Synthetic retinoids for RAR activation

Abstract

To provide compounds useful in the treatment of a condition or disease which is alleviated by the activation of retinoic acid receptors (RAR).SOLUTION: The present invention provides a compound of formula I in free or in salt form.SELECTED DRAWING: Figure 6

Description

Technical Field

[0001] Synthetic retinoids for RAR activation The present invention relates to compounds of formula I for use in the treatment of conditions or diseases alleviated by activation of the retinoic acid receptor (RAR):

Chemical Formula

[0002] More particularly, the present invention relates to the use of compounds of formula I in the treatment of conditions and / or diseases alleviated by activation of RAR, including neurological conditions such as neurodegenerative conditions including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and conditions such as spinal cord injury and the like. Retinoids are a class of natural or synthetic compounds that are analogs of vitamin A and its derivatives

[0003] ​​They are a group. Retinoids are essential for many cellular activities and act as signaling molecules in embryonic development. Control of important biological pathways from adult homeostasis to proliferation, differentiation, and apex formation. It is also involved in the development of stem cells such as cysts. All-trans retinoic acid (ATRA) is the most It is also an abundant endogenous retinoid and has been used as a model compound in retinoid research. .

[0004] Retinoids are a group of nuclear receptors known as retinoic acid receptors (RARs), that is, It acts on induced ligand-activated transcription factors that control various physiological mechanisms at the nom level. Therefore, synthetic retinoids are involved in, or potentially involved in, RAR. It has been studied as a therapeutic agent for use in various diseases and conditions. However, to date... Known compounds have drawbacks such as low potency or effectiveness, or poor solubility in water. It had poor physical properties, such as low quality.

[0005] Neurological conditions refer to the central and peripheral nervous systems, that is, the brain, spinal cord, cranial nerves, peripheral nerves, and nerves. These are diseases of the roots, autonomic nervous system, neuromuscular junction, and muscles. Neurological diseases include spinal cord injury and brain Sudden conditions such as stroke, intermittent conditions such as epilepsy, amyotrophic lateral sclerosis (ALS), Al This includes neurodegenerative conditions such as Zheimer's disease and Parkinson's disease, as well as stable conditions such as cerebral palsy. These neurological conditions tend to become chronic, many are life-threatening, and all are life-threatening. This has a significant negative impact on the quality of life. In total, hundreds of millions of people worldwide suffer from neurological disorders. It is presumed that the disease is affecting them (World Health Organization, May 2016).

[0006] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, involves motor neurons. It is a debilitating neurological condition characterized by the gradual loss of certain functions, resulting in paralysis. In Europe, it is estimated that there are 1.7 to 2.3 cases of ALS per 100,000 people per year [Logrosc ino et al. “Incidence of amyotrophic lateral sclerosis in Europe”. J Neurol Ne [urosurg. Psychiatry. (2009); 81(4):385-90], approximately 50% of patients within 30 months of symptom onset It is estimated to be fatal [Kiernan et al. "Amyotrophic lateral sclerosis". The lan cet; Vol.377(9769); (2011):942-955]. However, despite the devastating nature of this disease Currently, there is no cure, and the only drug approved in the UK for the treatment of ALS is It has been shown to extend patients' lives by an average of 2-3 months [Miller et al. "Riluzole fo r amyotrophic lateral sclerosis (ALS) / motor neuron disease (mND)".Cochrane Datab of Systematic Reviews (2012), Issue 3.CD001447].

[0007] ALS can be sporadic or familial, and the causative mutations are found in multiple genes, including C9ORF72 and SOD1. Yes. The fundamental cause of ALS is the death of motor neurons that control muscle movement, but The exact mechanism by which this occurs is currently unknown. However, (i) excitotoxicity: neurotransmission (ii) Excessive firing of nerve cells due to the toxic effects of the substance, and failure of autophagy: (iii) loss of the cellular detoxification system that removes insoluble molecules accumulated within the cell, Inflammation: When immune cells of the nervous system mistakenly attack motor nerve cells, (iv) Axonal disorder: Several of these include the loss of interconnecting fibers that are essential for intercellular communication. It is thought that the following mechanism is involved. Therefore, the drugs used in the treatment of ALS Ideally, it should exhibit multifaceted characteristics.

[0008] Therefore, it is used for neurological conditions such as neurodegenerative diseases including ALS and Alzheimer's disease. There is a pressing and unmet need for new treatments, particularly those with good solubility in water. Compounds with superior physical properties, such as properties of the material, would be useful.

[0009] Treatments to cure or prevent ALS, Alzheimer's disease, or related disorders are While this is the ultimate goal of many pharmaceutical companies' research projects, more realistically, it involves preventing the onset of disease. If there are treatments that can delay, slow down, or stop the progression of the disease, then there will be a great opportunity. This is an exhibition. Furthermore, methods for screening potential therapeutic compounds are also extremely useful. [Overview of the Initiative]

[0010] Therefore, the present invention relates to conditions or diseases that are alleviated by activation of retinoic acid receptors. This relates to compounds for use in the treatment of diseases. In one aspect, this relates to genome activity This includes sexualization. In aspects of the present invention, the compound activates both genomic and non-genomic pathways. do.

[0011] In one embodiment, the present invention relates to a pharmaceutical composition comprising such a compound, and a retinoid acid receptor. The use of such compounds and compositions in the treatment of conditions or diseases that are alleviated by their activation. Regarding use.

[0012] Conditions and diseases that can be alleviated by activation of retinoic acid receptors include neurodegenerative diseases. In addition to conditions involving the receptive neurotransmitter (RAR), RAR activity is also observed in conditions such as stroke, traumatic brain injury, epilepsy, and spinal cord injury. This includes things that are mitigated by the transformation.

[0013] In this embodiment, the present invention relates to conditions and diseases that are alleviated by activation of retinoic acid receptors. This concerns methods for screening compounds with therapeutic potential in the treatment of [condition].

[0014] Aspects of the present invention relate to the novel compound itself.

[0015] Further aspects and embodiments of the present invention are as defined in the claims. I will explain this in more detail below.

[0016] According to a first aspect of the present invention, the mitigation is achieved by activation of the retinoic acid receptor (RAR). Compounds of formula I, either in free or salt form, used to treat conditions or diseases: [ka] [In formula I, A 1 is N or CR 6 and; A 2 is N or CR 7 and; A 3 is N or CR 8 and; R 6 and R 8 These are, independently, hydrogen and C1-C 10 It is alkyl, F, Br, or Cl; R 7Independently, hydrogen, C1-C 10 Alkyl, F, Br, Cl or -OCR 9 And R 9 is H or C It is a 1-C6 alkyl group; R 1 ~R 4 These are, independently, C1-C 10 Alkyl or R 1 and R 2 and / if Kuha R 3 and R 4 They are bonded together to form a three-membered ring; A 4 is N or CR 12 And, A 5 is N or CR 13 And, A 6 is N or CR 14 And, A 7 is N or CR 15 And, Each R 12 ~R 15 These are independently H, halogen, or haloalkyl C1-C 10 and; R 5 is -C(=O)R 16 Or -C (=O) OR 16 And R 16 is H or C 1-10 It is alkyl; However, A 1 ~A 7 At least one of them is N, or R 12 ~R 15 At least one of them is F, and Cl is also [or it must be Br] The isomers thereof are provided.

[0017] In the compound of formula I, A 1 ~A 7 At least one of them is N, or R 12 ~R 15 fewer Each element is either F, Cl, or Br.

[0018] In this specification, the term "alkyl" refers to fully saturated, branched, unbranched, or cyclic aqueous carbonate. The elemental part, i.e., primary, secondary, or tertiary alkyl groups, or, where appropriate, cycloalkyl groups. This refers to alkyl groups substituted with cycloalkyl groups. Unless otherwise specified, alkyl groups are defined as alkyl groups. The group consists of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Includes children. Typical examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neo-butyl 1,2-dimethylpentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl Examples include, but are not limited to, n-heptyl, n-octyl, n-nonyl, and n-decyl. It is not something that should be done.

[0019] As used herein, the terms "halogen" or "halo" refer to fluoro, chloro, and bromo It means iodine.

[0020] In this specification, the term "haloalkyl" means that one or more hydrogen atoms are connected to a halogen atom. This refers to the substituted alkyl group.

[0021] Conditions or diseases that can be alleviated by activation of retinoic acid receptors include neurodegenerative diseases. In addition to conditions involving RAR such as stroke, traumatic brain injury, epilepsy, and spinal cord injury, RAR is also involved in other conditions. One example of a condition that can be alleviated by AR activation is:

[0022] Conditions involving RAR include amyotrophic lateral sclerosis (ALS), neuromuscular diseases, and Parkinson's disease. Diseases, multiple sclerosis (MS), Alzheimer's disease, early Alzheimer's disease, intermediate Alzheimer's disease - Disease, late-stage Alzheimer's disease, cognitive impairment, memory impairment, memory loss, senile dementia, vascular dementia These include neurodegenerative diseases such as intellectual disability, cognitive impairment, and mild cognitive impairment.

[0023] Therefore, the condition or disease that is alleviated by RAR activation is amyotrophic lateral sclerosis (ALS). (ALS), neuromuscular diseases, Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, early stage Alzheimer's disease, intermediate-stage Alzheimer's disease, late-stage Alzheimer's disease, cognitive impairment, memory impairment Memory loss, senile dementia, vascular dementia, cognitive impairment, mild cognitive impairment, stroke, The treatment may be selected from traumatic brain injury, epilepsy, and spinal cord injury.

