Cefin 1 and related compounds for the treatment of diseases and disorders that can be treated by AMPK activation and / or CHOP inhibition

Abstract

Methods for treating diseases and disorders treatable by AMPK activation with cefin-1 and related compounds, such as metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 2 diabetes, insulin resistance, glucose intolerance, chronic pain, muscle loss, neuromuscular disorders, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, cardiac reperfusion injury, chronic kidney disease, polycystic kidney disease, diabetic nephropathy, cardiovascular disease, inflammatory bowel disease, arthritis, hypertension, peripheral vascular disease, nephrogenic diabetes insipidus, glaucoma, eye diseases or disorders, ocular angiogenesis, β-hemochromocytic disorder, cancer, fibrosis, cancer cachexia, and mitochondrial diseases.

Description

[Technical Field]

[0001] 1. Cross-reference to related applications This application claims priority to U.S. Provisional Application No. 63 / 490,538, filed on 16 March 2023, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] 2.Background Cefin-1 (also known as IFB-088 and iserguastat) is a benzyliden guanidine derivative under development for the treatment of amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth disease (CMT). [Overview of the project]

[0003] 3. Overview This disclosure is partly based on the discovery that the compound cefin-1 activates AMP-activated protein kinase (AMPK). AMPK is a regulator of energy homeostasis, and high AMPK activity is associated with various health benefits (Steinberg & Carling, 2019, Nat. Rev. Drug Discov. 18(7):527-551). Activated AMPK phosphorylates C / EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-induced transcription factor. Phosphorylation of CHOP by AMPK induces proteasomal degradation of CHOP (Dai et al., 2016, Circ Res. 119(10):1089-1100). AMPK is a known target for addressing various diseases and disorders such as metabolic syndrome, type 2 diabetes, and cancer (Li et al., 2015, Oncotarget 6(10):7365-7378), and CHOP is also associated with various diseases and disorders, including cancer, diabetes, and fibrosis (Yang et al., 2017, Frontiers in Immunology 8:1612). CHOP also regulates GDF-15, which plays a role in increased lipid metabolism (Li et al., 2019, Biochem Biophys Res Commun 498(3):388-394, Townsend et al., 2022, J Appl Physiol 132: 413-422). Increased lipid metabolism is associated with diseases and disorders, including cancer cachexia, advanced cancer, and mitochondrial diseases (Sturm et al., 2023, Communications Biology 6:22).

[0004] Therefore, this disclosure provides novel uses of cefin 1 and related compounds in the treatment of diseases and disorders that can be treated, for example, by AMPK activation and / or by CHOP inhibition.

[0005] In one embodiment, the present disclosure describes the target cells (e.g., cells in vivo) as formula (I)

[0006] [Chemical formula] [wherein, R , , 8 , , 5 , 9 , , 7 , 6 , 11 , 5 , 11 , , 10 , 4 , 4 , , 9 , 7 , 8 , 11 , 7 , 10 , , 10 is alkyl, O-alkyl, Cl, F or Br, R 2 is H or F, R 3 is H or alkyl, R 4 is H or C(O)R 6 and R 5 is H, or, R 4 and R 5 are bonded to form a 5- to 6-membered saturated or unsaturated heterocyclic group optionally containing 1 or 2 heteroatoms (such as N) in addition to the N atom to which R 4 and R 5 are bonded, and the heterocyclic group is optionally substituted with one or more R 10 groups, R 6 is a selected R 7 , OR 7 or NR 8 R 9 and R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more R 10 groups, Each R 10 is independently selected from halogen, OH, =O, CN, COO-alkyl, aralkyl, SO2-alkyl, SO2-aryl, COOH, CO-alkyl, CO-aryl, NH2, NH-alkyl, N(alkyl)2, CF3, alkyl and alkoxy, X and Z are each independently CR 11 and Y is CR 11 or N, R 11 is H, alkyl or F] The present invention provides a method for activating AMPK in cells and / or increasing the phosphorylated AMPK (pAMPK) / AMPK ratio by contacting the cells with a drug that is a compound of the compound or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] Cefin 1 is an exemplary compound of formula (I).

[0008] The compounds of formula (I), their tautomers, and pharmaceutically acceptable salts thereof (for the sake of avoidance of doubt, “these pharmaceutically acceptable salts” means pharmaceutically acceptable salts of the compounds of formula (I) and pharmaceutically acceptable salts of the tautomers of the compounds of formula (I)) may, for convenience, be collectively referred to herein as “the Agents of the Disclosure.”

[0009] In another aspect, the Disclosure provides a method for inhibiting CHOP and / or increasing the phosphorylated CHOP (pCHOP) / CHOP ratio in cells by bringing cells of interest (e.g., cells in vivo) into contact with the Agent of the Disclosure.

[0010] In another aspect, the Disclosure provides a method for treating a subject having or at risk of having a disease or disorder treatable by AMPK activation and / or CHOP inhibition, comprising administering the agents of the Disclosure to the subject. Exemplary diseases and disorders treatable by AMPK activation and / or CHOP inhibition include metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 2 diabetes, insulin resistance, glucose intolerance, chronic pain, muscle loss, neuromuscular disorders, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, cardiac reperfusion injury, chronic kidney disease, polycystic kidney disease, acute kidney injury, diabetic nephropathy, cardiovascular disease, inflammatory bowel disease, arthritis, hypertension, peripheral vascular disease, nephrogenic diabetes insipidus, glaucoma, eye diseases or disorders, ocular angiogenesis, β-hemochromocytic disorder, cancer, and fibrosis. Further exemplary diseases and disorders treatable by AMPK activation and / or by inhibiting CHOP include cancer cachexia, advanced cancer, mitochondrial diseases, and amyotrophic lateral sclerosis (ALS).

[0011] In some embodiments of the methods of this disclosure, the agent is cefin 1 or its tautomers, a salt of cefin 1, or a salt of a cefin 1 tautomer.

[0012] The methods of this disclosure are further described in Section 5.2 and in the numbered embodiments 1 to 105 below.

[0013] The agents and compositions comprising the agents of this disclosure are further described in Section 5.3 and the numbered embodiments 1 to 108 below. [Brief explanation of the drawing]

[0014] 4. Brief explanation of the drawing [Figure 1] This figure shows the time schedule for the test in Example 1. [Figure 2]This figure shows Western blots of phosphorylated AMPK (pAMPK), AMPK, and GAPDH (control) derived from HK-2 cells treated with tunicamycin (Tu), tunicamycin + cefin-1 (Tu+Se), or untreated cells (CNTs) (Example 1). [Figure 3A] This graph shows the pAMPH / GAPDH ratio from HK-2 cells treated with tunicamycin (Tu), tunicamycin + cefin-1 (Tu+Se), or untreated cells (Sham) (Example 1). [Figure 3B] This graph shows the AMPK / GAPDH ratio from HK-2 cells treated with tunicamycin (Tu), tunicamycin + cefin-1 (Tu+Se), or untreated cells (Sham) (Example 1). [Figure 3C] This graph shows the pAMPK / AMPK ratio from HK-2 cells treated with tunicamycin (Tu), tunicamycin + cefin-1 (Tu+Se), or untreated cells (Sham) (Example 1). [Figure 4] This figure shows the time schedule for the test in Example 2. [Figure 5] This figure shows the protein expression levels of CHOP, p-CHOP, and α-tubulin from cells treated with tunicamycin (Tu), tunicamycin + cefin-1 (Tu+Se), or untreated cells (Sham) (Example 2). [Figure 6] This graph shows the relative levels of CHOP, p-CHOP, and p-CHOP / CHOP from the test in Example 2. [Figure 7] This figure shows the time schedule for the test in Example 3. [Figure 8][Figure 8] This figure shows the protein expression levels and relative protein expression levels of CHOP, p-CHOP, and α-tubulin from cells treated with tunicamycin (Tu), tunicamycin + cefine 1 (Tu+Se), or untreated cells (Sham) (Example 3). [Figure 8] This graph shows the cytoplasmic and nuclear protein expression levels and relative protein expression levels of CHOP, α-tubulin, and histones from cells treated with tunicamycin (Tu), tunicamycin + cefine 1 (Tu+Se), or untreated cells (CNT) (Example 3). [Figure 9] This graph shows the cell count and cell viability of the treatment group in Example 3. [Modes for carrying out the invention]

[0015] 5. Detailed explanation 5.1.Definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those ordinarily understood by those skilled in the art to which this invention belongs. The following definitions are provided for a full understanding of the terms used herein.

