reduced fasting glucose levels (*, p<0.05 compared to pre-treatment HFD-D5W or HFD-, n=10 mice).

[0037] [Figure 3H] Figure 3H shows that TTI-101 treatment improved the glucose tolerance of HFD-fed mice (*, p<0.05 vs. HFD-D5W, n=10 mice).

[0038] [Figure 3I]Figure 3I shows that TTI-101 treatment improved insulin resistance in HFD-fed mice (*, p<0.05 vs. HFD-D5W, n=10 mice).

[0039] [Figure 3J] Figure 3J shows muscle lysates from HFD mice treated with / without TTI-101, subjected to Western blotting to evaluate IRS1 or p-Akt protein. Image quantification is shown in the panel below (*, p<0.05 vs RD, #, p<0.05 vs HFD-D5W, n=10 mice).

[0040] [Figure 4A] Figure 4A shows body weight during 12 weeks of HFD feeding (*; p<0.05 vs. RD, n=10 mice).

[0041] [Figure 4B] Figure 4B shows muscle mass in mice after 16 weeks of HFD (*, p<0.05 vs RD, n=10 mice).

[0042] [Figure 4C] Figure 4C shows adipose tissue mass after 16 weeks of HFD (*, p<0.05 vs RD, n=10 mice).

[0043] [Figure 4D] Figure 4D shows that HFD-Stat3 KO mice reduced fasting blood glucose levels in mice (*, p<0.05 vs. RD-Stat3f / f, #p<0.05 vs. HFDStat3f / f, n=10 mice).

[0044] [Figure 4E] Figure 4E shows the glucose tolerance test in mice after 16 weeks of HFD (*, p<0.05 vs. HFD-Stat3f / f, n=10 mice).

[0045] [Figure 4F]Figure 4F shows the AUC calculated from 4E (*, p<0.05 vs RD-Stat3f / f, #p<0.05 vs HFD-Stat3f / fn=10 mouse).

[0046] [Figure 5] Figure 5 shows the CKD pathway that stimulates Stat3, leading to loss of muscle mass and IR. CKD induces IL-6 production, which stimulates Stat3. Activation of Stat3 induces myostatin production. Increased myostatin impairs satellite cell function. Myostatin also enhances the phosphorylation of Smad2 / 3 and suppresses the phosphorylation of Akt, leading to activation of the ubiquitin-proteasome system (UPS) and muscle atrophy. Stat3 also stimulates Fbxo40 expression, causing ubiquitination and degradation of IRS1, resulting in IR. [Modes for carrying out the invention]

[0047] definition As used herein, "a" or "an" may mean one or more. As used herein, when used with the word "to have", the word "a " or "an" can mean one or more. "Another" can mean at least a second or more. Furthermore, "to have" The terms “include,” “contain,” and “equip” are interchangeable, and those skilled in the art will recognize these It is recognized that the term is an open-ended term. Some embodiments of the present invention are The present invention may consist of one or more elements, method steps, and / or methods, or may be essentially composed of them. Any method, compound as described herein , or composition relating to any other method, compound, or composition described herein It is intended that this may be implemented.

[0048] As used herein, the term "inhibitor" refers to one or more molecules that perform one or more activities, including the ability to bind to Stat3 and / or the ability to be phosphorylated, and that at least partially interfere with the activity of Stat3 for the purpose of

[0049] As used herein, the term "therapeutically effective amount" refers to an amount of a compound, substance, or composition that contains a compound of the present invention and is effective to produce one or more desired therapeutic effects for treating (e.g., preventing and / or ameliorating) cancer in a subject, at a reasonable benefit / risk ratio applicable to any medical treatment, or for inhibiting protein-protein interactions mediated by the SH2 region in a subject In one embodiment, the therapeutically effective amount is at least sufficient to reduce or eliminate one symptom. One of ordinary skill in the art will recognize that an amount can be considered therapeutically effective even if the cancer is not completely eradicated and is only partially ameliorated. For example, the spread of cancer can be halted or reduced, the side effects from the cancer can be partially reduced or completely eliminated, the lifespan of the subject can be extended, and the subject can experience less pain etc.

[0050] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that exhibit a reasonable benefit / risk ratio

[0051] [[ID=4)1]] ​​​​​​​As used herein, "mammal" is a suitable subject for the methods of the present invention and may be any member of the mammalian class of higher vertebrates, including humans; characterized by live birth, body hair, and mammary glands in females that secrete milk to nourish the young Furthermore, mammals are characterized by the ability to maintain a constant body temperature despite changes in climatic conditions Examples of mammals are humans, cats, dogs, cows, mice, rats, and chimpanzees Mammals may be referred to as "patients" or "subjects" or "individuals".

[0052] The definitions of the terms used herein are set forth below. The initial definition provided for a group or term in this specification applies to that group or term throughout this specification, individually or as part of another group, unless otherwise indicated Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art

[0053] The terms "alkyl" and "alkylene" refer to straight-chain or branched-chain alkane (hydrocarbon) groups containing from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms Exemplary "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like The term "(C1-C4)alkyl" refers to straight-chain or branched-chain alkyl groups containing from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl ​​​​​​​​This refers to a branched alkane (hydrocarbon) group. "Substituting alkyl" refers to any available bond point. In this context, an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, is referred to. Examples of substituents include hydrogen and halogens (for example, a single halogen substituent or multiple halogen substituents). A number of halo substituents, in the latter case, form groups such as alkyl groups having CF3 or CCl3. (to form), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloal Kill, alkenyl, cycloalkenyl, alkenyl, heterocycle, aryl, OR a , SR a 、 S(=O)R e、 S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(= O)2OR e , NR b R c , NR b S(=O)2R e , NR b P(=O)2R e , S(= O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C( =O)NR b R c ,OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2 NRb R c , NR b C(=O)R a , or NR b P(=O)2R e However, Not limited to these, here each presence of Ra is independently hydrogen, alkyl, cycloalkyl R is an alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. b , R c , and R d Each of these entities independently contains hydrogen, alkyl, cycloalkyl, heterocycle, Aryl, or the above R b and R c They are optionally heterozygous with N to which they are bound. Form a seak, R e Each of these entities independently exists as alkyl, cycloalkyl, alkenyl, It is one of the following: cycloalkenyl, alkynyl, heterocyclic, or aryl. (Examples above) In the substituents, alkyl, cycloalkyl, alkenyl, alkynyl, cycloal Kenyl, heterocyclic, and aryl groups can be arbitrarily substituted for themselves.

[0054] The term "alkenyl" refers to a group of 2 to 12 carbon atoms and at least one carbon-carbon double. This refers to a linear or branched hydrocarbon group that contains a bond. Examples of such groups include ethenyl groups. It contains allyl. "C2-C6 alkenyl" means that it contains 2 to 6 carbon atoms and ethylene. Nyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2 -enyl, 2-methyl(E)-but-2-enyl, 2,3-dimethyl-but-2-enyl Examples include (Z)-pent-2-enyl and (E)-pent-1-enyl. (E)-hex-1-enyl, (Z)-pent-2-enyl 、 (E)-hex-2-enyl, (Z)-hex-1-enyl, (E)-hex-3-enyl, (E)-hex-1,3-dienyl, etc., meaning a straight-chain or branched-chain hydrocarbon radical containing at least one carbon-carbon double bond. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available bonding site. Exemplary substituents include hydrogen, halogen (e.g., a single halogen substituent or multiple halogen substituents having CCl3), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, heterocycle, aryl=, OR 、 SR 、 S(=O)R 、 S(=O)2R 、 P(=O)2R 、 S(=O)2OR 、 P(=O)2OR 、 NR a R a 、 NR e S(=O)2R e 、 NR e P(=O)2R 、 S(=O)2NR e R e 、 P(=O)2NR b R c 、 C(=O)OR b 、 C(=O)R e 、 C(=O)NR b R 、 OC(=O)R e 、 OC(=O)NR b R c 、 NR b C(=O)OR c 、 NR d C(=O)NR R a 、 NR b S(=O)2NR c 、 OC(=O)R a 、 OC(=O)NR b R c 、 NR b C(=O)OR e 、 NR d C(=O)NR b R c 、 NR d S(=O)2NRb R c 、 NR d P(=O)2NR b R c 、 NR b C(=O)R a 、 or NR b P(=O)2R e include, but are not limited to, where R a each presence of is hydrogen, cycloalkyl [[ID=2۳]]alkyl, alkenyl, heterocyclic, or aryl, and R b 、 R c 、 and R d each presence of is independently hydrogen, alkyl, cycloalkyl, heterocyclic ring, aryl, or the above R b and R c together with the N to which they are attached optionally form a heterocyclic ring; and each occurrence of R is independently alkyl, cycloalkyl, alkenyl, chloroalkenyl, alkynyl, heterocyclic, or aryl. Exemplary substituents may themselves be optionally substituted. e The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing from 2 to 12 carbon atoms and at least one carbon-carbon triple bond. Examples of such groups include ethynyl. The term "C2-C6 alkynyl" means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, or hex-3-ynyl. "Substituted alkynyl"[[ID=۴۲]] [[ID=۴۳]]is[[ID=۴۴]] [[ID=۴۵]]itself optionally substituted. [[ID=۴۶]] [[ID=۴۷]]

[0055] [[ID=۴۸]] [[ID=۴۹]] [[ID=۵۰]] [[ID=۵۱]] [[ID=۵۲]] [[ID=۵۳]] [[ID=۵۴]] [[ID=۵۵]] [[ID=۵۶]] [[ID=۵۷]] [[ID=۵۸]] [[ID=۵۹]] [[ID=۶۰]] [[ID=۶۱]] [[ID=۶۲]] At any available bonding site, one or more substituents, preferably 1 to 4 substituents This refers to a substituted alkynyl group. Exemplary substituents include hydrogen, halogens (e.g., C (single or multiple halogen substituents having Cl3), cyano, nitro, Oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, heterocycle, Ariel, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e S (=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O) 2R eThese are some examples, but are not limited to these, and here, R a Each of these entities is hydrogen, cysteine R is a rhalkyl, alkenyl, heterocyclic, or aryl molecule. b , R c and R d Each The elements are independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or the above R b and R c They arbitrarily form a heterocycle with N to which they are bonded; and R e of Each entity independently comprises alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkyl. It is quinyl, heterocyclic, or aryl. Exemplary substituents can be optionally substituted themselves. obtain.

[0056] The term "cycloalkyl" refers to a compound containing 1 to 4 rings and 3 to 8 carbon atoms per ring. This refers to a fully saturated cyclic hydrocarbon group. "C3-C7 cycloalkyl" is a cyclopropyl group. This refers to cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. A "converted cycloalkyl" has one or more substituents at any available bond site, preferably This refers to a cycloalkyl group substituted with 1 to 4 substituents. Exemplary substituents include hydrogen, Halogens (for example, a single halogen substituent, or in the latter case, a halogen having CCl3) Multiple halo substituents forming a lukyl group), cyano, nitro, oxo (i.e., =O), C F3, OCF3, cycloalkyl, alkynyl, heterocyclic, aryl, OR a , SR a S (=O)R e , S(=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O) 2ORe , NR b R c , NR b S(=O)2R e , NR b P(=O)2R e , S(=O) 2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O )NR b R c ,OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e One or more of the following This includes, and here, R a Each of these elements independently contains hydrogen, alkyl, cycloalkyl, and aldehyde. It is a quinyl, heterocyclic, or aryl, and R b , R c , and R d Each of these beings is independent , hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or the above R b and R c but They arbitrarily form a heterocycle with N to which they are bonded; and R e Each of these beings is independent Alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. Exemplary substituents can be optionally substituted themselves. The substitution group also includes spiro-type or condensed cyclic substituents, particularly spiro-type cycloalkyl and spiro-type substituents. Corrugated cycloalkenyl, spiro-modified heterocycle (excluding heteroaryl), condensed cycloalkyl , condensed cycloalkenyl, condensed heterocycle, or condensed aryl is the aforementioned cycloalkyl, Cycloalkenyls, heterocyclic compounds, and aryl substituents can be optionally substituted themselves.

[0057] The term "cycloalkenyl" refers to a compound containing 1 to 4 rings and 3 to 8 carbon atoms per ring. This refers to partially unsaturated cyclic hydrocarbon groups. Examples of such groups include cyclobutenyl and cyclopene. Examples include thenyl and cyclohexenyl, and "substituted cycloalkenyl" refers to any substitution. At usable bonding sites, one or more substituents, preferably 1 to 4 substituents, This refers to a cycloalkenyl group. Exemplary substituents include hydrogen and halogens (e.g., CCl (A single halogen substituent or multiple halogen substituents having 3), cyano, nitro, oxy So (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, heterocycle, ali ru, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(= O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR b P( =O)2R e , S(=O)2NR b R c , P(=O)2NR b Rc , C(=O)OR d , C(=O)R a , C(=O)NR b R c ,OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2 R e These are some examples, but are not limited to these, R a Each of these entities independently consists of hydrogen and alkyl Alkynyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or ali It is R b , R c , and R d Each of these entities independently contains hydrogen, alkyl, and cyclo Lukil, heterocycle, aryl, or the above R b and R c N and that are connecting them They also arbitrarily form complex rings; and R e Each of these entities independently exhibits alkyl and cycloalkyl properties. These are aryl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl compounds. The typical substituents can themselves be optionally substituted. Exemplary substituents may be spironate or contracted. This also includes cyclic substituents, particularly spiro-modified cycloalkyls, spiro-modified cycloalkenyls, and spiro substituents. Heterocyclic compounds (excluding heteroaryl compounds), condensed cycloalkyl compounds, condensed cycloalkenyl compounds, condensed Hybrid heterocycles, or condensed aryls, are the aforementioned cycloalkyls, cycloalkenyls, and heterocycles. The aryl substituents can be arbitrarily substituted themselves.