[0024] The condition may be a neurological condition. In this embodiment, the neurological condition may be ALS, Parkinson's disease. It may also be a neurodegenerative condition such as Sonnson's disease or Alzheimer's disease.

[0025] In one embodiment, R 5 It is -COOH.

[0026] In one embodiment, A 1 ~A 3 At least one of them is N, or A 4 at least One is CR 12 is or A 5 CR 13 And R 12 / R 13 It is a halogen. 12 / R 13 teeth, Preferably, it is F.

[0027] In one embodiment, A 1 From A 3At least one of them is N. In one embodiment, A 1 and A 3 are both N.

[0028] In one embodiment, A 2 is CR 7 and R 7 is H.

[0029] In one embodiment, at least one of A 4 , A 5 or A 6 is CF.

[0030] In this embodiment, A 4 may be CF. Alternatively, A 5 is CF and A 2 is CR 7 and that is also possible.

[0031] In one embodiment, A 5 and A 6 are CF.

[0032] In one embodiment, A 4 is CCl.

[0033] In one embodiment, A 1 and A 3 are both N, and A 2 is CR 7 as represented by formula IA, and R 7 is H.

Chemical Formula

[0034] Preferably, in formula IA, R 5 is -COOH.

[0035] Alternatively, in one embodiment, in formula I, at least one of A 4 ~A 7 is N.

[0036] In one embodiment, in formula I, A 4 It is N.

[0037] In one embodiment, in formula I, A 4 Or A 5 It is CF.

[0038] Generally speaking, the compound of formula I has a hydrophobic region and a linker region (-C≡C) as shown below. -) and has a polarity region: [ka]

[0039] The inventors have found that, advantageously, the conjugated ring in the hydrophobic region contains one, preferably two, nitrogen atoms. Elementary atoms are incorporated; or, nitrogen atoms are incorporated into the conjugated ring in the polar region; and / or the conjugated ring in the polar region is halogenated (or preferably fluorinated) The compound of formula I is remarkably effective in treating diseases or conditions that are alleviated by the activation of the RAR. I found it to be beneficial.

[0040] Exemplary compounds of formula I that can be mentioned are selected from the following group. Examples include: [ka]

[0041] In certain embodiments, the compound of formula I may be selected from the following: [ka]

[0042] In this embodiment, the compound of formula I may be selected from the following: [ka]

[0043] In this embodiment, the compound of formula I may be selected from the following: [ka]

[0044] In another aspect of the present invention, it is used to treat diseases or conditions that are alleviated by the activation of RAR. The use of a compound of formula I as defined herein in the manufacture of a drug is provided. In one embodiment, the drug comprises a compound of formula I.

[0045] Another aspect of the present invention includes the step of administering a therapeutically effective amount of the compound of formula I to a patient. Furthermore, the compound of formula I is as defined herein, and is relaxed by RAR activation. A method for treating patients with a disease or condition is provided.

[0046] In another aspect of the present invention, it is used to treat diseases or conditions that are alleviated by the activation of RAR. To do so, optionally one or more pharmaceutically acceptable compounds of formula I as defined herein. A pharmaceutical composition is provided which contains in combination with an excipient, diluent or carrier. The formulation may optionally include one or more additional therapeutic agents.

[0047] The term "therapeutically effective" or "effective dose" refers to the desired therapeutic effect, improvement effect, or inhibitory effect. This refers to the amount of the compound or composition of the present invention that is effective in producing a fruit or preventive effect.

[0048] The term "pharmaceutical composition" refers to a composition suitable for administration to a patient. Therefore, the term "Pharmaceutical composition" refers to the compound or mixture thereof of the present invention, or its salt, solvate, or p A drug, isomer, or tautomer, any one or more pharmaceutically acceptable drugs This refers to a composition containing an excipient, carrier, or diluent in combination with a pharmaceutical product. The term "composition" refers to a bulk composition (i.e., a composition that has not yet been formed into individual dose units). It is intended to include both the form and individual dose units. The units include tablets, pills, caplets, ampoules, etc.

[0049] Those skilled in the art will know that the compounds of the present invention can be converted into prodrugs and / or solvates. You will recognize cases such as the following. The term "prodrug" refers to the compound of the present invention or said compound Chemicals are converted in vivo to obtain pharmaceutically acceptable salts, hydrates, or solvates of the chemical. It means a compound (for example, a drug precursor). This transformation is, for example, hydrolysis in the blood. It can occur through various mechanisms (e.g., metabolic or chemical processes). be.

[0050] The compounds of the present invention may be nonsolvates, or pharmaceutically acceptable substances such as water or ethanol. It may be solvated with the solvent. For example, one or more solvent molecules are crystalline solid It is understood that solvates may be isolated, for example, when they are incorporated into the crystal lattice. It will be done. "Solvate" encompasses both the solution phase and the isolateable solvate. Appropriate Examples of solvates include ethanol hydrate, methanol hydrate, and hydrate, but It is not limited to them.

[0051] The compounds used in this invention include their salts, and references to the compounds of this invention are particularly... Unless otherwise stated, it is intended to include references to that salt. Suitable salts include, for example, no Acidic salts formed from inorganic and / or organic acids, formed from inorganic and / or organic bases Basic salts, as well as the zwitter which may be formed and which are included in the term "salt" as used herein. Contains ions ("internal salts"). Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable). Salts that are permissible are preferred, but other salts may also be useful in certain situations. Examples of acid addition salts include acetate, ascorbate, benzoate, and benzenesulfonic acid. Salts, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfonic acid Salt, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, meta Sulfonates, naphthalene sulfonates, nitrates, oxalates, phosphates, propionates Salic acid salts, salicylates, succinate salts, sulfates, tartrates, thiocyanates, toluenesulfate salts Examples include honates (also called tosylates). Examples of useful basic salts include For example, alkalis such as ammonium salts, sodium salts, lithium salts, and potassium salts. Metal salts, alkaline earth metal salts such as calcium salts and magnesium salts, dicyclohex Salts of t-butylamine and other organic bases (e.g., organic amines), as well as Examples include salts with amino acids such as ginine and lysine. Basic nitrogen-containing groups are lower Alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides) ), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl sulfates), Long-chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides) quaternized with agents such as arylalkyl halides (e.g., bromides of benzyl and phenethyl), etc. It may be quaternized with an agent.

[0052] The compounds used in the present invention include their pharmaceutically acceptable esters, and may include carboxylic acid esters obtained by esterification of hydroxyl groups. In this case, the non-carbonyl part of the carboxylic acid part of the ester group is a straight-chain or branched-chain alkyl (e.g., acetyl methyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (e.g., methoxy methyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., pheno xymethyl), aryl (e.g., phenyl optionally substituted with halogen, C alkyl, or C alkoxy, or 1-4 amino, etc.); (2) sulfonic acid esters such as alkyl- or aralkylsulfonyl 1-4 (e.g., methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonic acid esters; and (5) mo no-, di- or triphosphoric acid esters. are selected from (e.g., L-valyl or L-isoleucyl); (4) phosphonic acid esters; and (5) mono-, di- or triphosphoric acid esters.

[0053] Polymorphs of the compounds of the present invention, as well as polymorphs of salts, solvates, esters and prodrugs of the compounds of the present invention, are intended to be included in the present invention. are intended to be included in the present invention.

[0054] The appropriate dosage when administering the compounds of the present invention to a patient can be determined by those skilled in the art, such as a physician in charge, a pharmacist or other skilled persons, and may vary depending on factors such as the patient's body weight, health condition, age, dosing frequency dosing method, the presence of other active ingredients, and the condition in which the compound is administered. may vary.

[0055] Examples of excipients, diluents, and carriers include buffers, as well as starch, cellulose, and sugars. These include fillers and expanders such as mannitol and silicate derivatives. Binders are also included. In some cases, it may contain an adjuvant.

[0056] Optionally, the compound of formula I may be administered in combination with one or more additional therapeutic agents. When used in combination with one or more additional therapeutic agents, the compounds of the present invention together It may be administered as a single dose, or it may be administered sequentially.

[0057] This composition can be administered orally, parenterally (including subcutaneously, intravenously, intramuscularly, and intraperitoneally), rectally, through the skin, or via the transdermal sac. It can be administered via various routes, including the skin, intrapleural cavity, intrapulmonary cavity, mucous membrane, intraocular, and nasal cavity.

[0058] Appropriate dosage forms are recognized by those skilled in the art, and among the many available, are tablets, capsules, solutions, suspensions, Powder, aerosol, ampoules, pre-filled syringes, small volume infusion containers, or multi-dose. Containers, creams, milks, gels, dispersions, microemulsions, lotions, impregnated powders Examples include ointments, eye drops, nasal sprays, and lozenges.

[0059] Aspects of the present invention are A 1 From A 3 At least one of them is N, or A 4 At least one of them is C R 12 is or A 5 CR 13 And R 12 / R 13 The halogens described herein This relates to the compound of formula I. This particular embodiment concerns the novel compound itself.

[0060] R 12 / R13 It is preferably F.

[0061] In one embodiment, A 1 From A 3 At least one of them is N.

[0062] In one embodiment, A 1 and A 3 Both are N.

[0063] In one embodiment, the novel compound is selected from the following: [ka]

[0064] In one aspect of the present invention, a condition or disease that is alleviated by activation of the retinoic acid receptor. A method is provided for screening compounds with therapeutic potential in the treatment of [the condition]. The method is as follows: -As an indicator of genomic activity, the efficacy of the compound in RAR activation (E max ) to measure The steps include performing the assay; -As an indicator of non-genomic activity, the efficacy of the compound (E max Perform an assay to measure the following: Step and; In each assay, E max The step of comparing it to the baseline value; -E in both assays max Compounds that exceeded the baseline value will be further investigated. This includes the step of selecting.