[0016] As used herein, the following terms are intended to have the following meanings:

[0017] One (a, an), the: As used herein, the terms "one (a, an)," "the," and similar terms used in this disclosure (particularly in the claims) should be construed to encompass both singular and plural forms unless otherwise indicated herein or to be clearly contradicted by the content. Thus, the terms "one (a (or an))," "one or more," and "at least one" can be used interchangeably herein.

[0018] Alkenyl: As used herein, the term “alkenyl” refers to a group containing one or more carbon-carbon double bonds, which may or may not be branched. An alkenyl group is, for example, C 2~20 Alkenyl group, C 2~15 Alkenyl group, C 2~12 Alkenyl group, C 2~6 Alkenyl group, or C 2~3 It is an alkenyl group. The term "cyclic alkenyl" should be interpreted accordingly.

[0019] Alkyl: As used herein, the term “alkyl” includes both saturated linear and branched alkyl groups. For example, an alkyl group is C 1~20 Alkyl alkyl group, C 1~15 Alkyl alkyl group, C 1~12 Alkyl alkyl group, C 1~6 Alkyl alkyl group, or C 1~3 It may be an alkyl group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0020] AMPK: The term "AMPK" refers to AMP-activated protein kinase. AMPK is a heterotrimeric protein complex formed by α, β, and γ subunits. The α, β, and γ subunits can be found in the following different isoforms: the γ subunit can exist as γ1, γ2, or γ3 isoforms; the β subunit can exist as β1 or β2 isoforms; and the α subunit can exist as α1 or α2 isoforms. The α subunit is encoded by the genes PRKAA1 (α1 isoform) and PRKAA2 (α2 isoform), the β subunit is encoded by the genes PRKAB1 (β1 isoform) and PRKAB2 (β2 isoform), and the γ subunit is encoded by the genes PRKAG1 (γ1 isoform), PRKAG2 (γ2 isoform), and PRKAG3 (γ3 isoform). AMPK is activated when phosphorylation occurs at Thr-172 of the α-subunit (Sanders et al., 2007, Biochem J. 403(Pt.1):139-148, Steinberg & Carling, 2019, Nat. Rev. Drug Discov. 18(7):527-551). Phosphorylated AMPK is referred to herein as "pAMPK".

[0021] and / or: The term "and / or" means that one, both, or all of the components or features of each of the lists are possible variations, particularly in alternative or cumulative ways.

[0022] Aralkyl: As used herein, the term “aralkyl” refers to a group having both aryl and alkyl functional groups. For example, the term includes groups in which one of the hydrogen atoms of the alkyl group is replaced by an aryl group, such as a phenyl group. Exemplary aralkyl groups include benzyl and phenethyl.

[0023] Aryl: As used herein, the term "aryl" means C 6~12This refers to aromatic groups. Examples include phenyl and naphthyl.

[0024] CHOP: The term "CHOP" refers to the C / EBP homologous protein. CHOP is encoded by the DDIT3 gene and is a pro-apoptotic transcription factor induced in response to certain stressors (Yang et al., 2017, Frontiers in Immunology 8:1612). Phosphorylation of Ser-30 of CHOP by AMPK induces proteasomal degradation of CHOP (Dai et al., 2016, Circ Res. 119(10):1089-1100). Ser-30 phosphorylated CHOP is referred to herein as "phosphorylated CHOP," "pCHOP," or "p-CHOP." Expressions such as "inhibiting CHOP" or "CHOP inhibition" do not require complete inhibition of CHOP. Inhibition can be achieved, for example, by increasing the amount of pCHOP and / or increasing the pCHOP / CHOP ratio and / or decreasing the amount of CHOP, resulting in proteasomal degradation of pCHOP.

[0025] Cycloalkyl: As used herein, the term "cycloalkyl" refers to a cyclic alkyl group.

[0026] Effective Dose: The term “effective dose” or “therapeutic effective dose” means the amount or quantity of a drug or composition that is sufficient to induce a necessary or desired response, or in other words, sufficient to induce a recognizable biological response, for example, when administered to a subject. The amount preferably relates to an amount that is therapeutically effective against the progression of a disease or disorder disclosed herein, or more broadly, also prophylactically effective. It is understood that the “effective dose” or “therapeutic effective dose” may vary from subject to subject due to drug metabolism, age, body weight, the subject’s overall condition, the condition being treated, the severity of the condition being treated, and variability in the prescribing physician’s judgment.

[0027] Heteroaryl: As used herein, the term “heteroaryl” refers to a 4- to 12-membered aromatic group containing one or more heteroatoms. Exemplary heteroaryl groups are 4- to 12-membered aromatic groups containing one or more heteroatoms selected from N, O, and S. Exemplary heteroaryl groups include pyrrolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, thiophenyl, 1,2,3-triazolyl, 1,2,4-triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, and furanyl.

[0028] Heterocycle: As used herein, the term “heterocycle” (also referred to herein as “heterocyclyl” and “heterocyclic”) means a 4- to 12-membered, e.g., a saturated, unsaturated or partially unsaturated cyclic group containing one or more heteroatoms selected from N, O, and S, and optionally further containing one or more CO groups. The term “heterocycle” encompasses both heteroaryl and heterocycloalkyl groups as defined herein.

[0029] Heterocycloalkyl: As used herein, the term “heterocycloalkyl” refers to a 4- to 12-membered cyclic aliphatic group containing one or more heteroatoms. Exemplary heterocycloalkyl groups include piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl, and morpholinyl. Further examples include N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-thiomorpholinyl, and N-morpholinyl.

[0030] Or: Unless otherwise indicated, the conjunction “or” is intended to be used in its correct orientation as a Boolean logical operator, encompassing both binary selection of features (A or B, where the selection of A is mutually exclusive with B) and combined selection of features (A or B, where both A and B are selected). In parts of this specification, the terms “and / or” are used for the same purpose and shall not be construed as meaning that “or” is used to refer to mutually exclusive alternatives.

[0031] Subject: As used herein, the term "subject" means human beings.

[0032] To treat, to treat, treatment: The terms “to treat,” “to treat,” “treatment,” and their grammatical variations, as used herein, include reducing or relieving a disease or disorder and / or associated signs or symptoms, or slowing or halting their progression. It will be understood, though not prevented, that treating a disease or disorder does not require the complete elimination of the disease, disorder, or associated symptoms. Treatments provided herein may be applied prophylactically (e.g., to subjects at risk of developing the disease or disorder), mitigatingly, or therapeutically. Prophylactic treatment may be administered to a subject before the onset of signs or symptoms, during the early onset of signs or symptoms (e.g., at the time of initial signs and symptoms), or after the established onset of signs or symptoms. Prophylactic administration may be given several days to several years before the onset of symptoms.

