Synthetic retinoids for use in 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 a method for treating conditions or diseases that are alleviated by activation of retinoic acid receptors (RARs). A compound of formula I for use in therapy: [ka] [In formula I, A 1 -A 7 and R 1 From R 5 The present invention relates to such The invention also relates to pharmaceutical compositions comprising such compounds, and related methods of treatment. in the treatment of conditions or diseases that are alleviated by activation of retinoic acid receptors (RARs). In some embodiments, the present invention relates to a method for screening compounds for therapeutic potential. The present invention relates to A 1 ~A 3 At least one of is N or A 4 At least one of the following is CR 12 Yes or A 5 CR 13 and R 12 / R 13 is a halogen.

[0002] More specifically, the present invention relates to a method for treating amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and the like. Neurological conditions, including neurodegenerative conditions such as Son's disease, and conditions such as spinal cord injury, in which RAR activity is increased The present invention relates to the use of compounds of formula I in the treatment of conditions and / or diseases that are alleviated by oxidization. This is what we have in mind.

[0003] Retinoids are a group of natural or synthetic compounds that are analogues of vitamin A and its derivatives. Retinoids are essential for many cellular activities and act as signaling molecules during embryonic development. They regulate key biological pathways from embryonic to adult homeostasis, as well as proliferation, differentiation, and apoptosis. All-trans retinoic acid (ATRA) is also involved in stem cell development, such as retinal cytosis. It is the most abundant endogenous retinoid and has been used as a model compound in retinoid research. .

[0004] Retinoids bind to a group of nuclear receptors known as retinoic acid receptors (RARs), i.e. Acts on inducible ligand-activated transcription factors that control various physiological mechanisms at the genomic level Therefore, synthetic retinoids may be a potential treatment for RAR-mediated or potentially RAR-mediated cell death. It has been investigated as a potential treatment for a variety of diseases and conditions. Known compounds have drawbacks such as low potency or efficacy, or poor water solubility. It had poor physical properties such as low heat generation.

[0005] Neurological conditions are conditions that affect the central and peripheral nervous system, i.e. the brain, spinal cord, cranial nerves, peripheral nerves, and nervous These include disorders of the roots, autonomic nervous system, neuromuscular junction, and muscles. Neurological disorders include spinal cord injuries and brain Sudden conditions such as stroke, intermittent conditions such as epilepsy, amyotrophic lateral sclerosis (ALS), These include 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 of them life-threatening, and all of them are life-threatening. In total, hundreds of millions of people worldwide suffer from neurological disorders. It is estimated that 100,000 people are affected by the disease (World Health Organisation, May 2016).

[0006] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disease that affects motor neurons. A debilitating neurological condition characterized by a gradual loss of function, 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], and approximately 50% of patients The mortality rate is estimated to be 1.2% [Kiernan et al. "Amyotrophic lateral sclerosis". The lan cet; Vol.377(9769); (2011):942-955]. However, despite the devastating nature of the disease, There is currently no cure and the only medicine approved for the treatment of ALS in the UK is has been shown to extend patients' lives by an average of 2 to 3 months [Miller et al. "Riluzole for 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 is caused by mutations in multiple genes, including C9ORF72 and SOD1. The root cause of ALS is the death of motor neurons, which control muscle movement. The exact mechanism by which this occurs is currently unknown. However, (i) excitotoxicity: (ii) the toxic effects of delivered substances that cause excessive firing of neurons; and (iii) failure of autophagy. (iii) loss of cellular detoxification systems that remove insoluble molecules accumulated in the cytoplasm; Inflammation: Immune cells in the nervous system mistakenly attack motor neurons; (iv) Axonal disorganization: Some of these include the loss of interconnecting fibers essential for transcellular communication. Therefore, the mechanism of action of drugs used to treat ALS is Ideally, a product should exhibit multifaceted characteristics.

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

[0009] Treatments that cure or prevent ALS, Alzheimer's disease, or related disorders include: This is the ultimate goal of many pharmaceutical research projects, but more realistically, it is important to prevent disease onset. Treatments that could delay, slow or stop the progression of the disease would be a major breakthrough. Additionally, methods for screening potential therapeutic compounds would be highly beneficial. Summary of the Invention

[0010] Thus, the present invention relates to a method for treating a condition or disease that is alleviated by activation of a retinoic acid receptor. In one embodiment, the present invention relates to a compound for use in the treatment of a genome-wide disorder. In an embodiment of the invention, the compounds activate both genomic and non-genomic pathways. do.

[0011] In an embodiment, the invention relates to pharmaceutical compositions comprising such compounds, and to retinoid acid receptor antagonists. The use of such compounds and compositions in the treatment of conditions or diseases alleviated by activation of Regarding use.

[0012] Conditions and diseases that are alleviated by activation of retinoic acid receptors include neurodegenerative diseases. In addition to RAR-mediated conditions, RAR activation is also involved in stroke, traumatic brain injury, epilepsy, and spinal cord injury. These include those that are mitigated by

[0013] In an aspect, the present invention relates to a method for treating conditions or diseases that are alleviated by activation of retinoic acid receptors. The present invention relates to a method for screening compounds with therapeutic potential in the treatment of

[0014] Aspects of the present invention relate to the novel compounds per se.

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

[0016] According to a first aspect of the present invention, a method for treating rheumatoid arthritis, which is alleviated by activation of retinoic acid receptors (RAR) A compound of formula I, in free or salt form, for use in the treatment of a condition or disease: [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 are each independently hydrogen, C1-C 10 alkyl, F, Br or Cl; R 7are independently hydrogen, C1-C 10 Alkyl, F, Br, Cl or -OCR 9 and R 9 is H or C is 1-C6 alkyl; R 1 ~R 4 are each independently 10 alkyl or R 1 and R 2 And / If Kuha R 3 and R 4 are linked 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 are independently H, halogen or haloalkylC1-C 10 and; R 5 is -C(=O)R 16 OR -C(=O)OR 16 and R 16 is H or C 1-10 is alkyl; However, A 1 ~A 7 At least one of is N or R 12 ~R 15 At least one of the following is F, Cl is also or Br] and isomers thereof.

[0017] In the compound of formula I, A 1 ~A 7 At least one of is N or R 12 ~R 15 Less One of each is F, Cl, or Br.

[0018] As used herein, the term "alkyl" refers to a fully saturated, branched, unbranched, or cyclic hydrocarbon. The alkyl moiety is preferably a primary, secondary or tertiary alkyl or, where appropriate, a cycloalkyl group. Unless otherwise specified, alkyl refers to alkyl substituted with alkyl or cycloalkyl. The group has 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. Representative examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-Butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl n-Hexyl, 3-Methylhexyl, 2,2-Dimethylpentyl, 2,3-Dimethylpentyl These include, but are not limited to, n-hexyl, n-octyl, n-nonyl, and n-decyl. It is not something that is done.

[0019] As used herein, the term "halogen" or "halo" refers to any of fluoro, chloro, bromo, , or iodine.

[0020] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen atom. Refers to a substituted alkyl group.

[0021] Conditions or diseases that are alleviated by activation of retinoic acid receptors include neurodegenerative diseases. In addition to RAR-mediated conditions such as stroke, traumatic brain injury, epilepsy, and spinal cord injury, These conditions are alleviated by activation of the AR.

