Synthetic retinoids for RAR activation

Abstract

The present invention relates to compounds of formula I: wherein A<supgt;1< / supgt> - A<supgt;7< / supgt> and R<supgt;1 to R<supgt;5 are defined herein, and the compounds are useful for treating conditions or diseases alleviated by activation of retinoic acid receptors (RAR). The present invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In aspects, the present invention relates to methods of screening compounds for therapeutic potential against a condition or disease alleviated by activation of retinoic acid receptors (RAR). Aspects of the present invention relate to novel compounds of formula I, wherein at least one of A<supgt;1 to A<supgt;3 is N, or at least one of A<supgt;4 is CR<supgt;12 or A<supgt;5 is CR<supgt;13, wherein R<supgt;12 / R<supgt;13 is halogen.

Description

[0001] The present invention relates to compounds of formula I:

[0002]

[0003] Among them A 1 -A 7 and R 1 To R 5 As defined herein, the compounds are useful for treating conditions or diseases that are alleviated by activation of retinoic acid receptors (RARs). The present invention also relates to pharmaceutical compounds comprising such compounds, and related methods of treatment. In one aspect, the present invention relates to methods for screening compounds for their therapeutic potential to treat conditions or diseases that are alleviated by activation of retinoic acid receptors (RARs). In one aspect, the present invention relates to novel compounds of formula I, wherein A 1 To A 3 At least one of them is N, or A 4 Yes CR 12 or A 5 Yes CR 13 At least one of 12 / R 13 It's a halogen.

[0004] More particularly, the invention relates to the use of compounds of formula I in the treatment of conditions and / or diseases alleviated by activation of RARs, such as neurological conditions, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and Parkinson's disease, and conditions such as spinal cord injury.

[0005] Retinoids are a family of natural or synthetic compounds that are analogs of vitamin A and its derivatives. Retinoids are essential for many cellular activities and participate as signaling molecules in controlling important biological pathways from embryogenesis to adult homeostasis, as well as in aspects of stem cell development, such as proliferation, differentiation, and apoptosis. All-trans retinoic acid (ATRA) is the most abundant endogenous retinoid and has been used as a model compound for studying retinoids.

[0006] Retinoids act on a group of nuclear receptors called retinoic acid receptors (RARs); retinoic acid receptors (RARs) are inducible ligand-activated transcription factors that regulate a variety of physiological mechanisms at the genomic level. Therefore, synthetic retinoids have been studied as potential therapeutic agents for a range of diseases and conditions mediated or possibly mediated by RARs. However, to date, known compounds have suffered from shortcomings such as low efficacy or low effectiveness, or have presented poor physical properties, including low water solubility.

[0007] Neurological conditions are diseases of the central and peripheral nervous systems, i.e., the brain, spinal cord, cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junctions, and muscles. Neurological conditions include sudden onset conditions, such as those caused by spinal cord injury or stroke; intermittent conditions, such as epilepsy; neurodegenerative conditions, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease; and stable conditions, such as cerebral palsy. In general, the group of neurological conditions tends to be chronic; many are life-threatening, and all have a significant negative impact on quality of life. It is estimated that a total of hundreds of millions of people worldwide are affected by neurological disorders (World Health Organisation, May 2016).

[0008] Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a debilitating neurological condition characterized by progressive loss of motor neurons and resulting paralysis. In Europe, it is estimated that there are 1.7 to 2.3 cases of ALS per 100,000 population per year [Logroscino et al. "Incidence of amyotrophic lateral sclerosis in Europe", J Neurol Neurosurg. Psychiatry. (2009); 81(4): 385-90], and it is estimated that about 50% of patients die within 30 months of symptom onset [Kiernan et al. "Amyotrophic lateral sclerosis." The lancet; Vol. 377(9769); (2011): 942-955]. However, despite the devastating nature of the disease, there is currently no cure; the only drugs approved for the treatment of ALS in the UK have been shown to extend patients' lives by an average of two to three months [Miller et al. "Riluzole foramyotrophic lateral sclerosis (ALS) / motor neuron disease (MND)." Cochrane Database of Systematic Reviews (2012), Issue 3. CD001447].

[0009] ALS can be both sporadic and familial, with causative mutations described in multiple genes such as C9ORF72 and SOD1. The underlying cause of ALS is the death of motor neurons that drive muscle movement, but to date the exact mechanism by which this occurs is unknown. However, several mechanisms have been implicated, including (i) excitotoxicity; the toxic effects of neurotransmitters, which cause neurons to over-fire; (ii) autophagy failure; loss of the cell's detoxification system, which removes the accumulation of insoluble molecules in the cell; (iii) neuroinflammation; the inadvertent attack of motor neurons by immune cells of the nervous system; and (iv) axonal disorganisation; the loss of interconnecting fibres between neurons that are essential for their communication. Therefore, any therapeutic agent for the treatment of ALS would ideally exhibit multiple polypharmocological properties.

[0010] Therefore, there is an urgent and unmet need for new therapeutic agents for the treatment of neurological conditions such as neurodegenerative disorders, including ALS and Alzheimer's disease. Compounds that exhibit good physical properties, such as good aqueous solubility, would be particularly useful.

[0011] While therapeutics that can cure or prevent ALS, Alzheimer's disease, or related disorders represent the ultimate goal of most pharmaceutical research programs, more realistically, therapeutics that can delay the onset of disease, slow or stop the progression of disease would represent a significant advance. Methods for screening compounds for potential therapeutic use would also be very beneficial. SUMMARY OF THE INVENTION

[0013] Thus, the present invention relates to compounds for use in treating conditions or diseases alleviated by activation of retinoic acid receptors. In aspects, this includes genomic activation. In aspects of the invention, the compounds activate both genomic and non-genomic pathways.

[0014] In aspects, the invention relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in treating conditions or diseases alleviated by activation of retinoic acid receptors.

[0015] Conditions or diseases alleviated by activation of retinoic acid receptors include conditions mediated by RARs, such as neurodegenerative disorders, as well as conditions alleviated by activation of RARs, such as stroke, traumatic brain injury, epilepsy, spinal cord injury, and the like.

[0016] In one aspect, the invention relates to methods of screening compounds for therapeutic potential to treat a condition or disease that is alleviated by activation of a retinoic acid receptor.

[0017] Aspects of the invention relate to the novel compounds themselves.

[0018] Further aspects and embodiments of the invention are defined herein and described in more detail below.

[0019] According to a first aspect of the present invention, there is provided a compound of formula I:

[0020]

[0021] in:

[0022] A 1 Is N or CR 6 ;

[0023] A 2 Is N or CR 7 ;

[0024] A 3 Is N or CR 8 ;

[0025] R 6 and R 8 are independently hydrogen, C 1 -C 10 Alkyl, F, Br or Cl;

[0026] R 7 are independently hydrogen, C 1 -C 10 Alkyl, F, Br, Cl or -OCR 9 , where R 9 Is H or C 1 -C 6 alkyl;

[0027] R 1 To R 4 Each is independently C 1 -C 10 Alkyl, or R 1 and R 2 and / or R 3 and R 4 connected to form a 3-membered ring;

[0028] A 4 Is N or CR 12 ;

[0029] A 5 Is N or CR 13 ;

[0030] A 6 Is N or CR 14 ;

[0031] A 7 Is N or CR 15 ;

[0032] Each R 12 To R 15 are independently H, halogen or C 1 -C 10 haloalkyl; and

[0033] R 5 Yes-C(=O)R 16 OR -C(=O)OR 16 , where R 16 Is H or C 1-10 alkyl;

[0034] The condition is A 1 To A 7 At least one of them is N, or R12 To R 15 At least one of is F, Cl or Br;

[0035] and its isomers;

[0036] in free form or in salt form;

[0037] For the treatment of conditions or diseases alleviated by activation of retinoic acid receptors (RARs).

[0038] In the compound of formula I, A 1 To A 7 At least one of them is N, or R 12 To R 15 At least one of is F, Cl or Br.

[0039] As used herein, the term "alkyl" refers to a fully saturated, branched, unbranched or cyclic hydrocarbon moiety, i.e., a primary, secondary or tertiary alkyl, or, where appropriate, a cycloalkyl or cycloalkyl substituted alkyl. In the absence of additional indications, the alkyl group comprises 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

[0040] As used herein, the term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.

[0041] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom.

[0042] Conditions or diseases alleviated by activation of retinoic acid receptors include conditions mediated by RARs, such as neurodegenerative disorders, as well as conditions alleviated by activation of RARs, such as stroke, traumatic brain injury, epilepsy, spinal cord injury, and the like.

[0043] RAR-mediated conditions include neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), neuromuscular diseases, Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, early Alzheimer's disease, mid-stage Alzheimer's disease, late Alzheimer's disease, cognitive disorder, memory impairment, memory deficit, Alzheimer's disease, vascular dementia, cognitive impairment, and mild cognitive impairment.