[0033] 5.2. Method This disclosure provides novel uses for the compound of formula (I), its tautomers, and pharmaceutically acceptable salts thereof. The compound of formula (I), its tautomers, and pharmaceutically acceptable salts thereof are described in more detail in Section 5.3.

[0034] In one embodiment, the Disclosure provides a method for activating AMPK in cells and / or increasing the pAMPK / AMPK ratio by contacting cells of interest with an amount effective in activating AMPK in cells and / or increasing the phosphorylated AMPK (pAMPK) / AMPK ratio (e.g., Cefin 1). Contacting cells with the drug may be in vivo, for example, by orally administering an amount effective in activating AMPK and / or increasing the pAMPK / AMPK ratio to one or more target cell types, tissues, and / or organs, such as the heart, liver, kidney, lung, skeletal muscle, or eye.

[0035] In one embodiment, the Disclosure provides a method for inhibiting CHOP and / or increasing the pCHOP / CHOP ratio in cells by contacting cells of interest with an amount effective in inhibiting CHOP and / or increasing the phosphorylated CHOP (pCHOP) / CHOP ratio in cells with an amount effective in inhibiting CHOP and / or increasing the pCHOP / CHOP ratio in cells. Contacting cells with an agent may be in vivo, for example, by orally administering an amount effective in inhibiting CHOP and / or increasing the pCHOP / CHOP ratio to one or more target cell types, tissues, and / or organs, such as the heart, liver, kidney, lung, skeletal muscle, or eye.

[0036] In another embodiment, the Disclosure provides a method for treating a subject having or at risk of having a disease or disorder treatable by AMPK activation and / or CHOP inhibition, comprising administering a therapeutically effective amount of the Disclosure's agent (e.g., Cefin 1) to the subject. In some embodiments, the amount of the agent administered is an amount effective in activating AMPK and / or inhibiting CHOP in one or more cell types, tissues, and / or organs, such as the heart, liver, kidney, lung, skeletal muscle, or eye.

[0037] In some embodiments, the amount of the drug administered is an effective amount to increase the pAMPK / AMPK ratio in one or more cell types, tissues, and / or organs, such as the heart, liver, kidney, lung, skeletal muscle, or eye. In some embodiments, the amount of the drug administered is an effective amount to increase the pCHOP / CHOP ratio in one or more cell types, tissues, and / or organs, such as the heart, liver, kidney, lung, skeletal muscle, or eye. The levels and ratios of AMPK, pAMPK, CHOP, and pCHOP can be assessed by measuring their levels using standard testing techniques, such as Western blotting, flow cytometry, or fluorescence microscopy.

[0038] AMPK activation can suppress the synthesis of fatty acids and cholesterol. Therefore, in some embodiments, the amount of drug administered to the subject is an effective amount for suppressing fatty acid synthesis. In some embodiments, the amount of drug administered to the subject is an effective amount for suppressing cholesterol synthesis. In some embodiments, the amount of drug administered to the subject is an effective amount for reducing the subject's cholesterol levels, for example, by reducing serum and / or liver cholesterol levels.

[0039] AMPK activation can increase glucose uptake in skeletal muscle. Therefore, in some embodiments, the amount of drug administered to a subject is an effective amount for increasing glucose uptake in skeletal muscle in that subject. Skeletal muscle glucose uptake can be measured, for example, by measuring glucose uptake in the forearm.

[0040] Exemplary diseases and disorders treatable by inhibiting AMPK activation and / or CHOP include metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 2 diabetes, insulin resistance, glucose intolerance, chronic pain, muscle loss, neuromuscular disorders, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, cardiac reperfusion injury, chronic kidney disease, polycystic kidney disease, acute kidney injury, diabetic nephropathy, cardiovascular disease, inflammatory bowel disease, arthritis, hypertension, peripheral vascular disease, nephrogenic diabetes insipidus, glaucoma, eye diseases or disorders, ocular angiogenesis, β-hemochromocytic disorder, cancer, and fibrosis. Further exemplary diseases and disorders treatable by inhibiting AMPK activation and / or CHOP include cancer cachexia, advanced cancer, mitochondrial disease, and amyotrophic lateral sclerosis (ALS). Diseases and disorders treatable by AMPK activation and / or by inhibiting CHOP are, for example, listed in Steinberg & Carling, 2019, Nat. Rev. Drug Discov. 18(7):527-551; Li et al., 2015, Oncotarget 6(10):7365-7378; Yang et al., 2017, Frontiers in Immunology 8:1612; Dai et al., 2016, Circ Res. These are described in 119(10):1089-1100; U.S. Patent Application Publication No. 2017 / 0020909; U.S. Patent No. 10,016,486; U.S. Patent No. 10,143,703; U.S. Patent No. 10,596,144; International Publication No. 2007 / 097751; International Publication No. 2017 / 011917; International Publication No. 2019 / 063792; and International Publication No. 2022 / 072397, the contents of which are incorporated herein by reference in their entirety.

[0041] Therefore, in some embodiments, subjects receiving the agents of this disclosure have or are at risk of developing any of the diseases or disorders described in the preceding paragraph.

[0042] In some embodiments, the subject has metabolic syndrome or is at risk of having it.

[0043] In some embodiments, the subject has or is at risk of having non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH).

[0044] In some embodiments, the subjects are obese or at risk of obesity.

[0045] In some embodiments, the subjects have type 2 diabetes or are at risk of having it.

[0046] In some embodiments, the subject has insulin resistance or is at risk of having it.

[0047] In some embodiments, the subject has glucose intolerance or is at risk of having it.

[0048] In some embodiments, the subjects have or are at risk of having chronic pain, such as postoperative pain.

[0049] In some embodiments, the subject has or is at risk of muscle loss.

[0050] In some embodiments, the subjects have or are at risk of having a neuromuscular disorder, such as Duchenne muscular dystrophy or myotonic dystrophy type 1.

[0051] In some embodiments, the subjects have heart failure or are at risk of having it.

[0052] In some embodiments, the subject has or is at risk of cardiac hypertrophy.

[0053] In some embodiments, the subject has or is at risk of diabetic cardiomyopathy.

[0054] In some embodiments, the subject has or is at risk of cardiac reperfusion injury.

[0055] In some embodiments, the subjects have or are at risk of having a kidney disease (e.g., chronic kidney disease or acute kidney injury).

[0056] In some embodiments, the subjects have or are at risk of having chronic kidney disease.

[0057] In some embodiments, the subjects have or are at risk of having polycystic kidney disease, such as autosomal dominant polycystic kidney disease.

[0058] In some embodiments, the subject has or is at risk of acute kidney injury (AKI).

[0059] In some embodiments, the subject has or is at risk of diabetic nephropathy.

[0060] In some embodiments, the subjects have or are at risk of having cardiovascular disease, such as atherosclerosis, coronary artery disease, peripheral artery disease, or cerebrovascular disease. In some embodiments, the amount of drug administered is effective in reducing the risk of atherosclerotic plaque rupture and / or preventing atherosclerotic plaque rupture. Thus, in some embodiments, the method is a method for promoting the stability of atherosclerotic plaque. In some embodiments, the amount of drug administered is effective in inhibiting the onset of atherosclerosis or slowing its progression. Thus, in some embodiments, the administration of the drug can reduce the likelihood of acute coronary heart disease and / or stroke.