[0022] RAR-mediated conditions include amyotrophic lateral sclerosis (ALS), neuromuscular diseases, and Parkinson's disease. Alzheimer's disease, multiple sclerosis (MS), early stage Alzheimer's disease, mid-stage Alzheimer's disease Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, memory impairment, memory deficit, senile dementia, vascular dementia These include neurodegenerative diseases such as dementia, cognitive impairment, and mild cognitive impairment.

[0023] Thus, conditions or diseases that are alleviated by RAR activation include amyotrophic lateral sclerosis (ALS). ALS, neuromuscular diseases, Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, early Alzheimer's disease, mid-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 condition may be selected from traumatic brain injury, epilepsy, and spinal cord injury.

[0024] The condition may be a neurological condition. In embodiments, the neurological condition is ALS, Parkinson's disease, Parkinson's disease, or a combination of both. The condition may be a neurodegenerative condition, such as Johns Hopkins' disease, or Alzheimer's disease.

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

[0026] In one embodiment, A 1 ~A 3 At least one of is N or A 4 At least One is CR 12 or A 5 CR 13 and R 12 / R 13 R is a halogen. 12 / R 13 teeth, F is preferred.

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

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

[0029] In one embodiment, A 4 , A 5 Or A 6 At least one of these is CF.

[0030] In this embodiment, A 4 may be CF. Alternatively, A 5 is CF and A 2 is CR 7 And Good too.

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

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

[0033] In one embodiment, A 1 and A 3 Both are N, and A 2 is represented by formula IA, 7 Yes R 7 is H. [ka]

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

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

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

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

[0038] Generally speaking, compounds of formula I include a hydrophobic region, a linker region (-C≡C -) and polar regions: [ka]

[0039] The inventors have advantageously found that the hydrophobic region contains one, or preferably two, nitrogen atoms in the conjugated ring. incorporates an elemental atom; or incorporates a nitrogen atom in a conjugated ring in the polar region; and / or the conjugated rings in the polar regions are halogenated (or preferably fluorinated). Compounds of formula I have been surprisingly shown to be useful in treating diseases or conditions alleviated by activation of RAR. I found it to be beneficial.

[0040] Exemplary compounds of formula I that may be mentioned are selected from the group consisting of: Some of the things mentioned are: [ka]

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

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

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

[0044] In another aspect of the invention, the present invention is used to treat a disease or condition that is alleviated by activation of RAR. There is provided the use of a compound of formula I as defined herein in the manufacture of a medicament for In one embodiment, the medicament comprises a compound of formula I.

[0045] In another aspect of the invention, a method for treating a patient comprising administering to the patient a therapeutically effective amount of a compound of formula I. and the compound of formula I is as defined herein. Methods for treating a patient having a disease or condition are provided.

[0046] In another aspect of the invention, the present invention is used to treat a disease or condition that is alleviated by activation of RAR. for the treatment of a disease comprising administering to a patient a compound of formula I as defined herein, optionally in combination with one or more pharma- ceutically acceptable salts of In yet another aspect, a pharmaceutical composition is provided comprising the compound of formula (I) in combination with an excipient, diluent or carrier such as , optionally containing one or more additional therapeutic agents.

[0047] The term "therapeutically effective" amount, or "effective amount," refers to a compound that is capable of producing the desired therapeutic, ameliorative, or inhibitory effect. By "treatment" is meant an amount of a compound or composition of the invention effective to produce a therapeutic or prophylactic effect.

[0048] The term "pharmaceutical composition" means a composition suitable for administration to a patient. The term "pharmaceutical composition" refers to a compound of the present invention or a mixture thereof, or a salt, solvate, prodrug, or the like. Optionally, one or more pharma- ceutically acceptable prodrugs, isomers, or tautomers may be combined with The term "pharmaceutical composition" refers to a composition that includes the pharmaceutical agent in combination with an excipient, carrier, or diluent. The term "composition" refers to a bulk composition (i.e., a composition that has not yet been formed into individual dosage units). The term "individual dosage units" is intended to encompass both individual dosage forms (such as syrups) and individual dosage units. Dosage units include tablets, pills, caplets, ampoules, and the like.

[0049] Those skilled in the art will recognize that the compounds of the present invention may be converted into prodrugs and / or solvates. The term "prodrug" refers to a compound of the present invention or A compound which is converted in vivo to give a pharma- ceutically acceptable salt, hydrate or solvate of This conversion can occur, for example, by hydrolysis in blood. May occur by a variety of mechanisms (e.g., metabolic or chemical processes) be.

[0050] The compounds of the present invention may be unsolvated or may be dissolved in pharma- ceutically acceptable solvents such as water or ethanol. For example, one or more solvent molecules may be present in the crystalline solid. It is understood that the solvate may be capable of isolation, such as when incorporated into a crystal lattice of "Solvate" encompasses both solution-phase and isolatable solvates. Suitable solvates include ethanol solvates, methanol solvates, hydrates, etc. However, the present invention is not limited to the above.

[0051] The compounds for use in the present invention include salts thereof, and reference to the compounds of the present invention specifically refers to the salts thereof. Unless otherwise specified, reference to salts thereof is intended to include reference to such salts. Suitable salts include, for example, Acid salts formed with inorganic and / or organic acids, inorganic and / or organic bases Basic salts, as well as zwitterionic salts which may be formed, are included in the term "salt" as used herein. ions ("inner salts"); Pharmacologically acceptable (i.e., non-toxic and physiologically acceptable) Acceptable salts are preferred, although other salts may be useful in certain circumstances. Examples of acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, etc. Salt, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate Salt, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, meta sulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates Salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfate Examples of base salts that may be useful include benzoate, benzoyl salts (also called tosyl salts), and benzoyl salts. Examples of suitable salts include alkali salts such as ammonium, sodium, lithium, and potassium salts. Metal salts, alkaline earth metal salts such as calcium salts and magnesium salts, dicyclohexyl salts with organic bases (e.g., organic amines) such as arylamine, t-butylamine, etc., and salts with amino acids such as guanine and lysine. Alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, and iodides) ), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl sulfate), Long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides, and iodides) aryl alkyl halides (e.g., benzyl and phenethyl bromides); It may be quaternized with drugs.

[0052] The compounds used in the present invention include pharma- ceutically acceptable esters thereof, in which the hydroxyl group is substituted. It may contain a carboxylic acid ester obtained by esterification, in which the ester group The non-carbonyl portion of the carboxylic acid moiety of n-propyl, t-butyl, or n-butyl), alkoxyalkyl (e.g., methoxy methyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxy oxymethyl), aryl (e.g., halogen, C 1-4 Alkyl, or C 1-4 Alkoxy, or phenyl optionally substituted with amino; (2) alkyl- or aralkyl-sulfo (3) amino acid esters; (e.g., L-valyl or L-isoleucyl); (4) phosphonates; and (5) molybdenum esters. It is selected from no-, di- or triphosphate esters.

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

[0054] The appropriate dosage of the compounds of the present invention when administered to a patient can be determined by those skilled in the art, e.g., the attending physician, pharmacist, or other skilled person can determine, taking into account the patient's weight, health condition, age, frequency of administration, The dosage may vary depending on factors such as the method of administration, the presence of other active ingredients, and the condition to which the compound is administered. There is a possibility that it will become

[0055] Examples of excipients, diluents, and carriers include buffers, starches, celluloses, sugars, etc. Fillers and extenders such as silicic acid derivatives, mannitol, and silicic acid derivatives. Also contains binders. In some cases, an adjuvant may also be included.