[0044] Thus, the condition or disease alleviated by activating RARs can be selected from amyotrophic lateral sclerosis (ALS), neuromuscular disease, Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, early Alzheimer's disease, mid-stage Alzheimer's disease, late Alzheimer's disease, cognitive impairment, memory impairment, memory deficit, Alzheimer's disease, vascular dementia, cognitive impairment, mild cognitive impairment, stroke, traumatic brain injury, epilepsy and spinal cord injury.

[0045] The condition may be a neurological condition. In embodiments, the neurological condition may be a neurodegenerative condition, such as ALS, Parkinson's disease, or Alzheimer's disease.

[0046] In an embodiment, R 5 It is -COOH.

[0047] In an embodiment, A 1 To A 3 At least one of them is N, or A 4 Yes CR 12 or A 5 Yes CR 13 At least one of 12 / R 13 is a halogen. 12 / R 13 Preferably F.

[0048] In an embodiment, A 1 To A 3 At least one of is N. In an embodiment, A 1 and A 3 Both are N.

[0049] In an embodiment, A 2 Yes CR 7 , where R 7 It's H.

[0050] In an embodiment, A 4 , A 5 or A 6 At least one of them is CF.

[0051] In this embodiment, A 4 Can be CF. Optionally, A 5 It can be CF.

[0052] In an embodiment, A 5 and A 6 It's CF.

[0053] In an embodiment, A 4 It is CCl.

[0054] In an embodiment, A 1 and A 3 Both are N, and A 2 Yes CR 7 , where R 7 is H, as represented by Formula IA:

[0055]

[0056] Preferably, in Formula IA, R 5 It is -COOH.

[0057] Alternatively, in an embodiment, in Formula I, A 4 To A 7 At least one of them is N.

[0058] In an embodiment, in Formula I, A 4 It is N.

[0059] In an embodiment, in Formula I, A 4 or A 5 It's CF.

[0060] In general, compounds of Formula I have a hydrophobic region, a linker region (-C≡C-), and a polar region, as shown below:

[0061]

[0062] The present inventors have advantageously discovered that compounds of formula I in which one nitrogen atom or preferably two nitrogen atoms are incorporated into a conjugated ring in the hydrophobic region; or in which a nitrogen atom is incorporated into a conjugated ring in the polar region and / or the conjugated ring in the polar region is halogenated (or preferably fluorinated), can be surprisingly beneficial in treating diseases or conditions alleviated by activating RARs.

[0063] Exemplary compounds of formula I that may be mentioned include compounds selected from the group consisting of:

[0064]

[0065] In certain embodiments, the compound of formula I may be selected from:

[0066]

[0067] In an embodiment, the compound of Formula I may be selected from:

[0068] In an embodiment, the compound of Formula I may be selected from:

[0069]

[0070] In another aspect of the invention there is provided the use of a compound of formula I as defined herein in the manufacture of a medicament for the treatment of a disease or condition alleviated by activation of RAR.

[0071] In another aspect of the invention, there is provided a method of treating a patient suffering from a disease or condition which is alleviated by activation of RAR, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, wherein the compound of formula I is as defined herein.

[0072] In another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound of formula I as defined herein, optionally in combination with one or more pharmaceutically acceptable excipients, diluents or carriers, for treating a disease or condition alleviated by activating RAR. The composition may optionally comprise one or more additional therapeutic agents.

[0073] The term "therapeutically effective" amount or "effective amount" refers to an amount of the compound or composition of the present invention that is effective in producing the desired therapeutic effect, improvement effect, inhibition effect or prevention effect.

[0074] The term "pharmaceutical composition" refers to a composition suitable for administration to a patient. Therefore, the term "pharmaceutical composition" refers to a composition comprising a compound of the present invention or a mixture thereof, or a salt, solvate, prodrug, isomer or tautomer thereof, optionally in combination with one or more pharmaceutically acceptable excipients, carriers or diluents. The term "pharmaceutical composition" is also intended to encompass bulk compositions (i.e., in a form that has not yet been formed into a separate dosage unit) and separate dosage units. Such separate dosage units include tablets, pills, caplets, ampoules, etc.

[0075] Those skilled in the art will recognize those situations in which the compounds of the present invention can be converted into prodrugs and / or solvates. The term "prodrug" refers to a compound (e.g., a drug precursor) that is converted in vivo to produce a compound of the present invention or a pharmaceutically acceptable salt, hydrate, or solvate of the compound. The conversion can occur by a variety of mechanisms (e.g., by metabolic or chemical processes), such as, for example, by hydrolysis in the blood.

[0076] The compounds of the present invention may be unsolvated or may be solvated with pharmaceutically acceptable solvents such as water, ethanol and the like. For example, it should be understood that solvates may be capable of separation, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solvates" include both solution phases and separable solvates. Suitable solvates include, but are not limited to, ethanolates, methanolates, hydrates, etc.

[0077] Unless otherwise indicated, the compounds used in the present invention include their salts, and reference to the compounds of the present invention is intended to include reference to their salts. Suitable salts include, for example, acid salts formed with inorganic acids and / or organic acids, basic salts formed with inorganic bases and / or organic bases, and zwitterions ("inner salts") that can be formed and included in the term "salt" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts may be useful in some cases. Exemplary acid addition salts that may be useful include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthylsulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also known as tosylate), and similar acid addition salts. Exemplary basic salts that may be useful include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamine, tert-butylamine, and salts with amino acids such as arginine, lysine, and similar basic salts. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, and butyl), dialkyl sulfates (e.g., sulfates of dimethyl, diethyl, and dibutyl), long chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, and stearyl), arylalkyl halides (e.g., bromides of benzyl and phenethyl), and others.

[0078] The compounds used in the present invention include pharmaceutically acceptable esters thereof and may include carboxylic acid esters obtained by esterification of a hydroxyl group, wherein the non-carbonyl portion of the carboxylic acid portion of the ester group is selected from (1) linear or branched alkyl (e.g., acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., optionally substituted by, for example, halogen, C 1-4 Alkyl or C 1-4(e.g., phenyl substituted with alkyl or amino groups); (2) sulfonates such as alkylsulfonyl or aralkylsulfonyl (e.g., methylsulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonates; and (5) mono-, di-, or tri-phosphates.

[0079] Polymorphic forms of the compounds of the invention, as well as polymorphic forms of the salts, solvates, esters and prodrugs of the compounds of the invention, are intended to be included in the present invention.

[0080] Suitable dosages for administering a compound of the invention to a patient can be determined by one skilled in the art, such as by an attending physician, pharmacist or other technician, and may vary according to factors such as the patient's weight, health, age, frequency of administration, mode of administration, the presence of any other active ingredients, and the conditions under which the compound is administered.

[0081] Examples of excipients, diluents and carriers include buffers, and fillers and extenders such as starch, cellulose, sugar, mannitol and silicic derivatives. Binding agents may also be included. Adjuvants may also be included.

[0082] 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 or sequentially.

[0083] The compositions can be administered by a variety of routes including oral, parenteral (including subcutaneous, intravenous, intramuscular and intraperitoneal), rectal, cutaneous, transdermal, intrathoracic, intrapulmonary, mucosal, intraocular and intranasal.

[0084] Suitable dosage forms will be recognized by those skilled in the art and include tablets, capsules, solutions, suspensions, powders, aerosols, ampoules, pre-filled syringes, small volume infusion containers or multiple dose containers, creams, emulsions, gels, dispersions, microemulsions, lotions, impregnated pads, ointments, eye drops, nose drops, lozenges, etc., among others.

[0085] Aspects of the present invention relate to compounds of formula I as described hereinbefore, wherein A 1 To A 3 At least one of them is N, or A 4 Yes CR 12 or A 5 Yes CR 13 At least one of 12 / R13 is a halogen. Such aspects relate to novel compounds per se.

[0086] R 12 / R 13 Preferably F.

[0087] In an embodiment, A 1 To A 3 At least one of them is N.

[0088] In an embodiment, A 1 and A 3 Both are N.

[0089] In an embodiment, the novel compound is selected from:

[0090]

[0091] In an aspect of the invention, there is provided a method for screening compounds for therapeutic potential to treat a condition or disease that is alleviated by activation of a retinoic acid receptor, the method comprising:

[0092] - To determine the potency of the compound in activating RAR (E 最大 ) as an indicator of genomic activity;

[0093] - To determine the efficacy of the compound (E 最大 ) as an indicator of non-genomic activity;

[0094] For each determination, E 最大 compared with baseline values; and,

[0095] - Select the E with a value above baseline in both assays 最大 Those compounds were used for further studies.