[0061] In some embodiments, the subjects have or are at risk of having inflammatory bowel disease.

[0062] In some embodiments, the subject has arthritis or is at risk of having it.

[0063] In some embodiments, the subjects have or are at risk of hypertension.

[0064] In some embodiments, the subjects have or are at risk of peripheral vascular disease.

[0065] In some embodiments, the subject has or is at risk of nephrogenic diabetes insipidus.

[0066] In some embodiments, the subject has glaucoma or is at risk of having it.

[0067] In some embodiments, the subject has or is at risk of having an eye disease or disorder, such as retinopathy, a condition associated with microvascular disorders, neovascular glaucoma, corneal transplant rejection, glaucoma, herpetic and infectious keratitis, ocular ischemia, neovascular glaucoma, neovascularization of the cornea, uvea and / or iris, tumors of the orbit and / or eyelids, Stevens-Johnson syndrome, ocular scarring pemphigoid, injury, or ocular surface disease. In some embodiments, the eye disease or disorder is macular degeneration, such as wet age-related macular degeneration (AMD).

[0068] In some embodiments, the subject has or is at risk of ocular neovascularization, characterized, for example, by neovascularization of the surface, cornea, retina, choroid, uvea, or iris.

[0069] In some embodiments, the subjects have or are at risk of having β-hemochromosis.

[0070] In some embodiments, the subject has cancer or is at risk of having cancer. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is liver cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is leukemia.

[0071] In some embodiments, the subject has or is at risk of fibrosis. In some embodiments, fibrosis is pulmonary fibrosis. In some embodiments, fibrosis is renal fibrosis, such as glomerulosclerosis and / or tubulointerstitial fibrosis. In some embodiments, fibrosis is hepatic fibrosis. In some embodiments, fibrosis is cardiac fibrosis.

[0072] In some embodiments, the subject has cancer cachexia. In some embodiments, the subject has advanced cancer. In some embodiments, the subject has mitochondrial disease.

[0073] In some embodiments, the subjects have or are at risk of having a disease or disorder related to increased lipid metabolism, such as cancer cachexia, advanced cancer, mitochondrial disease, or ALS.

[0074] The agents of this disclosure can be administered to a subject by any preferred route. Preferred routes of administration include, but are not limited to, oral routes. Other routes include topical (including dermal, buccal, ocular, and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular, and intravenous), nasal, intraocular, and intrapulmonary administration, such as inhalation. The most preferred route may depend on the subject's condition or disorder. In some embodiments, the agent is administered orally.

[0075] Those skilled in the art can determine the appropriate dose of the drug of this disclosure to be administered to a subject. Typically, a physician will determine the actual dose that is most suitable for an individual patient, and this dose will depend on a variety of factors, including the activity of the specific drug used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, mode and timing of administration, rate of elimination, drug combinations, severity of a particular condition, and therapies being received individually. Exemplary dose ranges include 0.01 mg / kg to 100 mg / kg, 0.1 mg / kg to 20 mg / kg, 0.1 mg / kg to 50 mg / kg, and 0.1 mg / kg to 20 mg / kg. An exemplary daily dose range is 0.4 mg / kg / day to 400 mg / kg / day.

[0076] 5.3. Pharmaceuticals and Compositions A useful agent for the method disclosed herein is formula (I):

[0077] [ka] [In the formula, R 1 is alkyl, O-alkyl, Cl, F or Br, R 2 is H or F, R 3 is a selected H or alkyl, R 4 is H or C(O)R 6 And, R 5 Is it H? Or, R 4 and R 5 They are combined into R 4 and R 5 In addition to the bonded N atom, it forms a 5-6 member saturated or unsaturated heterocyclic group which optionally contains 1 or 2 heteroatoms, and the heterocyclic group comprises 1 or more R 10 It is arbitrarily substituted in the base, R 6 The selected R 7 , OR 7 or NR 8 R 9 And, R 7 , R 8 and R 9 Each is independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, and each of them is one or more R 10 It is arbitrarily substituted in the base, Each R 10 These are independently selected from halogens, OH, =O, CN, COO-alkyl, aralkyl, SO2-alkyl, SO2-aryl, COOH, CO-alkyl, CO-aryl, NH2, NH-alkyl, N(alkyl)2, CF3, alkyl, and alkoxy. X and Z are independent of each other, CR 11 And, Y is CR 11 or N, R 11 [is H, alkyl, or F] This includes compounds of the same substance, their tautomers, and pharmaceutically acceptable salts thereof.

[0078] Preferably, each alkyl group is C 1~20 It is an alkyl group, more preferably C 1~15 And, moreover, C 1~12 It is an alkyl group, and more preferably C 1~6 It is an alkyl group, more preferably C 1~3 It is an alkyl group. Particularly preferred alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0079] Preferably, each cycloalkyl group is C 3~12 It is a cycloalkyl group.

[0080] Preferably, each alkenyl group is C 2~20 Alkenyl group, C 2~15 Alkenyl group, C 2~12 Alkenyl group, C 2~6 Alkenyl group, or C 2~3 It is an alkenyl group.

[0081] Preferably, each "aryl" group is C 6~12 These are aromatic groups, such as phenyl or naphthyl.

[0082] In some embodiments, R 1 is Cl, Br, CH3, H, or F.

[0083] In some embodiments, R 2 H is H.

[0084] In some embodiments, Y is CR 11 That is the case.

[0085] In some embodiments, X, Y, and Z are each CH.

[0086] In some embodiments, R 3 and R 4 Both are H.

[0087] In some embodiments, R 3 H is R 4 is C(O)R 6 And R 6 It is either CH3 or OCH3.

[0088] In some embodiments, the compound of formula (I) has the following structure:

[0089] [ka] It has one of the following.

[0090] In some embodiments, the compound of formula (I) has the structure:

[0091] [ka] It has a structure (corresponding to that of Cefin 1).

[0092] In some embodiments, the compound of formula (I) has the structure:

[0093] [ka] It holds.

[0094] In some embodiments, the compound of formula (I) has the structure:

[0095] [ka] It holds.

[0096] In some embodiments, the compound of formula (I) has the structure:

[0097] [ka] It holds.

[0098] In some embodiments, the compound of formula (I) has the structure:

[0099] [ka] It holds.

[0100] In some embodiments, the compound of formula (I) has the structure:

[0101] [ka] It holds.

[0102] In some embodiments, the compound of formula (I) has the structure:

[0103] [ka] It holds.

[0104] In some embodiments, the compound of formula (I) has the structure:

[0105] [ka] It holds.

[0106] In some embodiments, the compound of formula (I) has the structure:

[0107] [ka] It holds.

[0108] In some embodiments, the compound of formula (I) has the structure:

[0109] [ka] It holds.

[0110] In some embodiments, the compound of formula (I) has the structure:

[0111] [ka] It holds.

[0112] In some embodiments, the compound of formula (I) has the structure:

[0113] [ka] It holds.

[0114] In some embodiments, the compound of formula (I) has the structure:

[0115] [ka] It holds.

[0116] In some embodiments, the compound of formula (I) has the structure:

[0117] [ka] It holds.

[0118] In some embodiments, the compound of formula (I) has the structure:

[0119] In some embodiments, the compound of formula (I) has the structure:

[0120] [ka] It holds.

[0121] In some embodiments, the compound of formula (I) has the structure:

[0122] [ka] It holds.

[0123] In some embodiments, the compound of formula (I) has the structure:

[0124] [ka] It holds.