[0056] Optionally, the compounds 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 invention may be administered together They may be administered either sequentially or in parallel.

[0057] The compositions are administered orally, parenterally (including subcutaneously, intravenously, intramuscularly, intraperitoneally), rectally, transderm ... Administration can be by a variety of routes, including dermally, intrathoracically, intrapulmonary, mucosal, intraocular, and intranasal.

[0058] Suitable dosage forms will be recognized by those of skill in the art and include, among others, tablets, capsules, solutions, suspensions, Powders, aerosols, ampoules, prefilled syringes, small volume infusion containers or multi-dose Cream, milk, gel, dispersion, microemulsion, lotion, impregnated powder These include medicines, ointments, eye drops, nasal drops, and lozenges.

[0059] An aspect of the present invention is 1 From A 3 At least one of is N or A 4 At least one of the following is C R 12 or A 5 CR 13 and R 12 / R 13 is a halogen. Such embodiments relate to novel compounds per se.

[0060] R 12 / R13 is preferably F.

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

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

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

[0064] In one aspect of the invention, a condition or disease that is alleviated by activation of a retinoic acid receptor is provided. A method for screening compounds with therapeutic potential in the treatment of Here's how: -Efficacy of compounds in activating RARs (E) as an index of genomic activity max ) is measured performing an assay for the - Compound efficacy (E) as an indicator of non-genomic activity max ) assay is performed Tep and; In each assay, E max comparing the measured value to a baseline value; -E in both assays max Compounds with values ​​above baseline were selected for further study. and selecting for said first and second bins.

[0065] Since it was discovered that RAR is a member of the nuclear receptor family of transcriptional 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), and the function of retinoids Based on this, synthetic retinoids have been produced. have been constructed and their genome activation properties have been investigated.

[0066] However, surprisingly, the inventors have discovered that retinoid acids (RAs) are involved in genomic and non-genomic signaling pathways. These mechanisms are independently regulated with respect to ligand-dependent RAR engagement. "Dual activity," i.e. activity in both non-genomic and genomic assays, was It has been found that there is a strong correlation between the promotion of neurite outgrowth and an increase in cell number and viability. This suggests that these dual-function compounds may be important therapeutic agents. It is something.

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

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

[0069] In one embodiment, the baseline value indicative of genomic activity is E max is 170.1.

[0070] In one embodiment, the baseline value indicative of non-genomic activity is E max is 48.55.

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

[0072] example: The invention will now be described, by way of example only, with reference to the accompanying drawings, in which: FIG. [Brief description of the drawings]