[0065] Since the discovery that RARs are a member of the nuclear receptor family, which are transcription regulators (P etkovich M et al. "A human retinoic acid receptor which belongs to the family of "Nuclear receptors"; Nature (1987):330, pp.444-450), on the function of retinoids The focus has been on regulating that gene expression. Based on this, synthetic retinoids were developed. This has been done, and its genome activation characteristics have been investigated.

[0066] However, surprisingly, the inventors have discovered the genome and non-genome of retinoid acids (RA). This mechanism is independently regulated with respect to ligand-dependent RAR involvement. It was stopped. "Dual effect," that is, activity in both non-genomic and genomic assays. It has been found to have a strong correlation with the promotion of neurite extension and an increase in cell number and survival rate. Therefore, this suggests that these compounds with dual effects are important as therapeutic agents. It is.

[0067] In one embodiment, compound E is used as an indicator of non-genomic activity. max The assay to determine this is quina This is a phosphorylation assay.

[0068] In one embodiment, the kinase phosphorylation assay is an ERK1 / 2 phosphorylation assay.

[0069] In one embodiment, the baseline value that serves as an indicator of genomic activity is E max The value is 170.1.

[0070] In one embodiment, the baseline value that serves as an indicator of non-genomic activity is E max The value is 48.55.

[0071] In the embodiment, one or both of the baseline values ​​are determined using a reference compound such as ATRA. It can be determined.

[0072] example: The present invention will be described illustratively below with reference to the attached figures. [Brief explanation of the drawing]

[0073] [Figure 1A] This figure shows an example of the synthesis of coupling partners. [Figure 1B] This figure shows an example of the synthesis of coupling partners. [Figure 1C] This figure shows an example of the synthesis of coupling partners. [Figure 1D] This figure shows an example of the synthesis of coupling partners. [Figure 1E] This figure shows an example of the synthesis of coupling partners. [Figure 1F] This figure shows an example of the synthesis of coupling partners. [Figure 1G] This figure shows an example of the synthesis of coupling partners. [Figure 1H] This figure shows an example of the synthesis of coupling partners. [Figure 1I] This figure shows an example of the synthesis of coupling partners. [Figure 1J] This figure shows an example of the synthesis of coupling partners. [Figure 1K] This figure shows an example of the synthesis of coupling partners. [Figure 1L] This figure shows an example of the synthesis of coupling partners. [Figure 1M] This figure shows an example of the synthesis of coupling partners. [Figure 1N] This figure shows an example of the synthesis of coupling partners. [Figure 2] This figure shows the synthesis of exemplary retinoid compounds DC526, DC528, DC641, and DC645. [Figure 3] This figure shows the genomic activity of retinoids using an X-Gal assay. [Figure 4] This figure shows the non-genomic activity of retinoids, as demonstrated by their ability to induce phosphorylation of ERK1 / 2. [Figure 5] This figure shows the average neurite length after treatment of differentiated SH-SY5Y cells with retinoids. [Figure 6] This figure shows the relationship between the ability of retinoids to induce both genomic activity [transcriptional activity: Emax (efficacy)] and non-genomic activity [ERK1 / 2 activity: Emax (efficacy)] and the induction of neurite outgrowth (increase in 10 μM), with highlighted retinoids showing activity in both areas. [Figure 7] This figure shows data on the transcriptional regulation of Alzheimer's disease-related genes after treatment of a mixed rat primary neuron / glial culture medium with retinoids. [Figure 8] Figure 8A compares the activity of the exemplary retinoid DC645 with that of ATRA and EC23, and shows a comparison of the genomic activity of retinoids by X-Gal assay. Figure 8B compares the activity of the exemplary retinoid DC645 with that of ATRA and EC23, and shows a comparison of the non-genomic activity of retinoids by measuring their ability to induce ERK1 / 2 phosphorylation. Figure 8C compares the activity of the exemplary retinoid DC645 with that of ATRA and EC23, and shows a comparison of the ability of compounds to induce neurite outgrowth in SH-SY5Y cells. Figure 8D compares the activity of the exemplary retinoid DC645 with that of ATRA and EC23, and shows the regulation of Alzheimer's disease-related genes by retinoid compounds. [Examples]

[0074] Example 1: Exemplary synthesis of compound I: 1.1 Synthesis of Coupling Partners 1.1.1. Synthesis of 6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene, 1 Synthesis of 6-Iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (1) As shown in Figure 1A, 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (11.46g, 60.9m) (mol), I2 (7.77g, 30.6 mmol) and H5IO6 (3.49g, 15.3 mmol) are mixed with ethane acid / acetic acid (AcO Add the mixture of H(250 mL), H2O(25 mL), and H2SO4(13 mL) to the solution and heat at 70°C. The mixture was stirred for 6 hours. The solution was cooled and extracted with ethyl ethanolate / ethyl acetate (₹). The organic matter was washed with saturated Na₂S₂O₃, H₂O, and brine, dried, and evaporated. Then, an orange crude oil (17g) was obtained. This was then subjected to dry column vacuum chromatography (H The compound was purified by elution with butan, and compound 1 was obtained as a white solid (16.3 g, 85%): 1 1H NMR (700 MHz, CDCl3) δ 1.25 (s, 6H), 1.26 (s, 6H), 1.66 (s, 4H), 7.04 (d, J = 8.4 Hz, 1H ), 7.43 (dd, J = 8.4, 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H); 13 ¹¹¹ NMR (176 MHz, ¹ DCl3) δ 31.9, 32.0, 34.4, 34.6, 35.0, 35.1, 91.3, 128.9, 134.8, 135.8, 144.8, 1 47.9; All other data were consistent with the literature (VB Christie et al, Org. Biomol. Ch em., 2008, 6, 3497-3507).

[0075] 1.1.2 Synthesis of 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene,3 Synthesis of 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (3) is shown in Figure 1B. As shown, triethylamine (Et3N) (150 mL) is spurged with N2 for 1 hour to remove air. Next, Compound 1 (10.0g, 31.8mmol), Pd(PPh3)2Cl2 (0.223g, 0.32mmol), CuI (0.061g, 0.32m (mol), and trimethylsilylacetylene (5.29 mL, 38.2 mmol) were added under N2 conditions, and the result was obtained. The slurry was stirred at room temperature for 20 hours, and this mixture was diluted with heptane. The solution was passed through a butane solution and evaporated to obtain a brown crude oil (10.36 g). The compound 2 was purified by SiO2 chromatography (100% heptane) and obtained as a yellow oil. 9.99g, >100%). Compound 2 (9.99g, 35.1 mmol) is mixed with methanol (MeOH) / methyl tert-butyl. It was dissolved in ruether (MTBE) (1:1, 160 mL). Then, sodium hydroxide (NaOH) (0. 96 g of H2O (15 mL) solution (24.0 mmol) was added, and the resulting solution was stirred at room temperature for 16 hours. The solution is diluted with MTBE, washed with H2O and brine, dried (MgSO4), and evaporated to obtain a yellow crude oil (6. 6g was obtained. This was purified by SiO2 chromatography (100% heptane), and compound 3 was slowly extracted. Obtained as a solidified, colorless oil (6.06g, 90% in two stages): All data are from reference (V. This was consistent with B. Christie et al., Org. Biomol. Chem., 2008, 6, 3497-3507.

[0076] 1.1.3 Synthesis of 4-bromo-3-fluorobenzoate,4 The synthesis of 4-bromo-3-fluorobenzoate (4) is shown in Figure 1C. After suspending benzoic acid (25.0 g, 114.2 mmol) in MeOH (250 mL), add concentrated H2SO4 (4 mL) and obtain The solution was stirred under reflux overnight. Then, the clear solution was cooled, and H2O (100 mL) was added. Upon inspection, a white precipitate formed. This was filtered, washed with H2O, and dried to obtain a rough sample. A white solid was obtained. This was recrystallized from heptane to obtain compound 4 as a colorless crystalline solid. (21.34g, 80%) 1 H NMR (600MHz, CDCl3) δ 3.91 (s, 3H), 7.31 - 7.36 (m, 2H), 7 .80 (t, J = 8.0 Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 52.4, 117.6 (d, J = 9.9 Hz) , 120.6 (d, J = 25.6 Hz), 127.5 (d, J = 3.9 Hz), 127.9 (d, J = 9.6 Hz), 133.1, 1 61.56 (d, J = 264.9 Hz), 164.1 (d, J = 3.9 Hz); 19 F NMR (376 MHz, CDCl3) δ -106 .6;IR(ATR)v max / cm -1 3104w, 3086w, 2961w, 1712s, 1599s, 1571m, 1403m, 1215s, 8 82s;MS(ASAP):m / z = 233.0 [M+H] + ;HRMS(ASAP)calcd. for C8H7O2BrF [M+H] + :twenty three 2.9613, first:232.9621 (Zimmerman et al, J. Med. Chem. 2014, 57:2334-2356).

