Triazoles for use in treatment of ocular diseases

Abstract

The present invention relates to substituted 1, 2, 3-triazoles of formula (I) which are useful in the treatment of ocular diseases, in particular those associated with retinal degeneration. The invention also relates to a pharmaceutical composition for treating retinal diseases through external administration. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to substituted 1,2,3-triazoles which are useful for treating ocular diseases, particularly those associated with retinal degeneration, such as retinitis pigmentosa. The present invention also relates to a subgroup of novel substituted 1,2,3-triazoles. Background Art

[0002] The retina is a transparent, light-sensitive structure located at the back of the eye. The cornea and lens focus light onto the retina. The retina contains millions of photoreceptor cells (rods and cones) and other nerve cells that receive and organize visual information. The retina sends this information to the brain via the optic nerve, allowing us to see. The central area of ​​the retina is called the macula, which contains a high density of color-sensitive photoreceptor (light-sensing) cells. These cells are called cones, and they produce the clearest visual images and are responsible for central vision and color vision. The peripheral areas of the retina surrounding the macula contain photoreceptor cells called rods, which respond to lower light levels but are not sensitive to color. Rods are responsible for peripheral vision and night vision.

[0003] Retinal diseases vary widely, but most of them cause visual symptoms. Some retinal diseases are more common with aging or diabetes. Others are hereditary, such as retinitis pigmentosa, or have genetic risk factors. Hereditary diseases of the retina often cause its degeneration, leading to irreversible vision loss fairly early in life, such as retinitis pigmentosa and Stargardt's disease.

[0004] Retinitis pigmentosa (RP) is the term used for a genetically heterogeneous group of inherited retinal degenerations. Symptoms include night blindness, development of tunnel vision, and slowly progressive loss of central vision. RP can be: (i) non-syndromic, i.e. it occurs in isolation without any other clinical manifestations; (ii) syndromic, with other neurosensory disorders, developmental abnormalities, or a complex clinical presentation; or (iii) secondary to other systemic diseases. RP combined with deafness (congenital or progressive) is called Usher syndrome. Alport's syndrome is associated with RP and abnormalities of the glomerular basement membrane leading to nephrotic syndrome. It is inherited in an X-linked dominant manner.

[0005] RP with ophthalmoplegia, dysphagia, ataxia, and cardiac conduction defects is seen in the mitochondrial DNA disorder Kearns–Sayre syndrome (also known as fragmented red fiber myopathy). RP with bradykinesia, peripheral neuropathy, spinous (thorny) RBCs, ataxia, steatorrhea, and loss of VLDL is seen in beta-lipoprotein deficiency. RP is seen clinically in association with several other rare genetic disorders as part of McLeod syndrome. This is an X-linked recessive phenotype characterized by a complete absence of the XK cell surface protein and, therefore, a markedly reduced expression of all Kell red cell antigens. RP is associated with hypogonadism and developmental delay with an autosomal recessive pattern of inheritance is seen in Bardet-Biedl syndrome.

[0006] Some major diseases affecting the macula, such as age-related macular degeneration and diabetic retinopathy, lead to impaired vision. Additional examples of retinal diseases are cone dystrophy, rod and cone degeneration, Leber's congenital amaurosis, white punctate retinitis, choroideremia, gyratory choroidal and retinal atrophy, generalized choroidal dystrophy, juvenile retinoschisis, Wagner's vitreoretinal degeneration, autosomal dominant vitreoretinal choroidopathy, Best's vitelliform macular dystrophy, Usher's syndrome, Bardet-Biedl syndrome, Sorsby's pseudoinflammatory macular dystrophy, and dominant drusen.

[0007] There is currently no treatment for retinitis pigmentosa, but the efficacy and safety of various prospective treatments are currently being evaluated. WO 2016 / 146669 A1 discloses the use of cyclic guanosine monophosphate (cGMP) inhibitors. The cGMP inhibitors must be encapsulated in liposomes and administered daily by intraperitoneal injection. ES2673942A1 discloses the use of acylated resveratrol derivatives. These compounds are administered subretinal or in combination with cyclodextrins. Clinical trials of metformin for the treatment of age-related macular degeneration are currently underway (https: / / curativebiotech.com / pipeline).

[0008] WO 2017 / 203083 A1 describes substituted 1,2,3-triazoles for regulating intracellular calcium homeostasis for use in preventing or treating degenerative disorders of the musculoskeletal, cardiac and nervous systems. However, the document does not mention the utility of these compounds in treating ocular diseases.

[0009] Substituted 1,2,3-triazoles with 4-(aryloxy)methyl groups are suitable for designing bioactive compounds, such as Grimster, et al. J. Am. Chem. Soc., 2012, 134 (15), 6732 on nicotinic acetylcholine receptor modulators and Li et al. J. Med. Chem. 2017, 60 (7), 2697 on free fatty acid receptor GRP40 agonists. These triazoles are also used as non-degradable bioligands, such as Hatit et al. Nature Commun. 2018, 9 (1), 4021.

[0010] Substituted 4-[(arylthio)alkyl]-1H-1,2,3-triazoles have been described in WO 2017 / 203083 A1 and Aizpurua et al., Eur. J. Med. Chem., 2021, 213 for use in regulating intracellular calcium homeostasis for the prevention or treatment of musculoskeletal, cardiac and nervous system degenerative diseases. However, these documents also do not mention the utility of these compounds in the treatment of ocular diseases.

[0011] There remains a need in the art for adequate treatments for ocular diseases, such as retinal diseases, particularly retinitis pigmentosa, and more particularly, treatments involving non-invasive dosing regimens. Summary of the invention

[0012] As shown in the examples, the inventors unexpectedly found that substituted 1,2,3-triazoles can be used to treat eye diseases, particularly retinal diseases, such as retinitis pigmentosa. Also as shown in the examples, after topical ocular administration, substituted 1,2,3-triazoles reach the posterior segment of the eye. Therefore, these substituted 1,2,3-triazoles can be applied topically and still reach their target sites. Topical administration is advantageous because it avoids the use of invasive routes of administration, such as intravitreal, and also avoids the use of systemic routes of administration, such as oral administration, resulting in improved patient compliance and comfort, as well as reduced side effects.

[0013] Therefore, in a first aspect, the present invention relates to a compound of formula (I):

[0014]

[0015] in

[0016] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , CN, F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0017] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0018] Z is selected from -S-, -S(=O)-, -S(=O) 2 A group consisting of - and -O-;

[0019] R 1 It is a straight chain C 1 -C 4 an alkylene diradical optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl and F;

[0020] R 2 It is a straight chain C 1 -C 4 an alkylene diradical, optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, allyl, propargyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, 1-naphthyl, 2-naphthyl, benzyl, 4-hydroxybenzyl, and CF 3 ;

[0021] R 3 Selected from the group consisting of H and I; and

[0022] W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 、-N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 , -CO 2 H and -SO 3 H;

[0023] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof;

[0024] For use in preventing and / or treating eye diseases.

[0025] The second aspect relates to a pharmaceutical composition, comprising a compound of formula (I) as defined in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof, and a pharmaceutically acceptable excipient, for use in preventing and / or treating eye diseases, preferably wherein the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and mixtures thereof.

[0026] The third aspect relates to a compound of formula (II):

[0027]

[0028] in

[0029] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C 4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0030] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0031] Z is selected from -S-, -S(=O)-, -S(=O)2 A group consisting of - and -O-;

[0032] Each R is independently selected from H and CH 3 The group composed of;

[0033] R 3 Selected from the group consisting of H and I;

[0034] When Z is -S-, -S(=O)- or -S(=O) 2 -, p is selected from the group consisting of 2, 3 and 4, and W is selected from the group consisting of: -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH and -N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 ;as well as

[0035] When Z is -O-, p is selected from the group consisting of 2 and 4, and W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4alkyl), -NHC(=NH)NHC(=NH)NH 2 、-N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 , -CO 2 H and -SO 3 H;

[0036] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof;

[0037] The proviso is that the compound is not 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole.