[0058] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, particularly phenyl Refers to monocyclic or bicyclic groups such as 1, 2, 3, or 4, or 4, or 4, or 5 When a ring (such as a bicyclic ring) is present, the aromatic ring of the aryl group has a single point (e.g., biphenyl They may be bonded together by ) or by condensation (e.g., naphthyl, phenantrenyl, etc.) It may be. A "substituted aryl" has one or more substituents at any available bond site. , preferably refers to an aryl group substituted with 1 to 3 substituents. Exemplary substituents and For example, hydrogen, halogen (e.g., a single halogen substituent having CCl3 or multiple halogen substituents) (Halogen substituents), cyano, nitro, oxo (i.e., =O), CF3, OCF3, cyano Chloalkyl, alkenyl, heterocyclic, aryl, OR a , SR a , S(=O)R e , S( =O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR b P(=O)2R e , S(=O)2NR b R c , P( =O)2NR b R c , C(=O)OR d , C(=O)Ra , C(=O)NR b R c , OC (=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)N R b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C( =O)R a , or NR b P(=O)2R e These are some examples, but are not limited to these. Here, R a The presence of each of these is hydrogen, cycloalkyl, alkenyl, heterocycle, or ali. It is R b , R c , and R d Each of these entities independently contains hydrogen, alkyl, and cyclo Lukil, heterocycle, aryl, or the above R b and R c N and that are connecting them They also arbitrarily form complex rings; and R e Each of these entities independently exhibits alkyl and cycloalkyl properties. These are aryl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl compounds. The typical substituents themselves can be arbitrarily substituted. Exemplary substituents are also fused cyclic groups, particularly It contains condensed cycloalkyl, condensed cycloalkenyl, condensed heterocycle, or condensed aryl. Here, the cycloalkyl, cycloalkenyl, heterocyclic, and aryl substituents mentioned above are , can be arbitrarily replaced by itself.

[0059] The term "carbocyclic ring" refers to a fully saturated ring containing 1 to 4 rings and 3 to 8 carbon atoms per ring. Or a partially saturated cyclic hydrocarbon group, or 1 to 5 aromatic rings, especially phenyl, biphenyl This refers to a cyclic aromatic hydrocarbon group having a monocyclic or bicyclic group, such as 140 or naphthyl. The term "carbocyclic ring" refers to the cycloalkyl, cycloalkenyl, and cycloalkyl compounds defined above. It includes aryl and ru. The term "substituted carbon ring" refers to a ring where any available bond site is present. a carbon ring or carbon ring group substituted with one or more substituents, preferably 1 to 4 substituents. This refers to substituted cycloalkyls, substituted cycloalkenyls, and substituted cyclo The above examples include, but are not limited to, roalkynyl and substituted aryls. Not applicable. Exemplary substituents also include any available addition sites, particularly spiromodulation cycloal Kill, spiro-added cycloalkenyl, spiro-added heterocycle (excluding heteroaryl), condensation Spin in cycloalkyl, condensed cycloalkenyl, condensed heterocycle, or condensed aryl The cycloalkyl, cycloalkenyl, and heterocyclic substituents are included, as mentioned above. , and the aryl substituent itself can be optionally substituted.

[0060] The terms "heterocycle" and "heterocycle" refer to a ring containing at least one carbon atom in which at least Aromatic (i.e., "heteroaryl") ring group having one heteroatom (e.g., 4-) Completely saturated ring systems (including 7-member monorings, 7-11 member birings, or 8-16 member trirings) This refers to being combined, partially, or completely unsaturated. A complex element containing a heteroatom. Each ring in the ring group is selected from a nitrogen atom, an oxygen atom, and / or a sulfur atom. 1, 2, 3 , or it may have four heteroatoms, where the nitrogen and sulfur heteroatoms are optional It may be oxidized, and the nitrogen heteroatom may optionally be quaternized. (Term "heteroary") "Lu" refers to a quaternary nitrogen atom, and therefore a heteroaryl group with a positive charge. (Heterocyclic group) It is bonded to the rest of the molecule at any heteroatom or carbon atom in the ring or ring system. This is also acceptable. Examples of monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, and pyrazo. Lil, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl Oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl Lu, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, Tetrahydrofuryl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, Tetrahydrofuryl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopi Rorodinil, 2-oxoazepinil, azepinil, hexahydrodiazepinil, 4-pipe Lidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tri Zolyl, tetrazolyl, tetrahydropyranil, morpholinil, thiamorpholinil, thia Morpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetra This includes hydro-1,1-dioxothienyl, etc. Examples of bicyclic heterocyclic groups include: Indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxadia Zolyl, benzothienyl, benzo[d][1,3]dioxolil, 2,3-dihydro Benzo[b][1,4]dioxynyl, quinuclidinyl, quinolinyl, tetrahydroiso Quinolinil, Isoquinolinil, Benzimidazolyl, Benzopyranil, Indolidinil, Quinuclidinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzui Midazolyl, benzopyranil, indolidinil, chromonil, coumarinil, benzopyranil Lu, cinolinil, quinoxalinil, indazolyl, pyrrolopyridyl, flupyridinil (examples) For example, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, and (e.g., furo[3,2-b]pyridinyl), dihydroisoindolyl, dihydrox Nazolinyl (3,4-dihydro-4-oxoquinazolin, etc.), triazinyl azepinine This includes tetrahydroquinolinyl, etc. Examples of tricyclic heterocyclic groups include carbazo. Lil, benzidrill, phenanthrolinyl, acridinyl, phenanthrolinyl, xane This includes senil, etc.

[0061] "Substitutional complex rings" and "substitutional complex rings" (such as "substitutional complex aryls") are available for any use. At a bonding site, a complex element substituted with one or more substituents, preferably 1 to 4 substituents. This refers to a ring or heterocyclic group. Exemplary substituents include hydrogen and halogens (e.g., CCl3). (having a single halogen substituent or multiple halogen substituents), cyano, nitro, oxo ( That is, =O), CF3, OCF3, cycloalkyl, alkenyl, heterocycle, aryl =, OR a , SR a , S(=O)R e , S(=O)2R e , P(=O)2R e , S(=O )2OR e , P(=O)2OR e , NR b R c , NR b S(=O)2R e , NR b P(= O) 2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C (=O)R a , C(=O)NR b R c ,OC(=O)R a , OC(=O)NR b R c , N R b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O)2NR b R c , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e These are some examples, but are not limited to these, and here, R a The existence of each of them is hydrogen, cyclo It is a lukil, alkenyl, heterocyclic, or aryl, and R b , R c , and R d Each existence These are independently hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, or the above R b and R c They arbitrarily form a heterocycle with N to which they are joined; and R e Each output These are independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, and alkynyl compounds. It is a heterocyclic or aryl compound. Exemplary substituents can be optionally substituted themselves. Example The exemplary substituents may also be spiro-added or contracted at any available addition point or addition point. Syncyclic substituents, especially spiro-added cycloalkyls, spiro-added cycloalkenyls, and spiro-added substituents. Heterocyclic compounds (excluding heteroaryl compounds), condensed cycloalkyl compounds, condensed cycloalkenyl compounds, condensed compounds Includes heterocycles or condensed aryls, and the aforementioned cycloalkyls, cycloalkenyls, heterocycles And the aryl substituents themselves may also have optional substitutions.

[0062] The term "alkylamino" refers to a group having the structure -NHR', where R' is the same as the present specification. As defined in the book, hydrogen, alkyl or substituted alkyl, or cycloalkyl Alternatively, it is a substituted cycloalkyl group. Examples of alkylamino groups include methylamino and ethylamino groups. Isopropylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino Luamino, tert-butyl-butylamino, neopentylamino, n-pentylamino This includes, but is not limited to, hexylamino acids and cyclohexylamino acids.

[0063] The term "dialkylamino" refers to a group having the structure -NRR', where R and R' are used in the formula. Each of these is independently an alkyl or substituted alkyl, as defined herein. loalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, It is an aryl or substituted aryl, or a heterosilyl or substituted heterocyclyl. And R' may be the same or different in the dialkylamino portion. Examples of methylamino groups include dimethylamino, methylethylamino, diethylamino, and Isopropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cy Clopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di( Neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclo)amino Examples include, but are not limited to, hexyl(amino) amino acids. In certain embodiments, R And R' are linked to form a cyclic structure. The resulting cyclic structure can be aromatic or non-aromatic. It may also be a group. Examples of cyclic diaminoalkyl groups include azilidinyl and pyrrolidinyl. Piperidinyl, Morpholinyl, Pyrrolyl, Imidazolyl, 1,3,4-Trianolyl, This includes, but is not limited to, tetrazolyl.

[0064] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0065] Unless otherwise specified, any heteroatom with an unsaturated valence satisfies its valence. It is assumed that it has enough hydrogen atoms.

[0066] The compounds disclosed herein can form salts which are also within the scope of this disclosure. Unless otherwise indicated, references to objects are understood to include references to their salts. The term "salt" as used refers to the acidic and / or organic salts formed by inorganic and / or organic acids and bases. / or means a basic salt. Furthermore, the compound of the present invention has a basic moiety (e.g., limited (but not limited to pyridine or imidazole) and acidic portion (e.g., a ka When both (rubonic acid) are present, an amphoteric ion ("internal salt") may be formed, and according to this specification The term "salt" is used within this context. Pharmacologically acceptable (i.e., non-toxic). A physiologically acceptable salt is preferred, but other salts may also be used, for example, during preparation. Useful in the isolation or purification process. Salts of the compounds of the present invention are, for example, as specified herein. The compound described is dissolved in an equivalent amount of acid or base in a medium or aqueous solution such that a salt precipitates. It can be formed by reacting it in a medium and then freeze-drying it.

[0067] Compounds of this disclosure containing a basic moiety such as an amine, pyridine, or imidazole ring The substance can form salts with various organic and inorganic acids, but is not limited to these. Examples of acid addition salts include acetates (acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid). (Such as those formed with acids), adipines, alginates, ascorbic acid, asparagus Ginates, benzoates, benzenesulfons, bisulfates, borates, butyrates, citric acid Salt, camphorate, camphor sulfonate, cyclopentane propionate, digluco Salts, dodecyl sulfate, ethanesulfonates, fumarates, glucoheptanates, glycansulfonates Ceroshumate, hemisulfate, heptanate, hexanoneate, hydrochloride, bromide Salts, iodates, hydroxyethanesulfons (e.g., 2-hydroxyethanesulfonates) (e.g., honate), lactate, maleate, methanesulfonate, naphthalenesulfonate) For example, 2-naphthalene sulfonate, nicotinate, nitrate, oxalate, pectinate Persulfates, phenylpropionates (e.g., 3-phenylpropionate), phosphoric acid Salt, piclate, pivalate, propionate, salicylate, succinate, sulfate (sulfur (e.g., those produced by acids), sultone salts, tartrates, thiocyanates, toluenesulfone It contains acids (such as tosylic acid) and undecanoic acid.

[0068] The compounds of this disclosure containing an acidic moiety such as a carboxylic acid and various organic and inorganic bases Salts may be formed, but are not limited to these. An example of a basic salt is ammonium salt. Alka salts such as sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts Earth metal salts, benzathine, dicyclohexylamine, hydravamin (N,N-bis(dehy) (formed with dipropyl ethyl ethylenediamine), N-methyl-D-glucamine, N-methyl - D-glycamide, t-butylamine, arginine, lysine, and other amino acid salts This includes salts with organic bases (e.g., organic amines). Basic nitrogen-containing groups are lower aluminum compounds. Kill halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides) ), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, diamyl sulfates), Chain halides (e.g., decyl, lauryl, myristyl, stearyl chlorides, bromides, yo) Quaternary compounds are produced using reagents such as hydroxyl halides (e.g., benzyl, phenethyl bromide) and aralkyl halides. It's okay to change it.

[0069] The compounds disclosed herein, and their salts or solvates, are in the form of tautomers (e.g., amides). It may exist as an iminoether or as an iminoether. All such tautomer forms are part of the present invention. As part of the foregoing,

[0070] All stereoisomers of this compound, including enantiomer and diastereomer forms. (For example, those that may exist due to chiral carbons on various substituents) are within the scope of the present invention. The intention is that the individual stereoisomers of the compounds of the present invention may be other isomers (for example, specific ones). It does not have to substantially contain active pure or substantially pure optical isomers, and This includes, for example, a racemic mixture, or all other, or other selected stereoisomers. It may be mixed with the following. The chiral center of the present invention is International Union of Pure and Applied Chemistry(IUPAC)197 4. Possibility of having an S or R configuration as defined by Recommendations There are racemic mixtures, for example, by fractional crystallization, separation or crystallization of diastereomer derivatives. Separation is performed by physical methods such as chemical separation or separation by chiral column chromatography. It is possible. Individual optical isomers are not limited to those mentioned, but for example, optically active acids and Racemic mixture by any suitable method, including conventional methods such as salt formation and subsequent crystallization. It can be obtained from.

[0071] The compounds of this disclosure are preferably isolated and purified following their preparation, and then 90 times A compound of a certain amount or more, for example, 95% by weight or more, 99% by weight or more ("substantially pure" compound) A composition containing the substance is obtained, and then used or formulated as described herein. Such "substantially pure" compounds of the present invention are also part of the present invention. It is intended in the book.