[0077] 1.1.4 Synthesis of methyl 4-ethynyl-3-fluorobenzoate, 6 The synthesis of methyl 4-ethynyl-3-fluorobenzoate (6) is shown in Figure 1D. Et3N (120 mL) is converted to N2 Then, it was spurged for 1 hour to remove gas. Subsequently, compound 4 (5.0 g, 21.45 mmol), trimethylsilicone Luacetylene (3.56 mL, 25.74 mmol), Pd(PPh3)2Cl2 (301 mg, 0.429 mmol), and CuI (82 (mg, 0.429 mmol) was added under N2 conditions, and the resulting suspension was stirred at room temperature for 16 hours. Diluted with heptane, passed through Celite® / SiO2, and then the extract was evaporated to obtain crude oil (6.4%). 4g) was obtained. This was then subjected to dry column vacuum chromatography (100% heptane to 9:1 heptane). The product is purified by (a) and isolated by Kugelloor distillation (150°C, 7.4 Torr). Further purification yields compound 5 as a yellow oil (5.58g, >100%), which is then directly used in the next step. Proceeded to the next stage: 1 H NMR (400 MHz, CDCl3) δ 0.27 (s, 9H), 3.92 (s, 3H), 7.50 (dd, J = 8.0, 6.8 Hz, 1H), 7.71 (dd, J = 9.6, 1.5 Hz, 1H), 7.75 (dd, J = 8.0, 1.6 Hz, 1H) ). Add compound 5 (5.58 g, 22.3 mmol) and K2CO3 (6.16 g) to a MeOH:MTBE solution (5:50, 55 mL). Add 44.6 mmol of , and stir the resulting mixture under N2 at room temperature for 6 hours. This solution is then prepared with . Diluted and washed with saturated NH4Cl, H2O, and Br. Washed with NH4Cl, H2O, and brine, and dried (Mg SO4 was evaporated to obtain a crude solid (3.6 g). This was then subjected to dry column vacuum chromatography. The compound 6 was purified (from 100% heptane to 8:2 heptane / RINKAN) and obtained as a white solid. (3.07g, 80% in 2 stages): 1 H NMR (600 MHz, CDCl3) δ 3.45 (s, 1H), 3.92 (s, 3H), 7 .53 (dd, J = 8.0, 6.8 Hz, 1H), 7.72 (dd, J = 9.6, 1.6 Hz, 1H), 7.77 (dd, J = 8.0 , 1.6 Hz, 1H); 13 C NMR (151 MHz, CDCl3) δ 52.5, 76.3, 85.1 (d, J = 3.3 Hz), 115 .3 (d, J = 16.0 Hz), 116.5 (d, J = 22.9 Hz), 124.9 (d, J = 3.7 Hz), 132.2 (d, J = 7.4 Hz), 133.9 (d, J = 1.3 Hz), 162.9 (d, J = 253.5 Hz), 165.3 (d, J = 2.7 Hz) ; 19 F NMR (376 MHz, CDCl3) δ -109.3; IR (ATR) vmax / cm -1 3238m, 3090w, 2967w, 21 11w, 1710s, 1564m, 1501m, 1440m, 1308s, 1212s, 766s; MS (ASAP) m / z = 179.0 [M+H] + HRMS (ASAP) calcd. for C 10 H8O2F [M+H] + : 179.0508, found 179.0495.

[0078] 1.1.5 Synthesis of 5-bromopyridine-2-carboxylate methyl, 8 The synthesis method for methyl 5-bromopyridine-2-carboxylate (8) is shown in Figure 1E. Suspend 5-bromopyridine-2-carboxylic acid (20.0 g, 99.0 mmol) in MeOH (150 mL), and then Concentrated H2SO4 (5 mL) was carefully added, and the resulting solution was stirred under reflux for 6 hours. Cool, dilute with HCl, wash with H2O and brine (50 mL), dry, and evaporate. A coarse, colorless solid was obtained. This was then subjected to vacuum distillation using a Kugellohr (200°C, 7.4 Torr). The resulting white solid was further recrystallized from heptane / MeOH (10:1) to obtain compound 8. Obtained as a colored solid (17.21g, 80%): 1 H NMR (700 MHz, CDCl3) δ 3.90 (s, 4H), 7.86- 7.93 (m, 3H), 8.68 (d, J = 2.0 Hz, 1H); 13 C NMR (176 MHz, CDCl3) δ 52.8, 124.8, 126.0, 139.5, 146.0, 150.7, 164.7; max / cm -1 3059w, 3008w, 2957w, 1710s, 1571w, 1558w, 1436m, 1305s, 1131s, 696s; MS (ASAP):m / z = 216.0 [M+H] + HRMS (ASAP) ca LCD for C 10 H9NOI [M+H] + :215.9660, found:215.9664 (Tung et al,Eur. J. Med. Chem (2017, 126, 1011-1020).

[0079] 1.1.6 Synthesis of 2,2,5,5-tetramethylhexanedioic acid, 9 The synthesis method for 2,2,5,5-tetramethylhexanedioxide (9) is shown in Figure 1F. (Mechanical stirrer) In a 2L three-necked flask equipped with [a specific component], add H2O (600mL), concentrated H2SO4 (7.5mL), and pivalic acid (51.0g, 500g). The following were added in order: H2O2(30%, 43 mL), and the resulting slurry was cooled to 0°C. Over 15 minutes, H2O2(30%, 43 mL) was added. ) and a solution of FeSO4.7H2O (139.0 g, 500 mmol) with H2O (288 mL) and concentrated H2SO4 (27.5 mL). The solution was added dropwise while stirring vigorously. After the addition was complete, the suspension was stirred for another 15 minutes, and then the solution was added. The solution was concentrated to approximately 250 mL. The precipitated solid was filtered and then vacuum-sealed using a rotary evaporator. Further drying was performed below to obtain a coarse residue. This was recrystallized from AcOH to obtain a colorless crystalline compound. Obtained as a solid (3.39g, 3%): 1 H NMR (400MHz, DMSO-d6) δ1.06 (s, 12H), 1.37 (s, 4H), 12.05 (s, 2H).

[0080] 1.1.7 Synthesis of 1,6-diethyl 2,2,5,5-tetramethylhexanedioate, 10 The synthesis of 1,6-diethyl 2,2,5,5-tetramethylhexanedioate (10) is shown in Figure 1G. 9 Add concentrated H2SO4 (2 mL) to a 40 mL solution of (3.39 g, 16.76 mmol) EtOH, and the resulting suspension The mixture was stirred under reflux for 16 hours. The solution was cooled and the solvent evaporated to obtain a crude residue, which was then toluene. It was dissolved in (MgSO4). The organic matter was washed with saturated NaHCO3, H2O, and brine, dried, and evaporated. This yielded crude oil (3.8g). This was then subjected to SiO2 chromatography (95:5, heptane / toluene). ) was refined, and 10 was obtained as a colorless oil (3.41g, 79%): 1 1H NMR (700 MHz, CDCl3) δ 1. 14 (s, 11H), 1.24 (t, J = 7.1Hz, 6H), 4.11 (q, J = 7.1 Hz, 4H); 13 13C NMR (176 MHz) , CDCl3) δ 14.2, 25.0, 35.5, 41.8, 60.2, 177.7; IR (ATR) v max / cm -1 2978m, 2934w , 2880w, 1726s, 1475m, 1308m, 1176s, 1110m, 771w; MS(ES):m / z = 259.5 [M+H] + .

[0081] 1.1.8 Trimethyl({3,3,6,6-tetramethyl-2-[(trimethylsilyl)oxy]cyclohexyl Synthesis of 11 cus-1-en-1-yl)silanes Trimethyl({3,3,6,6-tetramethyl-2-[(trimethylsilyl)oxy]cyclohex-1 The synthesis of (-en-1-yl)oxy)silane, 11 is shown in Figure 1H. In anhydrous toluene (50 mL), N2 Add sodium (1.20 g, 52.1 mmol) below and stir the resulting mixture until the sodium dissolves. The mixture was heated under reflux. Then, the flask was removed from the heat and 10 (2.69 g, 10.41 mmol) and chlorotrimethylamine were added. Add methylsilane (6.72 mL, 53.0 mmol), then stir the resulting suspension under reflux overnight. Then, the purple suspension was cooled and filtered while flowing N2 through it, and toluene and tetrahydrofoam were added. The oil was washed with ran (THF) in that order. The filtrate was then evaporated to obtain a pale yellow crude oil (3.2g). This was purified by Kugellohr distillation (120°C, 3.6 Torr) to obtain 11 as a clear oil. 2.64g, 81%) 1 H NMR (400MHz, CDCl3) δ 0.19 (s, 18H), 1.03 (s, 12H), 1.44 (s, 4 H). All other data were consistent with the literature (Kikuchi et al. J. Med. Chem. 2000; 43). (pp. 409-419).

[0082] 1.1.9 Synthesis of 3,3,6,6-tetramethylcyclohexane-1,2-dione, 12 The synthesis method for 3,3,6,6-tetramethylcyclohexane-1,2-dione is shown in Figure 1J. 11(2.6g) Add bromine (0.42 mL, 8.2 mmol) dropwise over 5 minutes to a dichloromethane (DCM) solution (8.2 mmol). The mixture was then added. The resulting yellow solution was stirred at room temperature for 1 hour, then diluted with DCM to obtain saturated NA2S2O3. After processing, wash with H2O, dry with (MgSO4), evaporate to obtain a rough yellow solid (1.5g). It was obtained. This was recrystallized from heptane and purified to obtain 12 as a yellow crystalline solid (1.07 g, 78%) 1 H NMR (700 MHz, CDCl3) δ 1.14 (s, 4H), 1.85 (s, 12H); 13 ¹¹¹ NMR (176 MHz) z, CDCl3) δ 22.9, 34.7, 48.6, 207.3; IR (ATR) v max / cm -1 2973m, 2940w, 2870w, 170 6s, 1599w, 1459m, 1372m, 1102m, 931m; MS(ES): m / z = 169.3 [M+H] + Other data All results were consistent with the literature (Kikuchi et al. J. Med. Chem. 2000; 43:pp.409-419).