[0096] Since the discovery of RAR as a member of the nuclear receptor family of transcriptional regulators (Petkovich M et al. "A human retinoic acid receptor which belongs to the family of nuclear receptors"; Nature (1987): 330, pp. 444-450], emphasis on the function of retinoids has been on their control of gene expression. On this basis, synthetic retinoids have been produced and their genome activation properties have been studied.

[0097] However, surprisingly, the inventors have determined that the genomic and non-genomic mechanisms of retinoic acid (RA) are independently regulated relative to the engagement of ligand-dependent RARs. "Dual-efficacy", i.e., activity in both non-genomic and genomic assays, has been found to be closely associated with the promotion of neurite outgrowth and increased cell number and survival, suggesting that these dual-acting compounds are important as potential therapeutic agents.

[0098] In an embodiment, determining the E of a compound 最大 An assay that serves as an indicator of non-genomic activity is the kinase phosphorylation assay.

[0099] In embodiments, the kinase phosphorylation assay is an ERK1 / 2 phosphorylation assay.

[0100] In the embodiment, the baseline value as an indicator of genomic activity is an E of 170.1 最大 .

[0101] In the embodiment, the baseline value as an indicator of non-genomic activity is an E of 48.55. 最大 .

[0102] In embodiments, one or both of the baseline values ​​may be determined using a reference compound such as ATRA. Example:

[0103] The present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0104] FIG1 schematically illustrates the synthesis of a coupling partner;

[0105] Figure 2 The synthesis of exemplary retinoid compounds DC526, DC528, DC641, and DC645 are illustrated;

[0106] Figure 3 Graphs show the genomic activity of retinoids as indicated by using the X-Gal assay;

[0107] Figure 4 The nongenomic activities of retinoids are shown, as indicated by their ability to induce phosphorylation of ERK1 / 2;

[0108] Figure 5 The graph shows the average neurite length of differentiated SH-SY5Y cells after treatment with retinoids;

[0109] Figure 6 It was shown that retinoids induce genomic activity [(transcriptional activity: E 最大(potency)] and non-genomic activity [ERK1 / 2 activity: E 最大 (potency)] relationship between the potency of both and the induction of neurite outgrowth (fold increase at 10 μM), with the highlighted retinoids showing both activities;

[0110] Figure 7 Data are shown regarding transcriptional regulation of Alzheimer's disease-associated genes in rat mixed primary neuronal / glial cultures following treatment with retinoids;

[0111] Figure 8 compares the activity of an exemplary retinoid DC645 with that of ATRA and EC23. Figure 8(a) compares the genomic activity of retinoids by means of an X-Gal assay; Figure 8(b) compares the non-genomic activity of retinoids by measuring their ability to induce ERK 1 / 2 phosphorylation; Figure 8(c) compares the ability of compounds to induce neurite outgrowth in SH-SY5Y cells; and Figure 8(d) shows the regulation of Alzheimer's disease-related genes by retinoid compounds.

[0112] Example 1: Synthesis of compounds of exemplary formula I:

[0113] 1.1 Synthesis of coupling partners

[0114] 1.1.1. Synthesis of 6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene, 1

[0115] The synthesis of 6-iodo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (1) is schematically shown in FIG1(a). 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (11.46 g, 60.9 mmol) and 1 2 (7.77 g, 30.6 mmol) and H 5 IO 6 (3.49 g, 15.3 mmol) was added to glacial acetic acid (gl.ethanoic acid) / acetic acid (AcOH) (250 mL), H 2 O (25 mL) and H 2 SO 4 (13 mL) and the resulting solution was stirred at 70°C for 6 hours. The solution was cooled and extracted with ethyl ethanoate / ethyl acetate (EtOAc). The organics were washed with saturated Na 2 S 2 O 3 , H 2 O and brine, dried (MgSO 4) and evaporated to give a crude orange oil (17 g). It was purified by dry column vacuum chromatography (eluting with heptane) 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); 13C NMR (176 MHz, CDCl3) δ 31.9, 32.0, 34.4, 34.6, 35.0, 35.1, 91.3, 128.9, 134.8, 135.8, 144.8, 147.9; all other data are consistent with the literature (VB Christie et al., Org. Biomol. Chem., 2008, 6, 3497-3507).

[0116] 1.1.2 Synthesis of 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene, 3

[0117] The synthesis of 6-ethynyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (3) is schematically shown in FIG1( b ). 3 N) (150 mL) by using N 2 The bubbling was continued for 1 h to degas. 2 Compound 1 (10.0 g, 31.8 mmol), Pd(PPh 3 ) 2 Cl 2 (0.223 g, 0.32 mmol), CuI (0.061 g, 0.32 mmol) and trimethylsilylacetylene (5.29 mL, 38.2 mmol) were added and the resulting slurry was stirred at RT for 20 h. The mixture was diluted with heptane and passed through Celite / SiO 2 (eluted with heptane) and the resulting solution was evaporated to give a crude brown oil (10.36 g). It was filtered through SiO 2 Chromatography (100% heptane) was performed to give compound 2 (9.99 g, >100%) as a yellow oil. Compound 2 (9.99 g, 35.1 mmol) was dissolved in methanol (MeOH) / methyl tert-butyl ether (MTBE) (1:1, 160 mL). Sodium hydroxide (NaOH) (0.96 g, 24.0 mmol) was then added in H 2 O (15 mL), and the resulting solution was stirred at RT for 16 h. The solution was diluted with MTBE and washed with H 2 O and brine, dried (MgSO4 ) and evaporated to give a crude yellow oil (6.6 g). It was filtered through SiO 2 Purification by chromatography (100% heptane) gave compound 3 as a colorless oil which slowly solidified (6.06 g, 90% over two steps): all data were consistent with the literature (VB Christie et al., Org. Biomol. Chem., 2008, 6, 3497-3507).

[0118] 1.1.3 Synthesis of 4-bromo-3-fluorobenzoate, 4

[0119] The synthesis of 4-bromo-3-fluorobenzoate (4) is schematically shown in Figure 1(c). 4-Bromo-2-fluorobenzoic acid (25.0 g, 114.2 mmol) was suspended in MeOH (250 mL) and concentrated H 2 SO 4 (4 mL) and the resulting solution was stirred at reflux overnight. The clear solution was then cooled and H 2 O (100 mL), after which a white precipitate formed. It was filtered and washed with H 2 O and dried to give a crude white solid. It was recrystallized from heptane to give compound 4 (21.34 g, 80%) as a colorless crystalline solid: 1 H NMR (600 MHz, CDCl 3 )δ3.91(s,3H),7.31-7.36(m,2H),7.80(t,J=8.0Hz,1H); 13 C NMR (151 MHz, CDCl 3 )δ52.4,117.6(d,J=9.9Hz),120.6(d,J=25.6Hz),127.5(d,J=3.9Hz),127.9(d,J=9.6Hz),133.1,161.56(d,J=264.9Hz),164.1(d,J=3.9Hz); 19 F NMR (376 MHz, CDCl 3 )δ-106.6; IR(ATR)v 最大 / cm -1 3104w, 3086w, 2961w, 1712s, 1599s, 1571m, 1403m, 1215s, 882s; MS (ASAP): m / z=233.0[M+H] + ; HRMS (ASAP) for C 8 H 7 O 2 BrF[M+H] +Calculated value: 232.9613, found value: 232.9621 (Zimmerman et al., J. Med. Chem. 2014, 57: 2334-2356).