[0072] All conformational isomers of the compounds disclosed herein are in mixture or in pure or substantially pure form. Intended in either state. The definition of a compound in this invention is cis (Z) and trans (E). Both alkene isomers, as well as cis and trans isomers of cyclic hydrocarbons or heterocyclic compounds. It includes.

[0073] Throughout the specification, the groups and substituents are selected to provide stable moieties and compounds. It can be chosen.

[0074] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are elements. Periodic Table, CAS version, Handbook of Chemistry and Physi CS, 75 th The identification is based on the cover and the specific functional groups are generally described there. It is defined as follows. Furthermore, it is defined as the general principles of organic chemistry, as well as specific functional parts and reactions. The term "organic chemistry" is used by Thomas Sorrell and Un International Science Books, Sausalito (1999) It is included, and its entire contents are incorporated herein by reference.

[0075] Certain compounds of this disclosure may exist in specific geometric or stereoisomer forms. The invention relates to cis isomers and trans isomers, R- and S-enantiomers, and diasteres. Omer, (d)-isomer, (l)-isomer, racemic mixtures thereof, and other thereof All such compounds, including mixtures, are intended to fall within the scope of this invention. Furthermore, asymmetric carbon atoms can exist as substituents such as alkyl groups. Such isomers of and mixtures thereof are intended to be included in this disclosure.

[0076] Isomer mixtures containing any of the various isomer ratios can be used in accordance with this disclosure. For example, when only two isomers are combined, the ratios are 50:50, 60:40, 70: 30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, All mixtures containing an isomer ratio of 100:0 are intended by this disclosure. It is easy to understand that similar ratios are intended for mixtures of complex isomers.

[0077] This disclosure also includes isotope-labeled compounds, which are identical to the compounds disclosed herein. However, one or more atoms have atomic masses or mass numbers different from those normally found in nature. This is due to the fact that it is substituted by an atom having mass or mass number. Examples of isotopes that can be incorporated into the compound include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, Fluorine and chlorine isotopes, for example, 2 H, 3 H, 13 C, 11 C, 14 C , 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl is included The compounds of this disclosure, which contain the aforementioned isotopes and / or other isotopes of other atoms, or its enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts The solvates are within the scope of the present invention. Specific isotope-labeled compounds of the present invention, for example, 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are drugs and / or bases. It is effective in tissue partitioning assays. Tritiation, i.e. 3 H, and carbon-14, Nawachi 14 13C isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium, that is 2 Substitution with heavier isotopes like H leads to greater metabolic stability. For example, certain therapeutic effects resulting from an increased in vivo half-life or a reduced dosage requirement. It may offer advantages and, therefore, may be preferable in some situations. Isotope labeling Compounds are generally created by substituting readily available isotope-labeled reagents with non-isotope-labeled reagents. This is achieved by performing the procedures disclosed in the scheme and / or the following embodiments. It can be manufactured.

[0078] For example, if a specific enantiomer of a compound of this disclosure is desired, it can be synthesized asymmetrically. It can be prepared by or by induction using a chiral auxiliary agent, and here the obtained dia The stereomeric mixture is separated, and the auxiliary groups are cleaved to obtain the pure desired enantiomer. - Provides. Alternatively, the molecule has basic functional groups such as amino or carboxyl groups. If an acidic functional group is present, the diastereomer salt is formed with a suitable optically active acid or base. Then, the diastereomers formed in this manner are subjected to fractionation known in the art. Separation by crystallization or chromatography, followed by the pure enantiomer. To collect.

[0079] The compounds described herein may be substituted with any number of substituents or functional moieties. It will be understood that... Generally, the term "replaced" is preceded by the term "arbitrarily". Whether or not, and the substituents included in the chemical formula of the present invention are hydrogen in a given structure This refers to substituting a radical with a radical of a specific substituent. When the upper position can be replaced by two or more substituents selected from the specified group, The substituents may be the same or different at all positions. The term "substitution" is intended to include all permissible substituents in an organic compound. In a broader embodiment, permissible substituents include acyclic and cyclic, branched and non-cyclic substituents of organic compounds. The present invention includes branched, carbocyclic and heterocyclic structures, aromatic and non-aromatic structures, and substituents. This refers to organic compounds described herein in which a heteroatom such as nitrogen satisfies the valence of the heteroatom. The substance may have hydrogen substituents and / or any other permissible substituents. Furthermore, the present invention It is not limited in any sense by the substituents of organic compounds that are permissible. The combinations of substituents and variables envisioned by the present invention are preferably, for example, infection This process results in the formation of stable compounds useful in the treatment of sexually transmitted diseases or proliferative disorders. As used herein, the term “stable” preferably means “stable enough to enable manufacturing.” Having and being detectable for a sufficient period, preferably useful for the purposes detailed herein. This refers to a compound that maintains its integrity for a sufficient period of time.

[0080] The term "STAT3 inhibitor" as used herein is defined herein. When used, STAT3's ability to bind to molecules and / or be phosphorylated This includes, at least partially, interfering with the activity of STAT3 in order to perform one or more activities. Refers to one or more molecules.

[0081] As used herein, the term “pharmaceutically acceptable” is within the bounds of sound medical judgment. Within the enclosure, without excessive toxicity, irritation, allergic reactions, or other problems or complications. Suitable for use in contact with human and animal tissues, and in proportion to a reasonable benefit / risk ratio. The terms used herein to refer to exemplify compounds, materials, compositions, and / or drug formulations are... It can be done.

[0082] IR contributes to the development of complications in CKD patients, but the cellular mechanisms that cause IR are It is not yet understood. One mechanism involved is CKD-induced inflammation, and in CKD mice, the muscles... Activation of signaling transcription factor 3 (Stat3) in meat was identified. As a result, Stat3 activation disrupts insulin signaling through insulin receptor substrate 1 (IR). Fbx is a muscle-specific E3 ubiquitin ligase involved in the ubiquitination and degradation of S1. Increased o40 expression. Low molecular weight inhibitor of Stat3 in CKD or HFD mice. Administration of TTI101 affects glucose tolerance and insulin signaling in skeletal muscle. This results in significant improvement. Muscle-specific Stat3 KO mice also show improved glucose tolerance with HFD. The disease developed. The result was that Stat3 activation in muscle leads to the occurrence of IR (inflammation) in Fbxo40. This indicates that it will be upregulated.

[0083] This disclosure covers any type of insulin resistance, including insulin resistance associated with CKD. This relates to methods, compounds, and compositions for the treatment of (IR).

[0084] Method of disclosure Disclosed herein are, in particular embodiments, the individual requiring it A method for treating insulin resistance, including those at risk of insulin resistance. In some embodiments, individuals have insulin resistance as a result of their underlying condition. In some embodiments, insulin resistance is related to the muscles of an individual. In this context, insulin resistance may be due to any reason for the individual (e.g., free fatty acids in the blood). Elevated blood sugar, obesity, overweight, visceral fat, high fructose intake, inflammation Having, being inactive, having an abnormality in the gut microbiota, and / or a genetic predisposition It is caused by (a certain condition). Individuals at risk of insulin resistance have a higher blood sugar level. Elevated fatty acids, obesity, overweight, visceral fat, high fructose intake, inflammation, inactive This could be due to an abnormality in the gut microbiota and / or a genetic predisposition in that individual.

[0085] In some embodiments of this disclosure, the methods, compounds, and / or compositions of this disclosure This is to treat and / or prevent insulin resistance and / or related conditions. It is useful for this purpose, and in certain cases, such treatment is useful for Stat3 activity and / or This is caused by inhibiting expression. In some embodiments, the compounds of this disclosure are, for example It interacts with the Stat3 SH2 domain and its immobilized pY-peptide ligand. Competitively inhibits recombinant Stat3 binding and / or IL-6-mediated tyrosine of Stat3. It inhibits phosphorylation. In certain embodiments, the compounds and compositions of this disclosure interact. Criteria for Analysis (CIA) met: 1) Overall minimum energy score ≤ -30; 2) Sta Formation of salt bridges and / or H bond networks within the pY residue binding sites of t3; and / or 3) For example, the formation of an H bond with the amide hydrogen of Stat3 E638 or Blocking access to. In some embodiments, compounds and compositions have hydrophobic bond pockets. It interacts with the Stat3 SH2 domain.

[0086] The underlying conditions related to insulin resistance may or may not be present, and are known about the individual. It may or may not be done. Individuals who require treatment for insulin resistance should receive insulin. This may include individuals who have resistance to at least one symptom or related condition. or a state of insulin resistance or insulin resistance as a direct or indirect cause Having an underlying condition that may lead to insulin resistance or related conditions It may also be an individual that is prone to having the trait.

[0087] Embodiments of this disclosure relate to an individual known to have insulin resistance, insulin In individuals suspected of having insulin resistance, or individuals at risk of having insulin resistance, The method includes a method for treating sulin resistance. The compound is a low molecular weight STA as described herein. This includes T3 inhibitors and functional derivatives. In some embodiments, the individual is Related to insulin resistance (and may be a direct or indirect cause of insulin addition) ) He is receiving further treatment for his underlying condition.

[0088] In some embodiments, the individual often acts as a precursor or with at least one symptom. It is known that these individuals have an underlying state of insulin resistance, and these individuals are insulin-resistant. They may or may not show signs of phosphorus resistance. Individuals often act as precursors. Or, if the underlying condition has insulin resistance as at least one symptom, The body takes an effective amount of one or more of the compounds of this disclosure before and / or after the onset of insulin resistance. A substance or composition may be provided. An individual may take one or more compounds before the appearance of insulin resistance. Or, if a composition is provided, for example, the state of an individual that has not received the compound or composition and In comparison, the onset of insulin resistance or related conditions may be delayed or completely inhibited. and / or the severity of insulin resistance or related conditions may be reduced.

[0089] Individuals suspected of having insulin resistance (IR) or a related condition, The diagnosis may or may not be part of the procedure. Having insulin resistance. Individuals suspected of having the condition can be tested for insulin, for example, through a blood test to check blood glucose levels. This may or may not be used in determining whether or not a substance is phosphorus-resistant. Individuals are free to disclose this information. Prior to the law, insulin resistance may be clinically determined, but such determination (1) Waistline of 40 inches or more for men, and 35 inches or more for women; (2) 130 (3) Blood pressure reading of 80 or higher; (4) Fasting glucose level of 100 mg / dL or higher; (5) Fasting triglyceride levels of 150 mg / dL or higher; (6) Less than 40 mg / dL in men. (6) HDL cholesterol levels of 50 mg / dL or higher in women; (6) skin tags; and (7) Analysis of one or more symptoms of dark, velvety skin patches called acanthosis nigricans. It can include. Therefore, as a determination that an individual has insulin resistance, Fasting plasma glucose test, oral glucose tolerance test, and / or hemoglobin A1 It may be subjected to test c. If such tests have the following outcomes, the individual may be subjected to the Ins Possible phosphorus resistance: Fasting plasma glucose test of 100-125; Oral glucose Lucausal loading test: After the second test, blood pressure was 140-199; A1c result was 5.7%-6.4%. .

[0090] Following such a decision, the individual may be subjected to the methods encompassed by this disclosure.

[0091] In certain embodiments, the disclosed method relates to the risk of a medical condition associated with insulin resistance. Insulin resistance is a complication of insulin resistance that reduces the severity of insulin resistance or reduces the severity of insulin resistance. Reduces, at least partially, the risk or severity of sexually transmitted diseases, for example, severe hyperglycemia; severe Hypoglycemia; heart attack; stroke; kidney disease (including chronic, e.g., chronic kidney disease (CKD)); eye Problems; cancer; non-alcoholic fatty liver disease (NAFLD); polycystic ovary syndrome (PCOS) S); metabolic syndrome; diabetes; or Alzheimer's disease. This method is an injection Prevention of such medical conditions associated with phosphorus resistance (delaying their onset, their severity) This may enable a reduction in the degree of the condition, and / or enable more effective treatment of the condition. Embodiments of this disclosure reverse insulin resistance and thereby relate This includes methods for reducing the risk of having a medical condition. In a particular embodiment, individual He was given an effective dose of one or more STAT3 inhibitors, and as a result, insulin To reverse resistance and treat or reduce the risk of associated medical conditions.

[0092] In certain embodiments, individuals may have, for example, chronic kidney disease (CKD) compared to the general population. Or, there is a risk of it happening. Risk factors for CKD include insulin resistance, diabetes, This includes a family history of hypertension, heart disease, and / or renal failure. CKD is related to glomerulonephrosis. This is called glomerular filtration rate (GFR). This can be checked in a blood test that examines how well the kidneys are filtering the blood. A high GFR can indicate CKD. Another test for CKD is when the kidneys are damaged. There is a urine test that checks for albumin that can be excreted in the urine when the person is urinated, and it is 30 mg / g albumin. Measuring the above will reveal the presence of kidney damage.

[0093] In certain embodiments, insulin resistance is associated with metabolic syndrome and type 2 diabetes. This is a prominent characteristic, and individuals may require treatment or prognosis for metabolic syndrome or type 2 diabetes. Insulin resistance is directly or indirectly suppressed by one or more STAT3 inhibitors. Sexual health can be treated. Metabolic syndrome is associated with type 2 diabetes and heart disease. These are the risk factors for [the condition]. Symptoms include high blood triglycerides, high blood pressure, abdominal fat, and blood sugar, as well as H This includes a decrease in DL (good) cholesterol levels. One or more STAT3 inhibitors are present. The method of administration, in certain embodiments of this disclosure, stops the development of insulin resistance. This makes it possible to prevent metabolic syndrome and type 2 diabetes.