[0083] 1.1.10 Methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carboc Syrah, 13 synthesizers Methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carboxylate The synthesis of 13 is shown in Figure 1J. 12 (0.80 g, 4.76 mmol) and DL-2,3-diaminopropionic acid HY Mixed 0.67g of chloride (4.76 mmol) in 30 mL of MeOH. (0.76g of NaOH, 19.04 mL) Add (mol) and stir the resulting mixture under reflux for 24 hours. Cool this solution to 0°C and add H2SO4 Carefully add the solution and stir under reflux for a further 6 hours. Cool the solution and evaporate the solvent. This was done to obtain the original residue. This was dissolved with siRNA, washed with saturated NaHCO3, H2O, and brine, and dried. The mixture was dried (MgSO4) and evaporated to obtain a yellow crude oil (0.9g). This was then subjected to SiO2 chromatography. It was refined with ethyl acetate (95:5, heptane / ethyl acetate) to obtain 13 as a colorless oil (0.633g, 54%): 1 H NMR (400 MHz, CDCl3) δ 1.33&1.36 (s, 12H), 1.81 (s, 4H), 3.98 (s, 3H), 9.00 (s, 1H). All other data were consistent with the literature (Kikuchi et al. J. Med. Chem. 200). 0; 43:pp.409-419).

[0084] 1.1.11 (5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-yl)methano 14 synthesis (5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-yl)methanol, 14 The synthesis is shown in Figure 1K. NaBH4 (2.33g, 61) is added to a solution of 13 (5.09g, 20.5 mmol) in THF (80 mL). (0.5 mmol) was added. Then, this solution was heated under reflux and MeOH (16 mL) was added over 1 hour. It was added slowly. Next, the resulting solution was stirred under reflux overnight. This solution was cooled and heated to 1 M H Quenched with Cl and evaporated the solvent. Dissolve the residue in DCM, wash with water, and dry (MgSO4 ), evaporated to obtain a yellow crude oil (4g). This was then subjected to SiO2 chromatography (using the eluent as the eluent). It was purified with 8:2 heptane / toluene to obtain 14 as a colorless oil (3.96g, 88%): 1 1H NMR (400 MHz, CDCl3) δ 1.33 & 1.36 (s, 12H), 1.80 (s, 4H), 3.50 (br, 1H), 4.75 (s, 2H), 8.32 (s, 1H); all other data are from the reference (Kikuchi et al. J. Med. Chem. 2000). 0; 43:pp.409-419).

[0085] 1.1.12 5,5,8,8-Tetramethyl-5,6,7,8-Tetrahydroquinoxaline-2-Caraldehyde , 15 synthesis 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde, 15 compounds The composition is shown in Figure 1L. Under N2 conditions, oxalyl chloride (2.28 mL, 26.96 mmol) was dissolved in anhydrous DCM (100 mL). The resulting solution was cooled to -78°C, and DMSO was added to maintain the temperature below -60°C. 3.83 mL (53.92 mmol) was added dropwise. After stirring this solution for 15 minutes, the solution was treated with anhydrous DCM. A certain 14 (3.96 g, 17.97 mmol, in 20 mL) was added dropwise while maintaining the temperature below -60°C. After stirring this solution for another 15 minutes, Et3N (18.03 mL, 129.38 mmol) was added. Next, The solution was stirred for 10 minutes, then allowed to cool to room temperature (RT) for 30 minutes. H2O was added, and the resulting mixture was added. The substance was diluted with DCM, washed with H2O, dried (MgSO4), and evaporated to obtain crude oil (4g). This was purified by dry column vacuum chromatography (DCVC) (from heptane 9:1, heptane / EtOA c to) to give 15 as a colorless oil that slowly crystallized (3.39 g, 86%): 1 H NMR (700 MHz, CDCl3) δ 1.35 & 1.37 (s, 12H), 1.83 (s, 4H), 8.90 (s, 1H), 10.08 (s, 1H); 13 C NMR (176 MHz, CDCl3) δ 29.7, 29.7, 33.8, 37.4, 37.9, 139.8, 144.2, 15 9.0, 163.7, 193.4; IR (ATR) v max / cm -1 2979m, 2964m, 2928m, 2862m, 2823w, 1707s, 1 553m, 1457m, 1126s, 1078s, 737s; MS(ES):m / z = 219.3 [M+H] + ; HRMS(ES)calcd. fo r C 13 H 19 ON2[M+H] + :216.1497, found 216.1503.

[0086] 1.1.13 Synthesis of dimethyl 1-diazo-2-oxopropylphosphonate, 16 The synthesis of dimethyl 1-diazo-2-oxopropylphosphonate, 16 is shown in Figure 1M. To a solution of dimethyl 2-oxopropylphosphonate (4.49 mL, 32.5 mmol) in anhydrous toluene (30 mL) at 0 °C, NaH (60% dispersion in mineral oil, 1.20 g, 30.00 mmol) was added portionwise with vigorous stirring. After the evolution of gas ceased, a solution of 4-acetamidobenzenesulfonyl azide (7.21 g, 30.0 mmol) in anhydrous THF (10 mL) was added dropwise. The resulting suspension was stirred at room temperature for 16 h, and then to it was added... Heptane was added, the suspension was filtered through Celite®, and washed with MTBE. Then, the organic The extract was evaporated to obtain crude oil (5g), which was then subjected to SiO2 chromatography (1:1, heptane / Refined with dimethyl 1-diazo-2-oxopropylphosphonate as a pale yellow oil. Obtained (3.14g, 54%): 1 H NMR (400 MHz, CDCl3) δ 2.24 (s, 3H), 3.82 (d, J = 11.9 Hz , 6H), all other data are from the reference (Pietruszka et al. Synthesis, 2006, pp.4266-42) This matched 68).

[0087] 1.1.14 2-Ethinyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline, 17 The synthesis of 2-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline, 17 is shown in the diagram. As shown in 1N. Under N2 conditions, add K2CO3 (1.49g) to 15 (1.18g, 5.40 mmol) of anhydrous MeOH (50 mL) solution. (10.80 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (0.98 mL, 6.48 mmol) Add ) and stir the resulting suspension at room temperature for 16 hours. Dilute this solution with ◦ and prepare 5% NaHC Wash with O3, H2O, and brine, dry (MgSO4), evaporate to obtain an orange crude oil (0. 4 g) was obtained. This was subjected to SiO2 chromatography (with heptane / ÃO as the eluent at a ratio of 95:5). After purification, 17 was obtained as a slowly crystallized, colorless oil (0.84g, 73%): 1 1H NMR (700 M) Hz, CDCl3) δ 1.30 & 1.31 (s, 12H), 1.77 (s, 4H), 3.22 (s, 1H), 8.45 (s, 1H); 13 C NMR (176 MHz, CDCl3) δ 29.6, 29.7, 33.8, 34.0, 37.2, 37.3, 79.0, 81.0, 135.4, 144.5, 158.1, 158.6; IR (ATR) v max / cm -1 3279s, 2986w, 2945m, 2917m, 2863w, 2110w , 1519w, 1470m, 1459m, 1274m, 1078s, 674s; MS(ES):m / z = 215.3 [M+H] + HRMS(ES) )calcd. for C 14 H 19 N2[M+H] + :215.1548, found 215.1548.

[0088] 1.2 3-Fluoro-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-i Synthesis of Ethinyl Benzoic Acid and DC526 The synthesis of the example compound DC526 is shown in Figure 2A.

[0089] Et3N (80 mL) was degassed by sparging with N2 for 1 hour. Next, compound 1 (0.80 g, 2.55 mmol) was added. Compound 6 (0.54 g, 3.05 mmol), Pd(PPh3)2Cl2 (179 mg, 0.255 mmol) and CuI (49 mg, 0 (0.255 mmol) was added under N2 conditions, and the resulting suspension was stirred at room temperature for 72 hours. The suspension was diluted with MTBE. After passing the solution through Celite® / SiO2, the extract was evaporated to obtain a crude solid (1.1 g). This was then subjected to dry column vacuum chromatography (100% heptane, 95:5, heptane / ethyl heptane). When refined, compound 7 was obtained as a slowly crystallized, colorless oil (0.82g, 88%). We proceeded directly to the next step. Compound 7 (0.80g, 2.20 mmol) was dissolved in THF (40mL). Then, 20% NaOH (3 mL) was added, and the resulting solution was stirred under reflux for 16 hours. The mixture was cooled, and 5 Acidify to pH 1 with %HCl, extract with dimethylammonium phosphate, wash with H2O and brine, dry (MgSO4), and evaporate. This yielded a rough white solid. This was recrystallized from acetonitrile (MeCN) to obtain DC526. Obtained as a colorless crystalline solid (0.60 g, 77%): 1 H NMR (600 MHz, DMSO-d6) 1.24 & 1.26 ( s, 12H), 1.64 (s, 4H), 7.32 (dd, J = 8.1, 1.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.70 - 7.78 (m, 2H), 7.80 (dd, J = 7.9, 1.6 Hz, 1H), 13.44 (br, 1H); 13 C NMR (151 MHz, DMSO-d6) δ 31.3, 31.4, 33.9, 34.1, 34.2, 34.3 , 81.0, 97.4 (d, J = 3.1 Hz), 115.2, 115.3 (d, J = 15.8 Hz), 116.0 (d, J = 22.3 Hz), 118.5, 125.4 (d, J = 3.4 Hz), 127.1, 128.7, 129.6, 132.7 (d, J = 7.1 Hz), 133.6, 145.2, 146.5, 161.4 (d, J = 250.3 Hz), 165.7 (d, J = 2.5 Hz); 1919F NMR (3 76 MHz, DMSO-d6) δ -110.0; IR (ATR) ν max / cm -1 2967m, 2928m, 2857m, 2210w, 1686s, 1617m, 1566m, 1421m, 1307m, 1218m, 834s, 764m; MS(ASAP):m / z = 351.2 [M+H] + ; HR MS(ASAP) calcd. for C 23 H24O2F [M+H] + : 351.1760, found 351.1766.