[0073] [Figure 1A] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1B] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1C] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1D] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1E] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1F] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1G] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1H] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1I] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1J] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1K] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1L] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1M] FIG. 1 shows an example of the synthesis of a coupling partner. [Figure 1N] FIG. 1 shows an example of the synthesis of a coupling partner. [Diagram 2] FIG. 1 shows the synthesis of exemplary retinoid compounds DC526, DC528, DC641 and DC645. [Diagram 3] FIG. 1 shows the genomic activity of retinoids using the X-Gal assay. [Figure 4] FIG. 1 shows the non-genomic activity of retinoids as demonstrated by their ability to induce phosphorylation of ERK1 / 2. [Diagram 5] FIG. 1 shows the average neurite length after treatment of differentiated SH-SY5Y cells with retinoids. [Figure 6] FIG. 1 shows the relationship between the ability of retinoids to induce both genomic [transcriptional activity: Emax(efficacy)] and non-genomic [ERK1 / 2 activity: Emax(efficacy)] activity and induction of neurite outgrowth (fold increase at 10 μM). Highlighted retinoids exhibit both activities. [Figure 7] FIG. 1 shows data on the transcriptional regulation of Alzheimer's disease-related genes following treatment of rat mixed primary neuronal / glial cultures with retinoids. [Figure 8] Figure 8A compares the activity of an exemplary retinoid DC645 with that of ATRA and EC23, and compares the genomic activity of retinoids by X-Gal assay. Figure 8B compares the activity of an exemplary retinoid DC645 with that of ATRA and EC23, and compares the non-genomic activity of retinoids by measuring their ability to induce ERK1 / 2 phosphorylation. Figure 8C compares the activity of an exemplary retinoid DC645 with that of ATRA and EC23, and compares the ability of the compounds to induce neurite outgrowth in SH-SY5Y cells. Figure 8D compares the activity of an 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: Synthesis of exemplary compounds of formula 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) FIG. 1A shows 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (11.46 g, 60.9 m mol), I2 (7.77 g, 30.6 mmol) and H5IO6 (3.49 g, 15.3 mmol) were added to ethanoic acid / acetic acid (AcO H) (250 mL), HO (25 mL), and HSO (13 mL) were added to the mixture, and the resulting solution was heated to 70 °C. The solution was cooled and extracted with ethyl acetate / ethyl acetate (EtOAc). The organics were washed with saturated Na2S2O3, H2O, and brine, dried (MgSO4), and evaporated. This gave an orange crude oil (17 g), which was purified by dry column vacuum chromatography (He The resulting mixture was purified by column chromatography (eluted with butane) to give compound 1 as a white solid (16.3 g, 85%): 1 H 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 C NMR (176 MHz, C 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) (Figure 1B) Triethylamine (Et3N) (150 mL) is degassed by sparging with N2 for 1 hour. Then, 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, and the resulting The resulting slurry was stirred at room temperature for 20 hours. The mixture was diluted with heptane and dispersed in Celite / SiO2 (Hexane). The resulting solution was evaporated to give a crude brown oil (10.36 g). was purified by SiO2 chromatography (heptane 100%) to give compound 2 as a yellow oil ( Compound 2 (9.99 g, 35.1 mmol) was dissolved in methanol (MeOH) / methyl tert-butyl ether. The solution was dissolved in 1:1 methylbutene (MTBE) (160 mL) and then in 0. A solution of 96 g (24.0 mmol) in H2O (15 mL) was added and the resulting solution was stirred at room temperature for 16 h. The solution was diluted with MTBE, washed with H2O and brine, dried (MgSO4) and evaporated to give a crude yellow oil (6. 6g) was obtained. This was purified by SiO2 chromatography (heptane 100%) to obtain compound 3. The product was obtained as a colorless oil that solidified with water (6.06 g, 90% over two steps); all data are from the literature (V. 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. Benzoic acid (25.0 g, 114.2 mmol) was suspended in MeOH (250 mL), and concentrated H2SO4 (4 mL) was added to obtain The resulting solution was stirred at reflux overnight. After that, the clear solution was cooled and H2O (100 mL) was added. Upon addition of the solvent, a white precipitate formed, which was filtered, washed with H2O, and dried to give a crude A white solid was obtained, which was recrystallized from heptane to give 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) was dissolved in N2 The mixture was degassed by sparging with 1000 ml of water for 1 hour. The mixture was stirred for 10 min at 37°C for 2 h. The mixture was cooled to 37°C and cooled to 37°C. The mixture was cooled to 37°C and cooled to 37°C. The mixture was cooled to 37°C and cooled to 37°C. The mixture was cooled to 37°C and cooled to 37°C. mg, 0.429 mmol) was added under N2 and the resulting suspension was stirred at room temperature for 16 h. After dilution with heptane and passing through Celite® / SiO2, the extract was evaporated to give a crude oil (6.4 This was purified by dry column vacuum chromatography (100% heptane to 9:1 heptane). The isolated product was purified by Kugelrohr distillation (150 °C, 7.4 Torr). Further purification gave compound 5 as a yellow oil (5.58 g, >100%), which was carried on directly to the next step. Progressed to: 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) In a MeOH:MTBE solution (5:50, 55 mL), compound 5 (5.58 g, 22.3 mmol) and K2CO3 (6.16 g (44.6 mmol) was added and the resulting mixture was stirred at room temperature under N2 for 6 hours. It was diluted and washed with saturated NH4Cl, H2O, and Br. It was washed with NH4Cl, H2O, and brine, dried (Mg SO4) and evaporation gave a crude solid (3.6 g), which was purified by dry column vacuum chromatography. Purification with (100% heptane to 8:2 heptane / EtOAc) gave compound 6 as a white solid. (3.07g, 80% in two steps): 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 , 1.6Hz, 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 methyl 5-bromopyridine-2-carboxylate, 8 The synthesis of methyl 5-bromopyridine-2-carboxylate (8) is shown in FIG. 1E. 5-Bromopyridine-2-carboxylic acid (20.0 g, 99.0 mmol) was suspended in MeOH (150 mL) and Concentrated H2SO4 (5 mL) was carefully added to the solution, and the resulting solution was stirred at reflux for 6 h. It was cooled, diluted with EtOAc, washed with H2O and brine (50 mL), dried (MgSO4) and evaporated. This gave a crude colorless solid, which was then vacuum distilled using a Kugelrohr (200°C, 7.4 Torr). The resulting white solid was further recrystallized from heptane / MeOH (10:1) to give compound 8 as a white solid. Obtained as a coloured 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 of 2,2,5,5-tetramethylhexanedioic acid (9) is shown in Figure 1F. In a 2 L three-neck flask equipped with The resulting slurry was cooled to 0 °C. H2O2 (30%, 43 mL) was added in this order over 15 min. ) and a solution of FeSO4.7H2O (139.0 g, 500 mmol) in HO (288 mL) and concentrated H2SO4 (27.5 mL). After the addition was complete, the suspension was stirred for an additional 15 minutes, after which the solution was The mixture was concentrated to about 250 mL. The precipitated solid was filtered and evaporated in vacuum using a rotary evaporator. Further drying under reduced pressure gave a crude residue which was recrystallized from AcOH to give 9 as a colorless crystalline Obtained as a solid (3.39 g, 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. To a solution of (3.39 g, 16.76 mmol) in EtOH (40 mL) was added concentrated H2SO4 (2 mL), and the resulting suspension was The solution was cooled and the solvent was evaporated to give a crude residue which was then diluted with EtOAc. The organics were washed with saturated NaHCO3, H2O, and brine, dried (MgSO4), and evaporated. This gave a crude oil (3.8 g), which was purified by SiO2 chromatography (95:5, heptane / EtOAc ) to give 10 as a colorless oil (3.41 g, 79%): 1 H 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 C 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 (1-hex-1-en-1-yl)oxysilane, 11 Trimethyl({3,3,6,6-tetramethyl-2-[(trimethylsilyl)oxy]cyclohex-1 The synthesis of the (1-en-1-yl)oxysilane, 11, is shown in Figure 1H. Sodium (1.20 g, 52.1 mmol) was added under reduced pressure, and the resulting mixture was heated until the sodium was dissolved. The flask was then removed from the heat and 10 (2.69 g, 10.41 mmol) and chlorotrifluoroacetate were added. Methylsilane (6.72 mL, 53.0 mmol) was added, and the resulting suspension was then stirred at reflux overnight. The purple suspension was then cooled and filtered under a stream of N2, and toluene, tetrahydrofuran, and hexane were removed. The filtrate was then evaporated to give a pale yellow crude oil (3.2 g). This was purified by Kugelrohr distillation (120 °C, 3.6 Torr) to give 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 of 3,3,6,6-tetramethylcyclohexane-1,2-dione is shown in Figure 1J. To a solution of 0.42 mL (8.2 mmol) of bromine in dichloromethane (DCM) was added dropwise over 5 min. The resulting yellow solution was stirred at room temperature for 1 h, then diluted with DCM and saturated Na2S2O3 After treatment with HCl, washing with H2O, drying (MgSO4) and evaporation gave a crude yellow solid (1.5 g). This was purified by recrystallization from heptane to give 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 C NMR (176 MH 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 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-carboxylate Synthesis of silate, 13 Methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carboxylate The synthesis of 13 is shown in Figure 1J. The reaction of 12 (0.80 g, 4.76 mmol) with DL-2,3-diaminopropionic acid hydride was carried out. Dodecyl chloride (0.67 g, 4.76 mmol) was combined in MeOH (30 mL). mol) was added and the resulting mixture was stirred at reflux for 24 h. The solution was cooled to 0 °C and H2SO4 was carefully added and the solution was stirred at reflux for an additional 6 hours. The solution was cooled and the solvent was evaporated. This was dissolved in EtOAc, washed with saturated NaHCO3, H2O, and brine, and dried. Drying (MgSO4) and evaporation gave a crude yellow oil (0.9 g), which was chromatographed on SiO2. Purification with hexanes (95:5, heptane / EtOAc) gave 13 as a colorless oil (0.633 g, 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-tetrahydroquinoxalin-2-yl)methano Synthesis of 14 (5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)methanol, 14 The synthesis of is shown in Figure 1K. A solution of 13 (5.09 g, 20.5 mmol) in THF (80 mL) was added to NaBH4 (2.33 g, 61 The solution was then heated to reflux and MeOH (16 mL) was added over 1 h. The resulting solution was then stirred at reflux overnight. The solution was cooled and diluted with 1M H The mixture was quenched with Cl and the solvent was evaporated. The residue was dissolved in DCM, washed with water, dried (MgSO4 ) and evaporated to give a yellow crude oil (4 g), which was purified by SiO2 chromatography (eluent Purification with 8:2 heptane / EtOAc gave 14 as a colorless oil (3.96 g, 88%): 1 H 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 literature (Kikuchi et al. J. Med. Chem. 200 0; 43: pp. 409-419).

[0085] 1.1.12 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde , 15 synthesis 5,5,8,8-Tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde, 15 The synthesis is shown in Figure 1L. Oxalyl chloride (2.28 mL, 26.96 mmol) was dissolved in anhydrous DCM (100 mL) under N2. The resulting solution was cooled to -78 °C, to which DMSO ( The solution was stirred for 15 min and then diluted with anhydrous DCM. 14 (3.96 g, 17.97 mmol, in 20 mL) was added dropwise, keeping the temperature below -60 °C. The solution was stirred for an additional 15 min, after which Et3N (18.03 mL, 129.38 mmol) was added. The solution was stirred for 10 min and then allowed to warm to room temperature (RT) over 30 min. H2O was added and the resulting mixture was The material was diluted with DCM, washed with H2O, dried (MgSO4) and evaporated to give a crude oil (4 g). This was purified by dry column vacuum chromatography (DCVC) (heptane to 9:1, heptane / EtOA c) 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 rC 13 H 19 ON2[M+H] + :216.1497, found 216.1503.