[0120] 1.1.4 Synthesis of methyl 4-ethynyl-3-fluorobenzoate, 6

[0121] The synthesis of methyl 4-ethynyl-3-fluorobenzoate (6) is schematically shown in Figure 1(d). 2 Bubbling continued for 1 h to remove Et 3 N (120 mL) was used for degassing. 2 Compound 4 (5.0 g, 21.45 mmol), trimethylsilylacetylene (3.56 mL, 25.74 mmol), Pd(PPh 3 )Cl 2 (301 mg, 0.429 mmol) and CuI (82 mg, 0.429 mmol), and the resulting suspension was stirred at room temperature for 16 hours. The suspension was diluted with heptane and / SiO 2 , and the extract was evaporated to give a crude oil (6.44 g). It was purified by dry column vacuum chromatography (100% heptane, to 9:1 heptane / EtoAc), and the isolated product was further purified by Kugelrohr distillation (150° C., 7.4 torr) to give compound 5 (5.58 g, >100%) as a yellow oil, which was directly transported to the next step: 1 H NMR (400 MHz, CDCl 3 )δ0.27 (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). Compound 5 (5.58 g, 22.3 mmol) and K were added to a MeOH:MTBE solution (5:50, 55 mL). 2 CO 3 (6.16 g, 44.6 mmol), and the resulting mixture was heated at room temperature under N 2 Stirring was continued for 6 hours. The solution was then diluted with EtOAc and washed with saturated NH 4 Cl, H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude solid (3.6 g). It was purified by dry column vacuum chromatography (100% heptane to 8:2 heptane / EtOAc) to give compound 6 as a white solid (3.07 g, 80% over two steps): 1H NMR (600 MHz, CDCl 3 )δ3.45(s,1H),3.92(s,3H),7.53(dd,J=8.0,6.8Hz,1H),7.72(dd,J=9.6,1.6Hz,1H),7.77(dd,J=8.0,1.6Hz,1H); 13 C NMR (151 MHz, CDCl 3 )δ52.5,76.3,85.1(d,J=3.3Hz),115.3(d,J=16.0Hz),116.5(d,J=22.9Hz),124.9(d,J=3 .7Hz), 132.2 (d, J = 7.4Hz), 133.9 (d, J = 1.3Hz), 162.9 (d, J = 253.5Hz), 165.3 (d, J = 2.7Hz); 19 F NMR (376 MHz, CDCl 3 )δ-109.3; IR(ATR)v 最大 / cm -1 3238m, 3090w, 2967w, 2111w, 1710s, 1564m, 1501m, 1440m, 1308s, 1212s, 766s; MS (ASAP) m / z=179.0[M+H] + ; HRMS (ASAP) for C 10 H 8 O 2 F[M+H] + Calculated value: 179.0508, measured value: 179.0495.

[0122] 1.1.5 Synthesis of methyl 5-bromopyridine-2-carboxylate, 8

[0123] The synthesis of methyl 5-bromopyridine-2-carboxylate (8) is schematically shown in Figure 1(e).

[0124] 5-Bromopyridine-2-carboxylic acid (20.0 g, 99.0 mmol) was suspended in MeOH (150 ml), and then concentrated H 2 SO 4 (5 mL) and the resulting solution was stirred at reflux for 6 h. The solution was cooled, diluted with EtOAc, and washed with H 2 O and brine (50 mL), and dried (MgSO 4) and evaporated to give a crude colorless solid. It was distilled in vacuo using Kugelrohr (200° C., 7.4 torr), and the resulting white solid was further recrystallized from heptane / MeOH (10:1) to give Compound 8 (17.21 g, 80%) as a white solid: 1 H NMR (700 MHz, CDCl 3 )δ3.90(s,4H),7.86-7.93(m,3H),8.68(d,J=2.0Hz,1H); 13 C NMR (176 MHz, CDCl 3 )δ52.8,124.8,126.0,139.5,146.0,150.7,164.7;v 最大 / cm -1 3059w, 3008w, 2957w, 1710s, 1571w, 1558w, 1436m, 1305s, 1131s, 696s; MS (ASAP): m / z=216.0[M+H] + ; HRMS (ASAP) for C 10 H 9 NOI[M+H] + Calculated value: 215.9660, found value: 215.9664 (Tung et al., Eur. J. Med. Chem. 2017, 126, 1011-1020).

[0125] 1.1.6 Synthesis of 2,2,5,5-Tetramethyladipic acid, 9

[0126] The synthesis of 2,2,5,5-tetramethyladipic acid (9) is schematically shown in Figure 1(f). H 2 O (600 mL), concentrated H 2 SO 4 (7.5 mL) was added followed by pivalic acid (51.0 g, 500 mmol) and the resulting slurry was cooled to 0 °C. Over 15 min, H 2 O 2 (30%, 43 mL) and FeSO 4 7H 2 O (139.0 g, 500 mmol) in H 2 O (288 mL) and concentrated H 2 SO 4(27.5mL). After the addition was complete, the suspension was stirred for an additional 15min and the solution was then concentrated to about 250mL. The precipitated solid was filtered and then further dried under vacuum using a rotary evaporator to give a crude residue. It was recrystallized from AcOH to give 9 (3.39g, 3%) as a colorless crystalline solid: 1 H NMR (400 MHz, DMSO-d 6 )δ1.06(s,12H),1.37(s,4H),12.05(s,2H).

[0127] 1.1.7 Synthesis of 1,6-diethyl 2,2,5,5-tetramethyl adipate, 10

[0128] The synthesis of 1,6-diethyl 2,2,5,5-tetramethyl adipate (10) is schematically shown in Figure 1(g). To a solution of 9 (3.39 g, 16.76 mmol) in EtOH (40 mL) was added concentrated H 2 SO 4 (2 mL) and the resulting suspension was stirred at reflux for 16 h. The solution was cooled and the solvent was evaporated to give a crude residue which was dissolved in EtOAc. The organics were washed with saturated NaHCO 3 , H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude oil (3.8 g). It was passed through SiO 2 Purification by chromatography (95:5, heptane / EtOAc) gave 10 (3.41 g, 79%) as a colorless oil: 1 H NMR (700 MHz, CDCl 3 )δ1.14(s,11H),1.24(t,J=7.1Hz,6H),4.11(q,J=7.1Hz,4H); 13 C NMR (176 MHz, CDCl 3 )δ14.2,25.0,35.5,41.8,60.2,177.7; IR(ATR)v 最大 / cm -1 2978m, 2934w, 2880w, 1726s, 1475m, 1308m, 1176s, 1110m, 771w; MS (ES): m / z=259.5[M+H] + .

[0129] 1.1.8 Trimethyl ({3,3,6,6-tetramethyl-2-[(trimethylsilyl)oxy]cyclohex-1-en-1-yl}oxy Synthesis of silane 11

[0130] The synthesis of trimethyl({3,3,6,6-tetramethyl-2-[(trimethylsilyl)oxy]cyclohex-1-en-1-yl}oxy)silane 11 is schematically shown in FIG1(h). 2 Under N 2 0, sodium (1.20 g, 52.1 mmol) was added to anhydrous toluene (50 mL), and the resulting mixture was heated to reflux until the sodium melted. The flask was then removed from the heat, and 10 (2.69 g, 10.41 mmol) and chlorotrimethylsilane (6.72 mL, 53.0 mmol) were then added, and the resulting suspension was then stirred at reflux overnight. The purple suspension was then cooled and heated at N 2 0. 2 The stream was filtered, washed with toluene and then with tetrahydrofuran (THF). The filtrate was then evaporated to give a crude light yellow oil (3.2 g), which was purified by Kugelrohr distillation (120° C., 3.6 Torr) to give 11 (2.64 g, 81%) as a clear oil: 1 H NMR (400 MHz, CDCl 3 )δ0.19 (s, 18H), 1.03 (s, 12H), 1.44 (s, 4H). All other data are consistent with the literature (Kikuchi et al. J. Med. Chem. 2000; 43: pp. 409-419).

[0131] 1.1.9 Synthesis of 3,3,6,6-tetramethylcyclohexane-1,2-dione, 12

[0132] The synthesis of 3,3,6,6-tetramethylcyclohexane-1,2-dione is schematically shown in Figure 1(i). Bromine (0.42 mL, 8.2 mmol) was added dropwise to a solution of 11 (2.6 g, 8.2 mmol) in dichloromethane (DCM) over 5 min. The resulting yellow solution was stirred at RT for 1 h, then diluted with DCM and washed with saturated Na 2 S 2 O 3 Processing, then use H 2 O washing and drying (MgSO 4 ) and evaporated to give a crude yellow solid (1.5 g). It was purified by recrystallization from heptane to give 12 (1.07 g, 78%) as a yellow crystalline solid: 1 H NMR (700 MHz, CDCl 3 )δ1.14(s,4H),1.85(s,12H); 13 C NMR (176 MHz, CDCl 3 )δ22.9,34.7,48.6,207.3; IR(ATR)v 最大 / cm -12973m, 2940w, 2870w, 1706s, 1599w, 1459m, 1372m, 1102m, 931m; MS (ES): m / z=169.3[M+H] + All other data are consistent with the literature (Kikuchi et al. J. Med. Chem. 2000; 43: pp. 409-419).

[0133] 1.1.10 Synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carboxylic acid methyl ester, 13

[0134] The synthesis of methyl 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carboxylate 13 is schematically shown in Figure 1(j). 12 (0.80 g, 4.76 mmol) and DL-2,3-diaminopropionic acid hydrochloride (0.67 g, 4.76 mmol) were combined in MeOH (30 mL). NaOH (0.76 g, 19.04 mmol) was added and the resulting mixture was stirred at reflux for 24 h. The solution was then cooled to 0 °C and H was carefully added. 2 SO 4 , and the solution was stirred at reflux for another 6 h. The solution was cooled, and the solvent was evaporated to give a crude residue which was dissolved with EtOAc and washed with saturated NaHCO 3 , H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude yellow oil (0.9 g). It was filtered through SiO 2 Purification by chromatography (95:5, heptane / EtOAc) gave 13 (0.633 g, 54%) as a colorless oil: 1 H NMR (400 MHz, CDCl 3 )δ1.33&1.36(s,12H),1.81(s,4H),3.98(s,3H),9.00(s,1H). All other data are consistent with the literature (Kikuchi et al. J. Med. Chem. 2000;43:pp.409-419).