[0038] The fourth aspect relates to the compound of formula (II) as defined in the third aspect or its pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide, or its isotope-labeled derivative, for use in medicine.

[0039] The fifth aspect relates to a pharmaceutical composition, comprising a compound of formula (II) according to the third aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof, and a pharmaceutically acceptable excipient; preferably, the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and a mixture thereof.

[0040] The present invention also relates to a compound of formula (II) according to the third aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof or a pharmaceutical composition according to the fifth aspect, for use in preventing and / or treating eye diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 The biodistribution of the compounds of the invention in four mammalian species is shown. ... 3 Biodistribution of [H]-35 (whose preparation is described in Example 52) in the rat retina. 3 The concentration of H]-35 reached a peak at about 8 h after administration and was detected until 24 h after administration (A). The columns represent the percentage of the administered dose per gram of retina in mice and rabbits 4 h after a single ocular instillation of compound 35 (in phosphate buffered saline (PBS) solution or formulated with 0.2% hyaluronic acid (HA)) (B); the six compounds of the present invention formulated with HA reached the retina of pig eyes at different concentrations (C).

[0042] Figure 2 Electroretinogram (ERG) analysis of rd10 mice is shown. Figure shows untreated rd10 mice (rd10), and b wave amplitude (in μV) treated for 11 days by daily ocular instillation of compound 35 (A); 1 (B); 50 (C); 56 (D) and 70 (E) (3 μL of 20mM solution per eye). Each line represents the average b wave + / - standard deviation of 9 mice per group. In order to determine the difference of group mean, two-tailed student's test was performed on unpaired samples with comparable variance. *p<0.05; **p<0.005; ***p<0.001rd10 treated compared to rd10 untreated.

[0043] Figure 3 The number of photoreceptor nuclei in the retina of rd10 and wild-type mice (WT) is shown. The data shown corresponds to the values ​​obtained from WT mice and rd10 mice treated for 11 days with untreated (rd10) or with compounds 1, 35, 36 and 53 (3 μL of 20mM solution per eye). The analysis was performed in the central (C), mid-peripheral (MP) and peripheral (P) retina. The column represents the mean + / - standard deviation (WT control, n=3; rd10 untreated, n=8; rd10 treated, n=4, each treatment). The statistical difference of unpaired samples was determined by a two-tailed student's test. *p<0,05y**p<0,01rd10 treated compared to rd10 untreated.

[0044] Figure 4 Morphometric analysis of mouse retinas is shown. Representative sections of rd10 (untreated) and rd10 retinas treated with compound 35 are labeled with specific markers for rod and cone photoreceptors. Significant protection of photoreceptors in the retina of rd10 mice treated with compound 35 (3 μL of 20 mM solution per eye) for 11 days was observed, as measured by the number of rods (B) and cones (C) per square mm, or rod outer and inner segments (D). Columns represent mean + / - standard error (rd10 untreated, n=3; rd10 treated with compound 35, n=5). To determine the difference in group means, a two-tailed Student's test was performed on unpaired samples with comparable variances. **p<0.01rd10 treated compared to rd10 untreated. Abbreviations: ONL: outer nuclear layer; OS: outer segment; C: central retina; MP: mid-periphery; P: periphery.

[0045] Figure 5Shown is the visual motion test evaluation of the vision (contrast sensitivity) of rd10 mice using the modified Morris (Morris) water maze test. The figure shows the contrast sensitivity of untreated rd10 mice (rd10) and processed for 16 days by daily eye instillation of compound 35 (20mM PBS buffer solution of 3 μL per eye). Vision is tested under different contrasts and spatial frequencies of moving visual stimulation. Each point represents a mouse. For each group + / - standard deviation: * P < 0.05; rd10 is processed compared to rd10 unprocessed. The maximum difference is observed in the outliers of spatial frequency, where it is more difficult to identify the moving bar pattern (0.01; 0.02; 0.17 and 0.35 cycles / degree).

[0046] Figure 6 The in vitro efficacy of compound 35 in preventing phototoxicity in 661W cells is shown. 661W cells were seeded onto 96-well MEA impedance plates (50,000 cells / well) and incubated at 37°C and 5% CO 2 Cells were grown in a Maestro Edge device (Axion Biosystems) at 4 °C until confluence. When the impedance reached a plateau, phototoxicity was induced by adding 20 μM 9-cis-retinal and 30,000 lux white light. Increasing concentrations of compound 35 were added (A). Impedance was recorded every minute for 24 hours and converted to percentage of cell lysis (B). DETAILED DESCRIPTION

[0047] In the context of the present invention, the following terms have the following indicated meanings:

[0048] The term "alkylene biradical" refers to a biradical formed by a straight hydrocarbon chain consisting of carbon and hydrogen atoms, which has no unsaturation and is bonded to the rest of the molecule at its terminus by a single bond, such as, for example, methylene, ethylene, propylene, butylene, etc. Referring to C 1 -C 4 The alkylene diradical refers to the diradical having 1 to 4 carbon atoms. The alkylene diradical can be selected from the group consisting of: 1 and R 2 The definition of the substituents specifies the substitutions to be carried out.

[0049] The term "alkyl" refers to a radical formed by a straight or branched hydrocarbon chain consisting of carbon and hydrogen atoms, which does not contain any saturation and is bonded to the rest of the molecule by means of a single bond, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, etc. Referring to C 1 -C 4 Alkyl refers to a group having 1 to 4 carbon atoms. 1 -C6 The alkyl group refers to the group having 1 to 6 carbon atoms.

[0050] The term "halogen" refers to F, Cl, Br and I.

[0051] The expression "isotopically labeled derivative" refers to a compound of formula (I) wherein at least one of its atoms is isotopically enriched. For example, wherein hydrogen is replaced by deuterium or tritium, carbon is replaced by 13 C or 14 C-rich atoms are replaced, or nitrogen is 15 Compounds of formula (I) substituted with N-rich atoms are within the scope of the present invention. In particular, isotopically labeled derivatives are those wherein R 3 The compound of formula (I) wherein the hydrogen atom at the position is replaced by deuterium or tritium.

[0052] The term "pharmaceutically acceptable salt or solvate" refers to any pharmaceutically acceptable salt or solvate that, when administered to a recipient, is capable of providing (directly or indirectly) a compound of formula (I) as described in this document. Salts may be prepared by methods known in the art.

[0053] For example, the pharmaceutically acceptable salt of the compound provided in this document is synthesized by a previously described compound containing alkaline or acidic units by conventional chemical methods. Such salts are usually prepared, for example, by reacting the free acid or alkaline form of these compounds with a suitable alkali or acid of a stoichiometric amount in water or an organic solvent or in a mixture of the two. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are usually preferred. The example of acid addition salts includes mineral acid addition salts, such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts, such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, mesylate and p-toluenesulfonate. Examples of base addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium, and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, glucosamine and basic amino acid salts.

[0054] Solvates refer to compounds of formula (I) in which molecules of a pharmaceutically suitable solvent are incorporated into the crystal lattice. Solvation methods are generally known in the art. Examples of pharmaceutically suitable solvents are ethanol, water, etc. In a specific embodiment, the solvate is a hydrate.

[0055] The compound of formula (I) or its salt or solvate is preferably in a pharmaceutically acceptable form or substantially pure form. Pharmaceutically acceptable form is understood to be especially with a pharmaceutically acceptable purity level, does not include normal pharmaceutical additives, such as diluents and excipients, and does not include any material that is considered to be toxic at normal dosage levels. The purity level of the drug is preferably higher than 50%, more preferably higher than 70%, and even more preferably higher than 90%. In a preferred embodiment, it is a compound of formula (I) or its salt or solvate higher than 95%.