[0125] Methods for synthesizing the compound of formula (I) are known in the art. See, for example, International Publication No. 2016 / 001389, the contents of which are incorporated herein by reference in their entirety.

[0126] Those skilled in the art will understand that the compound of formula (I) can be tautomerized. For example, the structure

[0127] [ka] Compounds having tautomers

[0128] [ka] It can be converted to [formula]. Therefore, tautomers (including tautomer mixtures) of the compound of formula (I) can be used in the methods and compositions of this disclosure.

[0129] Compounds of formula (I) and their tautomers can be used in salt form. Suitable pharmaceutically acceptable salts include their acid addition salts or base salts. A summary of suitable pharmaceutically acceptable salts can be found in Berge et al, 1977, J Pharm Sci 66:1-19.

[0130] Salts can be formed with, for example, strong inorganic acids such as mineral acids, hydrohalogens such as hydrochloric acid, hydrobromic acid and hydroiodic acid, sulfuric acid, sulfate phosphates, bisulfates, hemisulfates, thiocyanates, persulfates and sulfonic acids; strong organic carboxylic acids, such as alkane carboxylic acids with 1 to 4 carbon atoms that are unsubstituted or substituted (e.g., by halogens), such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as (C1-C4) alkyl or aryl sulfonic acids that are unsubstituted or substituted (e.g., by halogens), such as methane or p-toluenesulfonic acid.

[0131] Exemplary salts include acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipine, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentane, glucoheptane, glycerophosphate, oxalate, heptane, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrinate, pivalate, propionate, and tartrate. The salts include lactobionates, pivoates, camphorates, undecanoates, and succinates; organic sulfonic acids, such as methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, camphorsulfonates, 2-naphthalenesulfonates, benzenesulfonates, p-chlorobenzenesulfonates, and p-toluenesulfonates; and inorganic acids, such as hydrochlorides, hydrobroms, hydroiodides, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates, phosphoric acids, and sulfonic acids. In some embodiments, the salt is an acetate. In other embodiments, the salt is a carbonate.

[0132] In another aspect, the Disclosure provides agents of the Disclosure (e.g., Cefin 1) for use in the treatment of diseases or disorders treatable by AMPK activation, such as those identified in Section 5.2.

[0133] In another aspect, the Disclosure provides the use of the Agents of the Disclosure (e.g., Cefin 1) in the manufacture of a pharmaceutical product for treating diseases or disorders treatable by AMPK activation, such as those identified in Section 5.2.

[0134] The drugs of this disclosure (e.g., Cefin 1) are based on technologies known in the art, for example (e.g., Allen et al., eds., 2012, Remington: The Science and Practice of Pharmacy, 22 nd It can be formulated for the intended route of administration (as described in Edition, Pharmaceutical Press, London, UK).

[0135] The drugs of this disclosure (e.g., Cefin 1) are incorporated by reference by the drug and one or more pharmaceutical excipients, e.g., the whole thereof, as described in the Handbook of Pharmaceutical Excipients, 8. th The pharmaceutical composition may be formulated as a pharmaceutical composition comprising one or more excipients as described in Revised Ed. (2017). The pharmaceutical composition may exist in unit dosage forms (for example, containing 1 mg to 250 mg, 10 mg to 100 mg, 1 mg to 100 mg, 2.5 mg to 60 mg, or 15 mg to 50 mg of the drug of this disclosure). [Examples]

[0136] 6. Examples [Example 1] 6.1. AMPK activating activity of Cefin 1 The AMPK-activating activity of cefin-1 was evaluated in human kidney 2 (HK-2) cells. The HK-2 cell line is a normal kidney-derived proximal tubular cell line immortalized by transduction of the human papillomavirus 16 (HPV-16) E6 / E7 gene.

[0137] HK-2 cells were administered 24 hours before the start of the experiment (T -24 ), 7 x 10 per well 4 Cells were seeded in a 6-well plate at a cell density of 1 cell. At T0, tunicamycin (a chemical ER stress inducer) and cefin-1 were added to the culture medium at concentrations of 5 μg / ml and 1 μM, respectively. After 24 hours (T 24 The cells were collected and their proteins were analyzed by Western blot analysis. The timetable for the experiment is shown in Figure 1.

[0138] Western blots of phosphorylated AMPK (p-AMPK), AMPK, and GAPDH (control) are shown in Figure 2. The ratios of pAMPK / GAPDH, AMPK / GAPDH, and pAMPK / AMPK are shown in Figures 3A-3C. As shown in Figures 2 and 3A, pAMPK levels were significantly elevated in cells treated with cefin-1 compared to untreated cells (sham) and cells treated with tunicamycin (Tu) alone. As shown in Figures 2 and 3B, AMPK levels were not elevated with either tunicamycin or tunicamycin + cefin-1 treatment; rather, AMPK levels were decreased compared to untreated cells. As shown in Figures 2 and 3C, the pAMPK / AMPK ratio was significantly elevated in cells treated with cefin-1 compared to untreated cells (sham) and cells treated with tunicamycin (Tu) alone. Therefore, the data indicate that cefin-1 treatment resulted in AMPK activation.

[0139] [Example 2] 6.2. Cefin-1 treatment reduces CHOP expression and increases p-CHOP. The effects of cefin-1 on CHOP expression and p-CHOP levels were evaluated.

[0140] At the start of the experiment (T0), cells were treated with tunicamycin (Tu) and either 1 μM cefin-1 (Se) or DMSO (sham). After 24 and 48 hours, cells were again treated with 1 μM cefin-1 (Se) or DMSO (sham). Sampling was performed at 72 hours. The timeline of the experiment is shown in Figure 4.

[0141] Protein levels are shown in Figure 5, and relative protein expression is shown in Figure 6. Cefin 1 treatment reduced CHOP levels and increased p-CHOP compared to tunicamycin treatment alone (Figures 5 and 6).

[0142] [Example 3] 6.3. Treatment of HK-2 cells with Cefin-1 The effects of cefin-1 on CHOP expression and p-CHOP levels were evaluated in human kidney 2 (HK-2) cells.

[0143] HK-2 cells were introduced one day before the start of the trial (T -1日 Seeds were sown at ). Tunicamycin and cefin-1 were added to the culture medium at T0. After 24 hours (T 24 The cells were collected and their protein levels were analyzed. The timetable for the experiment is shown in Figure 7.

[0144] Protein levels are shown in Figures 8 and 9. Cell number and cell viability are shown in Figure 10. An increase in the p-CHOP / CHOP ratio was observed in cells treated with cefin-1 compared to cells treated with tunicamycin alone (Figure 8). Increased cytoplasmic CHOP expression, decreased nuclear CHOP expression, and a decrease in the nuclear / cytoplasmic CHOP ratio were observed in cells treated with cefin-1 compared to cells treated with tunicamycin alone (Figure 9).