[0135] 1.1.11 Synthesis of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)methanol, 14

[0136] The synthesis of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)methanol 14 is schematically shown in FIG. 1( k ). To a solution of 13 (5.09 g, 20.5 mmol) in THF (80 mL) was added NaBH 4(2.33 g, 61.5 mmol). The solution was then heated to reflux, after which MeOH (16 mL) was slowly added over 1 h. The resulting solution was then stirred at reflux overnight. The solution was cooled, quenched with 1 M HCl, and the solvent was then evaporated. The residue was dissolved in DCM, washed with water, dried (MgSO 4 ) and evaporated to give a crude yellow oil (4 g). It was filtered through SiO 2 Purification by chromatography (8:2, heptane / EtOAc as eluent) gave 14 (3.96 g, 88%) as a colorless oil: 1 H NMR (400 MHz, CDCl 3 )δ1.33&1.36(s,12H),1.80(s,4H),3.50(br,1H),4.75(s,2H),8.32(s,1H); all other data are consistent with the literature (Kikuchi et al. J. Med. Chem. 2000;43:pp.409-419).

[0137] 1.1.12 Synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde, 15

[0138] The synthesis of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline-2-carbaldehyde 15 is schematically shown in Figure 1(l). 2 Oxalyl chloride (2.28 mL, 26.96 mmol) was added to anhydrous DCM (100 mL) at 4 °C. The resulting solution was cooled to -78 °C before DMSO (3.83 mL, 53.92 mmol) was added dropwise to keep the temperature below -60 °C. The solution was stirred for 15 min before 14 (3.96 g, 17.97 mmol in 20 mL) was added dropwise as a solution in anhydrous DCM to keep the temperature below -60 °C. The solution was stirred for another 15 min before Et 3 N (18.03 mL, 129.38 mmol). The solution was then stirred for 10 min and then allowed to reach room temperature (RT) over 30 min. H 2 O, and the resulting mixture was diluted with DCM and washed with H 2 O washing and drying (MgSO 4 ) and evaporated to give a crude oil (4 g). It was purified by dry column vacuum chromatography (DCVC) (heptane to 9:1 heptane / EtOAc) to give 15 (3.39 g, 86%) as a colorless oil that slowly crystallized: 1 H NMR (700 MHz, CDCl 3)δ1.35&1.37(s,12H),1.83(s,4H),8.90(s,1H),10.08(s,1H); 13 C NMR (176 MHz, CDCl 3 )δ29.7,29.7,33.8,33.8,37.4,37.9,139.8,144.2,159.0,163.7,193.4; IR(ATR)v 最大 / cm -1 2979m, 2964m, 2928m, 2862m, 2823w, 1707s, 1553m, 1457m, 1126s, 1078s, 737s; MS (ES): m / z=219.3[M+H] + ; HRMS (ES) for C 13 H 19 ON 2 [M+H] + Calculated value: 216.1497, measured value: 216.1503.

[0139] 1.1.13 Synthesis of dimethyl 1-diazo-2-oxopropylphosphonate, 16

[0140] The synthesis of dimethyl 1-diazo-2-oxopropylphosphonate 16 is illustrated in Figure 1 (m). Under vigorous stirring, NaH (60% dispersion in mineral oil, 1.20 g, 30.00 mmol) was added in portions to a solution of dimethyl 2-oxopropylphosphonate (4.49 mL, 32.5 mmol) in anhydrous toluene (30 mL) at 0°C. After gas evolution ceased, 4-acetamidobenzenesulfonyl azide (7.21 g, 30.0 mmol) was added dropwise as a solution in anhydrous THF (10 mL). The resulting suspension was stirred at RT for 16 h, after which heptane was added and the suspension was filtered through a column chromatography column chromatography elution ... Filter and rinse with MTBE. The organic extract was then evaporated to give a crude oil (5 g) which was purified by SiO 2 Purification by chromatography (1:1, heptane / EtOAc) gave dimethyl 1-diazo-2-oxopropylphosphonate (3.14 g, 54%) as a light yellow oil: 1 H NMR (400 MHz, CDCl 3 )δ 2.24 (s, 3H), 3.82 (d, J=11.9 Hz, 6H), all other data are consistent with the literature (Pietruszka et al. Synthesis, 2006, pp. 4266-4268).

[0141] 1.1.14 Synthesis of 2-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline, 17

[0142] The synthesis of 2-ethynyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxaline 17 is schematically shown in Figure 1(n). 2 To a solution of 15 (1.18 g, 5.40 mmol) in anhydrous MeOH (50 mL) was added K 2 CO 3 (1.49 g, 10.80 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (0.98 mL, 6.48 mmol), and the resulting suspension was stirred at RT for 16 h. The solution was diluted with EtOAc and washed with 5% NaHCO 3 , H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude orange oil (0.4 g). It was filtered through SiO 2 Purification by chromatography (95:5, heptane / EtOAc as eluent) gave 17 (0.84 g, 73%) as a colorless oil which slowly crystallized: 1 H NMR (700 MHz, CDCl 3 )δ1.30&1.31(s,12H),1.77(s,4H),3.22(s,1H),8.45(s,1H); 13 C NMR (176 MHz, CDCl 3 )δ29.6,29.7,33.8,34.0,37.2,37.3,79.0,81.0,135.4,144.5,158.1,158.6; IR(ATR)v 最大 / cm -1 3279s, 2986w, 2945m, 2917m, 2863w, 2110w, 1519w, 1470m, 1459m, 1274m, 1078s, 674s; MS (ES): m / z=215.3[M+H] + ; HRMS (ES) for C 14 H 19 N 2 [M+H] + Calculated value: 215.1548, measured value: 215.1548.

[0143] 1.2 Synthesis of 3-fluoro-4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethynyl]benzoic acid, DC526

[0144] The synthesis of the exemplary compound DC526 was Figure 2 Medium picture.

[0145] By using N2 Bubbling continued for 1 hour to 3 N (80 mL) was used for degassing. 2 Compound 1 (0.80 g, 2.55 mmol), compound 6 (0.54 g, 3.05 mmol), Pd(PPh 3 )Cl 2 (179 mg, 0.255 mmol) and CuI (49 mg, 0.255 mmol), and the resulting suspension was stirred at room temperature for 72 hours. The suspension was diluted with MTBE and / SiO 2 , and the extract was evaporated to give a crude solid (1.1 g). It was purified by drying column vacuum chromatography (100% heptane to 95:5 heptane / EtOAc) to give compound 7 (0.82 g, 88%) as a colorless oil, which was slowly crystallized and was directly transported to the next step. Compound 7 (0.80 g, 2.20 mmol) was dissolved in THF (40 mL), 20% NaOH (3 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, and washed with H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude white solid which was recrystallized from acetonitrile (MeCN) to give DC526 (0.60 g, 77%) as a colorless crystalline solid: 1 H NMR (600 MHz, DMSO-d 6 )1.24&1.26(s,12H),1.64(s,4H),7.32(dd,J=8.1,1.8Hz,1H),7.40(d,J=8.2Hz,1H), 7.53(d,J=1.8Hz,1H),7.70-7.78(m,2H),7.80(dd,J=7.9,1.6Hz,1H),13.44(br,1H); 13 C NMR (151 MHz, DMSO-d 6 )δ31.3,31.4,33.9,34.1,34.2,34.3,81.0,97.4(d,J=3.1Hz),115.2,115.3(d,J=15.8Hz),116.0(d,J=22.3Hz),118.5,12 5.4(d,J=3.4Hz),127.1,128.7,129.6,132.7(d,J=7.1Hz),133.6,145.2,146.5,161.4(d,J=250.3Hz),165.7(d,J=2.5Hz);19 F NMR (376 MHz, DMSO-d 6 )δ-110.0; IR(ATR)v 最大 / cm -1 2967m, 2928m, 2857m, 2210w, 1686s, 1617m, 1566m, 1421m, 1307m, 1218m, 834s, 764m; MS (ASAP): m / z=351.2[M+H] + ; HRMS (ASAP) for C 23 H 24 O 2 F[M+H] + Calculated value: 351.1760, measured value: 351.1766.

[0146] 1.3 Synthesis of 5-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethynyl]pyridine-2-carboxylic acid, DC528

[0147] The synthesis of the exemplary compound DC528 was Figure 2 Medium picture.