[0056] Depending on the presence of chiral centers, the compounds of the present invention represented by the above formula (I) may include any stereoisomers, including enantiomers and diastereomers. Individual isomers, enantiomers or diastereomers and mixtures thereof are within the scope of the present invention.

[0057] As used herein, the term "tautomer" refers to structural isomers of a compound that differ in the position of protons and single bonds adjacent to double bonds, such as keto-enol tautomers, amide-imide tautomers, amine-imine tautomers, enamine-imine, lactam-lactim tautomers.

[0058] The term "N-oxide" refers to a derivative of a compound of formula (I) in which the nitrogen atom of the amine group has been oxidized, i.e. -N + O - In particular, N-oxide refers to the N-oxide of a tertiary amine, preferably to the N-oxide of a nitrogen atom present in an amine substituent as defined with respect to W, such as -N(O)(C 1 -C 4 alkyl) 2 , optionally C 1 -C 4 1-pyrrolidinyl N-oxide substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl N-oxide substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-morpholinyl N-oxide and optionally C 1 -C 4 Alkyl substituted 4-piperazinyl N-oxides.

[0059] As used herein, the term "treat", "treatment" or "treatment of" refers to reducing the potential of a disease or illness, reducing the occurrence of a disease or illness and / or reducing the severity of a disease or illness, preferably to the extent that the subject no longer suffers from discomfort and / or functional changes due to it. It also refers to alleviating or reducing at least one clinical symptom and / or inhibiting or delaying the progression of a disease and / or preventing or delaying the onset of a disease or illness.

[0060] As used herein, the terms "prevention," "preventing," or "prevent" refer to avoiding the occurrence of a disease or illness. Prevention can be complete (e.g., the complete absence of the disease). Prevention can also be partial, e.g., causing the subject to have a lower incidence of disease than would occur if the combination or composition of the invention were not administered. Prevention also refers to reducing susceptibility to a clinical condition. Prevention also includes reducing the risk of disease.

[0061] In a first aspect, the present invention relates to a compound of formula (I):

[0062]

[0063] in

[0064] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C 4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , CN, F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0065] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0066] Z is selected from -S-, -S(=O)-, -S(=O) 2 A group consisting of - and -O-;

[0067] R 1 It is a straight chain C 1 -C 4 an alkylene diradical optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl and F;

[0068] R2 It is a straight chain C 1 -C 4 an alkylene diradical, optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, allyl, propargyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, 1-naphthyl, 2-naphthyl, benzyl, 4-hydroxybenzyl, and CF 3 ;

[0069] R 3 Selected from the group consisting of H and I; and

[0070] W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 、-N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 , -CO 2 H and -SO 3 H;

[0071] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof;

[0072] For use in preventing and / or treating eye diseases.

[0073] This aspect can also be expressed as a compound of formula (I):

[0074]

[0075] in

[0076] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C 4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , CN, F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0077] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0078] Z is selected from -S-, -S(=O)-, -S(=O) 2 A group consisting of - and -O-;

[0079] R 1 It is a straight chain C 1 -C 4 an alkylene diradical optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl and F;

[0080] R 2 It is a straight chain C 1 -C 4 an alkylene diradical, optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, allyl, propargyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, 1-naphthyl, 2-naphthyl, benzyl, 4-hydroxybenzyl, and CF 3 ;

[0081] R 3 Selected from the group consisting of H and I; and

[0082] W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3, optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 、-N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 , -CO 2 H and -SO 3 H;

[0083] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof;

[0084] Use in the manufacture of a medicament for preventing and / or treating eye diseases.

[0085] This aspect can also be expressed as a method for preventing and / or treating eye diseases, the method comprising administering a compound of formula (I):

[0086]

[0087] in

[0088] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C 4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , CN, F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0089] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0090] Z is selected from -S-, -S(=O)-, -S(=O) 2 A group consisting of - and -O-;

[0091] R 1 It is a straight chain C 1 -C 4 an alkylene diradical optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl and F;

[0092] R 2 It is a straight chain C 1 -C 4 an alkylene diradical, optionally substituted with one or two substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, allyl, propargyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, 1-naphthyl, 2-naphthyl, benzyl, 4-hydroxybenzyl, and CF 3 ;

[0093] R 3 Selected from the group consisting of H and I; and

[0094] W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 、-N(C 1-C 4 Alkyl)C(=NH)NHC(=NH)NH 2 , -CO 2 H and -SO 3 H;

[0095] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof.

[0096] When m has a value other than 0, the X substituent is present. Similarly, when n has a value other than 0, the Y substituent is present.

[0097] Preferably, in the compounds of formula (I) for use according to the present invention, m is selected from the group consisting of 0, 1 and 2, more preferably m is 1.

[0098] Preferably, in the compounds of formula (I) for use according to the present invention, n is 0 or 1, more preferably n is 0.

[0099] Preferably, in the compounds of formula (I) for use according to the present invention, m is 1; n is 0; and X is located in the para position relative to Z.

[0100] Preferably, in the compounds of formula (I) for use according to the present invention, X and Y (when present, ie wherein m and / or n is non-0) are independently selected from C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), CF 3 , CN, F, Cl, Br and I; or X and Y together represent methylenedioxy or ethylenedioxydiradical. More preferably, in the compounds of formula (I) for use according to the present invention, X and Y (when present, i.e. wherein m and / or n is non-0) are independently selected from methyl, isopropyl, OH, methoxy, CF 3 or X and Y together represent a methylenedioxydiradical. Even more preferably, X is a methoxy group. Still more preferably, X is a methoxy group, m is 1, and Y is absent (i.e., n is 0).

[0101] Preferably, in the compounds of formula (I) for use according to the present invention, X (when present, ie wherein m is non-0) is independently selected from C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), CF 3, CN, F, Cl, Br and I; or X and Y together represent methylenedioxy or ethylenedioxydiradical. More preferably, in the compounds of formula (I) for use according to the present invention, X (when present, i.e., wherein m is non-0) is independently selected from methyl, isopropyl, OH, methoxy, CF 3 or X and Y together represent a methylenedioxydiradical. Even more preferably, X is a methoxy group. Still more preferably, X is a methoxy group and m is 1.

[0102] Preferably, in the compounds of formula (I) for use according to the present invention, Y (when present, ie wherein n is non-0) is independently selected from C 1 -C 6 Alkyl and O(C 1 -C 4 alkyl); or X and Y together represent a methylenedioxy or ethylenedioxydiradical. More preferably, in the compounds of formula (I) for use according to the present invention, Y (when present, i.e. wherein n is non-0) is independently selected from the group consisting of methyl and methoxy; or X and Y together represent a methylenedioxydiradical. Even more preferably, Y is absent (i.e. n is 0).

[0103] Preferably, in the compounds of formula (I) for use according to the present invention, X (when present, ie wherein m is non-0) is independently selected from C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), CF 3 , CN, F, Cl, Br and I; Y (when present, i.e., where n is non-0) is independently selected from the group consisting of C 1 -C 6 Alkyl and O(C 1 -C 4 or X and Y together represent a methylenedioxy or ethylenedioxydiyl radical. More preferably, in the compounds of formula (I) for use according to the present invention, X (when present, i.e. wherein m is non-0) is independently selected from methyl, isopropyl, OH, methoxy, CF 3 and Br; Y (when present, i.e. wherein n is non-0) is independently selected from the group consisting of methyl and methoxy; or X and Y together represent a methylenedioxydiradical. Even more preferably, X is methoxy. Still more preferably, X is methoxy, m is 1, and Y is absent (i.e. n is 0).

[0104] Preferably, in the compound of formula (I) for use according to the present invention, Z is selected from the group consisting of -S- and -O-, more preferably, Z is -S-.