[0090] 1.3 5-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethynyl] pyridine-2-carboxylic acid, synthesis of DC528 The synthesis of the exemplary compound DC528 is shown in Figure 2B.

[0091] Et3N / THF (1:1, 120 mL) was sparged with N2 for 1 hour to degas, and Pd(PPh3)2Cl2 (0.265 g, 0. 38 mmol), CuI (0.072 g, 0.38 mmol), compound 3 (0.8 g, 4.80 mmol) and compound 8 (0.98 g , 4.52 mmol) were added, and the resulting solution was stirred at 50 °C for 40 hours. This solution was diluted with heptane and eluted with heptane through a Celite® / SiO2 plug. Then, the organic matter was washed with saturated NH4Cl, H2O, and brine, dried (MgSO4), evaporated to give a brown crude solid (1.9 g). This was purified by dry column vacuum chromatography (from 100% heptane to 8:2, hept tane / EtOAc) to give compound 9 as a white solid (0.36 g, 27%), which was carried on to the next step as such: 1 ​H NMR (400 MHz, CDCl3) δ 1.29 (d, J = 7.9 Hz, 12H), 1.69 (s, 4H), 4.02 (s, 3H), 7.31 (d, J = 1.1 Hz, 2H), 7.51 (s, 1H), 7.94 (dd, J = 8.1, 2.1 Hz, 1H), 8.12 (dd, J = 8.1, 0.9 Hz, 1H), 8.85 (dd, J = 2.1, 0.9 Hz, (1H). Dissolve compound 9 (0.33g, 0.95 mmol) in THF (30mL), add 20% NaOH (3mL), and obtain The solution was stirred under reflux for 16 hours. The mixture was cooled, acidified to pH 1 with 5% HCl, and then ammonium was added. The material was extracted, washed with H2O and brine, dried (MgSO4), and evaporated to obtain a white crude solid. This was recrystallized from MeCN to obtain DC528 as a colorless crystalline solid (0.30 g, 96%): 1 1H NMR (700 MHz, DMSO-d6) δ 1.25 & 1.27 (s, 12H), 1.65 (s, 4H), 7.35 (dd, J = 8.1, 1. 8 Hz, 1H), 7.41 (dd, J = 8.1 Hz, 1H), 7.57 (dd, J = 1.8 Hz, 1H), 8.06 (dd, J = 8 .1, 0.9 Hz, 1H), 8.12 (dd, J = 8.1, 2.1 Hz, 1H), 8.85 (dd, J = 2.1, 0.9 Hz, 1H), 13.35 (s, 1H); 13 C NMR (176 MHz, DMSO-d6) δ 31.3, 31.4, 33.9, 34.1, 34.2, 34.3 , 39.5, 84.8, 95.4, 118.4, 122.7, 124.3, 127.1, 128.7, 129.8, 139.5, 145.2, 146. 4, 146.9, 151.3, 165.6; IR (ATR) v max / cm -1 3283br, 2955m, 2920m, 2856m, 2208m, 1 752s, 1586m, 1336s, 1247m, 1017m, 833m; MS(ES):m / z = 334.2 [M+H] + HRMS (ES) ca LCD for C 22 H 24 NO2 [M+H] + : 334.1807, found 334.1808.

[0092] 1.4 Methyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-yl) Synthesis of Ethynyl Benzoate (DC641) The synthesis of the exemplary compound DC641 is shown in Figure 2C. Et3N (20 mL) was sparged with Ar for 1 hour to degas it. Next, methyl 4-iodobenzoate (0.31g, 1.20 mmol), DC640 (0.30g, 1.40 mmol), P d(PPh3)2Cl2 (83 mg, 0.12 mmol) and CuI (22 mg, 0.12 mmol) were added under Ar, and the resulting solution was obtained. The turbidity was stirred at room temperature for 16 hours. This suspension was diluted with MTBE and then mixed with Celite® / SiO2. After passing through the column, the extract was evaporated to obtain a crude solid (0.5 g). This was then subjected to dry column vacuum chromatography. Purified by Graph (100% heptane to 85:15, heptane / acetyl) to obtain an off-white solid. After obtaining the solid, DC641 was recrystallized from MeOH to obtain a colorless crystalline solid (0.29 g, 71%). We proceeded directly to the next step: 1 H NMR (400 MHz, CDCl3) δ 1.33 & 1.35 (s, 1 2H), 1.81 (s, 4H), 3.94 (s, 3H), 7.64 - 7.71 (m, 2H), 8.01 - 8.08 (m, 2H), 8.52 (s, 1H).

[0093] 1.5 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-yl)ethinyl [L] Benzoic acid, synthesis of DC645 The synthesis of the example compound DC645 is shown in Figure 2D. DC641 (0.28 g, 0.8 mmol) is dissolved in THF (20 mL). Dissolve the mixture, add 2 mL of 20% NaOH, and stir the resulting solution under reflux for 16 hours. Cool the mixture. Instead, acidify to pH 1 with 5% HCl, extract with dimethylammonium O4) was evaporated to obtain a white crude solid. This was recrystallized from MeCN to obtain a colorless crystal of DC645. Obtained as a crystalline solid (0.24g, 89%): 1 H NMR (700MHz, DMSO-d6) δ 1.29 (s, 12H), 1. 78 (s, 4H), 7.73 - 7.79 (m, 2H), 7.98 - 8.02 (m, 2H), 8.68 (s, 1H), 13.24 (br, 1 H); 13 C NMR (176 MHz, DMSO-d6) δ 29.4, 29.4, 33.1, 33.2, 37.0, 37.1, 88.9, 89.8 , 125.2, 129.6, 131.3, 131.9, 135.2, 144.4, 157.6, 158.0, 166.5; IR (ATR) v max / c m -1 2961w, 2925w, 2958w, 2223w, 1683s, 1606m, 1558w, 1428m, 1282s, 862s, 769m S(ASAP): m / z = 334.2 [M]+ HRMS (ASAP) calcd. for C 21 H 22 N2O2[M] + :334.1681, fou nd 334.1686.

[0094] Example 2: Biological evaluation 2.1 Genomic activity of synthetic retinoids The efficiency of inducing transcription of synthetic retinoids into the genome using an X-Gal assay was measured. The evaluation was performed by the following: The X-Gal assay is linked to the retinoic acid response element (RARE). Sil-15 reporter cells in which the transcription of the LacZ gene is controlled by a linked promoter It is used. After treating reporter cells with retinoids, the β-gall produced by the reporter cells is used. By monitoring and quantifying the activity of kutosidase, the transcription-inducing ability of compounds can be obtained. can.

[0095] 100 Sil-15 cells per well were placed in a 96-well plate coated with 0.1% gelatin. They were sown in batches of 000. The next day, Dulbecco's modified Eagle medium containing 10% fetal calf serum (FCS) was used. 10 serial dilutions of retinoid ligands prepared with (DMEM) -6 M to 10 -14 Add at concentration M The plates were incubated overnight. ATRA standard curves and concentrations of other retinoid ligands were measured. All tests were conducted using a 3-unit setup.

[0096] The following day, the assay plate was washed twice with phosphate-buffered saline (PBS), and 1% of the PBS solution was removed. Taraldehyde and 1 mM MgC l2 Use 100 μL of the solution in each well and fix for 15 minutes, then rinse twice with PBS. Washed. β-galactosidase activity was measured in PBS with 1 mM MgCl2 and 3.3 mM potassium ferrocyanide. Prepare a new 0.2% X-Gal solution by dissolving it in 3.3 mM potassium ferrocyanide, and fill one well with... Detection was performed by adding 100 μL. The plate was incubated at 37°C in 5% CO2 for 6 hours. The plate was scanned using an Emax Precision Microplate Reader (Molecular Devices) at 650nm The color change was detected by reading it.

[0097] As a result, as shown in Table 1 and Figure 3, the ability to induce transcription in reporter cells was high. As can be seen from this, some synthetic retinoids are more effective than endogenous ligands (ATRAs). It was demonstrated that they exhibited genomic activity. In particular, DC527, DC540, DC525, DC528, DC526 and All of DC645 showed higher genomic activity and efficacy compared to retinoic acid (ATRA).

[0098] 2.2 Non-genomic activity of synthetic retinoids Non-genomic activity of synthetic retinoids, AlphaLISA® SureFire® Ult The ability to induce phosphorylation of ERK1 / 2 was evaluated by measuring the ability of the ra ERK1 / 2 kit to do so. .

[0099] In this assay, SH-SY5Y cells (100,000 cells / well) were seeded in a 96-well plate, and DM In EM, the subjects were subjected to serum starvation for 24 hours. Retinoids were added to the culture medium at concentrations of 10⁻⁵ M to 10⁻¹¹ M. The test was performed with a final DMSO concentration of 0.1%. SH-SY5Y cells in serum-free DMEM were tested at 37°C. The cells were stimulated with retinoids for 30 minutes, and the assay was performed.