[0094] compound Disclosed herein, in a particular embodiment, one of the disclosures herein The administration of the above STAT3 inhibitor compounds is included in insulin resistance and This involves addressing the risks associated with the condition, and providing treatment, prevention, and / or other measures for individuals who need them. or is a method of reduction. Certain compounds are disclosed herein, but those skilled in the art will know It is recognized that functional derivatives of the compound are also included in the disclosure. When used herein, "a" means that one atom is replaced by another atom or group of atoms. In such cases, it can be considered to be formed from a compound that is similar to or from another compound. It is a compound that is formed. Derivatives can also be formed, at least theoretically, from the precursor compound. This can refer to compounds that can produce [the desired result]. Derivatives of the compounds disclosed herein may be used in specific embodiments. It has the ability to inhibit STAT3 directly or indirectly.

[0095] In certain embodiments, the STAT3 inhibitor compound is 4-[3-(2,3-dihydro-1,4 -benzodioxin-6-yl)-3-oxo-1-yl]benzoic acid; 4-[(3-ethino) Ru-4-oxo-1,3-thiazolidined-5-yllidene)methyl]-2-furyl]benzo Aromatic acid; 4-[(3-[(carboxymethyl)thio]-4-hydroxy-1-naphthyl}a Mino]sulfonyl]benzoic acid; 3-({2-chloro-4-[(1,3-dioxo-1,3 -Dihydro-2H-inden-2-yllidene)methyl]-6-ethoxyphenoxy}methyl Selected from the group consisting of benzoic acid ([3-(2-methoxy-2-oxoethyl )-4,8-dimethyl-2H-chromen-7-yl]oxy}methyl benzoate; 4-chrome Ro-3-{5-[(1,3-diethyl-4,6-dioxo-2-thioxotetrahydro- 5(2H)-pyrimidinylidene)methyl]-2-furyl}benzoic acid, its functionally active Derivatives and mixtures thereof.

[0096] In other embodiments, the STAT3 inhibitor compound is a compound according to formula I: [ka] or a pharmaceutically acceptable salt thereof In the formula, R1 and R2 may be the same or different, and may be hydrogen, carbon, sulfur, or nitrogen. Element, oxygen, fluorine, bromine, iodine, alkanes, cyclic alkanes, cyclic alkanes, alkenes, Cyclic alkenes, cyclic alkenes, alkene derivatives, alkynes, alkyne derivatives, ketones Ketone derivatives, ketone derivatives, aldehydes, aldehyde derivatives, carboxylic acids, Rubonic acid derivatives, ethers, ether derivatives, esters and ester derivatives, Mins, amino derivatives, amides, amide derivatives, monocyclic or polycyclic arenes, hetero Arenes, arene derivatives, heteroarene derivatives, phenols, phenol derivatives Selected from the group consisting of isomers, benzoic acid, and benzoic acid derivatives.

[0097] In some embodiments, the STAT3 inhibitor compound is a compound of chemical formula II. : [ka] or a pharmaceutically acceptable salt thereof In the formula, R1 and R3 may be the same or different, and may be hydrogen, carbon, nitrogen, sulfur, Oxygen, fluorine, chlorine, bromine, iodine, alkanes, cyclic alkanes, alkane-based derivatives Alkenes, cyclic alkenes, alkene-based derivatives, alkynes, alkyne-based derivatives Body, alkynes, alkyne-based derivatives, ketones, ketone-based derivatives, aldehydes, Aldehyde-based derivatives, carboxylic acids, carboxylic acid-based derivatives, ethers, ethers Amino-based derivatives, esters and ester-based derivatives, amines, amino-based derivatives Conductors, amides, amide-based derivatives, monocyclic or polycyclic arenes, heteroarenes. Arene derivatives, heteroarene derivatives, phenol, phenol derivatives, benzoic acid Selected from the group consisting of acids and benzoic acid derivatives, R2 and R4 may be the same or different. Often, hydrogen, alkanes, cyclic alkanes, alkane-based derivatives, alkenes, cyclic alke Alkene-based derivatives, alkynes, alkyne-based derivatives, alkynes, alkynes Base derivatives, ketones, ketone-based derivatives, aldehydes, aldehyde-based derivatives isomer, carboxylic acid, carboxylic acid-based derivative, ether, ether-based derivative, es Tel and ester-based derivatives, amines, amino-based derivatives, amides, amide-based Derivatives of acetone, monocyclic or polycyclic arenes, heteroarenes. Arene derivatives, heteroarenes. Roarene derivatives, phenol, phenol derivatives, benzoic acid, benzoic acid derivatives Selected from the following group.

[0098] In some embodiments, the STAT3 inhibitor compound is a compound of chemical formula III. ru: [ka] or a pharmaceutically acceptable salt thereof In the formula, R1, R2, and R3 may be the same or different, and may be hydrogen, carbon, nitrogen, or Oxygen, fluorine, chlorine, bromine, iodine, carboxyl, alkanes, cyclic alkanes, alpha Lukane-based derivatives, alkenes, cyclic alkenes, alkene-based derivatives, alkynes, Alkyne-based derivatives, alkynes, alkyne-based derivatives, ketones, ketone-based Derivatives, aldehydes, aldehyde-based derivatives, carboxylic acids, carboxylic acid-based derivatives Body, ether, ether-based derivatives, ester and ester-based derivatives, amine N, amino-based derivatives, amides, amide-based derivatives, monocyclic or polycyclic arrays Heteralene. Arene derivatives, heteroarene derivatives, phenol, pheno It is selected from the group consisting of benzoyl derivatives, benzoic acid, and benzoic acid derivatives.

[0099] In some embodiments, the STAT3 inhibitor compound is N-(1',2'-bina Phthalen-4'-yl)-4-methoxybenzenesulfonamide, N-(1,2'-dihydroxy Droxy-[1,2']binaphthaleneyl-4'-yl)-4-methoxybenzenesulfate Honamide, N-(5,1'-dihydroxy-[1,2']binaphthaleneyl-4'- (Lu)-4-methoxybenzenesulfonamide, N-(7,1'-dihydroxy-[1, 2']binaphthalenyl-4'-yl)-4-methoxybenzenesulfonamide, 4- Romo-N-(1,6'-dihydroxy-[2,2']binaphthalenyl-4-yl)-ben Zensulfonamide, and 4-bromo-N-[4-hydroxy-3-(1H-[1, 2,4]triazole-3-ylsulfanyl)-naphthalene-1-yl]benzenes Selected from the group consisting of luchonamide or a pharmaceutically acceptable salt thereof.

[0100] In some aspects, the STAT3 inhibitor compound is N-(1',2-dihydr Roxy-1,2'-binaphthalene-4'-yl)-4-methoxybenzenesulfonamide or a pharmaceutically acceptable salt thereof. In the example, TTI-101 refers to N-(1 ,2-dixy-1,2'-binaphthalen-4'-yl)-4-methoxybe This refers to sulfonamide.

[0101] In some embodiments, the STAT3 inhibitor compound is a compound of formula IV. [ka] Or a pharmaceutically acceptable salt thereof is listed. In the formula, the presence of each of R1 independently corresponds to hydrogen, halogen, cyano, nitro, CF3, and O CF3, OR a , SR a , C(=O)Ra ,OC(=O)R a , C(=O)OR a , NR b R c , NR b C(=O)R c , C(=O)NR b R c , NR b C(=O)OR c , OC (=O)NR b R c , NR a C(=O)NR b R c ,alkyl, alkenyl, cyclo Luquil, aryl as needed, or heterocyclic ring as needed. ; n1 is 0, 1, 2, 3, or 4; Each of the R2 entities is independently hydrogen, halogen, cyano, nitro, CF3, and OCF3. , OR a , SR a , C(=O)R a ,OC(=O)R a , C(=O)OR a , NR b R c , NR b C(=O)R c , C(=O)NR b R c , NR b C(=O)OR c OC(=O )NR b R c、 NR a C(=O)NR b R c , alkyl, alkenyl, cycloalkyl, Cycloalkenyl, optionally substituted aryl, optionally substituted aryl, or It is a complex algebra into which arbitrary substitutions are made; n2 is 0, 1, 2, 3, 4, or 5; R3 is hydrogen, halogen, cyano, nitro, CF3, OCF3, OR a , SR a , OC (=O)R a ,alkyl, alkenyl, cycloalkyl, or possibly substituted a It is either a reel or a heteroaryl; R4 is hydrogen, halogen, cyano, nitro, CF3, OCF3, OR a , SR a , NR b R c ,OC(=O)R a , alkyl, alkenyl, or cycloalkyl; The presence of R5, R6, and R7, respectively, independently corresponds to hydrogen, halogen, cyano, and nitro CF3, OCF3, OR a , SR a , C(=O)R a ,OC(=O)R a , C(=O) Ure a , NR b R c , NR b C(=O)R c , C(=O)NR b R c , NR b C(=O) Ure c , OC(=O)NR b R c , NR a C(=O)NR b R c ,alkyl, alkenyl cycloalkyl, optionally substituted aryl, or optionally substituted polyalkyl It is an elementary algebra; n3 is 0, 1, 2, 3, or 4. R a , R b and R c These are, independently, hydrogen, alkyl, cycloalkyl, and ammonium compounds. It is a kenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl; or the above R b and R c Together with the nitrogen atom to which they are bonded, they form 1 to 4 heteroatoms. We arbitrarily form a complex ring containing .

[0102] In any one or more embodiments of chemical formula IV, the generation of each R1 is independent. H, halogen, cyano, nitro, CF3, OCF3, OR a , or SR a That is the case.

[0103] In another embodiment of Equation IV, the presence of each R1 corresponds to C(=O)R 、 OC(=O)R a , C(=O)OR a , NR a R b , NR b C(=O)R a , C(=O)NR b R c , N R b C(=O)OR a , OC(=O)NR b R c , or NR a C(=O)NR b R c in be.

[0104] In any one or more embodiments of Chemical Formula IV, the presence of R1 is, in each case independently , alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally placed It is a complex ring that has been replaced.

[0105] In one or more embodiments of chemical formula IV, R1 is H.

[0106] In one or more embodiments of chemical formula IV, n1 is 0, 1, or 2. .

[0107] In one or more embodiments of chemical formula IV, n1 is 1.

[0108] In one or more embodiments of chemical formula IV, n1 is 0.

[0109] In any one or more embodiments of chemical formula IV, the presence of each R2 independently H, halogen, cyano, nitro, CF3, OCF3, OR a , or SR a That is the case.

[0110] In another embodiment of Equation IV, the presence of each R2 is C(=O)R a , OC (=O) R a , C(=O)OR a , NR a R b , NR b C(=O)R a , C(=O)NR b R c , NR b C(=O)OR a , OC(=O)NR b R c , or NR a C(=O)NR b R c That is the case.

[0111] In any one or more embodiments of Chemical Formula IV, the presence of R2 is independently , alkyl, alkenyl, cycloalkyl, optionally substituted aryl, or optionally placed It is a complex ring that has been replaced.

[0112] In one or more embodiments for chemical formula IV, R2 is H.

[0113] In one or more embodiments of chemical formula IV, n2 is 0, 1, or 2. .

[0114] In one or more embodiments of chemical formula IV, n2 is 1.

[0115] In one or more embodiments of chemical formula IV, n2 is 0.

[0116] In one or more embodiments of chemical formula IV, R3 is H, halogen, cyano, It's Nitro, or CF3.

[0117] In one or more embodiments of chemical formula IV, R3 is OCF3, OR a , SR a , or OC(=O)R a That is the case.

[0118] In one or more embodiments of Chemical Formula IV, R3 is alkyl, alkenyl, Alternatively, it is cycloalkyl.

[0119] In one or more embodiments of chemical formula IV, R3 is H.

[0120] In one or more embodiments of chemical formula IV, R4 is H, halogen, cyano, Nitro, or OR a That is the case.

[0121] In one or more embodiments of chemical formula IV, R4 is OCF3, SR a ,Also is OC(=O)R a That is the case.

[0122] In one or more embodiments of Chemical Formula IV, R4 is alkyl, alkenyl, Alternatively, it is cycloalkyl.

[0123] In another embodiment of the compound of chemical formula IV, R4 is OH.

[0124] In another embodiment of the compound of chemical formula IV, R4 is OMe.

[0125] In one or more embodiments of Chemical Formula IV, R5, R6, and R7 are... Each is independently selected from the group consisting of H, halogens, cyano, nitro, and CF3. .

[0126] In one or more embodiments of Chemical Formula IV, R5, R6, and R7 are OC F3, OR a , and SR a Each is independently selected from the group consisting of these elements.

[0127] In one or more embodiments of Chemical Formula IV, R5, R6, and R7 are OC F3 and OR a Each is independently selected from the group consisting of these elements.

[0128] In alternative embodiments of the compound of formula IV, R5, R6, and R7 are each independently C (=O)R a ,OC(=O)R a , C(=O)OR a , NR a R b , NR b C(=O)R a , C(=O)NR b R c , NR b C(=O)OR a , OC(=O)NR b R c , oyo NR a C(=O)NR b R c It is selected from the group consisting of the following.

[0129] In one or more embodiments of Chemical Formula IV, R5, R6, and R7 are each These are independently alkyl, alkenyl, cycloalkyl, optionally substituted aryl, and The group is selected from the group consisting of arbitrarily substituted complex algebras.

[0130] In one or more embodiments of Chemical Formula IV, each of R5, R6, and R7 Its existence is H.

[0131] In one or more embodiments of chemical formula IV, n3 is 0, 1, or 2. .

[0132] In one or more embodiments of chemical formula IV, n3 is 1.