[0105] Preferably, in the compounds of formula (I) for use according to the present invention, R 1 It is a straight chain C 1 -C 4 An alkylene diradical, which is optionally substituted by one or two substituents independently selected from the group consisting of a methyl group and an ethyl group. More preferably, R 1 It is C 1 -C 2 An alkylene diradical, which is optionally substituted with two methyl substituents. Even more preferably, R 1 Choose from -CH 2 - and -C(CH 3 ) 2 -a group consisting of. Still more preferably, R 1 Yes-CH 2 -.

[0106] Preferably, in the compounds of formula (I) for use according to the present invention, R 2 It is a straight chain C 1 -C 4 An alkylene diradical, which is optionally substituted by one or two substituents independently selected from the group consisting of a methyl group and a benzyl group. More preferably, R 2 It is a straight chain C 2 -C 3 An alkylene diradical optionally substituted by one or two substituents independently selected from the group consisting of a methyl group and a benzyl group. Even more preferably, R 2 Choose from -CH 2 -CH 2 -、-CH(Bn)-CH 2 -、-CH 2 -CH 2 -CH 2 - and - C(CH 3 ) 2 -CH 2 -a group consisting of. Still more preferably, R 2 Choose from -CH 2 -CH 2 -and-CH 2 -CH 2 -CH 2 -a group consisting of. Still more preferably, R 2 Yes-CH 2 -CH 2 -.

[0107] Preferably, in the compounds of formula (I) for use according to the present invention, R 3 It's H.

[0108] Preferably, in the compounds of formula (I) for use according to the present invention, W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 and -N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 More preferably, W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-morpholinyl, -NHC(=NH)NH 2 and -NHC(=NH)NHC(=NH)NH 2 Even more preferably, W is selected from the group consisting of: -NH 2 、-NH(CH 3 )、-N(CH 3 )2 、-N(CH 2 CH 3 ) 2 , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, -NHC(=NH)NH 2 and -NHC(=NH)NHC(=NH)NH 2 Still more preferably, W is selected from -N(CH 3 ) 2 , 1-piperidinyl, 4-morpholinyl and NHC(=NH)NHC(=NH)NH 2 Still more preferably, W is -N(CH 3 ) 2 .

[0109] In one embodiment, in the compound of formula (I) for use according to the present invention, m is 1; n is 0; X is selected from O(C 1 -C 4 Alkyl), C 1 -C 6 Alkyl and CF 3 Group composed of 1 Yes-CH 2 -; R 2 Choose from -CH 2 -CH 2 -and-CH 2 -CH 2 -CH 2 -Group composed of; R 3 is H; and W is selected from the group consisting of: -N(C 1 -C 4 alkyl) 2 , 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 4-piperazinyl, which are optionally substituted by C 1 -C 4 Alkyl substitution, and NHC(=NH)NHC(=NH)NH 2 .

[0110] In one embodiment, in the compound of formula (I) for use according to the present invention, m is 1; n is 0; X is selected from the group consisting of methoxy, isopropyl and CF 3 Group composed of 1 Yes-CH 2 -; R 2 Choose from -CH 2 -CH 2 -and-CH 2 -CH 2 -CH 2 -Group composed of; R 3is H; and W is selected from -N(CH 3 ) 2 , 1-piperidinyl, 4-morpholinyl and NHC(=NH)NHC(=NH)NH 2 Composed of groups.

[0111] In one embodiment, in the compound of formula (I) for use according to the present invention, Z is O or S; m is 1; n is 0; X is methoxy; R 1 Yes-CH 2 -; R 2 Yes-CH 2 -CH 2 -; R 3 is H; and W is -N(CH 3 ) 2 .

[0112] In one embodiment, in the compound of formula (I) for use according to the present invention, Z is O or S; m is 1; n is 0; X is methoxy; R 1 Yes-CH 2 -; R 2 Yes-CH 2 -CH 2 -; R 3 is H; W is -N(CH 3 ) 2 ; and X is located in the para position relative to Z.

[0113] In another embodiment, in the compounds of formula (I) for use according to the present invention, Z is -S-; R 1 Yes-CH 2 -; and R 3 It's H.

[0114] In a preferred embodiment, the compound of formula (I) for use according to the present invention is selected from the group consisting of:

[0115] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0116] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0117] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0118] 4-[(3,5-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole;

[0119] 1-[2-(N,N-dimethylamino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0120] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0121] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4,5-trimethoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0122] 4-[(3,4-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole;

[0123] 1-[2-(N,N-dimethylamino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0124] 4-[(4-methoxyphenoxy)methyl]-1-[2-(N-methylamino)ethyl]-1H-1,2,3-triazole;

[0125] 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0126] 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0127] 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0128] 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0129] 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0130] 4-[(4-methoxyphenoxy)methyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0131] 4-[(4-methoxyphenoxy)methyl]-1-[2-(morpholin-4-yl)ethyl]-1H,1,2,3-triazole;

[0132] 4-[(4-methoxyphenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0133] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0134] 1-[2-(Piperidin-1-yl)ethyl]-4-[(4-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0135] 1-[2-(Piperidin-1-yl)ethyl]-4-[(2-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0136] (Guanidinyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0137] 1-[2-(Guandino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0138] 1-[2-(Guandino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0139] 1-[2-(Guandino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0140] 1-[2-(Guandino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0141] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0142] 1-[2-(Biguanidino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0143] 1-[2-(Biguanidino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0144] 1-[2-(Biguanidino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0145] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0146] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenoxy)methyl]-1H-1,2,3-triazole;

[0147] 5-iodo-4-[(4-methoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole;

[0148] 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0149] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0150] 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0151] 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0152] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-(trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole;

[0153] 4-[(4-methoxyphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0154] 4-[(4-tert-Butylphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0155] 4-[(4-isopropylphenyl)thiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole;

[0156] 1-[2-(4-morpholinyl)ethyl]-4-(phenylthiomethyl)-1H,1,2,3-triazole;

[0157] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0158] 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0159] 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole;

[0160] 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-tert-butylphenyl)thiomethyl]-1H-1,2,3-triazole;

[0161] 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0162] 1-[2-(Guandino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0163] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0164] 1-[3-(Biguanidino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0165] 1-[2-(N,N-dimethylamino)ethyl]-5-iodo-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0166] 1-[2-(N,N-dimethylamino)ethyl]-5-tritiated-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0167] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0168] 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0169] 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0170] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0171] 4-[(4-isopropylphenyl)sulfinylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole;

[0172] 4-[(2,6-dimethylphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0173] 1-[2-(4-morpholinyl)ethyl]-4-(phenylsulfinylmethyl)-1H,1,2,3-triazole;

[0174] 4-[(4-methoxyphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0175] 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0176] 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0177] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0178] 1-(2-aminoethyl)-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0179] 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0180] 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole;

[0181] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole;

[0182] 1-[2-(N,N-diethylamino)ethyl]-4-[(4-bromophenyl)sulfonylmethyl]-1H-1,2,3-triazole;

[0183] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-dimethoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole;

[0184] 4-[(4-isopropylphenyl)sulfonylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole;

[0185] 4-(phenylsulfonylmethyl)-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole;

[0186] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenyl)sulfonylmethyl]-1H-1,2,3-triazole;

[0187] 1-(2-aminoethyl)-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole; and

[0188] 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole.