[0100] After the assay is complete, remove the culture medium and add 50 μL of freshly prepared 1X lysis buffer (included in the kit). The cells were lysed using ) and the 96-well plate was shaken in an orbital shaker (SO1, Stuart Scient). The mixture was stirred at approximately 350 rpm for 10 minutes at room temperature using an ific (manufactured by ific).

[0101] Meanwhile, the activation buffer was diluted 25-fold with the reaction buffer. In a dark room under green light, the accelerator was used. The putter beads were diluted 50-fold with a freshly prepared reaction mixture, while the donor beads were diluted slowly. The mixture was diluted 50-fold with a volcanic ash solution to obtain two final reaction mixtures.

[0102] Next, 10 μL of cell lysate was placed in a 384-well white Proxiplates plate (PerkinElmer). Transfer each well and mix the prepared acceptor and donor reactions in a dark room under green light. 5 μL of each substance was added. The plate was wrapped in aluminum foil and incubated at room temperature for at least 3 hours. I did. Using the Envision system (PerkinElmer Life Sciences), I used AlphaScreen ( The reading was performed using the registered trademark settings.

[0103] The results shown in Table 1 and Figure 4 indicate that in SH-SY5Y cells, the phosphate of retinoid Erk1 / 2 is present. The ability to induce transformation has been demonstrated. Retinoin, such as DC527, DC540, DC528, DC526, DC645, etc. Retinoids have been identified that possess both higher potency and effectiveness than acids, and among them, DC525 has high potency. It was confirmed that it possesses [this characteristic].

[0104] 2.3 Induction of neurite outgrowth SY-SY5Y cells were acid-treated and included in a coverslip coated with poly-L-lysine. Cells were seeded at a rate of 10,000 cells / well in well plates. After 24 hours, each retinoid was administered at a concentration of 10 nM. The culture medium was added and the plates were incubated for 5 days. After retinoid treatment, the coverslip was removed. The SH-SY5Y cells on the substrate were washed twice with PBS and then treated with 4% paraformaldehyde (PFA) at room temperature for 20 minutes. The specimens were fixed and washed twice with PBS.

[0105] For immunocytochemical staining of neurites, wash the cells on the coverslip three times with PBS. In a blocking solution (10% Donkey serum and 0.1% Triton X-100 in PBS) at room temperature for 1 hour. It was incubated. Then, β-III tubulin was diluted 1:1000 with blocking buffer. Cells were labeled by incubating them overnight at 4°C using the primary antibody (sigma-Aldrich). After incubation, wash the cells three times with PBS containing 0.1% Triton X-100 solution (PBST). From there, anti-mouse monoclonal secondary antibody (1:300 in PBST, Jackson Immunoresearch) and ro Incubated at warm temperature for 2 hours. Finally, washed three times with PBST and then a final wash with PBS. The coverslip was placed on a slide and stored at 4°C.

[0106] To quantify the extension of neurites on stained cells, use Image with the NeuronJ plugin. J software was used. In each experiment, a Nikon Eclipse E400 fluorescence microscope was used for each experiment. Ten images were randomly selected from the bar slip and photographed. Each image was then converted into an 8-bit image (Neu (Required for ronJ plugin) Convert to GIMP (GNU Image Manipulation Program) Brightness and Optimized using contrast tools. For each image, NeuronJ plugin trace Using a tool, individual traces were drawn for each clearly identifiable nerve process. The length was measured in pixels and converted to μm units according to the magnification used. The average neurite length in an image can be calculated by dividing the total neurite length by the total number of neurites in each image. The calculation was performed by measuring 10 images for each coverslip and calculating the average value for the entire coverslip. I prepared three coverslips for each retinoid and concentration.

[0107] The data shown in Figure 5 indicates that some retinoids induce neurite outgrowth in SY-SY5Y cells. This demonstrates that they have demonstrated their capabilities. Furthermore, some of these compounds (DC527, D Cells treated with C525, DC528, DC526, and DC645 were significantly larger than cells treated with ATRA. It showed an average neurite length.

[0108] Table 1 below shows the genomic activity (transcriptional activity) and non-genomic activity of the tested retinoid compounds. The p-ERK1 / 2 activity was summarized in relation to the increase in neurite outgrowth, and these results are shown in Figure 5. The data was plotted. This figure shows that high efficacy was demonstrated in both genomic and non-genomic assays. The compound clearly shows increased induction of neurite outgrowth. This is related to genomic activity and non- Compounds with "dual efficacy" that induce both genomic activity are more effective in clinical use. This suggests the possibility of a strong screening of new therapeutic compounds using this dual assay method. It has the potential to become a learning tool.

[0109] [Table 1]

[0110] 2.4 Regulation of Alzheimer's disease-related genes To investigate the effects of retinoids on the expression of genes involved in Alzheimer's disease, In a mixed primary neuronal / glial culture medium of a certain type, Alzheimer's disease after retinoid treatment. The expression of related gene groups was evaluated.

[0111] Approximately 300,000 rat nerve cells / glial cells were first treated with 1 μg / mL lipopolysaccharide ( Inflammation was induced by treating cells with sigma-Aldrich for 6 hours. After inflammation, cells were treated with 10 nM of The subjects were treated with retinoids for 24 hours. In this experiment, we found that this assay was the most potent to date. A retinoid was selected and used, which was identified as having the following properties. After treatment, RNA was extracted from the treated cells, and q PCR analysis was performed.

[0112] Total RNA was obtained using the Qiagen RNeasy mini kit (CAT# 74104, Qiagen), manufactured by the manufacturer. Extraction was performed according to the protocol. Briefly speaking, cell and brain tissue samples were extracted, respectively. Homogenization was performed using 350 μL of β-ME mixed with 1200 μL of RLT buffer (1 mL buffer: 10 μL β-ME). The sample was then centrifuged at 13,000 rpm for 3 minutes. The supernatant was collected in 70% ethanol. Mix with (CAT# E7023, Sigma-Aldrich) in a 1:1 volume ratio, then put into a collection tube. The sample was transferred to the spin column. The sample was centrifuged at 10,000 rpm for 1 minute, and the RNA was separated by the spin column. It was bonded to the lamb membrane.

[0113] In on-column DNase digestion, the sample in the column is washed with 350 μL of RW1 buffer, and 10,000 The mixture was centrifuged at rpm for 1 minute. Then, 80 μL of DNase mixture (10 μL of DNase enzyme and 70 μL of RDD) was added. Buffer (CAT# 79254, Qiagen) was added to each sample. The samples were left in the refrigerator at room temperature for 15 minutes. After incubation, 350 μL of RW1 buffer was added. The sample was centrifuged at 10,000 rpm for 1 minute. did.

[0114] Then, 500 μL of RPE buffer (a mixture of 100% ethanol in a 1:4 ratio) is added to the sample. It was added on top of the bacon. The sample was centrifuged at 10,000 rpm for 1 minute (this step was repeated twice). (Done). The spin column was centrifuged again at 13,000 rpm for 1 minute to dry the membrane. The sample was removed from the collection tube and placed in another 1.5 mL RNase-free collection tube. 30 μL of RNase-free The RNA was eluted by directly adding water to the spin column membrane. The sample was then eluted at room temperature for 5 minutes. After heating, it was rotated at 10,000 rpm for 1 minute.

[0115] RNA concentration was measured using a NanoDrop® 2000c spectrophotometer (Thermo Fisher Scientific). Measurements were taken. RNase-free water used for RNA elution was used as a blank, and 2 μL of each RNA sample was used. The instrument was calibrated using this method. RNA samples were used to minimize RNA degradation. Therefore, it was stored in a -70°C freezer.

[0116] The qPCR reaction was performed using PerfeCTa SYBR Green SuperMix (CAT# 733-1246, VWR). Place three 10 μL portions of the reaction mix into each well of a 384-well plate (CAT# 04729749001, Roche). The mixtures were added in pairs. Each reaction included 2 μL of 4-fold diluted cDNA template and 2X SYBR Green Mix. This included 5 μL of 250 nM primer.

[0117] The primers were designed using Primer-BLAST with a melting point of approximately 60°C. These were then used for qPCR. Previously, we confirmed the specificity of the primers using PCR, and then sent the PCR products for sequencing.

[0118] For all primer sets tested with qPCR, standard curve (5x of stock cDNA) A blank control was performed using a diluted solution. Then, the plate was sealed and short After centrifuging for a set time, we confirmed that all reagents were at the bottom of the wells. This was performed on a Roche LightCycler 480 programmed to maintain a temperature of 95°C for 5 minutes. After that, qPCR was performed for 45 cycles at 95°C for 15 seconds, 60°C for 15 seconds, and 72°C for 15 seconds. The melting curve was obtained by running the process at 95°C for 5 seconds, followed by 58°C for 1 minute.

[0119] The results were analyzed using the delta-delta CT method in LightCycler 480 1.5 software. The expression of the target gene was normalized to an appropriate reference gene for each experiment.

[0120] The data shown in Figure 7 indicates that DC645, DC528, and DC526 are involved in the production of inflammatory genes (Ccl5, TNFα, Nos2). Unregulated neuroprotective genes (AbcA1, Abcg1, Igf1, Igf2) and non-amyloid Upregulating the gene pathways (Nep, Ide, Adam10) to toxic the amyloid precursor. This indicates that it leads to a pathway that does not generate sexually active amyloid fragments.

[0121] Example 3: Permeability assay of MDCK-MDR1: This assay measures the apex-to-basal (AB) and lateral directions of the test compound in MDCK-MDR1 cells. Emission is measured by measuring permeability in the bottom-to-top (BA) direction, indicating whether the compound is actively eluted. It is used to determine the rate (ER). Thus, this assay is used to determine blood-brain permeability and It serves as a valuable in vitro surrogate for CNS exposure.