[0148] By using N 2 Bubbling continued for 1 h to remove Et 3 N / THF (1:1, 120 mL) was degassed. 2 Add Pd(PPh 3 ) 2 Cl 2 (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), and the resulting solution was stirred at 50 ° C for 40 h. The solution was diluted with heptane and / SiO 2 The plug was eluted with heptane. Then, the organic matter was washed with saturated NH 4 Cl, H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude brown solid (1.9 g). It was purified by dry column vacuum chromatography (100% heptane to 8:2 heptane / EtOAc) to give compound 9 (0.36 g, 27%) as a white solid which was carried directly to the next step: 1 H NMR (400 MHz, CDCl 3)δ1.29(d,J=7.9Hz,12H),1.69(s,4H),4.02(s,3H),7.31(d,J=1.1Hz,2H),7.51(s,1H),7.94(dd,J=8.1,2.1Hz,1H),8.12(dd,J=8.1,0.9Hz,1H),8.85(dd,J=2.1,0.9Hz,1H). Compound 9 (0.33 g, 0.95 mmol) was dissolved in THF (30 mL), 20% NaOH (3 mL) was added, and the resulting solution was stirred at reflux for 16 h. The mixture was cooled, acidified to pH 1 with 5% HCl, extracted with EtOAc, and washed with H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude white solid. This was recrystallized from MeCN to give DC528 (0.30 g, 96%) as a colorless crystalline solid: 1 H NMR (700 MHz, DMSO-d 6 )δ1.25&1.27(s,12H),1.65(s,4H),7.35(dd,J=8.1,1.8Hz,1H),7.41(d,J=8.1Hz,1H),7.57(d,J=1.8Hz, 1H),8.06(dd,J=8.1,0.9Hz,1H),8.12(dd,J=8.1,2.1Hz,1H),8.85(dd,J=2.1,0.9Hz,1H),13.35(s,1H); 13 C NMR (176 MHz, DMSO-d 6 )δ31.3,31.4,33.9,34.1,34.2,34.3,39.5,84.8,95.4,118.4,122.7,124. 3,127.1,128.7,129.8,139.5,145.2,146.4,146.9,151.3,165.6;IR(ATR)v 最大 / cm -1 3283br, 2955m, 2920m, 2856m, 2208m, 1752s, 1586m, 1336s, 1247m, 1017m, 833m; MS (ES): m / z=334.2[M+H] + ; HRMS (ES) for C 22 H 24 NO 2 [M+H] + Calculated value: 334.1807, measured value: 334.1808.

[0149] 1.4 Synthesis of methyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethynyl]benzoate, DC641

[0150] The synthesis of the exemplary compound DC641 was Figure 2 By bubbling Ar for 1 h, Et 3 N (20 mL) was used for degassing. Then, methyl 4-iodobenzoate (0.31 g, 1.20 mmol), DC640 (0.30 g, 1.40 mmol), Pd(PPh 3 ) 2 Cl 2 (83 mg, 0.12 mmol) and CuI (22 mg, 0.12 mmol), and the resulting suspension was stirred at RT for 16 h. The suspension was diluted with MTBE and passed through / SiO 2 , and the extract was evaporated to give a crude solid (0.5 g). It was purified by dry column vacuum chromatography (100% heptane to 85:15 heptane / EtOAc) to give an off-white solid, which was subsequently recrystallized from MeOH to give DC641 (0.29 g, 71%) as a colorless crystalline solid, which was carried directly to the next step: 1 H NMR (400 MHz, CDCl 3 )δ1.33&1.35(s,12H),1.81(s,4H),3.94(s,3H),7.64-7.71(m,2H),8.01-8.08(m,2H),8.52(s,1H).

[0151] 1.5 Synthesis of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydroquinoxalin-2-yl)ethynyl]benzoic acid, DC645

[0152] The synthesis of the exemplary compound DC645 was Figure 2 DC641 (0.28 g, 0.8 mmol) was dissolved in THF (20 mL), 20% NaOH (2 mL) was added, and the resulting solution was stirred at reflux for 16 h. The mixture was cooled, acidified to pH 1 with 5% HCl, extracted with EtOAc, and washed with H 2 O and brine, dried (MgSO 4 ) and evaporated to give a crude white solid which was recrystallized from MeCN to give DC645 (0.24 g, 89%) as a colorless crystalline solid: 1 H NMR (700 MHz, DMSO-d 6)δ1.29(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,1H); 13 C NMR (176 MHz, DMSO-d 6 )δ29.4,29.4,33.1,33.2,37.0,37.1,88.9,89.8,125.2,129.6,131.3,131.9,135.2,144.4,157.6,158.0,166.5; IR(ATR)v 最大 / cm -1 2961w, 2925w, 2958w, 2223w, 1683s, 1606m, 1558w, 1428m, 1282s, 862s, 769m; MS (ASAP): m / z=334.2[M] + ; HRMS (ASAP) for C 21 H 22 N 2 O 2 [M] + Calculated value: 334.1681, measured value: 334.1686.

[0153] Example 2: Biological Evaluation:

[0154] 2.1 Genomic activity of synthetic retinoids

[0155] The genomic activity of synthetic retinoids was evaluated by determining their efficiency in inducing transcription using the X-Gal assay. The X-Gal assay utilizes Sil-15 reporter cells, in which the transcription of the LacZ gene is controlled by a promoter linked to a retinoic acid response element (RARE). After treating the reporter cells with retinoids, the ability of the compound to induce transcription can be obtained by monitoring and quantifying the activity of β-galactosidase produced by the reporter cells.

[0156] Sil-15 cells were plated at 100,000 cells per well in 96-well plates coated with 0.1% gelatin. The next day, a series of dilutions of retinoid ligands prepared in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal calf serum (FCS) were added to the culture medium at a concentration of 100,000 cells / well. -6 M to 10 -14 A concentration of 100 M was added and the plates were incubated overnight. All concentrations for the ATRA standard curve and other retinoid ligands were tested in triplicate.

[0157] The next day, the assay plates were washed twice with phosphate-buffered saline (PBS) and 100 μl per well of 1% glutaraldehyde and 1 mM MgCl in PBS. 2 Fixation was continued for 15 min and the cells were washed twice with PBS. The cells were fixed by adding 100 μl of freshly prepared PBS containing 1 mM MgCl 2 β-galactosidase activity was detected by 0.2% X-Gal in PBS containing 3.3 mM potassium ferrocyanide and 3.3 mM potassium ferrocyanide. The plates were incubated at 5% CO 2 The cells were incubated at 37 °C for 6 h and the 最大 The plates were read at 650 nm on an Emax Precision Microplate Reader (Molecular Devices) to detect color changes.

[0158] As shown in Table 1 and Figure 3 As shown in Figure , the data obtained demonstrate that several synthetic retinoids exhibit greater genomic activity than that of the endogenous ligand (ATRA), as demonstrated by the increased ability to induce transcription in reporter cells. It is noteworthy that DC527, DC540, DC525, DC528, DC526, and DC645 all exhibited increased genomic activity and potency when compared to retinoic acid (ATRA).

[0159] 2.2 Non-genomic activities of synthetic retinoids

[0160] By using The Ultra ERK1 / 2 Kit measures the ability of synthetic retinoids to induce phosphorylation of ERK1 / 2 to assess their non-genomic activity.

[0161] In this assay, SH-SY5Y cells (100,000 cells / well) were plated in 96-well plates and serum starved for 24 hours in DMEM. Retinoids were tested at concentrations from 10M-5M to 10M-11M and a final concentration of 0.1% DMSO in the culture medium. SH-SY5Y cells were assayed in serum-free DMEM, and cells were stimulated with retinoids for 30 minutes at 37°C.

[0162] At the end of the assay, the medium was removed and the cells were lysed in 50 μl of freshly prepared IX lysis buffer (provided in the kit).The 96-well plate was agitated on an orbital shaker (S01, Stuart Scientific) at approximately 350 rpm for 10 minutes at room temperature.

[0163] At the same time, the activation buffer was diluted 25-fold in the reaction buffer. Under green light in a dark room, the acceptor beads were diluted 50-fold in the freshly prepared reaction mixture, while the donor beads were diluted 50-fold in the dilution buffer to obtain two final reaction mixtures.

[0164] Then 10 μl of cell lysate per well was transferred to a 384-well white Proxiplates plate (PerkinElmer), and 5 μl of each prepared acceptor and donor reaction mixture was added in a dark room under green light. The plate was wrapped with aluminum foil and incubated at room temperature for at least 3 hours. The Envision system (PerkinElmer Life Sciences) was used. Set to read.

[0165] Table 1 shows that Figure 4 The results shown in Figure 5 demonstrate the ability of retinoids to induce Erk 1 / 2 phosphorylation in SH-SY5Y cells. Several retinoids were identified to have higher potency and efficacy than retinoic acid such as DC527, DC540, DC528, DC526 and DC645, with DC525 being identified as having higher potency.