[0133] In one or more embodiments of chemical formula IV, n3 is 0.

[0134] In one or more embodiments of Chemical Formula IV, R a The existence of each is independent of the others. It is hydrogen, alkyl, heterocyclic, or aryl.

[0135] In one or more embodiments of Chemical Formula IV, R a The existence of each is independent of the others. , hydrogen or alkyl.

[0136] In one or more embodiments of Chemical Formula IV, R b and R c Each existence They are independently hydrogen, alkyl, heterocyclic, or aryl.

[0137] In one or more embodiments of chemical formula IV, R b and R c Each of their existences These are independently halogens or alkyl groups.

[0138] In one or more embodiments of Chemical Formula IV, R b and R c They combine Along with the nitrogen atom present, 1 to 4 atoms are selected from the group consisting of N, O, and S. A heterocycle containing heteroatoms is formed of any choice.

[0139] In any one or more embodiments described herein, STAT3 inhibitor - The compound has the structure of chemical formula V: [ka] or a pharmaceutically acceptable salt thereof.

[0140] In one or more embodiments of chemical formula V, R2 is H, OH, alkyl, or aldehyde. Coxi, halogen, NR b R c , CF 3、 It is OCF3 or CN.

[0141] In one or more embodiments of chemical formula V, R2 is NH2, OH, OMe, O It is Et, OCH2CH2CH3, or OCH(CH3)2.

[0142] In one or more embodiments of chemical formula V, R2 is hydrogen, methyl, ethyl, and p Ropil, tert-butyl, F, Cl, Br, CF3, nitro, methoxy, ethoxy, O CF3, -C(=O)Me, -C(=O)OMe, -NHC(=O)Me, 1,4-dio Xanyl, cyclohexanyl, cyclohexenyl, phenoxy, 2-methoxyphenoxy , 3-methoxyphenoxy, 4-methoxyphenoxy, 2-chlorophenoxy, 3-chloro 4-chlorophenoxy, 4-methylphenoxy, 3-methylphenoxy, The group is selected from the group consisting of and 4-methylphenoxy.

[0143] In one or more embodiments of chemical formula V, R2 is OMe.

[0144] In one or more embodiments of chemical formula V, R3 is H, OH, alkyl, or aldehyde. It is a coxy or halogen.

[0145] In one or more embodiments of chemical formula V, R3 is H.

[0146] In one or more embodiments of chemical formula V, R4 is H, alkyl, OH, or NH. 2. It is an alkoxy, halogen, CF3, or CN.

[0147] In one or more embodiments of chemical formula V, R4 is H, OH, or alkoxy It is C.

[0148] In one or more embodiments of chemical formula V, R4 is OH.

[0149] In one or more embodiments of chemical formula V, R4 is OMe.

[0150] In any one or more embodiments described herein, STAT3 inhibitor - The compound has the structure of chemical formula VI. [ka] or a pharmaceutically acceptable salt thereof.

[0151] In any one or more embodiments described herein, the compound is the chemical shown in Table 1a. Selected from the group consisting of compounds or pharmaceutically acceptable salts thereof.

[0152] In any one or more embodiments described herein, STAT3 inhibitor - The compound is selected from the group consisting of the compounds in Table 1b or their pharmaceutically acceptable salts. ru.

[0153] In some embodiments, the compound of formula IV is an example of the compound shown in Table 1a, and The compound is selected from its pharmaceutically acceptable salts. The compounds listed in Table 1a are of chemical formula IV. This is a representative and non-restrictive example of a compound. [Table 1] JPEG2026048875000009.jpg173128

[0154] In some embodiments, the compound of formula V is an example of the compounds shown in Table 1b, or It is selected from the pharmaceutically acceptable salts. The compounds listed in Table 1b are compounds of formula V. This is a representative and non-restrictive example. [Table 2] JPEG2026048875000011.jpg149140

[0155] The Stat3 inhibitor intended in this invention is one of the following in the table below. Including non-complexization with structure: [Table 3] JPEG2026048875000013.jpg220160JPEG2026048875000014.jpg213156 JPEG2026048875000015.jpg 222 158 JPEG2026048875000016.jpg 209 169 JPEG2026048875000017.jpg 214 158 JPEG2026048875000018.jpg 228 159 JPEG2026048875000019.jpg 225 160 JPEG2026048875000020.jpg 205 161 JPEG2026048875000021.jpg 205 157 JPEG2026048875000022.jpg 242 160 JPEG2026048875000023.jpg 237 163 JPEG2026048875000024.jpg 208 169 JPEG2026048875000025.jpg 228 165 JPEG2026048875000026.jpg 226 158 JPEG2026048875000027.jpg 232 153 JPEG2026048875000028.jpg 231 155 JPEG2026048875000029.jpg 242 149 JPEG2026048875000030.jpg 184 153 JPEG2026048875000031.jpg 240 150 JPEG2026048875000032.jpg 249 150 JPEG2026048875000033.jpg 235 160 JPEG2026048875000034.jpg 134 141

[0156]

Table 4

[0157]

Table 5

[0158]

Table 6

[0159]

Table 7

[0160]

Table 8

[0161] Any chemicals disclosed herein for use in conjunction with any method disclosed herein The mixture is delivered by any suitable route, including systemic or topical, but in certain embodiments For example, the delivery routes are oral, intravenous, local, subcutaneous, intra-arterial, intraperitoneal, oral cavity, aerosomal This includes exposure to stimulants, inhalation, etc.

[0162] The individuals used in the method disclosed herein are exposed to one or more doses of STAT3 inhibitors. Furthermore, each dose may contain one or more STAT3 inhibitors. Multiple doses may contain 1 to Any appropriate interval during that time, such as 24 hours, 1-7 days, 1-4 weeks, or 1-12 months between doses. It can be taken over a short period of time. Multiple dosages are available, such as daily, weekly, bi-weekly, monthly, and yearly. It is possible. An individual may be administered one STAT3 inhibitor at a specific dose, and different... A STAT3 inhibitor may be administered in subsequent doses.

[0163] In certain embodiments, any Stat3 inhibitor for a treatment or prevention method The appropriate dose for this is approximately 25-50 mg / kg or for an individual weighing 70 kg. The amount is 1.75 to 3.5 grams. In other embodiments, regarding insulin resistance, Stat 3. The inhibitor dose is less than 25-50 mg / kg for an individual weighing 70 kg or 1 It is between 0.75 and 3.5 grams.

[0164] Combination therapy In some embodiments of the methods disclosed herein, the method is used to treat another insulin resistance Treatment or prevention, and / or treatment for underlying conditions related to insulin resistance. This further includes administering additional drugs or treatment methods. Compound (STAT3 inhibitor) (Whether or not it is necessary) may be, for example, at intervals ranging from a few minutes to several weeks, in conjunction with other drug treatments. It may precede or follow. Other agents and compounds of the present disclosure that have insulin resistance When delivering to individuals suspected of having insulin resistance, or Individuals with insulin resistance, such as those at risk of developing insulin resistance, may require separate treatment. In the embodiments used, the agents and compounds of this disclosure generally combine favorably with an organism. A significant period of time should be between each delivery so that the effect can still be exerted. Ensure that it does not expire.

[0165] In certain embodiments, the individual is subjected to the STAT3 inhibitor method of this disclosure. Furthermore, to treat or reverse insulin resistance and / or any related medical conditions. It is used in conjunction with one or more other treatments. Examples include exercise, smoking cessation, reduced sugar intake, and a healthy diet. These include increasing omega-3 fatty acid intake, reducing stress, or a combination of both.

[0166] In certain embodiments, cells, tissues, or organisms are subjected to substantially simultaneous interaction with the compounds of this disclosure. (That is, within approximately one minute) one, two, three, four or more touches It is intended that this may be possible. In another embodiment, one or more agents administer the compounds of the Disclosure. Before and / or after administration, wait approximately 1 minute, 5 minutes, 10 minutes, 20 minutes, and 45 minutes. Approximately 60 minutes, approximately 2 hours, approximately 3 hours, approximately 4 hours, approximately 5 hours, approximately 6 hours, approximately 7 hours, approximately 8 hours, Approximately 9 hours, approximately 10 hours, approximately 11 hours, approximately 12 hours, approximately 13 hours, approximately 14 hours, approximately 15 hours Approximately 16 hours, approximately 17 hours, approximately 18 hours, approximately 19 hours, approximately 20 hours, approximately 21 hours, approximately 22 hours Time, approximately 23 hours, approximately 24 hours, approximately 25 hours, approximately 26 hours, approximately 27 hours, approximately 28 hours, approximately 29 hours, approximately 30 hours, approximately 31 hours, approximately 32 hours, approximately 33 hours, approximately 34 hours, approximately 35 hours Approximately 36 hours, approximately 37 hours, approximately 38 hours, approximately 39 hours, approximately 40 hours, approximately 41 hours, approximately 42 hours Time: Approximately 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, or within 48 hours. , or may be administered within a certain period. In certain other embodiments, the drug may be, for example, Approximately 1 day, approximately 2 days, approximately 3 days, approximately 4 days, approximately before and / or after administration of the compounds disclosed herein. 5th, approximately 6th, approximately 7th, approximately 8th, approximately 9th, approximately 10th, approximately 11th, approximately 12th, approximately 13th, approximately Within the following timeframes: 14th, 15th, 16th, 17th, 18th, 19th, 20th, and 21st It may be administered. In some situations, several weeks (for example, about a week) may be used between each administration. Approximately 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more In some cases, such as when the following period has elapsed, it may be desirable to significantly extend the treatment period. In this situation, several months may pass between each administration (for example, about 1 week, about 2 weeks, about 3 weeks, about If 4 weeks, approximately 5 weeks, approximately 6 weeks, approximately 7 weeks, or approximately 8 weeks or more have passed, In some cases, it is desirable to significantly extend the treatment period.

[0167] The administration of the therapeutic compounds disclosed herein to an individual is subject to general considerations for drug administration, taking toxicity into account. Follow the protocol. The treatment cycle is expected to be repeated if necessary.

[0168] STAT3 inhibitor formulations Pharmaceutical compositions for use in conjunction with the methods disclosed herein are pharmaceutically acceptable. One or more STAT3 inhibitors disclosed herein, dissolved or dispersed in a carrier Contains an effective amount of tar. The term "pharmaceutically or pharmacologically acceptable" means that the animal (for example, When administered to humans, it may cause harmful, allergic, or other adverse reactions. This refers to molecular entities and compositions that do not result in the formation of a STAT3 inhibitor. Preparation of pharmaceutical compositions is Remington: The Science and Practice ice of Pharmacy, 21 st Ed. Lippincott Willi As illustrated by ams and Wilkins, 2005, this disclosure is relevant to those skilled in the art. It is publicly known. Furthermore, for administration to animals (e.g., humans), the preparation is FDA-approved. Meets sterility, pyrogenicity, general safety, and purity standards as required by the quasi-governmental authority. It is understood that it should be done.

[0169] As used herein, “pharmaceutically acceptable carrier” means any carrier of the art all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents) Agents, antifungal agents, isotonic agents, absorption retarders, salts, preservatives, drugs, drug stabilizers, gels, binders, Contains excipients, disintegrants, lubricants, and sweeteners (e.g., Remington's Pharmaceutical Science) s, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329 (in this specification) See (referenced for reference). Except for the above, its use in pharmaceutical compositions is intended.

[0170] The compositions comprising the STAT3 inhibitor disclosed herein may be solid, liquid, or ethereal. Whether it should be administered in allosol form, and whether it should be sterile for administration routes such as injection. Depending on whether it is necessary, it may include different types of carriers. The present invention is for intravenous, cutaneous use. Internal, intradermal, intraarterial, intraperitoneal, intranasal, transnasal, intrarectal, local, intramuscular, subcutaneous, intramucosal, oral Local, inhalation (e.g., aerosol inhalation), injection, infusion, continuous infusion, local perfusion bath target cells The solution is then applied via a catheter to wash, in a cream, or in a lipid composition (e.g., liposomes). Alternatively, administer directly by other methods known to those skilled in the art or any combination of the above. (For example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Print) (ing Company, 1990, incorporated herein by reference).

[0171] Compositions containing STAT3 inhibitors are formulated in the form of free bases, neutrals, or salts. It can be converted into an acid addition salt. Pharmaceutically acceptable salts include acid addition salts, for example, protein compounds. Formed by the free amino groups of the compound, or inorganic acids, such as hydrochloric acid or phosphoric acid, Examples include those formed from organic acids, such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. Salts formed with free carboxyl groups can also be formed with inorganic bases (e.g., sodium hydroxide). Um, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide); or organic bases (e.g., isopropylamine, trimethylamine, histidine or p) It can be derived from (locaine). When prescribing, the solution should be in a form that conforms to the administration prescription, and the treatment It will likely be administered in a dose that is therapeutically effective. The preparation will be administered as a parenteral solution, such as an injectable solution. It can be easily administered in various dosage forms, such as formulations for administration or aerosols for delivery to the lungs. It is administered or formulated for digestive administration, such as in drug-release capsules.

[0172] Furthermore, according to this disclosure, the composition of this disclosure suitable for administration depends on the presence or absence of an inert diluent. However, it is provided in a pharmaceutically acceptable carrier. The carrier should be assimilated and liquid. A body, semi-solid, i.e., paste, or solid carrier. Any conventional medium, drug, dilution. If the agent or carrier is detrimental to the therapeutic efficacy of the recipient or the composition contained therein Except in cases of use in carrying out the methods disclosed herein, the use of the dosable composition thereof Appropriate use is required. Examples of carriers or diluents include fats, oils, water, physiological saline solution, lipids, etc. The composition includes posomes, resins, binders, fillers, or combinations thereof. Furthermore, it may contain various antioxidants to slow down the oxidation of one or more components. The action of microorganisms is prevented by parabens (e.g., methylparaben, propylparaben), chloro Contains butanol, phenol, sorbic acid, thimerosal, or a combination thereof. However, this is brought about by various preservatives, including antibacterial and antifungal agents, which are not limited to these. obtain.