[0189] Even more preferably, the compound of formula (I) for use according to the present invention is chosen from the group consisting of 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole, 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole, 1-[2-(guanidino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole and 1-[2-(biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0190] Still more preferably, the compound of formula (I) for use according to the invention is 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0191] In a preferred embodiment, the ocular disease is a retinal disease. Preferably, the retinal disease is selected from the group consisting of: retinitis pigmentosa (such as autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other syndromes), diabetic retinopathy, cone dystrophy, rod and cone degeneration, Lebel congenital amaurosis, white punctate retinitis, choroideremia, gyratory choroidal and retinal atrophy, generalized choroidal dystrophy, juvenile retinoschisis, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinal choroidopathy, Starcharts disease, Best vitelliform macular dystrophy, Usher syndrome, Bard-Biedel syndrome, Thorsby pseudoinflammatory macular dystrophy, age-related macular degeneration, autosomal dominant congenital stationary night blindness, achromatopsia and dominant drusen. More preferably, the eye disease is selected from the group consisting of: retinitis pigmentosa (such as autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other syndromes), Starcharts disease, Lebel congenital amaurosis, age-related macular degeneration and diabetic retinopathy. Still more preferably, the eye disease is retinitis pigmentosa (such as autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other syndromes).

[0192] In another preferred embodiment, the retinal disease is selected from retinitis pigmentosa, autosomal dominant congenital stationary night blindness and achromatopsia.

[0193] The subject to which the compounds and pharmaceutical compositions described herein are administered is a human or an animal; preferably the subject is a mammal, more preferably a human.

[0194] In order to administer it to a subject in need of treatment (such as a mammal, for example, a human), the compounds and pharmaceutical compositions described herein can be administered by any appropriate route, such as topical, intraocular, oral (e.g., oral, sublingual, etc.), parenteral (e.g., subcutaneous, intramuscular, intravenous, intramuscular, etc.), rectal, nasal, etc. Therefore, in one embodiment, the compounds and pharmaceutical compositions described herein are administered topically, intraocular (e.g., subretinal or intravitreal), oral (including sublingual administration), parenteral (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous), transdermal, intranasal or rectal. In a preferred embodiment, the compounds and pharmaceutical compositions defined herein are administered topically on the corneal surface, preferably in the form of drops, gels, creams, sprays, contact lenses or intraocular rings.

[0195] Pharmaceutical compositions include a compound described herein and one or more pharmaceutically acceptable excipients or carriers.

[0196] The pharmaceutically acceptable carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and harmless to its recipient. The pharmaceutically acceptable carrier can be selected from organic and inorganic materials used in pharmaceutical preparations and incorporated as analgesics, pH regulators, linkers, disintegrants, diluents, emulsifiers, fillers, glidants, solubilizers, stabilizers, suspending agents, tonicity agents and thickeners. In addition, pharmaceutical additives such as antioxidants, aromatics, dyes, flavoring agents, preservatives and sweeteners can be added.

[0197] The compounds and pharmaceutical compositions described herein can be administered in different formulations. Examples are formulations for oral administration, i.e., tablets, capsules, syrups, or suspensions. In addition, the pharmaceutical compositions of the present invention may include topical compositions, i.e., creams, ointments, or pastes, or transdermal formulations, such as patches or plasters. The pharmaceutical compositions of the present invention may also be prepared for rectal administration, i.e., rectal gels or rectal capsules.

[0198] Suitable dosage forms for oral administration may be tablets, capsules, syrups or solutions, and may contain conventional excipients known in the art, such as binders, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example, magnesium stearate; disintegrants, for example, starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents, such as sodium lauryl sulfate.

[0199] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms. Appropriate excipients such as fillers, buffers or surfactants may be used.

[0200] In a preferred embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient selected from the group consisting of hyaluronic acid, carboxymethylcellulose, carbomer and mixtures thereof.

[0201] Even more preferably, the pharmaceutical composition comprises a compound of formula (I) selected from the group consisting of 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole, 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole, 1-[2-(guanidino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole and 1-[2-(biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole, and a pharmaceutically acceptable excipient selected from the group consisting of hyaluronic acid, carboxymethylcellulose, carbomer and mixtures thereof.

[0202] Still more preferably, the pharmaceutical composition comprises 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole and hyaluronic acid.

[0203] An "effective" amount or "therapeutically effective amount" of a compound means an amount of a drug or agent that is non-toxic but sufficient to provide the desired effect. The "effective" amount will vary from subject to subject, depending on the age and general condition of the individual, the specific active agent or agents, etc. Therefore, it is not always possible to specify an exact "effective amount". However, one of ordinary skill in the art can determine the appropriate "effective" amount in any individual case using routine experiments. The compound will generally be administered once or more daily, for example 1, 2, 3 or 4 times daily, with a typical total daily dose in the range of 0.001 to 500 mg / day, preferably at a dose of 0.001 to 10 mg / day.

[0204] In another aspect, the present invention relates to a compound of formula (II), which is a subgroup of the compound of formula (I):

[0205]

[0206] in

[0207] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C 4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0208] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0209] Z is selected from -S-, -S(=O)-, -S(=O) 2 A group consisting of - and -O-;

[0210] Each R is independently selected from H and CH 3 The group composed of;

[0211] R 3 Selected from the group consisting of H and I;

[0212] When Z is -S-, -S(=O)- or -S(=O) 2 -, p is selected from the group consisting of 1, 2, 3 and 4, and W is selected from the group consisting of: -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 and -N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 ;as well as

[0213] When Z is -O-, p is selected from the group consisting of 1, 2, and 4, and W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 、-N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 , -CO 2 H and -SO 3 H;

[0214] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof;

[0215] The proviso is that the compound is not 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole.

[0216] When m has a value other than 0, the X substituent is present. Similarly, when n has a value other than 0, the Y substituent is present.

[0217] In a preferred embodiment, in the compound of formula (II), when Z is -O-,

[0218] m is selected from the group consisting of 0, 1, 2 and 3;

[0219] n is selected from the group consisting of 0, 1 and 2;

[0220] When X is present, it is located at the meta or para position relative to Z and is selected from OH, O(C 1 -C 4 Alkyl), OCF 3 and CF 3 The group composed of;

[0221] When Y is present, it is located in the ortho position relative to Z and is CF 3 ;

[0222] or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0223] Each R is independently selected from H and CH 3 The group composed of;

[0224] R 3 Selected from the group consisting of H and I;

[0225] p is selected from the group consisting of 2 and 4;

[0226] W is selected from the group consisting of: -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 、-N(C 1 -C 4 alkyl) 3 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl, optionally with C 1 -C 4 4-morpholinyl substituted with alkyl, optionally with C 1 -C 4 Alkyl-substituted 4-piperazinyl, -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 and -N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 .

[0227] In the above embodiments, when Z is -S-, -S(=O)- or -S(=O) 2 -hour,

[0228] X and Y are independently selected from the group consisting of: C 1 -C 6 Alkyl, OH, O(C 1 -C 4 Alkyl), OCF 3 、S(C 1 -C 4 alkyl), NHC(O)(C 1 -C 4 Alkyl), CF 3 , F, Cl, Br and I; or X and Y together represent a methylenedioxy or ethylenedioxydiradical;

[0229] m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4;

[0230] Each R is independently selected from H and CH3 The group composed of;

[0231] R 3 Selected from the group consisting of H and I;

[0232] p is selected from the group consisting of 2, 3 and 4;

[0233] W is selected from the group consisting of: -NHC(=NH)NH 2 、-NHC(=NH)NH(C 1 -C 4 alkyl), -NHC(=N(C 1 -C 4 Alkyl)NH(C 1 -C 4 alkyl), -NHC(=NH)NHC(=NH)NH 2 and -N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2 .

[0234] In a preferred embodiment of the compound of formula (II), m is 1; n is 0; X is located in the para position relative to Z; X is O(C 1 -C 4 alkyl); Z is -S- or -O-; R is H; p is 2; R 3 is H; when Z is -S-, W is NHC(=NH)NHC(=NH)NH 2 ; and when Z is -O-, W is -N(C 1 -C 4 alkyl) 2 .