[0166] 2.3 Induction of neurite outgrowth

[0167] SY-SY5Y cells were plated at 10,000 cells / well in 12-well plates containing acid-treated / poly-L-lysine coated coverslips. After 24 hours, each retinoid was added to the culture medium at a concentration of 10 nM, and the plate was incubated for 5 days. After retinoid treatment, the SH-SY5Y cells on the coverslips were washed twice in PBS, fixed in 4% paraformaldehyde (PFA) at room temperature for 20 minutes, and washed twice with PBS.

[0168] For immunocytochemical staining of neurites, the cells on the coverslips were washed three times in PBS and incubated at room temperature for 1 hour in blocking solution (10% donkey serum and 0.1% triton X-100 in PBS). The cells were then labeled by incubating overnight at 4°C with a β-III tubulin primary antibody (Sigma-Aldrich) diluted at 1:1000 in blocking buffer. After overnight incubation, the cells were washed three times with PBS containing 0.1% Triton X-100 solution (PBST), and then incubated at room temperature for 2 hours with an anti-mouse monoclonal secondary antibody (1:300 in PBST; Jackson Immunoresearch). Finally, after three washes in PBST and the final wash in PBS, the coverslips were mounted on slides and stored at 4°C.

[0169] ImageJ software with NeuronJ plug-in is used for neurite outgrowth on the cell of quantitative staining.For each experiment, 10 different randomly selected images were taken from each coverslip using Nikon Eclipse E400 fluorescence microscope.Each image is converted into 8-bit image (necessary for NeuronJ plug-in), and optimized using the brightness and contrast tools in GIMP (GNU image processing program).For each image, a separate track is drawn for each clearly distinguishable neurite using the tracking tool (tracing tool) in the NeuronJ plug-in.Neurite length is measured in pixels, and is converted into corresponding length in μm depending on the magnification used.The average neurite length for each image is calculated by dividing the total neurite length of each image by the total number of neurites.10 images per coverslip are measured, and the mean value for the whole coverslip is calculated.For each retinoid and concentration, coverslips are triplicate.

[0170] Figure 5 The data shown in prove that several of retinoids show the ability to induce neurite outgrowth in SY-SY5Y cells. In addition, cells treated with several of these compounds (DC527, DC525, DC528, DC526 and DC645) show significantly greater average neurite length than cells treated with ATRA.

[0171] Table 1 below summarizes the genomic (transcriptional) and non-genomic (p-ERK1 / 2) activities for the retinoid compounds tested, along with the increase in neurite outgrowth, and these results are presented in Figure 5Figure 2. It is evident from the figure that compounds that showed high potency in both genomic and non-genomic assays demonstrated increased neurite outgrowth induction. This suggests that "dual-effect" compounds, i.e., compounds that induce both genomic and non-genomic activity, may prove to be more effective in clinical use, allowing this dual assay approach to serve as a potentially powerful screening tool for new therapeutic compounds.

[0172]

[0173] Table 1: Genomic activity, nongenomic activity and neurite outgrowth

[0174] 2.4 Regulation of Alzheimer's disease-related genes

[0175] To examine the effects that retinoids may have on the expression of genes involved in Alzheimer's disease, the expression of a panel of Alzheimer's disease-associated genes in rat mixed primary neuronal / glial cultures was assessed following retinoid treatment.

[0176] Approximately 300,000 rat neurons / glial cells were first treated with 1 μg / ml lipopolysaccharide (Sigma-Aldrich) for 6 hours to induce inflammation. After induction of inflammation, cells were treated with 10 nM retinoid for 24 hours. The most effective retinoids were selected for these experiments in previous assays. After treatment, RNA was extracted from treated cells for qPCR analysis.

[0177] According to the manufacturer's protocol, Qiagen RNeasy micro kit (Cat. No. 74104, Qiagen) was used to extract total RNA. In brief, cells and brain tissue samples were homogenized in 350 μl and 1200 μl of RLT buffer mixed with β-ME (1 ml buffer: 10 μl β-ME ratio) respectively. Then, the sample was centrifuged at 13,000 rpm for 3 min. First, the supernatant was mixed with 70% ethanol (Cat. No. E7023, Sigma-Aldrich) at a volume ratio of 1: 1, and then transferred to a spin column placed in a collection tube. The sample was centrifuged at 10,000 rpm for 1 min to bind RNA to the membrane of the spin column.

[0178] For on-column DNase digestion, the sample in the column was washed with 350 μl RW1 buffer and centrifuged at 10,000 rpm for 1 min. Then, 80 μl of DNase mixture (10 μl DNase and 70 μl RDD buffer; Cat. No. 79254, Qiagen) was added to each sample. The sample was incubated at room temperature for 15 min, and then 350 μl RW1 buffer was added. The sample was centrifuged at 10,000 rpm for 1 min.

[0179] Then, 500 μ l of RPE buffer (mixed with 100% ethanol in a ratio of 1: 4) is added to the sample. The sample is centrifuged at 10,000 rpm for 1 min (this step is repeated 2 times). The spin column is centrifuged at 13,000 rpm for 1 min to dry the film. The spin column is removed from the collection tube and placed in another 1.5 ml collection tube without RNase. RNA is eluted by directly adding 30 μ l of RNase-free water to the spin column membrane. The sample is incubated at room temperature for 5 min, and then they are rotated at 10,000 rpm for 1 min.

[0180] Using NanoDrop TM RNA concentration was measured with a 2000c spectrophotometer (Thermo Fisher Scientific). The instrument was calibrated using RNase-free water, which was used to elute RNA as a blank, and 2 μl was used for each RNA sample. RNA samples were stored in a freezer at -70°C to minimize RNA degradation.

[0181] qPCR reactions were performed using PerfeCTa SYBR Green SuperMix (Cat. No. 733-1246, VWR). 10 μl of reaction mixture was added to each well of a 384-well plate (Cat. No. 04729749001, Roche) in triplicate. Each reaction contained 2 μl of 4-fold diluted cDNA template, 5 μl 2X SYBR green mix, and 250 nM primers.

[0182] Primers were designed using Primer-BLAST with a melting temperature of approximately 60° C. Before using the primers for qPCR, the specificity of the primers was checked by PCR and the PCR products were sent for sequencing.

[0183] Standard curves (made with 5-fold dilutions of stock cDNA) and blank controls were run for all primer sets tested in qPCR. The plate was then sealed and briefly centrifuged to ensure that all reagents were at the base of the wells. The plate was run on a Roche LightCycler 480, which was programmed to keep the plate at 95°C for 5 min. Then, the qPCR run lasted 45 cycles: 95°C for 15 seconds (s), 60°C for 15s, and 72°C for 15s. Then, a melting curve was obtained by running the plate at 95°C for 5s, followed by 58°C for 1min.

[0184] Results were analyzed using the δδCT method in the LightCycler 480 1.5 software. According to each experiment, the expression of the gene of interest was normalized to the appropriate reference gene.

[0185] Figure 7 The data shown in demonstrate that DC645, DC528 and DC526 downregulate inflammatory genes (Ccl5, TNFα and Nos2) and upregulate neuroprotective genes (Abca1, Abcg1, Igf1 and Igf2) and non-amyloid precursor pathway genes (Nep, Ide and Adam10) that direct amyloid precursor to follow a pathway that does not generate toxic amyloid fragments.

[0186] Example 3: MDCK-MDR1 permeability assay:

[0187] The assay was used to measure the permeability of test compounds in the apical to basolateral (AB) and basolateral to apical (BA) directions across MDCK-MDR1 cells and was used to determine the efflux ratio (ER), which shows whether a compound undergoes active efflux. Therefore, the assay is a valuable in vitro surrogate for blood-brain permeability and CNS exposure.