[0086] 1.1.13 Synthesis of 1-diazo-2-oxopropylphosphonic acid dimethyl ester, 16 The synthesis of dimethyl 1-diazo-2-oxopropylphosphonate, 16, is shown in Figure 1M. To a solution of dimethyl xopropylphosphonate (4.49 mL, 32.5 mmol) in anhydrous toluene (30 mL), NaH (60% dispersion in mineral oil, 1.20 g, 30.00 mmol) was added in portions with vigorous stirring. After the generation of acetamidobenzenesulfonyl azide (7.21 g, 30.0 mmol) Anhydrous THF (10 mL) solution was added dropwise. The resulting suspension was stirred at room temperature for 16 hours, whereupon Heptane was added and the suspension was filtered through Celite® and washed with MTBE. The extract was evaporated to give a crude oil (5 g), which was purified by SiO2 chromatography (1:1, heptane / EtOAc) to give 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), and all other data are from the literature (Pietruszka et al. Synthesis, 2006, pp.4266-42 68).

[0087] 1.1.14 2-Ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline, 17 Figure 1 Synthesis of 2-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline, 17 1N. A solution of 15 (1.18 g, 5.40 mmol) in anhydrous MeOH (50 mL) was added to KCO (1.49 g , 10.80 mmol) and dimethyl-1-diazo-2-oxopropylphosphonate (0.98 mL, 6.48 mmol) ) was added and the resulting suspension was stirred at room temperature for 16 h. The solution was diluted with EtOAc and 5% NaHC O3, H2O, and brine, dried (MgSO4), and evaporated to give a crude orange oil (0. 4 g) was obtained, which was purified by SiO2 chromatography (95:5 heptane / EtOAc as eluent). Purification gave 17 as a colorless oil that slowly crystallized (0.84 g, 73%): 1 H 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-yl] Synthesis of ethyl)ethynyl]benzoic acid, DC526 The synthesis of an exemplary compound, DC526, is shown in FIG. 2A.

[0089] EtN (80 mL) was degassed by sparging with N for 1 h. Compound 1 (0.80 g, 2.55 mmol) was then 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 and the resulting suspension was stirred at room temperature for 72 h. The suspension was diluted with MTBE. After passing through Celite® / SiO2, the extract was evaporated to give a crude solid (1.1 g). This was purified by dry column vacuum chromatography (100% heptane, then 95:5, heptane / EtOAc) Purification by hexane afforded compound 7 (0.82 g, 88%) as a colorless oil that slowly crystallized. This was carried to the next step as is. Compound 7 (0.80 g, 2.20 mmol) was dissolved in THF (40 mL). Then, 20% NaOH (3 mL) was added and the resulting solution was stirred at reflux for 16 h. Acidified to pH 1 with % HCl, extracted with EtOAc, washed with H2O and brine, dried (MgSO4), and evaporated. This gave a crude white solid, which was recrystallized from acetonitrile (MeCN) to give 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); 19F NMR (3 76 MHz, DMSO-d6) δ -110.0; IR (ATR) v 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] Synthesis of pyridine-2-carboxylic acid, DC528 The synthesis of the exemplary compound DC528 is shown in FIG. 2B.

[0091] Et3N / THF (1:1, 120 mL) was degassed by sparging with N2 for 1 h 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) was added and the resulting solution was stirred at 50° C. for 40 hours. The solution was diluted with heptane The organics were then saturated with heptane and eluted through a Celite® / SiO2 plug. NH4Cl, H2O, and brine, dried (MgSO4), and evaporated to give a crude brown solid (1.9 g) was obtained. This was purified by dry column vacuum chromatography (100% heptane to 8:2, The resulting mixture was purified by hexane / EtOAc to give compound 9 as a white solid (0.36 g, 27%), which was subsequently Continue to the next step: 1H 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). Compound 9 (0.33 g, 0.95 mmol) was dissolved in THF (30 mL), and 20% NaOH (3 mL) was added to obtain The resulting solution was stirred at reflux for 16 h. The mixture was cooled, acidified to pH 1 with 5% HCl, and diluted with EtOAc. Extraction, washing with H2O and brine, drying (MgSO4) and evaporation gave a crude white solid. This was recrystallized from MeCN to give DC528 as a colorless crystalline solid (0.30 g, 96%): 1 H 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-tetrahydroquinoxalin-2-yl) Synthesis of ethynyl]benzoate (DC641) The synthesis of the exemplary compound DC641 is shown in Figure 2C. Et3N (20 mL) was degassed by sparging with Ar for 1 h. Next, methyl 4-iodobenzoate (0.31 g, 1.20 mmol), DC640 (0.30 g, 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 suspension was The suspension was stirred at room temperature for 16 hours. The suspension was diluted with MTBE and then coated with Celite® / SiO2. After passing through the column, the extract was evaporated to give a crude solid (0.5 g), which was then purified by dry column vacuum chromatography. Chromatography (100% heptane to 85:15 heptane / EtOAc) gave an off-white solid. The solid was subsequently recrystallized from MeOH to give DC641 as a colorless crystalline solid (0.29 g, 71%). This was carried forward 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-tetrahydroquinoxalin-2-yl)ethynyl Synthesis of benzoic acid, DC645 The synthesis of the exemplary compound DC645 is shown in Figure 2D. DC641 (0.28 g, 0.8 mmol) was dissolved in THF (20 mL). The mixture was dissolved in water, 20% NaOH (2 mL) was added, and the resulting solution was stirred at reflux for 16 hours. The mixture was cooled, acidified to pH 1 with 5% HCl, extracted with EtOAc, washed with HO and brine, dried (MgSO O4) and evaporation gave a crude white solid, which was recrystallized from MeCN to give DC645 as a colorless crystal. Obtained as a crystalline solid (0.24 g, 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 n.d. 334.1686.

[0094] Example 2: Biological evaluation 2.1 Genomic activity of synthetic retinoids The genomic activity of synthetic retinoids was evaluated by measuring their efficiency in inducing transcription using the X-Gal assay. The X-Gal assay was performed to evaluate the expression of retinoic acid responsive elements (RAREs). Sil-15 reporter cells in which the transcription of the LacZ gene is controlled by the ligated promoter After treating the reporter cells with retinoids, the β-galactam produced by the reporter cells was By monitoring and quantifying the activity of cytosidase, the transcription-inducing ability of the compound can be obtained. can.

[0095] Sil-15 cells were plated in a 96-well plate coated with 0.1% gelatin at 100 cells / well. The next day, the cells were cultured in Dulbecco's modified Eagle medium containing 10% fetal calf serum (FCS). Serial dilutions of retinoid ligands were prepared in DMEM (10 -6 M to 10 -14 Add at a concentration of M The plates were incubated overnight. ATRA standard curve and other retinoid ligand concentrations All tests were performed in triplicate.