[0145] 7. Specific Embodiments This disclosure is illustrated by the following specific embodiments. 1. A method for activating AMP-activated protein kinase (AMPK) and / or increasing the phosphorylated AMPK (pAMPK) / AMPK ratio, wherein the target cells are given formula (I):

[0146] [Chemical formula] [wherein, R 1 is alkyl, O-alkyl, Cl, F or Br, R 2 is H or F, R 3 is H or alkyl, R 4 is H or C(O)R 6 and R 5 is H, or, R 4 and R 5 are combined to form a 5- to 6-membered saturated or unsaturated heterocyclic group optionally containing 1 or 2 heteroatoms in addition to the N atom to which R 4 and R 5 are attached, and the heterocyclic group is optionally substituted with one or more R 10 groups, R 6 is a selected R 7 , OR 7 or NR 8 R 9 and R 7 , R 8 and R 9 are each independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl and aryl, each of which is optionally substituted with one or more R 10 groups, Each R 10 is independently selected from halogen, OH, =O, CN, COO-alkyl, aralkyl, SO2-alkyl, SO2-aryl, COOH, CO-alkyl, CO-aryl, NH2, NH-alkyl, N(alkyl)2, CF3, alkyl, and alkoxy, X and Z are each independently CR 11 and Y is CR 11 or N, R11 [is H, alkyl, or F] A method comprising contacting a drug, which is a compound of or a tautomer thereof, or a pharmaceutically acceptable salt thereof, with an amount effective in activating AMPK and / or increasing the pAMPK / AMPK ratio in cells. 2. A method for inhibiting C / EBP homologous protein (CHOP) and / or increasing the phosphorylated CHOP (pCHOP) / CHOP ratio in cells, wherein the target cells are given formula (I):

[0147] [ka] [In the formula, R 1 is alkyl, O-alkyl, Cl, F or Br, R 2 is H or F, R 3 is H or alkyl, R 4 is H or C(O)R 6 And, R 5 Is it H? Or, R 4 and R 5 They are combined into R 4 and R 5 In addition to the bonded N atom, it forms a 5-6 member saturated or unsaturated heterocyclic group which optionally contains 1 or 2 heteroatoms, and the heterocyclic group comprises 1 or more R 10 It is arbitrarily substituted in the base, R 6 The selected R 7 , OR 7 or NR 8 R 9 And, R 7 , R 8 and R 9 Each is independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, and each of them is one or more R 10 It is arbitrarily substituted in the base, Each R10 These are independently selected from halogens, OH, =O, CN, COO-alkyl, aralkyl, SO2-alkyl, SO2-aryl, COOH, CO-alkyl, CO-aryl, NH2, NH-alkyl, N(alkyl)2, CF3, alkyl, and alkoxy. X and Z are independent of each other, CR 11 And, Y is CR 11 or N, R 11 [is H, alkyl, or F] A method comprising contacting a drug, which is a compound or a tautomer thereof, or a pharmaceutically acceptable salt thereof, with a cell in an amount effective to inhibit C / EBP homologous protein (CHOP) and / or increase the pCHOP / CHOP ratio. 3. The method according to Embodiment 1 or Embodiment 2, wherein contact is in vivo. 4. A method for treating a subject who has or is at risk of having a disease or disorder treatable by (a) AMP-activated protein kinase (AMPK) activation and / or (b) C / EBP homologous protein (CHOP) inhibition, wherein the therapeutically effective dose is given by formula (I):

[0148] [ka] [In the formula, R 1 is alkyl, O-alkyl, Cl, F or Br, R 2 is H or F, R 3 is H or alkyl, R 4 is H or C(O)R 6 And, R 5 Is it H? Or, R 4 and R 5 They are combined into R 4 and R 5In addition to the bonded N atom, it forms a 5-6 member saturated or unsaturated heterocyclic group which optionally contains 1 or 2 heteroatoms, and the heterocyclic group comprises 1 or more R 10 It is arbitrarily substituted in the base, R 6 The selected R 7 , OR 7 or NR 8 R 9 And, R 7 , R 8 and R 9 Each is independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, and each of them is one or more R 10 It is arbitrarily substituted in the base, Each R 10 These are independently selected from halogens, OH, =O, CN, COO-alkyl, aralkyl, SO2-alkyl, SO2-aryl, COOH, CO-alkyl, CO-aryl, NH2, NH-alkyl, N(alkyl)2, CF3, alkyl, and alkoxy. X and Z are independent of each other, CR 11 And, Y is CR 11 or N, R 11 [is H, alkyl, or F] A method comprising administering a drug that is a compound of or a tautomer thereof, or a pharmaceutically acceptable salt thereof, to a target. 5. The method according to any one embodiment of Embodiments 2 to 4, wherein the amount of the drug is an amount effective to activate AMPK in one or more cell types, tissues, and / or organs. 6. The method according to any one embodiment of Embodiments 2 to 5, wherein the amount of the drug is an amount effective in increasing the pAMPK / AMPK ratio in one or more cell types, tissues, and / or organs. 7. The method according to any one embodiment of Embodiments 2 to 6, wherein the amount of the drug is an amount effective in inhibiting the synthesis of fatty acids and / or cholesterol in the subject. 8. The method according to any one embodiment of Embodiments 2 to 7, wherein the amount of the drug is an amount effective in reducing serum and / or liver cholesterol levels. 9. The method according to any one embodiment of Embodiments 2 to 8, wherein the amount of the drug is an amount effective in increasing glucose uptake by skeletal muscle. 10. The method according to any one embodiment of Embodiments 2 to 9, wherein the amount of the drug is an amount effective in inhibiting CHOP in one or more cell types, tissues, and / or organs. 11. The method according to any one embodiment of Embodiments 2 to 10, wherein the amount of the drug is an amount effective in increasing the pCHOP / CHOP ratio in one or more cell types, tissues, and / or organs. 12. The method according to any one embodiment of Embodiments 1 to 11, wherein the subject has or is at risk of having a disease or disorder that is metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 2 diabetes, insulin resistance, glucose intolerance, chronic pain, muscle loss, neuromuscular disorders, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, cardiac reperfusion injury, chronic kidney disease, polycystic kidney disease, diabetic nephropathy, cardiovascular disease, inflammatory bowel disease, arthritis, hypertension, peripheral vascular disease, nephrogenic diabetes insipidus, glaucoma, eye disease or disorder, ocular angiogenesis, β-hemochromocytic disorder, cancer, fibrosis, cancer cachexia, or mitochondrial disease. 13. The method according to any one embodiment of Embodiments 1 to 11, wherein the subject has or is at risk of having a disease or disorder that is metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 2 diabetes, insulin resistance, glucose intolerance, chronic pain, muscle loss, neuromuscular disorders, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, cardiac reperfusion injury, chronic kidney disease, polycystic kidney disease, acute kidney injury, diabetic nephropathy, cardiovascular disease, inflammatory bowel disease, arthritis, hypertension, peripheral vascular disease, nephrogenic diabetes insipidus, glaucoma, eye disease or disorder, ocular angiogenesis, β-hemochromocytic disorder, cancer, fibrosis, cancer cachexia, or mitochondrial disease. 14. The method according to any one embodiment of Embodiments 1 to 11, wherein the subject has or is at risk of having a disease or disorder related to increased lipid metabolism. 15. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is metabolic syndrome. 16. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is non-alcoholic fatty liver disease. 17. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH). 18. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is obesity. 19. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is type 2 diabetes. 20. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is insulin resistance. 21. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is glucose intolerance. 22. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is chronic pain. 23. The method according to Embodiment 22, wherein the chronic pain is postoperative pain. 24. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is muscle loss. 25. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is a neuromuscular disorder. 26. The method according to Embodiment 25, wherein the neuromuscular disorder is Duchenne muscular dystrophy or myotonic dystrophy type 1. 27. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is heart failure. 28. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is cardiac hypertrophy. 29. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is diabetic cardiomyopathy. 30. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is cardiac reperfusion injury. 31. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is chronic kidney disease. 32. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is polycystic kidney disease. 33. The method according to Embodiment 32, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease. 34. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is diabetic nephropathy. 35. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is a cardiovascular disease. 36. The method according to embodiment 35, wherein the cardiovascular disease is atherosclerosis. 37. The method according to Embodiment 35, wherein the cardiovascular disease is coronary artery disease. 38. The method according to Embodiment 35, wherein the cardiovascular disease is peripheral artery disease. 39. The method according to embodiment 35, wherein the cardiovascular disease is a cerebrovascular disease. 40. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is inflammatory bowel disease. 41. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is arthritis. 42. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is hypertension. 43. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is a peripheral vascular disease. 44. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is nephrogenic diabetes insipidus. 45. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is a disease or disorder of the eye. 46. ​​The method according to Embodiment 45, wherein the eye disease or disorder is retinopathy, a condition associated with microvascular disorders, neovascular glaucoma, corneal transplant rejection, glaucoma, herpetic and infectious keratitis, ocular ischemia, neovascular glaucoma, neovascularization of the cornea, uvea and / or iris, orbital and / or eyelid tumor, Stevens-Johnson syndrome, ocular scarring pemphigoid, injury, or ocular surface disease. 47. The method according to embodiment 45, wherein the disease or disorder is macular degeneration. 48. The method according to Embodiment 46, wherein the disease or disorder is wet age-related macular degeneration (AMD). 49. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is ocular neovascularization. 50. The method according to Embodiment 45, wherein the angiogenesis is characterized by angiogenesis of the surface, cornea, retina, choroid, uvea, or iris. 51. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is glaucoma. 52. The method according to any one embodiment of Embodiments 2 to 51, wherein the amount of drug is an amount effective in reducing intraocular pressure. 53. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is β-hemochromocytosis. 54. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is cancer, and optionally the cancer is advanced cancer. 55. The method according to embodiment 54, wherein the cancer is hepatocellular carcinoma. 56. The method according to embodiment 54, wherein the cancer is lung cancer. 57. The method according to embodiment 54, wherein the cancer is colorectal cancer. 58. The method according to embodiment 54, wherein the cancer is liver cancer. 59. The method according to embodiment 54, wherein the cancer is melanoma. 60. The method according to embodiment 54, wherein the cancer is breast cancer. 61. The method according to embodiment 54, wherein the cancer is prostate cancer. 62. The method according to Embodiment 54, wherein the cancer is ovarian cancer. 63. The method according to embodiment 54, wherein the cancer is leukemia. 64. The method according to Embodiment 12 or Embodiment 13, wherein the disease or disorder is fibrosis. 65. The method according to embodiment 64, wherein the fibrosis is pulmonary fibrosis. 66. The method according to embodiment 64, wherein the fibrosis is renal fibrosis. 67. The method according to embodiment 66, wherein the fibrosis is glomerulosclerosis and / or tubulointerstitial fibrosis. 68. The method according to embodiment 66 or embodiment 67, wherein the renal fibrosis is renal fibrosis resulting from chronic kidney disease (CKD), optionally wherein the CKD is hypertensive CKD. 69. The method according to embodiment 64, wherein the fibrosis is liver fibrosis. 70. The method according to embodiment 64, wherein the fibrosis is cardiac fibrosis. 71. The method according to embodiment 12 or embodiment 13, wherein the disease or disorder is cancer cachexia. 72. The method according to embodiment 12 or embodiment 13, wherein the disease or disorder is a mitochondrial disease. 73. The method according to any one of embodiments 13 and embodiments 1 to 11, wherein the subject has or is at risk of having a disease or disorder that is a disease or disorder of the kidney. 74. The method according to embodiment 13 or embodiment 73, wherein the disease or disorder is acute kidney injury. 75. The method according to any one of embodiments 12 to 74, wherein the subject has a disease or disorder. 76. The method according to any one of embodiments 12 to 74, wherein the subject is at risk of having a disease or disorder. 77. R 1 is Cl, Br, CH3, H, or F, the method according to any one of embodiments 1 to 76. 78. R 1 is Cl, the method according to embodiment 77. 79. R 2 is H, the method according to any one of embodiments 1 to 78. 80. Y is CR 11 the method according to any one of embodiments 1 to 79. 81. X, Y, and Z are each CH, the method according to any one of embodiments 1 to 80. 82. R 3 and R 4 are both H, the method according to any one of embodiments 1 to 81. 83.R 3 H is R 4 C(O)R 6 And R 6 The method according to any one embodiment of Embodiments 1 to 81, wherein is CH3 or OCH3. 84. The drug,