[0188] 3.1 Experimental Procedure

[0189] MDCK-MDR1 cells obtained from NIH (Rockville, MD, USA) were used between passages 6 and 30. The cells were cultured at 3.4 × 10 5 cells / cm 2 The cells were plated onto Millipore Multiscreen Transwell plates. The cells were cultured in DMEM and the medium was changed on day 3. Permeability studies were performed on day 4. Cell culture and assays were incubated at 37°C in 5% CO with 95% relative humidity. 2The assay was performed in an atmosphere of . On the day of the assay, the monolayer was prepared by rinsing both the apical surface and the basolateral surface twice with Hanks balanced salt solution (HBSS) at the desired pH warmed to 37°C. The cells were then incubated with HBSS at the desired pH in both the apical compartment and the basolateral compartment for 40 min to stabilize physiological parameters. The dosing solution was prepared by diluting the test compound with assay buffer to give a final test compound concentration of 10 μM. The analytical standard was prepared from the test compound DMSO dilution and transferred to the buffer, maintaining a 1% v / v DMSO concentration; the buffer contained supplemented HBSS at pH 7.4. To evaluate AB permeability, HBSS was removed from the apical compartment and replaced with the test compound dosing solution. The apical compartment insert was then placed in a companion plate containing a new buffer (containing 1% v / v DMSO). To evaluate BA permeability, HBSS was removed from the companion plate and replaced with the test compound dosing solution. New buffer (containing 1% v / v DMSO) was added to the apical compartment insert, which was then placed in the paired plate. At 60 min, the apical compartment insert and paired plate were separated, and the apical and basolateral samples were diluted for analysis. Test compound permeability was assessed in duplicate. Compounds with known permeability properties were run on each assay plate as controls. Test and control compounds were quantified by LC-MS / MS cassette analysis using a 7-point calibration with appropriate sample dilutions. The starting concentration (C 0 ) is determined by the dosing solution, and the experimental recovery is determined by C 0 and the concentrations of both the apical and basolateral compartments were calculated.

[0190] 3.2 Data Analysis

[0191] The permeability coefficient (P app ) is calculated by the following equation:

[0192]

[0193] where dQ / dt is the rate of drug permeation across the cell, C 0 is the donor compartment concentration at time zero, and A is the area of ​​the cell monolayer. 0 Obtained from analysis of the dosing solution. The efflux ratio (ER) was calculated from the averaged AB and BA data. This was derived from:

[0194]

[0195] 3.3. Biological studies

[0196] The membrane permeability of a number of compounds of Formula I was measured in the MDCK-MDR1 assay described previously. The permeability (P app , nm / s) and efflux ratio (ER) were determined and compared with the permeability and efflux ratio of the closely related reference compound EC23. The results are summarized in Table 2:

[0197]

[0198] Table 2: Permeability and efflux ratios of compounds of formula I relative to the reference compound EC23.

[0199] The results shown in Table 2 prove that in MDCK-MDR1 assay, some compounds of formula (I) can show considerable improvement in permeability and lack of outflow, and therefore, can be expected to show considerable improvement in blood-brain barrier penetration and CNS exposure. Due to the need to expose the CNS target to a sufficiently high concentration of therapeutic agents for the treatment of CNS disorders including ALS and Alzheimer's disease, it is obvious that optimal CNS exposure is a basic characteristic of drugs for the treatment of these disorders. Therefore, compared with literature compound EC23, the compound of formula (I) studied shows a significantly improved drug-like characteristic. The improvement of this CNS exposure represents a surprising and unexpected discovery.

[0200] Example 4: Turbidimetric Aqueous Solubility:

[0201] Example 4.1 Experimental procedures

[0202] Test compound (10mM in DMSO) is diluted continuously to give 0.1mM, 0.3mM, 1mM and 3mM solution in DMSO.Then each test compound concentration is further diluted with 1:100 in buffer (0.01M phosphate buffered saline pH 7.4) so ​​that final DMSO concentration is 1% and final test compound concentration is 1 μM, 3 μM, 10 μM, 30 μM and 100 μM.The experiment is carried out at 37 ° C, and each concentration sample is incubated in 7 parallel wells.Plate is incubated at 37 ° C for 2h, then absorbance is measured at 620nm.The solubility of the sample is estimated from the concentration of the test compound, and the test compound produces an increase in absorbance higher than the vehicle control (that is, 1% DMSO in buffer).

[0203] 4.2 Biological research

[0204] The solubility of a number of compounds of formula (I) was measured in the previously described turbidometric water solubility assay. The solubility of the compounds was determined and compared with the solubility of the closely related reference compound EC23. The results are summarized in Table 3:

[0205]

[0206] Table 3: Solubility of compounds of formula I relative to reference compound EC23.

[0207] The results shown in the above table demonstrate that compounds of Formula I can show considerable improvements in solubility and, therefore, can also be expected to show considerable improvements in a number of biological properties including absorption and target exposure. Again, this represents a surprising and unexpected discovery.

[0208] It will be understood that when throughout the specification compounds are described as being useful for treating conditions or diseases which are alleviated by activation of retinoic acid receptors (RARs), this represents a disclosure of the compounds themselves.

[0209] All features disclosed in this specification (including any accompanying claims, abstracts and drawings) and / or all steps of any method or process so disclosed may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Unless expressly stated otherwise, each feature disclosed in this specification (including any accompanying claims, abstracts and drawings) may be replaced by an optional feature for the same, equivalent or similar purpose. Therefore, unless expressly stated otherwise, each feature disclosed is only an example of a general series of equivalent or similar features. The present invention is not limited to the details of the foregoing embodiments. The present invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstracts and drawings), or to any novel step or any novel combination of steps in the steps of any method or process so disclosed.

[0210] With respect to the use of substantially any plural and / or singular terms herein, those skilled in the art may translate the plural to the singular and / or the singular to the plural, as appropriate, as context and / or application. Various singular / plural arrangements may be expressly set forth herein for clarity.

[0211] Those skilled in the art will understand that, in general, the terms used herein, and particularly the terms used in the appended claims, are generally intended to refer to "open-ended" terms (e.g., the term "including" should be understood to mean "including but not limited to," the term "having" should be understood to mean "having at least," the term "includes" should be understood to mean "including but not limited to," etc.). Those skilled in the art will also understand that if a specific number of an introduced claim recitation is intended, such intent will be expressly stated in the claim, and in the absence of such a statement, such intent is absent. For example, as an aid to understanding, the following appended claims may contain the use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such words should not be interpreted as meaning that a claim recitation, through the introduction of the indefinite article "a" or "an", limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory words "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be interpreted as meaning "at least one" or "one or more"); this also applies to the use of definite articles used to introduce claim recitations. In addition, even if a specific number of introduced claim recitations is explicitly stated, a person skilled in the art will recognize that such a statement should be understood to mean at least the stated number (e.g., the plain statement of "two recitations" without other modifiers means at least two recitations, or two or more recitations).

[0212] It will be understood that various embodiments of the present disclosure have been described herein for illustrative purposes, and that various modifications may be made without departing from the scope of the present disclosure. Therefore, the various embodiments disclosed herein are not intended to be limiting, and the true scope is defined by the accompanying claims.

Claims

1. A compound of formula I: in: A 1 Is N or CR 6 ; A 2 Is N or CR 7 ; A 3 Is N or CR 8 ; R 6 and R 8 are independently hydrogen, C1-C 10 Alkyl, F, Br or Cl; R 7 are independently hydrogen, C1-C 10 Alkyl, F, Br, Cl or -OCR 9 , where R 9 is H or C1-C6 alkyl; R 1 To R 4 each is a methyl group; A 4 Is N or CR 12 ; A 5 Is N or CR 13 ; A 6 Is N or CR 14 ; A 7 Is N or CR 15 ; Each R 12 To R 15 are independently H, halogen or C1-C 10 haloalkyl; and R 5 Yes-C(=O)R 16 OR -C(=O)OR 16 , where R 16 Is H or C 1-10 alkyl; The condition is A 1 To A 3 At least one of them is N; In free form or in salt form.

2. The compound according to claim 1, wherein A 1 and A 3 It is N.

3. The compound according to claim 1 or 2, wherein A 2 Yes CR 7 .

4. The compound according to claim 3, wherein R 7 It's hydrogen.

5. A compound according to any one of claims 1, 2 and 4, wherein R 5 It is -COOH.

6. The compound according to claim 3, wherein R 5 It is -COOH.

7. The compound according to claim 1, wherein the compound is selected from:

8. The compound according to claim 7, which is:

9. Use of a compound according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment of a disease or condition alleviated by activation of retinoic acid receptors (RARs).

10. The use according to claim 9, wherein the disease or condition is selected from amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, memory impairment, dementia, cognitive impairment, stroke, traumatic brain injury, epilepsy and spinal cord injury.

11. The use according to claim 10, wherein the disease or condition is selected from early Alzheimer's disease, mid-stage Alzheimer's disease, late Alzheimer's disease, mild cognitive impairment, cognitive disorder and memory deficit.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, optionally in combination with one or more pharmaceutically acceptable carriers.

13. Use of the pharmaceutical composition according to claim 12 in the manufacture of a medicament for treating a disease or condition alleviated by activation of RAR.

14. The use according to claim 13, wherein the disease or condition is selected from amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis (MS), Alzheimer's disease, memory impairment, dementia, cognitive impairment, stroke, traumatic brain injury, epilepsy and spinal cord injury.

15. The use according to claim 14, wherein the disease or condition is selected from early Alzheimer's disease, middle Alzheimer's disease, late Alzheimer's disease, mild cognitive impairment, cognitive disorder and memory deficit.

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