[0096] The next day, the assay plates were washed twice with phosphate-buffered saline (PBS) and incubated with 1% glutathione in PBS. Tyraldehyde and 1mM MgC l2 Fix the plate with 100 μL of PBS for 15 minutes. β-galactosidase activity was determined by centrifugation of 1 mM MgCl2, 3.3 mM potassium ferrocyanide in PBS. 0.2% X-Gal dissolved in 3.3 mM potassium ferrocyanide was freshly prepared and placed in one well. The plates were incubated at 37°C, 5% CO2 for 6 hours. The plate was read at 650 nm using an Emax Precision Microplate Reader (Molecular Devices). The color change was detected by reading it with a

[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 the results, some synthetic retinoids have a higher activity than the endogenous ligand (ATRA). In particular, DC527, DC540, DC525, DC528, DC526 and and DC645 all showed higher genomic activity and potency compared to retinoic acid (ATRA).

[0098] 2.2 Non-genomic activity of synthetic retinoids The non-genomic activity of synthetic retinoids was assessed using AlphaLISA® SureFire® Ult The ability to induce phosphorylation of ERK1 / 2 was assessed using the ra ERK1 / 2 kit. .

[0099] In this assay, SH-SY5Y cells (100,000 cells / well) were plated in 96-well plates and incubated with DM The cells were serum-starved for 24 hours in EM. Retinoids were added to the medium at concentrations ranging from 10-5M to 10-11M. For SH-SY5Y cells in serum-free DMEM, cells were incubated at 37°C for 1 h at 4°C for 1 h. The assay was performed by stimulating with retinoids at 4 °C for 30 min.

[0100] After the assay is complete, remove the medium and add 50 μL of freshly prepared 1X lysis buffer (supplied with the kit). The cells were lysed using an orbital shaker (SO1, Stuart Scientific The mixture was stirred at about 350 rpm in a mixing bowl (manufactured by ific) at room temperature for 10 minutes.

[0101] Meanwhile, the activation buffer was diluted 25-fold with the reaction buffer. The adapter beads were diluted 50-fold in the freshly prepared reaction mixture, while the donor beads were diluted 50-fold. Two final reaction mixtures were obtained by 50-fold dilution with buffer.

[0102] Then, 10 μL of the cell lysate was transferred to a 384-well white Proxiplates plate (PerkinElmer). Transfer each of the prepared acceptor and donor reaction mixtures into a well under green light in a dark room. The plate was wrapped in aluminum foil and incubated at room temperature for at least 3 hours. The Envision system (PerkinElmer Life Sciences) was used to measure the The reading was performed using the registered trademark setting.

[0103] From the results shown in Table 1 and Figure 4, retinoids inhibited the phosphorylation of Erk1 / 2 in SH-SY5Y cells. DC527, DC540, DC528, DC526, and DC645 have been shown to have the ability to induce retinoic acid synthesis. Retinoids with both higher potency and efficacy than acids have been identified, with DC525 being the most potent. It was confirmed that they have.

[0104] 2.3 Induction of neurite outgrowth SY-SY5Y cells were cultured on 12 well plates containing acid-treated / poly-L-lysine-coated coverslips. After 24 hours, each retinoid was added at a concentration of 10 nM. Retinoids were added to the medium and the plates were incubated for 5 days. Wash the SH-SY5Y cells on the plate twice with PBS and incubate in 4% paraformaldehyde (PFA) for 20 min at room temperature. The sections were fixed and washed twice with PBS.

[0105] For immunocytochemical staining of neurites, cells on coverslips were washed three times with PBS. Immunize in blocking solution (10% donkey serum and 0.1% Triton X-100 in PBS) for 1 h at room temperature. After incubation, the cells were incubated with β-III tubulin diluted 1:1000 in blocking buffer. Cells were labeled by overnight incubation at 4°C with primary antibody (Sigma-Aldrich). After incubation, cells were washed three times with PBS containing 0.1% Triton X-100 solution (PBST). Anti-mouse monoclonal secondary antibody (1:300 in PBST, Jackson Immunoresearch) from The plates were then incubated at room temperature for 2 hours. Finally, the plates were washed three times with PBST and a final wash with PBS. , coverslips were placed on the slides and stored at 4°C.

[0106] To quantify neurite outgrowth on stained cells, use the ImageScan tool with the NeuronJ plugin. In each experiment, a Nikon Eclipse E400 fluorescence microscope was used to image each cell. Ten randomly selected images were taken from the bar slip. Each image was an 8-bit image (Neu ronJ plugin) and then use the brightness and The contrast was optimized using the NeuronJ plugin's training tool. Using a stool, individual traces were drawn for each clearly identifiable neurite. The length of the ridges was measured in pixels and converted to length in μm depending on the magnification used. The average neurite length of an image was calculated by dividing the sum of the neurite lengths by the total number of neurites per image. Ten images were measured for each coverslip and the average was calculated for the entire coverslip. Triplicate coverslips were prepared for each retinoid and concentration.

[0107] Data shown in Figure 5 indicate that some retinoids induce neurite outgrowth in SY-SY5Y cells. Furthermore, some of these compounds (DC527, D C525, DC528, DC526, DC645) showed significantly greater IL-1 expression than ATRA-treated cells. The mean neurite length was 1.01 mm.

[0108] Table 1 below shows the genomic (transcriptional) and non-genomic ( p-ERK1 / 2 activity) along with the increase in neurite outgrowth. These results are shown in Figure 5. From this figure, we can see that the compounds that showed high efficacy in both genomic and non-genomic assays were The compound showed increased induction of neurite outgrowth. This is due to the genomic activity and non- “Dual-potency” compounds that induce both genomic activities may be more effective in clinical use. This dual assay method is a powerful screening method for new therapeutic compounds. It has the potential to become a valuable learning tool.

[0109] [Table 1]

[0110] 2.4 Regulation of Alzheimer's disease-related genes To investigate the effect of retinoids on the expression of genes involved in Alzheimer's disease, Alzheimer's disease after retinoid treatment in mixed neuronal / glial cultures from rats The expression of related genes was evaluated.

[0111] Approximately 300,000 rat neuronal / glial cells were first incubated with 1 μg / mL lipopolysaccharide ( Inflammation was induced by treatment with 10 nM of Sigma-Aldrich for 6 hours. The retinoids were then treated for 24 hours. In this experiment, the retinoids were found to be the most potent in the assay to date. After treatment, RNA was extracted from the treated cells and q PCR analysis was performed.

[0112] Total RNA was prepared using the Qiagen RNeasy mini kit (CAT# 74104, Qiagen) according to the manufacturer's instructions. Briefly, cells and brain tissue samples were extracted according to the protocol of Homogenize 350 μL of β-ME mixed with 1200 μL of RLT buffer (1 mL of buffer: 10 μL of β-ME). The samples were then centrifuged at 13,000 rpm for 3 minutes. The supernatant was diluted with 70% ethanol. (CAT# E7023, Sigma-Aldrich) in a 1:1 volume ratio and then transferred to a collection tube. The sample was centrifuged at 10,000 rpm for 1 minute, and the RNA was transferred to the spin column. The antibody was bound to a ram membrane.

[0113] For on-column DNase digestion, the sample in the column was washed with 350 μL of RW1 buffer and then diluted with 10,000 The mixture was centrifuged at 400 rpm for 1 min. Then, 80 μL of DNase mixture (10 μL of DNase enzyme and 70 μL of RDD) was added. Buffer (CAT# 79254, Qiagen) was added on top of each sample. Samples were incubated at room temperature for 15 minutes. After incubation, 350 μL of RW1 buffer was added, and the samples were centrifuged at 10,000 rpm for 1 min. did.