[0122] 3.1 Experimental Procedure MDCK-MDR1 cells obtained from the NIH (Rockville, MD, USA) are used between passage 6 and 30. The cells were placed in Millipore Multiscreen Transwell plates at a rate of 3.4 × 10⁵ cells / cm². 2 Sow the seeds. Cells are cultured in DMEM, and the culture medium is changed on the third day. A permeability test is performed on the fourth day. Cell culture and The assay incubation is performed at 37°C in an atmosphere of 5% CO2 and 95% relative humidity. On the day of the test, both the apical and basal sides were treated with Hanks equilibrium salt solution (HBSS) at the desired pH, warmed to 37°C. The surface of the material is washed twice to prepare a monolayer film. Next, to stabilize the physiological parameters... In both the apical and basal compartments, the cells were incubated for 40 minutes using HBSS at the desired pH. Incubate. The administration solution is prepared by diluting the test compound with assay buffer and then... Prepare the solution to a concentration of 10 μM. The analytical standard solution is prepared from a DMSO dilution of the test compound. Then, transfer the solution to the buffer solution while maintaining a 1% v / v DMSO concentration. The buffer solution consists of supplemented HBSS pH 7.4. To evaluate the permeability of AB, HBSS was removed from the apical compartment, and the test compound was... Replace with the administration solution. Next, insert the apical compartment insert with fresh buffer (1% v Place in a companion plate containing DMSO (to evaluate BA permeability). Remove the HBSS from the companion plate and replace it with the test compound administration solution. Add the buffer (containing 1% v / v DMSO) to the apical compartment insert, and the companion Place on the plate. After 60 minutes, the top compartment insert and companion plate The samples are separated, and the apical and lateral samples are diluted and analyzed. The permeability of the test compound is double-layered. Evaluate the compounds. Use compounds with known permeability as controls in each assay plate. The test compound and control compound were calibrated at 7 points using appropriately diluted samples. The concentration is quantified using LCMS / MS cassette analysis. The initial concentration (C0) is determined from the administered solution, and C Experimental recovery rates from concentrations of 0 and both the apical and lateral compartments. Calculate.

[0123] 3.2 Data Analysis Permeability coefficient (P) of each compound app ) is calculated using the following formula.

[0124]

number

number

[0125] 3.3. Biological research In the aforementioned MDCK-MDR1 assay, the membrane permeability of numerous compounds of formula I was measured. Transparency (P app The emission rate (ER) was measured (nm / s) and the emission rate was measured to determine the permeability of the highly relevant reference compound EC23. We compared it with transient cases. The results are summarized in Table 2.

[0126] [Table 2]

[0127] The results shown in Table 2 indicate that among the compounds of formula (I), permeability in the MDCK-MDR1 assay is And the lack of excretion has been considerably improved in some cases, and therefore, the permeability of the blood-brain barrier And CNS exposure can be expected to be significantly improved. Treatment of CNS diseases requires exposure of CNS targets to sufficiently high concentrations of therapeutic agents. Therefore, it is clear that optimal exposure to the CNS is an essential characteristic for therapeutic drugs for these diseases. Thus, the compound of formula (I) that was studied is the compound EC23 described in the literature. In comparison, the drug-like properties have improved remarkably. This improvement in CNS exposure is astonishing. This is an unexpected discovery.

[0128] Example 4: Water solubility by turbidimetric method Example 4.1 Experimental Procedure The test compound (10 mM in DMSO) was successively diluted to obtain solutions of 0.1, 0.3, 1, and 3 mM in DMSO. The results were obtained. Subsequently, the concentration of each test compound was further adjusted using a buffer solution (0.01 M phosphate-buffered saline, pH 7.4). Diluted to 1 / 100, the final DMSO concentration is 1%, and the final test compound concentrations are 1, 3, 10, and 30. The concentration was adjusted to 100 μM. The experiment was conducted at 37°C, and samples of each concentration were measured in seven replicated webs. The plates were incubated at 37°C for 2 hours, and then the absorbance was measured at 620 nm. The following was measured. The solubility of the sample was greater than that of the solvent control group (i.e., 1% DMSO in buffer). This was estimated from the concentration of the test compound that caused the increase in absorbance.

[0129] 4.2 Biological research The solubility of numerous compounds in formula (I) was measured using the water solubility assay by the turbidimetric method described above. The solubility of the compound was measured and compared with that of the highly relevant reference compound EC23. The results are summarized in Table 3.

[0130] [Table 3]

[0131] The results shown in the table above indicate that the compound of formula I can significantly improve solubility. Therefore, it is expected that many biological properties, including absorption and exposure to targets, will also be significantly improved. It's possible to wait. This, too, is a surprisingly unexpected discovery.

[0132] In this specification, conditions that are alleviated by activation of the retinoic acid receptor (RAR) If it is stated that the compound is to be used to treat a disease, then it is these compounds themselves. It will be understood that this means disclosure.

[0133] All of the information disclosed herein (including the attached claims, abstract and drawings) The characteristics of, and / or any method or process disclosed in that manner All steps are such that at least some of the features and / or steps are mutually exclusive. Except for combinations that are otherwise identical, any combination is possible. Each feature disclosed in this document (including the attached claims, abstract, and drawings) is clearly Unless otherwise explicitly stated, alternatives that serve the same, equivalent, or similar purposes are not specified. Features can be replaced. Therefore, unless explicitly stated otherwise, disclosure is Each of the features described is merely an example of a general series of equivalent or similar features. The present invention is above The present invention is not limited to the details of the embodiments described herein. Any new one of the features disclosed in the scope, abstract, and drawings, or any A new combination, or any step of any method or process disclosed in this way This extends to any new one or any new combination of P.

[0134] Regarding the use of substantially any plural and / or singular terms in this specification: Those skilled in the art will know, depending on the context and / or use, to change from plural to singular, and / or It can be translated from singular to plural. Various singular / plural permutations are clarified. This may be explicitly stated in this specification.

[0135] Generally, the terms used herein, and especially in the appended claims, are generally "open" Those skilled in the art will understand that this is intended to be a term that includes "~" (for example, "~including"). The term should be interpreted as "including but not limited to ~" and "having ~" The term "ru" should be interpreted as "to have at least ~" rather than "to include ~". The term should be interpreted as "including but not limited to ~" (e.g., Introduction). If a particular number of claims described is intended, such intent is not explicitly stated in the claims. If such a description is not present, it means that such intent does not exist. This will be further understood. For example, to aid understanding, the following attached claims include In order to introduce the wording of the claims, the phrases "at least one" and "one or more" are used. This may include the use of an introductory phrase. However, the use of such a phrase means that the same claim has an introductory phrase "one "or multiple" or "at least one" and indefinite articles such as "a" or "an" Even if so, the introduction of the indefinite article "a" or "an" in the description of a claim leads to such a development. A specific claim containing the description of the submitted claim, in an embodiment containing only one such description. It should not be interpreted as meaning to limit (for example, "a" and "an" mean "a small number of" (This should be interpreted as meaning "at least one" or "one or more"). The same applies to the use of the definite article in introductions. Furthermore, the description of the introduced claims. Even if a specific number is explicitly stated, a person skilled in the art would know that such description It should be recognized that this should be interpreted to mean at least the number stated. For example, the bare description "two mentions" without other modifiers means at least two or so. (This means the description is above.)

[0136] Various embodiments of this disclosure are described herein for illustrative purposes and may not be within the scope of this disclosure. It will be understood that various changes can be made without deviating from the original plan. The various embodiments disclosed herein are not intended to be limiting. The true scope is defined by the following claims.

Claims

1. A pharmaceutical composition for use in the treatment of a condition or disease relieved by activation of the retinoic acid receptor (RAR), comprising a compound of formula I in the form of a free or salt: 【Chemistry 1】 [In formula I, A 1 CR 6 And; A 2 CR 7 And; A 3 CR 8 And; R 6 and R 8 each independently is hydrogen, C 1 -C 10 alkyl, F, Br or Cl; R 7 These are, independently, hydrogen and C 1 -C 10 Alkyl, F, Br, Cl or -OR 9 And R 9 is H or C 1 -C 6 It is alkyl; R 1 ~R 4 Each of them is independent of C 1 -C 10 Alkyl or R 1 and R 2 and / or R 3 and R 4 They are bonded together to form a three-membered ring; A 4 CR 12 And, A 5 CR 13 And, A 6 CR 14 And, A 7 CR 15 And, Each R 12 ~R 15 These are independently H, halogen, or haloalkyl C 1 -C 10 And; R 5 is -C(=O)R 16 or -C (=O) OR 16 And R 16 is H or C 1-10 It is alkyl; However, A ４ is CF, or A 5 [Assuming that it is a CF] A pharmaceutical composition comprising in combination with one or more pharmaceutically acceptable excipients, diluents, or carriers.

2. R 7 The pharmaceutical composition according to claim 1, wherein is hydrogen.

3. R 5 The pharmaceutical composition according to claim 1 or 2, wherein is -COOH.

4. below: 【Chemistry 2】 A pharmaceutical composition according to claim 1, selected from the following.

5. below: 【Transformation 3】 A pharmaceutical composition according to claim 4, selected from the above.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the disease or condition alleviated by activation of RAR is selected from amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, early Alzheimer's disease, middle Alzheimer's disease, late Alzheimer's disease, cognitive impairment, memory impairment, memory loss, senile dementia, cognitive dysfunction, mild cognitive impairment, stroke, traumatic brain injury, epilepsy, and spinal cord injury.

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