[0235] In a preferred embodiment of the compound of formula (II), m is 1; n is 0; X is located in the para position relative to Z; X is O(C 1 -C 4 alkyl); Z is -O-; R is H; p is 2; R 3 is H; and W is -N(C 1 -C 4 alkyl) 2 .

[0236] When m has a value other than 0, the X substituent is present. Similarly, when n has a value other than 0, the Y substituent is present.

[0237] Preferably, in the compounds of formula (II) according to the present invention, m is selected from the group consisting of 0, 1 and 2, more preferably m is 1.

[0238] Preferably, in the compounds of formula (II) according to the present invention, n is 0 or 1, more preferably n is 0.

[0239] Preferably, in the compounds of formula (II) according to the present invention, m is 1; n is 0; and X is located in the para position relative to Z.

[0240] Preferably, in the compounds of formula (II) according to the present invention, X and Y (when present, ie wherein m and / or n is non-0) are independently selected from O(C 1 -C 4 alkyl), OH and CF 3 or X and Y together represent a methylenedioxy or ethylenedioxydiradical. More preferably, in the compounds of formula (II) according to the present invention, X and Y (when present, i.e. wherein m and / or n are non-0) are independently selected from methoxy, OH and CF 3 or X and Y together represent a methylenedioxydiradical. Even more preferably, X is a methoxy group. Still more preferably, X is a methoxy group, m is 1, and Y is absent (i.e., n is 0).

[0241] In a specific embodiment, when X is present, it is located at the meta or para position relative to Z and is selected from O(C 1 -C 4 alkyl), OH and CF 3 and when Y is present, it is located in the ortho position relative to Z and is CF 3 .

[0242] Preferably, in the compounds of formula (II) according to the present invention, X (when present, ie wherein m is non-0) is independently selected from O(C 1 -C 4 alkyl), OH and CF 3 or X and Y together represent a methylenedioxy or ethylenedioxydiradical. More preferably, in the compounds of formula (II) according to the present invention, X (when present, i.e., wherein m is non-0) is independently selected from methoxy, OH and CF 3 or X and Y together represent a methylenedioxydiradical. Even more preferably, X is a methoxy group. Still more preferably, X is a methoxy group and m is 1.

[0243] Preferably, in the compounds of formula (II) for use according to the present invention, Y (when present, ie wherein n is non-0) is independently O(C 1 -C 4alkyl); or X and Y together represent methylenedioxy or ethylenedioxydiradical. More preferably, in the compounds of formula (II) according to the invention, Y (when present, i.e. wherein n is non-0) is independently methoxy; or X and Y together represent methylenedioxydiradical. Even more preferably, Y is absent (i.e. n is 0).

[0244] Preferably, in the compounds of formula (II) according to the present invention, X (when present, ie wherein m is non-0) is independently selected from O(C 1 -C 4 alkyl), OH and CF 3 Y (when present, i.e., where n is non-0) is independently O(C 1 -C 4 More preferably, in the compounds of formula (II) according to the present invention, X (when present, i.e. wherein m is non-0) is independently selected from methoxy, OH and CF 3 or X and Y together represent a methylenedioxydiradical. Even more preferably, X is methoxy. Still more preferably, X is methoxy, m is 1, and Y is absent (i.e., n is 0).

[0245] Preferably, in the compounds of formula (II) according to the invention, X (when present, ie wherein m is 0) is located in the meta or para position relative to Z, even more preferably in the para position.

[0246] Preferably, in the compounds of formula (II) according to the invention, Y (when present, ie wherein n is 0) is located in the ortho position relative to Z.

[0247] Preferably, in the compound of formula (II) according to the present invention, Z is selected from the group consisting of -S- and -O-. In one embodiment, Z is -S-. In another embodiment, Z is -O-.

[0248] Preferably, in the compounds of formula (II) according to the present invention, each R is independently selected from H and CH 3 ; Even more preferably, R is H.

[0249] Preferably, in the compounds of formula (II) according to the present invention, p is selected from 2 and 4. More preferably, p is 2.

[0250] Preferably, in the compounds of formula (II) according to the present invention, R 3 It's H.

[0251] Preferably, in the compounds of formula (II) according to the present invention, when Z is -S-, -S(=O)- or -S(=O) 2 -, W is selected from -NHC(=NH)NH 2 and -NHC(=NH)NHC(=NH)NH 2 Still more preferably, when Z is -S-, S(=O)- or -S(=O) 2 -, W is -NHC(=NH)NHC(=NH)NH 2 .

[0252] Preferably, in the compounds of formula (II) according to the present invention, when Z is -O-, W is selected from -NH 2 、-NH(C 1 -C 4 Alkyl), -N(C 1 -C 4 alkyl) 2 , optionally C 1 -C 4 1-pyrrolidinyl substituted with alkyl, optionally with C 1 -C 4 1-piperidinyl substituted with alkyl and optionally with C 1 -C 4 Even more preferably, when Z is -O-, W is selected from -NH 2 、-NH(CH 3 )、-N(CH 3 ) 2 More preferably, when Z is -O-, W is -N(CH 3 ) 2 .

[0253] In a specific embodiment, in the compound of formula (II) according to the present invention, m is 1; n is 0; X is selected from O(C 1 -C 4 alkyl), OH and CF 3 The group consisting of: R is H; p is 2; R 3 is H; Z is -O- or -S-, when Z is -O-, W is selected from the group consisting of: -N(C 1 -C 4 alkyl) 2 , 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, which is optionally substituted by C 1 -C 4 alkyl, and when Z is -S-, W is NHC(=NH)NHC(=NH)NH 2 .

[0254] In a specific embodiment, in the compound of formula (II) according to the present invention, m is 1; n is 0; X is selected from the group consisting of methoxy, OH and CF 3 The group consisting of: R is H; p is 2; R 3 is H; and Z is -O- or -S-, and when Z is -O-, W is selected from -N(C 1 -C 4 alkyl) 2 , 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, and when Z is -S-, W is NHC(=NH)NHC(=NH)NH 2 .

[0255] In another specific embodiment, in the compound of formula (II) according to the present invention, Z is -O-; m is 1; n is 0; X is methoxy; R is H; p is 2; R 3 is H; and W is -N(CH 3 ) 2 .

[0256] In another specific embodiment, in the compound of formula (II) according to the present invention, Z is -O-; m is 1; n is 0; X is methoxy; R is H; p is 2; R 3 is H; W is -N(CH 3 ) 2 ; and X is located in the para position relative to Z.

[0257] In a preferred embodiment, the compound of formula (II) is selected from the group consisting of:

[0258] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0259] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0260] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0261] 4-[(3,5-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole;

[0262] 1-[2-(N,N-dimethylamino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0263] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0264] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4,5-trimethoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0265] 4-[(3,4-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole;

[0266] 1-[2-(N,N-dimethylamino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0267] 4-[(4-methoxyphenoxy)methyl]-1-[2-(N-methylamino)ethyl]-1H-1,2,3-triazole;

[0268] 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0269] 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0270] 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0271] 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0272] 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0273] 4-[(4-methoxyphenoxy)methyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0274] 4-[(4-methoxyphenoxy)methyl]-1-[2-(morpholin-4-yl)ethyl]-1H,1,2,3-triazole;

[0275] 4-[(4-methoxyphenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole;

[0276] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0277] 1-[2-(Piperidin-1-yl)ethyl]-4-[(4-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0278] 1-[2-(Piperidin-1-yl)ethyl]-4-[(2-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole;

[0279] (Guanidinyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0280] 1-[2-(Guandino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0281] 1-[2-(Guandino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0282] 1-[2-(Guandino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0283] 1-[2-(Guandino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0284] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0285] 1-[2-(Biguanidino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0286] 1-[2-(Biguanidino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole;

[0287] 1-[2-(Biguanidino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole;

[0288] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole;

[0289] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenoxy)methyl]-1H-1,2,3-triazole;

[0290] 5-iodo-4-[(4-methoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole;

[0291] 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole;

[0292] 1-[2-(Guandino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0293] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0294] 1-[3-(Biguanidino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole;

[0295] Even more preferably, the compound of formula (II) is selected from the group consisting of 1-[2-(guanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole and 1-[2-(biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0296] Still more preferably, the compound of formula (II) is 1-[2-(biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0297] As shown in the examples and as explained for the compounds of the formula (I), the compounds of the formula (II) are also suitable for the treatment and / or prevention of eye diseases.