[0149] [ka] The method according to any one embodiment of Embodiments 1 to 76, or its tautomers, or pharmaceutically acceptable salts thereof. 85. The drug,

[0150] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 86. The drug,

[0151] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 87. The drug,

[0152] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 88. The drug,

[0153] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 89. The drug,

[0154] [Chemistry] The method according to embodiment 84, which is or its tautomer, or a pharmaceutically acceptable salt thereof. 90. The agent is

[0155] [Chemistry] The method according to embodiment 84, which is or its tautomer, or a pharmaceutically acceptable salt thereof. 91. The agent is

[0156] [Chemistry] The method according to embodiment 84, which is or its tautomer, or a pharmaceutically acceptable salt thereof. 92. The agent is

[0157] [Chemistry] The method according to embodiment 84, which is or its tautomer, or a pharmaceutically acceptable salt thereof. 93. The agent is

[0158] [Chemistry] The method according to embodiment 84, which is or its tautomer, or a pharmaceutically acceptable salt thereof. 94. The agent is

[0159] [Chemistry] The method according to embodiment 84, which is or its tautomer, or a pharmaceutically acceptable salt thereof. 95. The agent is

[0160] [Chemistry] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 96. The drug,

[0161] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 97. The drug,

[0162] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 98. The drug,

[0163] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 99. The drug,

[0164] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 100. The drug,

[0165] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 101. The drug,

[0166] [ka] The method according to Embodiment 84, or its tautomers, or pharmaceutically acceptable salts thereof. 102. The method according to any one embodiment of Embodiments 1 to 101, wherein the drug is a pharmaceutically acceptable salt of a compound of formula (I) or a tautomer thereof. 103. The method according to Embodiment 102, wherein the salt is an acetate salt. 104. The method according to Embodiment 102, wherein the salt is a carbonate. 105. The method according to any one embodiment of Embodiments 1 to 104, wherein the drug is administered orally to the target. 106. A drug according to any one embodiment of the prior embodiments for use in the method described in any one embodiment of the prior embodiments. 107. A pharmaceutical composition comprising a drug and a pharmaceutically acceptable excipient described in any one embodiment of the prior embodiments for use in the method described in any one embodiment of the prior embodiments. 108. Use of a drug according to any one embodiment of a prior embodiment for the manufacture of a drug for treating a disease or disorder described in any of the prior embodiments.

[0167] 8. Citation of References All publications, patents, patent applications, and other documents described herein are incorporated herein by reference in their entirety for all purposes to the same extent that each individual publication, patent, patent application, or other document is individually indicated as being incorporated herein by reference for all purposes. In the event of any inconsistency in teachings between one or more of the references incorporated herein and this disclosure, the teachings herein shall prevail.