[0114] Then, 500 μL of RPE buffer (mixed with 100% ethanol in a ratio of 1:4) was added to the sample. The samples were centrifuged at 10,000 rpm for 1 minute (this step was repeated twice). The spin column was centrifuged again at 13,000 rpm for 1 minute to dry the membrane. The pellet was removed from the collection tube and placed in a separate 1.5 mL RNase-free collection tube. The RNA was eluted by adding 100 ml of water directly to the membrane of the spin column. The samples were incubated at room temperature for 5 min. After incubation, the mixture was spun at 10,000 rpm for 1 minute.

[0115] RNA concentration was determined using a NanoDrop™ 2000c spectrophotometer (Thermo Fisher Scientific). The RNase-free water used for RNA elution was used as a blank, and 2 μL of each RNA sample was added. The instrument was calibrated using the following procedure. RNA samples were then sampled using a 100% RT-PCR kit to minimize RNA degradation. Therefore, it was stored in a freezer at -70°C.

[0116] qPCR reactions were performed using PerfeCTa SYBR Green SuperMix (CAT# 733-1246, VWR). Add 10 μL of the reaction mix to each well of a 384-well plate (CAT# 04729749001, Roche) in triplicate. Each reaction contained 2 μL of 4-fold diluted cDNA template, 2X SYBR Green mix, The solution contained 5 μL of 250 nM primer.

[0117] Primers were designed using Primer-BLAST with a melting temperature of approximately 60°C and used for qPCR. Previously, the specificity of the primers was confirmed by PCR and the PCR products were subjected to sequencing.

[0118] For all primer sets tested in qPCR, standard curves (5x of stock cDNA) A blank control was performed using the diluent. The plate was then sealed and Centrifugation was performed for 1 h to ensure that all the reagents were at the bottom of the wells. The assay was run on a Roche LightCycler 480 programmed to hold at 95°C for 5 minutes. After this, qPCR was performed with 45 cycles of 95°C for 15 s, 60°C for 15 s, and 72°C for 15 s. Melting curves were obtained by running the rate at 95°C for 5 seconds, then 58°C for 1 minute.

[0119] Results were analyzed using the delta delta CT method of the LightCycler 480 1.5 software. Expression of genes of interest was normalized to appropriate reference genes for each experiment.

[0120] The data shown in Figure 7 indicate that DC645, DC528, and DC526 downregulated inflammatory genes (Ccl5, TNFα, and Nos2). It down-regulates neuroprotective genes (AbcA1, Abcg1, Igf1, Igf2) and non-amyloid Upregulates genes in the amyloid precursor pathway (Nep, Ide, Adam10) to poison amyloid precursors These results suggest that the drug directs the drug into a pathway that does not generate potentially harmful amyloid fragments.

[0121] Example 3: Permeability assay of MDCK-MDR1: This assay involves the apical-basolateral (AB) and basolateral (AB) determination of test compounds in MDCK-MDR1 cells. Efflux, which measures permeability in the basolateral-apical (BA) direction and indicates whether a compound is actively excreted Thus, this assay is used to determine blood-brain permeability and and CNS exposure

[0122] 3.1 Experimental procedure MDCK-MDR1 cells obtained from NIH (Rockville, MD, USA) were used at passages 6-30. Cells were plated in Millipore Multiscreen Transwell plates at 3.4 × 105 cells / cm. 2 Sow seeds in thin The cells are cultured in DMEM and the medium is changed on day 3. The permeability test is performed on day 4. Assay incubation is performed at 37°C in an atmosphere of 5% CO2 and 95% relative humidity. On the day of the experiment, both the apical and basolateral sides were pre-warmed to 37°C with Hanks' Balanced Salt Solution (HBSS) of the desired pH. The surface is washed twice to prepare a monolayer. Then, to stabilize physiological parameters, Incubate the cells for 40 min with HBSS of the desired pH in both the apical and basolateral compartments. The dosing solution is prepared by diluting the test compound in assay buffer to the final concentration of the test compound. Prepare a concentration of 10 μM. Analytical standard solutions are prepared from DMSO dilutions of test compounds. and transferred to a buffer solution maintaining a DMSO concentration of 1% v / v. The buffer solution consists of supplemented HBSS pH 7.4. To assess AB permeability, remove HBSS from the apical compartment and add the test compound. The apical compartment insert was then replaced with fresh buffer (1% v Place the cells in a companion plate containing 0.1% DMSO (without DMSO) to assess the permeability of BA. Remove the HBSS from the companion plate and replace it with test compound dosing solution. Fresh Buffer (containing 1% v / v DMSO) was added to the apical compartment insert, and the companion After 60 min, the apical compartment insert and companion plate were placed on The permeability of the test compound is measured in duplicate. A compound with known permeability should be run as a control on each assay plate. Test and control compounds were assayed in a 7-point calibration set with appropriate dilutions of the samples. The initial concentration (C0) is calculated from the administered solution, and the C Experimental recoveries were calculated from the concentrations of 0 and both the apical and basolateral compartments. Calculate.

[0123] 3.2 Data analysis The permeability coefficient of each compound (P app ) is calculated using the following formula:

[0124]

number

number

[0125] 3.3.Biological research The membrane permeability of a number of compounds of formula I was measured in the MDCK-MDR1 assay described above. Permeability (P app , nm / s) and excretion rate (ER) were measured to determine the permeability of the relevant reference compound EC23. The results are summarized in Table 2.

[0126] [Table 2]

[0127] From the results shown in Table 2, it was found that some of the compounds of formula (I) exhibited permeability in the MDCK-MDR1 assay. and lack of efflux has been significantly improved, thus improving blood-brain barrier permeability. and CNS exposure are expected to improve significantly. Treatment of CNS diseases requires exposure of CNS targets to sufficiently high concentrations of therapeutic agents. It is clear that optimal CNS exposure is a critical property for therapeutics to treat these diseases. Thus, the compound of formula (I) studied is similar to compound EC23 described in the literature. In comparison, the drug-like properties are significantly improved. This improvement in CNS exposure is surprising. This is an unexpected discovery.

[0128] Example 4: Water solubility by turbidimetry Example 4.1 Experimental Procedure Test compounds (10 mM in DMSO) were serially diluted to give solutions of 0.1, 0.3, 1, and 3 mM in DMSO. Then, each test compound concentration was further diluted with a buffer solution (0.01M phosphate buffered saline, pH 7.4). Dilute 1:100 to a final DMSO concentration of 1% and final test compound concentrations of 1, 3, 10, 30, The experiment was carried out at 37°C, and each concentration was measured in seven replicate wells. The plates were incubated at 37°C for 2 hours and then the absorbance was measured at 620 nm. The solubility of the samples was measured at 0.05% solubility in the solvent control (i.e., 1% DMSO in buffer). It was estimated from the concentration of test compound that produced an increase in absorbance.

[0129] 4.2 Biological research The solubility of a number of compounds of formula (I) was measured using the turbidimetric aqueous solubility assay described above. The solubility of the compounds was measured and compared to that of a closely related 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 the solubility. Therefore, many biological properties, including absorption and target exposure, are expected to be significantly improved. This, too, is a surprising and unexpected finding.