[0173] According to this disclosure, compositions can be expressed in any convenient and practical form, namely, as solutions, suspensions, It is combined with a carrier through emulsification, mixing, encapsulation, absorption, etc. The order is commonplace for those skilled in the art.

[0174] In certain embodiments of this disclosure, the composition is fully combined with a semi-solid or solid carrier. They are either separated or mixed. Mixing can be done by any convenient method such as grinding. Stabilizers also protect the composition from loss of therapeutic activity, i.e., degeneration in the stomach. Therefore, it can be added in the mixing process. Examples of stabilizers for use in compositions It contains buffering agents, amino acids such as glycine and lysine, dextrose, mannose, and galangal. Cactose, fructose, lactose, sucrose, maltose, sorbitol, mannitol Examples of carbohydrates include tall.

[0175] In further embodiments, the present disclosure provides one or more STAT3 inhibitors and an aqueous solvent. This specification may relate to the use of pharmaceutical lipid vehicle compositions containing the following: The term "lipid" refers to a wide range of substances that are characteristically insoluble in water and can be extracted with organic solvents. It is defined as including any of the following. This broad class of compounds is well known to those skilled in the art, and the terminology is... As used herein, "lipids" are not limited to any specific structure. For example... Examples include compounds containing long-chain aliphatic hydrocarbons and their derivatives. Lipids are natural It may exist naturally or be synthesized (i.e., designed or produced by humans). However, lipids are usually biological substances. Biological lipids are well known in this field. And for example, triglycerides, phospholipids, ringglycers, steroids, terpenes, Lysolipids, glycosphingolipids, glycolipids, sulfatides, ethers and ester bonds This includes lipids containing fatty acids, polymerizable lipids, and combinations thereof. Of course, other compounds not specifically described herein that are understood by those skilled in the art as lipids. Compounds are also included in the compositions and methods of the present invention.

[0176] Those skilled in the art will know the range of techniques that can be used to disperse a composition in a lipid vehicle. They are likely well-versed in this. For example, one or more STAT3 inhibitors are publicly known to those skilled in the art. By any means of knowledge, containing lipids, dissolved in lipids, dissolved in lipids, milk in lipids Modified, mixed with lipids, bound to lipids, covalently bonded to lipids, suspension in lipids Contained as a liquid, contained in micelles or liposomes, or complexed, If not, lipids or lipid-associated substances can be dispersed in a liquid. The dispersion is liposomes. It may or may not lead to the formation of [something].

[0177] Actual dosages of the compositions of this disclosure administered to animal patients depend on body weight, severity of condition, and treatment. The type of disease being treated, previous or concurrent therapeutic interventions, the patient's idiopathic nature, and physical factors such as the route of administration. and may be determined by physiological factors. Depending on the dose and route of administration, the preferred dose The number of doses and / or effective doses may vary depending on the subject's response. The responsibility for administration rests with the individual. In any case, the physician will determine the concentration of the active ingredient in the composition and the appropriateness for each individual subject. Determine the appropriate dosage.

[0178] In certain embodiments, the pharmaceutical composition comprises, for example, at least about 0.1% of the active compound. In other embodiments, the active compound is present in an amount of about 2% to about 75% of the unit weight, or, for example, This includes approximately 25% to 60%, and any range that can be derived within that range. Yes, it is possible. Naturally, the amount of active compound in each therapeutically useful composition depends on the compound. It can be prepared in a manner that allows for the acquisition of an appropriate dosage at a given unit dose. , bioavailability, biological half-life, route of administration, product shelf life, and other drugs Factors such as physical considerations are intended by those skilled in the art who prepare such pharmaceutical formulations, and Various dosages and treatment regimens may be desired.

[0179] In other non-limiting examples, the dose is also approximately 1 microgram / kg body weight, or approximately 5 micrograms. micrograms / kg body weight, approximately 10 micrograms / kg body weight, approximately 50 micrograms / kg body weight Weight, approximately 100 micrograms / kg body weight, approximately 200 micrograms / kg body weight, approximately 350 micrograms / kg body weight, approximately 500 micrograms / kg body weight, approximately 1 milligram / kg Body weight, approximately 5 mg / kg; Body weight, approximately 10 mg / kg; Body weight, approximately 50 mg / kg g body weight, approximately 100 mg / kg body weight, approximately 200 mg / kg body weight, approximately 350 mg grams / kg body weight, approximately 500 milligrams / kg body weight, approximately 1000 mg / kg body weight, or This may include more than / amount of doses and any range that can be induced therein. Enumerated herein In non-limiting examples of the derivable range from the given number, approximately 5 mg / kg / body weight to approximately 100 mg / kg / body weight, approximately 5 micrograms / kg / body weight to approximately 500 milligrams / kg / body weight These ranges can be administered based on the above numbers.

[0180] Compositions and preparations for the digestive system In preferred embodiments of this disclosure, one or more STAT3 inhibitors are located in the digestive pathway. It is prescribed to be administered via the gastrointestinal route. The gastrointestinal route is one in which the composition comes into direct contact with the gastrointestinal tract. This includes all possible routes of administration. Specifically, the pharmaceutical compositions disclosed herein. However, they may be administered orally, orally, rectally, or sublingually. The composition may be formulated with an inert diluent or an assimilated food carrier, or These may be encapsulated in hard-shell or soft-shell gelatin capsules, or These may be compressed into tablets, or they may be directly incorporated into dietary foods.

[0181] In certain embodiments, the active compound may be mixed with an excipient to form an ingestible tablet or oral tablet. It is used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. It can be used (Mathiowitz et al., 1997; Hwang et al., 1998; US Pat.5,641,515;5,580,579 and 5,792,451 (each (The whole is incorporated specifically herein by reference). Tablets, lozenges, pills, etc. Capsules may also contain the following: for example, tragacanth rubber, ara Binders such as gum, cornstarch, gelatin, or combinations thereof; for example , dicalcium phosphate, mannitol, lactose, starch, magnesium stearate Sodium saccharin, cellulose, magnesium carbonate, or combinations thereof. Excipients such as corn starch, potato starch, alginic acid, or the like; for example, corn starch, potato starch, alginic acid, or the like. Disintegrants such as combinations of these; for example, lubricants such as magnesium stearate; for example Sweeteners such as sucrose, lactose, saccharin, or combinations thereof; for example It has a peppermint, wintergreen oily flavor, cherry flavor, and orange flavor. - Flavoring agents such as: If the unit dosage form is a capsule, in addition to the above substances, It may contain a liquid carrier. Various other substances may be used as a coating or as an agent. A shape may exist to change its form. For example, tablets, pills, or capsules may exist to change their shape. It can be coated with lac, sugar, or both. If the medication form is a capsule, In addition to the above-mentioned types of substances, it may also contain carriers such as liquid carriers. Gelatin Capsules, tablets, or pills may be enterically coated. Enteric coating is , preventing the denaturation of the composition in the stomach or upper intestine where the pH is acidic. For example, in the United States See 5,629,001. When it reaches the small intestine, the basic pH inside is coated. The ing is dissolved, and the composition is released, and then special cells (e.g., epithelial intestinal cells and It allows absorption by Peyer's patch M cells. The elixir syrup is active. Sucrose compound is used as a sweetener, methyl and propylparaben as preservatives, and dyes are used. and may contain flavorings (e.g., cherry or orange flavoring). Any substance used in the preparation of any of the unit dosage forms must be of a purity suitable for pharmaceutical use. It must be highly toxic and sufficiently non-toxic in the amount used. Furthermore, the active compound must be sustained-release. It can be incorporated into property preparations and formulations.

[0182] For oral administration, the STAT3 inhibitor composition of this disclosure may be used instead of an oral rinse. In the form of toothpaste, oral tablets, oral spray, or sublingual oral formulations, one or more excipients It may be incorporated together with the agent. For example, sodium borate solution (Dobell's solution). A mouthwash can be prepared by incorporating the required amount of active ingredient into a suitable solvent such as [mention a suitable solvent]. Alternatively, the active ingredients may include sodium borate, glycerin, and potassium bicarbonate. It can be incorporated into oral solutions such as, dispersed in toothpaste, or mixed with water, binders, abrasives, It can be added in therapeutically effective amounts to compositions that may contain fragrances, foaming agents, and humectants. Alternatively, the composition may be placed under the tongue or dissolved in the mouth in tablet form. It can be formed in solution form.

[0183] Further formulations suitable for other modes of digestive administration include suppositories. Suppositories are inserted rectally. For this purpose, it is a solid medication form that is usually medicinal and comes in various weights and shapes. After insertion, the suppository is in the cavity. In liquids, it softens, melts, or dissolves. Generally, for suppositories, traditional Typical carriers include, for example, polyalkylene glycols, triglycerides, or combinations thereof. This may include combinations. In certain embodiments, the suppository may contain, for example, about 0.5% to about 10%, preferably Alternatively, it may be formed from a mixture containing an active ingredient in the range of approximately 1% to 2%.

[0184] Parenteral compositions and formulations In a further embodiment, one or more STAT3 inhibitors are transmitted via parenteral pathways. It may be administered by bypassing the gastrointestinal tract. As used herein, the term "parenteral" means that it bypasses the gastrointestinal tract. This includes routes such as intravenous and intradermal administration. Specifically, the pharmaceutical compositions disclosed herein may be administered intravenously or intradermally. It may be administered intramuscularly, intra-arterially, intrathecally, subcutaneously, or intraperitoneally, but is not limited to these. i (US 6,7537,514,6,613,308, 5,466,468, 5, 543,158; 5,641,515; and 5,399,363 respectively, the whole (This is incorporated herein by reference.)

[0185] A solution of the active compound as a free base or pharmacologically acceptable salt is hydroxypro It can be prepared in water appropriately mixed with a surfactant such as pyrucellulose. In licerol, liquid polyethylene glycol, and mixtures thereof, a dispersion is prepared in oil. They can also be prepared. Under normal storage and use conditions, these preparations will not increase the number of microorganisms. Contains preservatives to prevent proliferation. Suitable pharmaceutical forms for injectable use are sterile aqueous solutions or fractions. Includes sterile powder for the immediate preparation of powders and sterile injectable solutions or dispersions (US Special Patent). License No. 5,466,468 (which is incorporated herein by reference in its entirety). In all cases, this form must be sterile and easily injectable. It must be liquid to a certain extent. It must be stable under manufacturing and storage conditions. It must be protected from contamination by microorganisms such as bacteria and fungi. No. The carrier is, for example, water, ethanol, polyol (i.e., glycerol, polyol). Polypropylene glycol and liquid polyethylene glycol, etc., and suitable mixtures thereof. , and / or a solvent or dispersion medium containing vegetable oil. Suitable fluidity is, for example For example, by using a coating such as lecithin, the required particles in the case of a dispersion can be removed. Maintaining the size, and maintaining it by using surfactants. Yes, it is possible. Prevention of microbial activity can be achieved with various antibacterial and antifungal agents, such as parabens and chlorophyll. This can be done using tanol, phenol, sorbic acid, thimerosal, etc. In many cases, etc. It is preferable to include a tensor, such as sugar or sodium chloride. The absorption of the injectable mixture is by injection. An absorption retarder, such as aluminum stearate or gelatin, is added to the mixture. This makes it possible to extend the extension.

[0186] For parenteral administration in aqueous solution, for example, the solution should be appropriately buffered if necessary. And the liquid diluent is first made isotonic with a sufficient amount of physiological saline or glucose. These specific aqueous solutions are specifically for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. Suitable for. In connection therewith, the sterile aqueous media that can be used are, in light of this disclosure This is probably known to those skilled in the art. For example, one dose is dissolved in an isotonic NaCl solution. It can be added to the subcutaneous injection solution or injected into the proposed site of injection (e.g.) For example, "Remington's Pharmaceutical Sciences" (See pages 1035-1038 and 1570-1580 of the 15th edition.) Depending on the condition of the subject being treated, some degree of dose variation may inevitably occur. Even so, the person in charge of administration determines the appropriate dose for each individual subject. Furthermore, for human administration For this to be possible, the formulation must meet the sterility, pyrogenicity, and general safety standards required by the FDA's Biologics Administration. And it must meet purity standards.

[0187] The sterile injection solution is prepared by dissolving the required amount of the active compound together with the various other components exemplified above in a suitable solvent. It is prepared by compounding and, if necessary, subsequently by sterilizing by filtration. Generally, a dispersion. This is a sterilization medium containing the basic dispersion medium and other necessary components from those listed above. It is prepared by incorporating various sterile active ingredients into the body. Preparation of sterile injection solution. For sterile powders, a preferred preparation method is to use a powder of the active ingredient + a previously sterile filtered powder. This is a vacuum drying and freeze-drying technique that produces any further desired components from a prepared solution. The powder composition, with or without a stabilizer, can be carried by a liquid carrier such as water or saline solution. It gets mixed with it.

[0188] Other pharmaceutical compositions and formulations In other specific embodiments of this disclosure, the STAT3 inhibitor may have various different paths, e.g. For example, by topical (i.e., transdermal) administration, mucosal administration (intranasal cavity, vagina, etc.), and / or by inhalation. It may be formulated for administration.