Claims

1. A method for activating AMP-activated protein kinase (AMPK) and / or increasing the phosphorylated AMPK (pAMPK) / AMPK ratio, wherein the target cells are given formula (I): 【Chemistry 1】 [In the formula, R １ is alkyl, O-alkyl, Cl, F or Br, R ２ is H or F, R ３ is H or alkyl, R ４ is H or C(O)R ６ And, R ５ Is it H? Or, R ４ and R ５ are combined to form a 5- or 6-membered saturated or unsaturated heterocyclic group optionally containing one or two heteroatoms in addition to the N atom to which R ４ and R ５ are attached, and the heterocyclic group is optionally substituted with one or more R １０ groups, R ６ The selected R ７ , OR ７ or NR ８ R ９ And, R ７ , R ８ and R ９ Each is independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, and each is one or more R １０ It is arbitrarily substituted in the base, Each R １０ These are halogens, OH, =O, CN, COO-alkyl, aralkyl, and SO ２ - Alkyl, SO ２ -aryl, COOH, CO-alkyl, CO-aryl, NH ２ NH-alkyl, N(alkyl) ２ CF ３ Selected independently from alkyl and alkoxy, X and Z are each independent of CR １１ And, Y is CR １１ or N, R １１ [is H, alkyl, or F] A method comprising contacting a drug, which is a compound or a tautomer thereof, or a pharmaceutically acceptable salt thereof, with the cells in an amount effective for activating AMPK and / or increasing the pAMPK / AMPK ratio.

2. A method for inhibiting C / EBP homologous protein (CHOP) and / or increasing the phosphorylated CHOP (pCHOP) / CHOP ratio in cells, wherein the target cells are given formula (I): 【Chemistry 2】 [In the formula, R １ is alkyl, O-alkyl, Cl, F or Br, R ２ is H or F, R ３ is H or alkyl, R ４ is H or C(O)R ６ And, R ５ Is it H? Or, R ４ and R ５ They combine into R ４ and R ５ In addition to the bonded N atom, a 5-6 member saturated or unsaturated heterocyclic group is formed which optionally contains 1 or 2 heteroatoms, and the heterocyclic group comprises 1 or more R １０ It is arbitrarily substituted in the base, R ６ The selected R ７ , OR ７ or NR ８ R ９ And, R ７ , R ８ and R ９ Each is independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, and each is one or more R １０ It is arbitrarily substituted in the base, Each R １０ These are halogens, OH, =O, CN, COO-alkyl, aralkyl, and SO ２ - Alkyl, SO ２ -aryl, COOH, CO-alkyl, CO-aryl, NH ２ NH-alkyl, N(alkyl) ２ CF ３ Selected independently from alkyl and alkoxy, X and Z are each independent of CR １１ And, Y is CR １１ or N, R １１ [is H, alkyl, or F] A method comprising contacting a drug, which is a compound or a tautomer thereof, or a pharmaceutically acceptable salt thereof, with an amount effective in inhibiting C / EBP homologous protein (CHOP) and / or increasing the pCHOP / CHOP ratio in the cells.

3. The method according to claim 1 or claim 2, wherein the contact is made in vivo.

4. A method for treating a subject having or at risk of having a disease or disorder treatable by (a) AMP-activated protein kinase (AMPK) activation and / or (b) C / EBP homologous protein (CHOP) inhibition, wherein the therapeutically effective dose is formula (I): 【Transformation 3】 [In the formula, R １ is alkyl, O-alkyl, Cl, F or Br, R ２ is H or F, R ３ is H or alkyl, R ４ is H or C(O)R ６ And, R ５ Is it H? Or, R ４ and R ５ They combine into R ４ and R ５ In addition to the bonded N atom, a 5-6 member saturated or unsaturated heterocyclic group is formed which optionally contains 1 or 2 heteroatoms, and the heterocyclic group comprises 1 or more R １０ It is arbitrarily substituted in the base, R ６ The selected R ７ , OR ７ or NR ８ R ９ And, R ７ , R ８ and R ９ Each is independently selected from alkyl, cycloalkyl, aralkyl, cycloalkenyl, heterocyclyl, and aryl, and each is one or more R １０ It is arbitrarily substituted in the base, Each R １０ These are halogens, OH, =O, CN, COO-alkyl, aralkyl, and SO ２ - Alkyl, SO ２ -aryl, COOH, CO-alkyl, CO-aryl, NH ２ NH-alkyl, N(alkyl) ２ CF ３ , independently selected from alkyl and alkoxy, X and Z are each independent of CR １１ And, Y is CR １１ or N, R １１ [is H, alkyl, or F] A method comprising administering to a subject a drug which is a compound of the said, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

5. The amount of the aforementioned drug is (a) Activating AMPK in one or more cell types, tissues, and / or organs; and / or (b) Increasing the pAMPK / AMPK ratio in one or more cell types, tissues, and / or organs; and / or (c) Inhibiting the synthesis of fatty acids and / or cholesterol in the subject; and / or (d) reducing serum and / or hepatic cholesterol levels; and / or (e) increasing glucose uptake by skeletal muscle; and / or (f) Inhibiting CHOP in one or more cell types, tissues, and / or organs; and / or (g) Increasing the pCHOP / CHOP ratio in one or more cell types, tissues, and / or organs. The method according to any one of claims 2 to 4, wherein the amount is effective for [the purpose].

6. The method according to any one of claims 1 to 5, wherein the subject has or is at risk of having a disease or disorder which is metabolic syndrome, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), obesity, type 2 diabetes, insulin resistance, glucose intolerance, chronic pain, muscle loss, neuromuscular disorders, heart failure, cardiac hypertrophy, diabetic cardiomyopathy, cardiac reperfusion injury, chronic kidney disease, polycystic kidney disease, diabetic nephropathy, cardiovascular disease, inflammatory bowel disease, arthritis, hypertension, peripheral vascular disease, nephrogenic diabetes insipidus, glaucoma, eye disease or disorder, ocular angiogenesis, β-hemochromocytic disorder, cancer, fibrosis, cancer cachexia, or mitochondrial disease.

7. The method according to any one of claims 1 to 5, wherein the subject has or is at risk of having a disease or disorder related to increased lipid metabolism.

8. The method according to any one of claims 1 to 5, wherein the subject has a disease or disorder that is a kidney disease or disorder, or is at risk of having such a disease or disorder.

9. The method according to any one of claims 1 to 5, wherein the subject has or is at risk of acute kidney injury.

10. The method according to any one of claims 6 to 9, wherein the subject has the disease or disorder.

11. The method according to any one of claims 6 to 9, wherein the subject has a risk of the disease or disorder.

12. R １ Cl, Br, CH ３ The method according to any one of claims 1 to 11, wherein H or F.

13. R １ The method according to claim 12, wherein R is Cl.

14. R ２ The method according to any one of claims 1 to 13, wherein is H.

15. Y is CR １１ The method according to any one of claims 1 to 14.

16. The method according to any one of claims 1 to 15, wherein X, Y, and Z are each CH.

17. R ３ and R ４ The method according to any one of claims 1 to 16, wherein both are H.

18. R ３ is H, or R ４ is C(O)R ６ or R ６ is CH ３ or OCH ３ The method according to any one of claims 1 to 16.

19. The aforementioned drug, 【Chemistry 4】 The method according to any one of claims 1 to 11, wherein the method is a tautomer thereof, or a pharmaceutically acceptable salt thereof.

20. The aforementioned drug, 【Transformation 5】 The method according to claim 19, wherein the method is a tautomer thereof, or a pharmaceutically acceptable salt thereof.

21. The method according to any one of claims 1 to 20, wherein the drug is a pharmaceutically acceptable salt of a compound of formula (I) or a tautomer thereof.

22. The method according to claim 21, wherein the salt is an acetate salt.

23. The method according to claim 21, wherein the salt is a carbonate.

24. The method according to any one of claims 1 to 23, wherein the drug is administered orally to the subject.

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