[0132] As used herein, a condition that is alleviated by activation of a retinoic acid receptor (RAR) or describes the use of compounds in the treatment of diseases, it does not include those compounds themselves It will be understood that this disclosure is intended to

[0133] All that is disclosed in this specification (including the accompanying claims, abstract and drawings) any of the features of any method or process so disclosed. All steps are contemplated as being in accordance with the present invention, provided that at least some of such features and / or steps are mutually exclusive. The present invention can be combined in any combination except for combinations that are different from the above. Each feature disclosed in the specification (including the accompanying claims, abstract, and drawings) is expressly incorporated herein by reference. Unless expressly stated otherwise, alternative devices serving the same, equivalent or similar purpose may be used. Therefore, unless expressly stated otherwise, the disclosed Each feature is merely an example of a generic series of equivalent or similar features. The present invention is not limited to the details of the embodiments described herein. Any one of the novel features disclosed in the claims (including the scope, abstract, and drawings) or any any novel combination or step of any method or process so disclosed The present invention extends to any novel one or any novel combination of the above groups.

[0134] With respect to the use of virtually any plural and / or singular terminology herein, , those skilled in the art will readily appreciate the need to convert from plural to singular and / or abbreviated forms as appropriate to the context and / or application. can be translated from singular to plural. Various singular / plural permutations can be used to clarify. For this reason, they may be expressly set forth herein.

[0135] Generally, the term used in this specification, and particularly in the appended claims, generally means "open Those skilled in the art will recognize that the term "includes" is intended to be used interchangeably (e.g., "includes"). The term "including but not limited to" should be interpreted as "having" rather than "having The term "comprises" should be interpreted as "having at least..." and not as "including...". (The term "includes but is not limited to" should be interpreted as "including but not limited to" etc.) Introduction If a specific number of recited claims is intended, such intention shall be expressly set forth in the claim. In the absence of such a statement, it is understood by those skilled in the art that no such intention exists. It will be further understood that, for example, to aid in understanding, the following appended claims are In order to introduce the claim recitation, the terms "at least one" and "one or more" may be used. However, the use of such a phrase may be used to clarify whether the same claim includes the introductory phrase "a "or more than one" or "at least one" and an indefinite article such as "a" or "an" Even if the indefinite article "a" or "an" is used to introduce a claim, such introduction is not Any particular claim containing an inserted claim recitation may be combined with an embodiment containing only one such recitation. should not be construed to mean limiting (e.g., "a" or "an" means "at least (The term "at least one" or "one or more" should be interpreted as meaning "at least one" or "one or more"). The same applies to the use of definite articles in introductions. Even if a specific number is explicitly stated, a person skilled in the art would understand such a statement. should be interpreted to mean at least the numbers recited ( For example, the bare phrase "mentioned twice" without any other modifier means at least twice or more. (This means the above description.)

[0136] Various embodiments of the present disclosure have been described herein for purposes of illustration and are within the scope of the present disclosure. It will be understood that various modifications can be made without departing from the spirit and scope of the invention. Therefore, the various embodiments disclosed herein are not intended to be limiting. Rather, the true scope is defined by the following claims.

Claims

1. For use in the treatment of conditions or diseases that are alleviated by activation of retinoic acid receptors (RARs) The compound of formula I, in free or salt form, 【Chemistry 1】 [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 are each independently hydrogen, C 1 -C 10 alkyl, F, Br or Cl; R 7 are independently hydrogen, C 1 -C 10 Alkyl, F, Br, Cl or -OCR 9 and R 9 is H or C 1 -C 6 is alkyl; R 1 ~R 4 are each independently an alkyl group C 1 -C 10 alkyl or R 1 and R 2 Oh and / or R 3 and R 4 are linked 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 are independently H, halogen or haloalkylC 1 -C 10 and R 5 is -C(=O)R 16 OR -C(=O)OR 16 and R 16 is C 1-10 is alkyl; However, A 1 ~A 7 At least one of is N or R 12 ~R 15 At least one of the following is F, and Cl is also or Br] and its isomers.

2. A 1 From A 3 At least one of is N.

3. A 1 and A 3 The compound of claim 1 , wherein

4. A 2 is CR 7 The compound according to any one of claims 1 to 3,

5. R 7 The compound of claim 4 , wherein is hydrogen.

6. R 5 The compound according to any one of claims 1 to 5, wherein is -COOH.

7. A 4 , A 5 , A 6 The compound according to any one of claims 1 to 6, wherein at least one of is CF.

8. below: 【Chemistry 2】 2. The compound of claim 1 selected from:

9. below: 【Chemistry 3】 9. The compound of claim 8, selected from:

10. The disease or condition that is alleviated by activation of RAR is amyotrophic lateral sclerosis (ALS), Parkinson's disease, Multiple Sclerosis (MS), Alzheimer's disease, Early Alzheimer's disease, Mid-stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, memory impairment, memory deficit, geriatric cognition dementia, cognitive impairment, mild cognitive impairment, stroke, traumatic brain injury, epilepsy, and spinal cord injury The compound according to any one of claims 1 to 9, which is selected from the group consisting of nicotinamide adenine diamine esters, ...

11. For the manufacture of a medicament for use in the treatment of a disease or condition alleviated by activation of RAR.

11. A compound of formula I as defined in any one of claims 1 to 10.

12. The method comprises administering to the patient a therapeutically effective amount of a compound of formula I, A patient having a disease or condition that is alleviated by activation of RAR, as defined. Treatment method.

13. A method for treating a disease or condition that is alleviated by activation of RAR, as defined herein. The compound of formula I is optionally combined with one or more pharma- ceutically acceptable excipients, diluents or carriers. In combination with the body, a pharmaceutical composition.

14. A compound of formula I in free or salt form: 【Chemistry 4】 [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 are each independently hydrogen, C 1 -C 10 alkyl, F, Br or Cl; R 7 are independently hydrogen, C 1 -C 10 Alkyl, F, Br, Cl or -OCR 9 and R 9 is H or C 1 -C 6 is alkyl; R 1 ~R 4 are each independently an alkyl group C 1 -C 10 alkyl or R 1 and R 2 Oh and / or R 3 and R 4 are linked 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 are independently H, halogen or haloalkylC 1 -C 10 and R 5 is -C(=O)R 16 OR -C(=O)OR 16 and R 16 is C 1-10 is alkyl; However, A 1 ~A 3 At least one of is N or A 4 At least one of the following is CR 12 Is it , or A 5 CR 13 and R 12 / R 13 is a halogen. and its isomers.

15. A 1 From A 3 At least one of is N or A 4 At least one of the following is CR 12 Or Or A 5 CR 13 and R 12 / R 13 The compound of claim 14, wherein is F.

16. A 1 From A 3 16. The compound of claim 14 or claim 15, wherein at least one of is N.

17. A 1 and A 3 The compound according to any one of claims 14 to 16, wherein both of are N.

18. - The efficacy of compounds in activating RARs (E max ) performing an assay; - Compound efficacy (E) as an indicator of non-genomic activity max ) is measured using an assay Top and; In each assay, max comparing the measured value to a baseline value; - E in both assays max Compounds with values ​​above the baseline were considered for further study. and selecting for the Has therapeutic potential in the treatment of conditions or diseases that are alleviated by activation of RAR A method for screening compounds.

19. E of a compound as an indicator of non-genomic activity max The assay measures kinase phosphorylation 20. The method of claim 18, which is an assay.

20. 20. The method of claim 19, wherein the kinase phosphorylation assay is an ERK1 / 2 phosphorylation assay. method.

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