[0298] Therefore, another aspect relates to a compound of formula (II) as defined above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labelled derivative thereof, for use in medicine.

[0299] Another aspect relates to a compound of formula (II) as defined above, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof, for use in preventing and / or treating eye diseases.

[0300] This aspect can also be expressed as the use of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof in the manufacture of a medicament for preventing and / or treating eye diseases.

[0301] This aspect can also be expressed as a method for preventing and / or treating eye diseases, which comprises administering a compound of formula (II) as defined above or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof.

[0302] Preferably, the ocular disease is a retinal disease. More preferably, the retinal disease is selected from the group consisting of: retinitis pigmentosa (such as autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other syndromes), diabetic retinopathy, cone dystrophy, rod and cone degeneration, Lebel congenital amaurosis, white punctate retinitis, choroideremia, gyratory choroidal and retinal atrophy, generalized choroidal dystrophy, juvenile retinoschisis, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinal choroidopathy, Starcharts disease, Best vitelliform macular dystrophy, Usher syndrome, Bard-Biedel syndrome, Thorsby pseudoinflammatory macular dystrophy, age-related macular degeneration, autosomal dominant congenital stationary night blindness, achromatopsia and dominant drusen. More preferably, the eye disease is selected from the group consisting of: retinitis pigmentosa (such as autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other syndromes), Starcharts disease, Lebel congenital amaurosis, age-related macular degeneration and diabetic retinopathy. Still more preferably, the eye disease is retinitis pigmentosa (such as autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other syndromes).

[0303] In another preferred embodiment, the retinal disease is selected from retinitis pigmentosa, autosomal dominant congenital stationary night blindness and achromatopsia.

[0304] Another aspect relates to a pharmaceutical composition comprising a compound of formula (II) as defined above or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof, and a pharmaceutically acceptable excipient.

[0305] Pharmaceutically acceptable excipients, administration routes and dosage forms are as defined above. Preferably, the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethylcellulose, carbomer and mixtures thereof.

[0306] Compounds of formula (I) and formula (II) can be synthesized according to the procedures described in WO 2017 / 203083 A1, especially when Z is S, SO or SO 2 hour.

[0307] When Z is O, the following general synthetic routes can be used: a) reacting ω-chloroalkylamine hydrochloride with sodium azide in water at 80°C to form a solution of the corresponding ω-azidoalkylamine hydrochloride; b) mixing an aqueous solution of the ω-azidoalkylamine intermediate with a terminal aryloxyalkylalkyne in the presence of a catalytic amount of a copper salt (e.g., copper(II) sulfate, copper(I) acetate, copper(I) iodide), optionally in the presence of a base (e.g., potassium carbonate, sodium acetate, triethylamine, N,N-diisopropylethylamine), optionally in the presence of a copper reducing agent (e.g., sodium ascorbate), optionally in the presence of an added organic solvent (e.g., methanol, acetonitrile, tetrahydrofuran, tert-butanol); c) stirring the reaction mixture at room temperature until completion (usually overnight) and continuing with work-up. These routes are embodied in Examples 1, 9, and 33.

[0308] When W is a guanidine derivative, the following general synthetic route can be used: a) prepare 1-(ω-aminoalkyl)-1H-1,2,3-triazole as outlined above; b) react a primary amine with a stoichiometric amount of di-tert-butoxycarbonylthiourea S=C(NHBoc) at 0°C. 2 , molecular iodine and triethylamine in an aprotic solvent (e.g., dichloromethane) until completion (usually, 2 h); when W is an N-alkylated guanidine, a Boc-protected N-alkylthiourea S=C(NHBoc)[N(C 1 -C 4 -alkyl)Boc] or S=C[N(C 1 -C 4 -alkyl)Boc] 2 c) deprotecting the intermediate 1-[ω-(di-tert-butoxycarbonylguanidino)alkyl]-1H-1,2,3-triazole with a suitable acid (e.g., anhydrous HCl, trifluoroacetic acid in 1,4-dioxane). This synthetic route is described in Example 22.

[0309] When W is a biguanide derivative, the following general synthetic route can be used: a) prepare 1-(ω-aminoalkyl)-1H-1,2,3-triazole as outlined above; b) react the primary amine with stoichiometric amounts of cyanoguanidine and chlorotrimethylsilane in an aprotic solvent such as acetonitrile using an ACE pressure tube at 150°C until completion (typically, 15 min); when W is -N(C 1 -C 4 Alkyl)C(=NH)NHC(=NH)NH 2When N-alkylated biguanides of the type are prepared, the primary amine is replaced by 1-[ω-(N-alkyl-amino)alkyl]-1H-1,2,3-triazole, as embodied in Example 10; c) the mixture is cooled, isopropanol is added and the hydrochloride is recrystallized. This synthetic route is detailed in Example 27.

[0310] Example:

[0311] The following examples illustrate specific embodiments of the invention.

[0312] A) Synthesis A compound of formula (I), wherein Z is -O-

[0313] Example 1: (Compound 1)

[0314] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0315]

[0316] A solution of 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g) and sodium azide (13 mmol, 0.84 g) in water (10 mL) was heated at 80°C overnight. To the resulting solution of 2-azidoethyl-N,N-dimethylamine hydrochloride were added 4-methoxyphenyl propargyl ether (10 mmol, 1.63 g) dissolved in MeOH (40 mL), water (8 mL), CuOAc (0.5 mmol, 60 mg), NaOAc (30 mmol, 2.46 g) and sodium ascorbate (5 mmol, 0.99 g) in sequence, and the mixture was stirred at 30°C overnight. The organic solvent was evaporated, and the remaining aqueous solution was stirred with 20% ammonia (25 mL) for 30 min and extracted with EtOAc (3×50 mL). The organic phase was acidified with 2M HCl, and the aqueous layer was washed with EtOAc (50 mL). Use 20% Na for the aqueous phase 2 CO 3 The mixture was basified and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried (Na 2 SO 4 ) and evaporated under reduced pressure. The product was purified by column chromatography (silica gel, CH 2 Cl 2 / MeOH 95:5) to purify the crude product. Yield: 2.62 g (95%). White solid (Mp: 68°C). 1 H NMR (400 MHz, CDCl 3)δ7.76(s,1H),7.05–6.89(m,2H),6.89–6.69(m,2H),5.16(s,2H),4.45(t,J=6.3Hz,2H),3.77(s,3H),2.77(t,J=6.3Hz,2H),2.28(s,6H). 13 C NMR (126 MHz, CDCl 3 ): δ154.0,152.3,144.1,123.2,115.7,114.5,62.6,58.6,55.6,48.1,45.3. IR(cm –1 ):3142,2954,2789,2764,1739,1508,1466,1454,1285,1230,1213,1108,1059,1028,940,817,779,734,661,520. ESI-MS:HRMS:(M+H)C 14 H 20 N 4 O 2 , m / z calculated value 276.1586, found value 276.1591.