[0189] Pharmaceutical compositions for topical administration include ointments, pastes, creams, or powders. It may contain active compounds formulated for use. The ointment is all oily for topical application. This includes adsorbent, emulsion, and water-soluble based compositions, as well as creams and lotions. This is a composition containing only an emulsion base. Drugs administered topically pass through the skin. It may contain a penetration enhancer that facilitates the adsorption of the active ingredient. Suitable penetration enhancers include glycerin. It contains alcohol, alkylmethyl sulfoxide, pyrrolidone, and luarocaprum. Possible bases for compositions for topical application include polyethylene glycol. Lanolin, cold cream and petrolatum, as well as any other suitable absorbent, emulsion. Examples include ointment bases or water-soluble ointment bases. Topical preparations also preserve the active ingredient and To provide a homogeneous mixture, emulsifiers, gelling agents, and antimicrobial preservatives are added as needed. It may include. Transdermal administration of the present invention may also include the use of a “patch”. For example, a patch is One or more active substances are dispensed at a predetermined rate and in a continuous manner over a fixed period of time. It can be supplied.

[0190] In certain embodiments, the pharmaceutical composition is used as eye drops, intranasal spray, inhalation, and / or It can also be delivered by other aerosol delivery vehicles, via nasal aerosol spray. Methods for directly delivering a composition to the lungs include, for example, U.S. Patent No. 5,756,353 The following are described in 5,804,212 (each in its entirety as described herein by reference). (Physically supported). Similarly, intranasal microparticle resin (Takenaga et al., 1998) and Lysophosphatidyl-glycerol compounds (U.S. Patent No. 5,725, 871, in particular) The delivery of drugs using (the entirety of which is incorporated herein by reference) is also a pharmaceutical technology. This is well known in the field. Similarly, the form of the polytetrafluoroethylene support matrix. Transmucosal drug delivery is described in U.S. Patent No. 5,780,045 (see the full text for reference). (As specifically incorporated herein by reference).

[0191] The term aerosol refers to finely divided liquid particles dispersed in a liquefied or pressurized gas propellant. This refers to a solid colloid system. A typical aerosol of the present invention for inhalation is a liquid propellant in It consists of a suspension of the active ingredient, or a mixture of a liquid propellant and a suitable solvent. This includes hydrocarbons and hydrocarbon ethers. A suitable vessel shall conform to the pressure requirements of the propellant. It changes. Aerosol administration depends on the age, weight, and severity of symptoms of the subject. It changes depending on the answer.

[0192] Disclosure kit Any of the compounds or compositions described herein may be included in the kit. In a typical example, the kit includes one or more Stat3 inhibitors. 3. Inhibitor components can be packaged in either an aqueous medium or a lyophilized form. The kit's container means generally includes at least one vial, test tube, flask, bottle, or silicone bottle. It includes a range or other container device, in which a Stat3 inhibitor can be placed. Preferably, it can be appropriately divided into equal parts. If there are two or more components in the kit, The kit also typically includes a second, third, or other additional container containing additional ingredients. These can be arranged separately. However, various combinations of components can be included in a single vial. It may also be necessary to use a commercial container for Stat3 inhibitor and any other reagents. Includes means for sealing and storing for commercial sale. Such containers are the desired bags This includes injection-molded or disposable plastic containers containing ial.

[0193] The Stat3 inhibitor in the kit can be supplied as a dry powder. Reagents and If the ingredients are provided as a dry powder, the powder can be dissolved by adding a suitable solvent. It can be reconstituted. It is assumed that the solvent is also provided in another container. Yes, they are.

[0194] Regardless of the number and / or type of containers, the kits of this disclosure also contain the contents of an animal body. It may include devices for assisting in the injection / administration and / or placement of the final composition, / or may be packaged together with the instrument. Such instruments include syringes, pipettes, forceps, and / or any such medically approved delivery vehicle. [Examples]

[0195] The following examples are included to illustrate preferred specific examples of the present invention. The disclosed technology has been found by the inventors to function well in carrying out the present invention. This represents the technology described and therefore constitutes a preferred form for carrying out the present invention. It should be understood by those skilled in the art that this can be obtained. However, those skilled in the art will understand this In consideration of the disclosure of the invention, in specific embodiments that are disclosed and yield similar results, the present invention It is understandable that many changes are possible without deviating from the spirit and scope of the Ming Dynasty. It is likely.

[0196] Example 1 Underlying mechanisms of insulin resistance development in CKD or high-fat diet models method

[0197] Animals: The experimental procedure was approved by the Animal Experimentation Committee of Baylor College of Medicine. Wild-type (WT) The mouse (C57BL / 6) was bred at Jackson Lab (Bar Harbor, ME). I purchased it from [source]. In order to create a model of CKD, I used 8-10 week old mice as described. The patient underwent subtotal nephrectomy or sham surgery management; had a BUN level of ~80 mg / dl. 31 CKD We studied mice. CKD or sham surgery control mice were assigned to two subgroups: 1. One subgroup received TTI-101 (12.5 mg / kg body weight at D5W) every other day for two weeks. Intraperitoneal injection was administered, but another subgroup received the same dose of D5W for two weeks.

[0198] Wild-type mice were fed a high-fat diet (HFD: 58% fat-derived, Research Di (ets, New Brunswick, NJ) was given to control mice on a normal diet (R A different model of insulin resistance was created by administering (D: 11% kcal derived from fat). To study the effect of p-Stat3 on insulin resistance, we used HFD-fed mice. Two subgroups were randomly assigned: one subgroup was TTI-101(D5 W administered 12.5 mg / kg body weight intraperitoneally (IP) every other day for 4 weeks, but other subacute doses were also administered. The group received the same dose of D5W for four weeks.

[0199] Stat3 KO mice are mice that express Floxed-Stat3, as described above. To achieve this, cross them with mice that express muscle creatine kinase Cre (MCK-Cre). It was created by the following: 33 From 4 weeks of age, Floxed-Stat3 or Sta T3 KO mice were given HFD for 16 weeks.

[0200] For the glucose tolerance test (GTT), mice were given free access to water for 16 hours. The animal was fasted, then 2 mg / kg of glucose was administered intraperitoneally (IP) and tail vein blood was reduced to zero. Collected at 30, 60, and 120 minute intervals using True Track Glucomet. Blood glucose concentration was measured using an ER for the insulin loading test (ITT). The mice were fasted for 4 hours, then given 2 units / kg of insulin via IP injection; 0, 3 Tail vein blood was collected at 0, 60, and 120 minutes and blood glucose concentration was measured. Change, Statstodo Program (http: / / www.statstodo.com / A The analysis was performed using the "Area Under the Curve" (AUC) method with UC_Exp.php).

[0201] Cell culture: Mouse C2C12 myoblasts are American Type Cultur Obtained from e Collection (ATCC, Manassas, VA). Cells The Invitrogen Neon transfection system (Invitrog Using Madison, Wisconsin, Fbxo40 SiRNA(S anta Cruze Biotechnology, Dallas, TX) or C2C12 myoblasts were transfected with control siRNA. The cells are grown to 85% confluence, then treated with DMEM + 2% HS and 1% P / S. Differentiation culture consisting of (PS; Invitrogen Madison, Wisconsin) Switched to ground. Myotubes were treated with 100 ng / ml IL-6 (Biolegend, San The cells were treated for 24 hours with or without Diego (CA). The lysates were then blotted in a Western blot. It was used for testing.

[0202] Luciferase reporter assay: Human Fbxo40 promoter, GeneCo Gaussia-L obtained from poeia, Inc. (Rockville, MD) It was cloned into a cyferase reporter with a 1226 bp Fbxo40 promoter. The sequence included a 1062bp upstream and a 163bp downstream potential Stat3 binding site. TTCCAGGAA is located upstream at 520-529 bp. Constitutively active Stat Fbxo40 promoter clones and plasmids expressing 3 or cDNA3, Using the Invitrogen Neon transfection system, C2C12 myoblasts were transfected. Transfected. 24 hours after transfection, Gaussia lucifer The activity of the enzyme is controlled by Thermo Scientific® Pierce® G Measured using the Aussia Luciferase Flash Assay Kit did.

[0203] Chromatin immunoprecipitation (CHIP) assay: C2C12 myoblasts, Invitrog Using the en Neon transfection system, Stat3C or GFP is expressed. The cells were transfected with a plasmid. After differentiating C2C12 cells for 24 hours, they were treated with 1% hormone. The cells were treated with smaldehyde (Sigma-Aldrich) for 10 minutes. Ice-cooled PB containing zein inhibitor (Sigma-Aldrich, St. Louis) Washed three times with S. Then, the myotube was dissolved, vortexed, and as described. The Millipore Kit was ultrasonically treated according to the manufacturer's instructions. After 34 centrifugal separation, The protein-DNA lysate was diluted 10-fold with CHIP buffer, and salmon sperm DNA and proteoprotein were mixed. The samples were pre-washed with Tein A / G agarose beads at 4°C for 1 hour. 100 μL of each protein Protein-DNA lysates were used as input controls. Cell protein-DNA lysates were used as St at3 or rabbit IgG (Santa Cruz Biotechnology, Da Immunoprecipitation was performed overnight at 4°C using antibodies against Illas (Texas). Subsequently, the solution was dissolved. The solution was incubated with protein A / G agarose beads (SCBT) at 4°C for 1 hour. The complex was washed as described by the manufacturer. Next, the DNA was immunoprecipitated. The mixture was reverse-crosslinked at 65°C for 4 hours in the presence of 0.2M NaCl, and the mixture was then mixed with phenol / chloro The DNA was purified using form / isoamyl alcohol. A total of 5 μl of purified DNA was used in mouse F Using a primer that covers the Stat3 binding site in the bxo40 promoter, PC The R amplification was performed. The primers were from Sabiosciences (Frederick, M). Purchased from D). Calculated the factor enrichment of Stat3 relative to IgG.

[0204] RNA extraction and quantitative real-time PCR (qPCR): RNA is extracted according to company instructions. It was isolated using the RNeasy kit (Qiagen, Valencia, CA). RT-PCR was performed, and the cycle threshold (Ct) value was determined using GAPDH as an internal control. Relative gene expression was obtained by calculation (relative expression = 2(sample C t - GAPD) 35 sequences of H Ct)) primers are provided upon request.

[0205] Antibody: p-Akt(Ser473)(D9E)#4060, Akt(40D4)#29 20, p-Stat3(Tyr705)(D3A7)#9145, Stat3(124H 6) The primary antibody for #9139 is Cell Signaling Technology ( It was from Beverly, MA, USA. Fbxo40 #ab19068 The antibody against 8 was from Abcam (Cambridge, MA, USA). The antibody against IRS1 #611395 was developed by BD Biosciences (San Obtained from Jose, CA). Anti-GAPDH#PA1-987 is Thermo F Obtained from Isher Scientific. Antibodies are molecules of recognized proteins. I checked by size.

[0206] Statistical analysis: When comparing two experimental groups, use Student's t-test; when comparing three groups, use Student's t-test. Alternatively, ANOVA was used when examining data from four groups. After ANOVA analysis, Stud Pairwise comparisons were performed using the ent-Newman-Keuls test. Expressed as ± SEM

[0207] result

[0208] CKD induces insulin resistance (IR) in mice via Stat3 activation.

[0209] Previously, mice with CKD or cancer cachexia showed signs of muscle wasting due to Sta in the muscles. It was determined that this indicates t3 activation. 33,34 In these experiments, low molecular weight proteins Suppression of p-Stat3 after administration of bitter, C188-9 (TTI-101) is associated with CKD. It was demonstrated that it causes weight gain in mice despite its presence. In this study, T TI-101 was administered to CKD mice every other day. Two weeks after treatment, body weight increased and blood glucose levels increased. It decreased (Figures 1A and 1B). Treatment of mice using TTI-101 was performed using CKD This significantly improved glucose tolerance in mice (Figure 1C). CKD was used to study mouse-derived muscle. Western blotting of the lysate was performed, and TTI-101 treatment increased p-Akt. We found that it suppresses p-Stat3 (Figure 1D). This result indicates that CKD is a mouse disease It activates Stat3 in muscles, which causes insulin resistance, while low molecular weight inhibitors It has been shown that inhibiting p-Stat3 using this method blocks these reactions, and patients It is thought that the effectiveness of reversing the IR can be verified.

[0210] Fbxo40 expression is induced by Stat3 activation.

[0211] To determine the downstream target of Stat3, the E3 ubiquitin ligase, Fbxo40, was used. I investigated the current situation because the Fbxo40 promoter contains a consensus Stat3 binding site. This is because the sequence was identified (Figure 2A). Stat3 binds to the Fbxo40 promoter. And, in order to test whether it stimulates its expression, CHIP and promoter activity A study was conducted. First, constitutively active Stat3 (Stat3C) was expressed in C2C12 cells. The plasmid was transfected; GFP-transfected cells were used as a control. The chromatin from these cells was immunoprecipitated with IgG or anti-Stat3 antibody. The DNA isolated from the immune complex is processed using F, which contains the consensus sequence of the Stat3 binding site. PCR analysis was performed using primers derived from the bxo40 promoter. GFP or The relative enrichment of Stat3 to IgG in cells expressing Stat3 is Stat Figure 2B shows that 3 binds to the Fbxo40 gene. Secondly, Fbxo40 promo Promoter activity was measured. Fbxo40-promoter-lucifer was used in C2C12 myoblasts. Transtrans a plasmid expressing the enzyme + Stat3C or cDNA3 (as a control) The cells were fused. After 24 hours, the cells were lysed with a passive lysis buffer and Gauss-Luciferated. -ase activity was evaluated (see Materials Method). Stat3C is Fbxo40 promo It significantly increased ter activity (Figure 2C). Western blot results showed that Stat3C There was an increase in Fbxo40 protein in cells transfected with (Figure 2D). ).

[0212] In mice or CKD patients, circulating levels of IL-6 are high, and IL-6 is present in the muscles. It is known to stimulate Stat3 activation. Physiological relationship of these IL-6 responses. Sex 33,35,36 To investigate, C2C12 myotubes were treated with IL-6, and it was pS tat3 and Fbxo 40 It increases expression but decreases IRS1 concentration, and Akt phosphorus We found that it impairs oxidation (Figure 2E). Furthermore, Fbxo40 in C2C12 cells The knockdown of IRS1 and p-Akt is even observed in myotubes treated with IL-6. Protein levels were increased (Figure 2F). This is because the SCF-Fbxo40 complex reacted with IGF Inducing IRS1-ubiquitin binding in skeletal muscle, which leads to the limitation of signal transduction, It has been reported, therefore it is relevant. 25Stat3 activation stimulates Fbxo40, It causes a disruption in ncerin signaling.

[0213] Consistent with the increase in p-Stat3 in the muscles of CKD mice, Fbxo40 mRN A was increased in the muscles of CKD mice (Figure 2G), particularly the low molecular weight inhibitor TTI- When p-Stat3 was inhibited in CKD mice using 101, Fbxo40 mRNA Suppression was observed (Figure 2G). In contrast, in CKD mice treated with TTI-101, This increased IRS1 mRNA compared to results from CKD mice treated with a diluent. (D5W; Figure 2H). The results of the Western blot of the tibialis anterior (TA) muscle lysis were C Treatment of KD mice with TTI-101 significantly increased Fbxo40 protein in mouse muscle. We revealed that it was reduced (Figures 2I and 2J). Stat3 activation is linked to ubiquitin - IR is induced via the proteasome system-mediated Fbxo40-stimulated IRS1 degradation pathway.

[0214] Stat3 inhibition improves HFD-induced insulin resistance (IR) in mice.

[0215] To determine whether the IR induced by p-Stat3 activation represents a general mechanism, Therefore, we studied mice that were given a different type of IR, namely a high-fat diet (HFD). After two weeks of dietary therapy, the results were compared to those of mice that consumed standard solid feed. Increased muscle expression of tat3 was observed (Figure 3A). Mice treated with HFD showed increased Fbxo4 It showed increased muscle expression of mRNA 0, but the expression of Atrogin-1 or MuRF-1 was not observed. The results were not shown (Figure 3B-3D). These results indicate that E3 ubiquitin ligase, Atr Activation of ogin-1 and MuRF-1 leads to the development of muscle atrophy from muscle protein breakdown and high levels of muscle growth. Therefore, it is related to dietary factors. These results do not represent a standardized response. These results were obtained by administering HFD to 12 mice in a different group. These mice were prolonged by feeding for several weeks (Figure 3E); these mice developed glucose intolerance. The disease developed (Figure 3F). Mice given HFD for 12 weeks were divided into two subgroups. Continue HFD feeding for another 4 weeks and treat with either TTI-101 or a diluted solution. In addition, one subgroup received intraperitoneal injection of the diluent, while the other subgroup of mice received a diluent injection. The patient was treated with intraperitoneal injection of TTI-101. The results from these studies showed that HFD was given Nevertheless, the fasting blood glucose levels in mice treated with TTI-101 Treatment with reduced diluents (Figure 3G) was also performed on HFD mice with TTI-101. It improved glucose and insulin resistance (Figures 3H and 3I). Western blot Rotation is rare when mice given HFD are treated with TTI-101. Compared to results from mice treated with the eluent, higher levels of IRS1 were observed in the muscles. It was revealed that both and p-Akt are present (Figure 3J). The result is HFD-Mau Inhibition of p-Stat3 in the muscle leads to an increase in insulin signaling pathways in the muscle. To indicate that it was long.

[0216] Stat3KO in muscle suppresses HFD-induced IR in mice.

[0217] Previous studies have shown that CKD impairs p-Akt in muscles and suppresses p-Stat3. The system is p-Akt 33It was revealed that this improves Stat3 activity in muscle. It has been confirmed that the chemical reaction causes IR. To investigate these relationships in a different way, Transgenic mice expressing floxed-Stat3 and MCK-Cre mice The results were examined using muscle-specific Stat3 KO mice created by crossing [specific organisms]. 33,34 . Stat3 KO and floxed-Stat3 mice were fed HFD for 16 weeks. The study showed that HFD caused a decrease in muscle mass when compared to mice fed a normal diet. However, this caused an increase in adipose tissue. After 16 weeks of HFD, the Stat3 K group in two groups In O and floxed-Stat3 mice, body weight (Figure 4A) or muscle weight (Figure 4A) There was no significant difference in muscle-specific (4B) or adipose tissue mass (Figure 4C). However, muscle-specific HFD feeding in Stat3 KO mice improved fasting blood glucose (Figure 4D) and glucose tolerance (Figure 4E). This resulted in a substantial decrease in p-Stat3 in muscle in mice. It plays an important role in the development of HFD-induced IR.

[0218] Importance of specific embodiments

[0219] Previously, complications of CKD included increased protein breakdown and loss of muscle mass. It was found that this included impairment of crystalline synthesis (Figure 5). 31,35 Increased protein breakdown is due to muscle This is mediated by stimulation of the ubiquitin-proteasome signaling pathway in meat. It was decided 37 In particular, two muscle-specific E3 ubiquitin ligases (Atrogin-1 MuRF-1) was increased in the muscles of rodents with CKD. 22 In these experiments, p - Akt is disabled, infrared is 38 He developed the condition. Currently, Stat3 activated in the muscles is It has been determined that this is associated with increased expression of ubiquitin E3 ligase, Fbxo40. Fbxo40 is a key insulin signaling molecule, ubiquitin-bound to IRS1.25. This was interesting because it induces both and decomposition (IRS1.25, this The response impairs p-Akt levels in the muscle, leading to the generation of IR (Figure 5). p-St Further support for the pathway from at3 to Fbxo40 to IR is provided by the small molecule inhibitor, TT. Inhibition of p-Stat3 by I-101 in CKD mice and HFD-induced diabetic mice The goal is to improve insulin sensitivity in both aspects.

[0220] In studies of rodents with CKD, streptozotocin-induced acute diabetes, or cancer cachexia, An increase in p-Stat3 levels in muscles is a cause of increased muscle protein breakdown. It is associated with the CEBPδ / myostatin pathway. In particular, p-Stat3 is a small molecule inhibitor. If inhibited by ter, or if Stat3 KO is specifically tested in muscle In mice with cancer or CKD, body weight and muscle mass increased. 33, 34 IR commonly occurs in patients with CKD, diabetes, or cancer cachexia, so these disorders The harm is that Stat3 activation in the muscles of catabolic mice induces IR, which is an important mediator. It is explored to determine whether it is a marker. In fact, Stat3 activation is detected in IR. There is evidence that it reaches [a certain level]. A report by Mashili et al. showed that the skeletal muscle of patients with type 2 diabetes [is [a certain level]] Stat3 was constitutively phosphorylated 21 This demonstrated that the Sta of myotubes We revealed that silencing the t3 gene prevents lipid-induced intra-inflammatory response (IR). The results in mice are consistent with these studies. For example, CKD or type 2 glycosylation. Glucose tolerance and insulin tolerance in mice with either of the following urinary tract diseases are measured using p-Stat. It was found that the condition improves when it is inhibited by the low-molecular-weight inhibitor TTI-101. When Stat3 is specifically knocked out in the muscles of mice given HFD, Stat3 Muscle-specific knockout showed improved glucose tolerance. This result indicates that muscle-specific Stat3 knockout is This differs from the results of White et al., who studied mice given HFD for 20 days. The researchers found that Stat3 KO mice and control mice exhibited similar phenotypes, including differences in fat mass and energy consumption. It was concluded that no significant difference was observed in the measured values ​​of fat expenditure or systemic fatty acid oxidation in skeletal muscle. Stat3 KO concluded that it does not interfere with HFD-induced IR. 39 The research results and White et al. There is a difference between the results and those of the inventors: muscle-specific Stat3 KO or control mice. Mice with the specified trait were given HFD for 16 weeks, and the results obtained from the control mice were compared to those from Stat. White et al. demonstrated improved IR in 3 KO mice. Although the knockout mice were fed for only 20 days, insulin or glucose levels could not be measured. It was not provided.

[0221] To explain why IRS1 levels in muscle are low in diabetes, several Cell-based mechanisms have been proposed; these include phosphotyrosine dephosphorylation, This includes serine-threonine phosphorylation and IRS1 degradation. 40-42 . Specific E3 ubiquity This study demonstrated that chitin ligase interacts with IRS1, leading to its proteasome-mediated degradation. There are also reports that suggest this is instigating. 43-45;37,44 For example, inflammation is caused by a separate E3 ubiquitin ligament. It was found that it stimulates the activity of -ase, SOCS1 and SOCS3, and these stimulate IRS1 Alternatively, it may interact with IRS2 and lead to its degradation. 44,45 Or E3 Ubiquitous The enzyme Cbl-b has been found to be associated with the breakdown of IRS1, which causes muscle atrophy. Ta 46 Interestingly, Cbl-b activation is also HFD 10 It arises from giving It was found that it induces infrared radiation. Finally, the E3 ubiquitin ligase Fbxw Carlin-7 complexes containing 8 result in mTOR-dependent negative reaction leading to IRS1 degradation. It can be activated by the back-up mechanism, and therefore IR. 47 Shi and others are E3 Fbxo, a biquitin ligase 40 In particular, in skeletal muscle cells, in response to IGF1 stimulation We have reported that it induces ubiquitin binding and degradation of IRS1. 25 Stat A series of changes from stimulation of Fbxo40 expression to IRS1 degradation have been demonstrated.

[0222] In addition to increased p-Stat3 in the muscles of mice fed CKD or HFD, Akt A decrease in phosphorylation was consistently observed in the same muscle. However, p-Stat3 was reduced to TTI-1 Inhibition at 01 resulted in CKD mice and HF mice, similar to muscle-specific Stat3 KO mice. Improved insulin sensitivity was observed in both D mice. p-Stat3 stimulates IR. While exploring the molecular mechanisms involved, p-Stat3 strongly induces Fbxo40 expression. When xo40 was knocked down, or when Stat3 was inhibited using TTI-101 In this case, a route from Stat3 to Fbxo40 and IRS1 was confirmed. These results This strongly suggests that Fbxo40 is a mediator of p-Stat3 expression that leads to IR. In line with this conclusion, p-Stat3 and Fbx in the skeletal muscle of CKD mice A greater increase in o40 protein levels was observed in CKD mice treated with TTI-101. When processed, it increases p-Akt while generating both p-Stat3 and Fbxo40 The present was obstructed.

[0223] For the first time, it is revealed how CKD or HFD induces IR:Sta T3 activation leads to IRS1 degradation, and therefore IR. The mediator of these changes The TA is an upregulation of ubiquitin E3 ligase, Fbxo40. Some researchers have reported that Stat3 induces IR, so this result suggests that Stat3 is associated with type 2 diabetes. To clarify the general mechanisms that influence responses to obesity and other diseases such as cardiovascular disease. This result is that St is used to treat IR resulting from complex disorders such as inflammation. This provides a foundation for designing clinical strategies targeting at3.

[0224] While this disclosure and its advantages have been described in detail, the attached claims define the following: Without deviating from the spirit and scope of the design, various changes, substitutions, and modifications are permitted. Please understand that this can be done in detail. Furthermore, the scope of this application is described herein. In specific embodiments of the processes, machines, manufacturing, compositions, means, methods, and steps described It is not intended to be limiting. As will be readily apparent to those skilled in the art from this disclosure, Performs substantially the same function as the corresponding embodiment described herein, or substantially the same function as the corresponding embodiment described herein. Processes, machines, manufacturing methods, and materials that currently exist or will be developed to achieve the same result. The composition, means, methods, or steps of the quality may be utilized in accordance with this disclosure. Therefore, the attached claims include, within their scope, such processes, machines, manufactures, and compositions. It is intended to include things, means, methods, or steps.

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Claims

1. A method for treating, preventing, or reducing the risk or severity of insulin resistance or insulin resistance-related conditions in an individual requiring insulin resistance, comprising administering to an individual a therapeutically effective amount of a signal transducer and one or more inhibitors of transcription factor 3 (STAT3).

2. The method according to claim 2, wherein insulin resistance in an individual is related to inflammation.

3. The method according to claim 1 or 2, wherein the individual has chronic kidney disease (CKD).

4. The method according to any one of claims 1 to 3, wherein the individual has diabetes.

5. The method according to any one of claims 1 to 4, wherein the individual is obese.

6. The method according to any one of claims 1 to 5, wherein the individual has a cardiovascular disease or disorder.

7. The method according to any one of claims 1 to 6, wherein the individual does not have cachexia or muscle wasting.

8. The method according to any one of claims 1 to 7, wherein the condition associated with insulin resistance is severe hyperglycemia, severe hypoglycemia, heart attack; stroke, kidney disease, eye problems, cancer, non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), metabolic syndrome, diabetes mellitus, or Alzheimer's disease.

9. A method for treating, preventing or reducing the risk or severity of diabetes in an individual in need thereof, comprising administering to the individual one or more signal transducers and activator 3 (STAT3) inhibitors in therapeutically effective amounts.

10. The method according to claim 9, wherein the diabetes is type II diabetes.

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