[0317] Example 2: (Compound 2)

[0318] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole

[0319]

[0320] Following the procedure of Example 1, starting from 3,4-methylenedioxyphenyl propargyl ether (10 mmol, 1.76 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g). Yield 2.34 g (80%). White solid (Mp: 44° C.). 1 HNMR (400MHz, CDCl 3 )δ7.78(s,1H),6.73(d,J=8.5Hz,1H),6.59(d,J=2.5Hz,1H),6.45(dd,J=8.5Hz,2.5Hz,1 H), 5.94 (s, 2H), 5.15 (s, 2H), 4.50 (t, J = 6.3Hz, 2H), 2.83 (t, J = 6.3Hz, 2H), 2.33 (s, 6H). 13 C NMR (75MHz, CDCl 3)δ154.4,148.9,144.7,142.7,124.0,108.6,106.8,101.8,99.2,63.7,59.3,48.8,46.0. IR(cm –1 ):3139,3101,2953,2884,2824,2765,1738,1638,1610,1500,1458,1358,1281,1257,1189,1035,926,836,800,670,606,541,432. ESI-MS:HRMS:(M+H)C 14 H 18 N 4 O 3 , m / z calculated value 290.1379, found value 290.1384.

[0321] Example 3: (Compound 3)

[0322] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0323]

[0324] Following the procedure of Example 1, starting from 3-methoxyphenyl propargyl ether (10.0 mmol, 1.78 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.62 g). Yield 2.24 g (81%). Oil. 1 H NMR (400 MHz, CDCl 3 )δ7.79(s,1H),7.21(t,J=8.2Hz,2H),6.65–6.53(m,3H),5.21(s,2H),4.47(t,J=6.3Hz,2H),3.80(s,3H),2.79(t,J=6.3Hz,2H),2.30(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ161.1,159.7,144.2,130.2,123.6,107.1,107.0,101.5,62.3,59.0,55.5,48.4,45.6.

[0325] Example 4: (Compound 4)

[0326] 4-[(3,5-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole

[0327]

[0328] Following the procedure of Example 1, starting from 3,5-dimethoxyphenyl propargyl ether (10.0 mmol, 1.92 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g). Yield 1.80 g (59%). White solid (Mp: 43° C.). 1 HNMR (400MHz, CDCl 3 )δ7.79(s,1H),6.20(d,J=2.1Hz,2H),6.13(t,J=2.2Hz,1H),5.18(s,2H),4.47(t,J=6.3Hz,2H),3.78(s,6H),2.79(t,J=6.3Hz,2H),2.31(s,6H). 13 C NMR (126 MHz, CDCl 3 ): δ161.7,160.3,143.9,123.5,93.8,93.7,62.3,58.9,55.5,48.4,45.5. IR(cm –1 ):2946,2767,1589,1449,1394,1361,1205,1147,1051,957,815,677,538. ESI-MS:HRMS:(M+H)C 15 H 22 N 4 O 3 , m / z calculated value 306.1692, found value 306.1698.

[0329] Example 5: (Compound 5)

[0330] 1-[2-(N,N-dimethylamino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole

[0331]

[0332] Following the procedure of Example 1, starting from phenyl propargyl ether (10 mmol, 1.32 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g). Yield 1.88 g (76%). White solid (Mp 34° C.). 1 H NMR (400 MHz, CDCl 3 )δ7.78(s,1H),7.35–7.25(m,2H),7.05–6.89(m,2H),5.22(s,2H),4.45(t,J=6.3Hz,2H),2.78(t,J=6.3Hz,2H),2.29(s,6H).

[0333] Example 6: (Compound 6)

[0334] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0335]

[0336] Following the procedure of Example 1, starting from 3-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 2-chloroethyl-N,N-dimethylammonium chloride (6 mmol, 0.86 g). Yield 1.41 g (90%). Pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ7.80(s,1H),7.36(t,J=8.0Hz,1H),7.24–7.07(m,3H),5.20(s,2H),4.42(t,J=6.2Hz,2H),2.73(t,J=6.2Hz,2H),2.24(s,6H).

[0337] Example 7: (Compound 7)

[0338] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4,5-trimethoxyphenoxy)methyl]-1H-1,2,3-triazole

[0339]

[0340] Following the procedure of Example 1, starting from 3,4,5-trimethoxyphenyl propargyl ether (5 mmol, 1.11 g) and 2-chloroethyl-N,N-dimethylammonium chloride (6 mmol, 0.86 g). Yield 1.44 g (86%). Pale yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ7.72(s,1H),6.18(s,2H),5.07(s,2H),4.34(t,J=6.2,2H),3.72(s,6H),3.67(s,3H),2.66(t,J=6.2,2H),2.17(s,6H). 13 C NMR (126 MHz, CDCl 3 ): δ155.0,153.8,144.0,132.7,123.5,92.8,62.6,61.1,58.8,56.2,48.4,45.5. IR(cm –1):2941,2824,2772,1737,1592,1504,1458,1420,1226,1192,1124,1046,1029,809,730. ESI-MS:HRMS:(M+H)C 16 H 24 N 4 O 4 , m / z calculated value 336.1798, found value 336.1801.

[0341] Example 8: (Compound 8)

[0342] 4-[(3,4-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole

[0343]

[0344] Following the procedure of Example 1, starting from 3,4-dimethoxyphenyl propargyl ether (10.0 mmol, 1.92 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g). Yield 1.89 g (62%). White solid (Mp: 39° C.). 1 HNMR (400MHz, CDCl 3 )δ7.76(s,1H),6.77(d,J=8.6Hz,1H),6.65(s,1H),6.57(d,J=8.5Hz,1H),5.18(s,2H) ,4.44(t,J=6.3Hz,2H),3.82(s,3H),3.86(s,3H),2.81(t,J=6.3Hz,2H),2.30(s,6H).

[0345] Example 9: (Compound 9)

[0346] 1-[2-(N,N-dimethylamino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole

[0347]

[0348] To a solution of 2-methyl-3-butyn-2-ol (57.2 mmol, 5.59 mL) and DBU (74.6 mmol, 11.13 mL) in dry acetonitrile (50 mL) cooled at 0°C under nitrogen atmosphere was added trifluoroacetic anhydride (57.2 mmol, 7.99 mL) dropwise, and the reaction mixture was stirred at 0°C for 30 minutes. This solution was added via cannula to 4-methoxyphenol (49.7 mmol, 6.17 g), DBU (64.6 mmol, 9.64 mL) and CuCl cooled to -5°C. 2 (0.05mmol, 6.7mg) was added to a stirred solution of dry acetonitrile (50mL). After the addition was complete, stirring was continued at room temperature for 16 hours. The organic solvent was evaporated in vacuo, and the residue was redissolved in EtOAc and washed with water (25mL), 1M HCl (25mL) and brine (25mL) in sequence. Finally, the organic layer was dried (Na2O3) and precipitated with 4% paraformaldehyde. 2 SO 4 ) and evaporated under reduced pressure to give the crude product, which was used in the subsequent reaction without further purification. 4-Methoxyphenyl 1,1-dimethyl-2-propynyl ether. Yield 9.00 g (95%). Dark brown oil. 1 H NMR (400 MHz, CDCl 3 )δ7.15(d,J=9.0Hz,1H),6.83(d,J=9.0Hz,1H),3.77(s,3H),2.57(s,1H),1.62(s,6H). 13 CNMR (126MHz, CDCl 3 ): δ155.9,149.0,123.8,114.0,86.5,73.9,55.6,29.6. IR(cm –1 ):3284,2988,2936,2835,1724,1606,1588,1503,1464,1441,1230,1211,1135,1034,949,890,843,756,733,640,532. According to the procedure of Example 1, the alkyne was reacted with 2-azidoethyl-N,N-dimethylammonium chloride. Yield 2.71 g (89%). White solid (Mp: 37°C). 1 H NMR (400 MHz, CDCl 3 )δ7.47(s,1H),6.59–6.51(m,4H),4.30(t,J=6.4Hz,2H),3.60(s,3H),2.62(t,J=6.4Hz,2H),1.92(s,6H),1.60(s,6H).

[0349] Example 10: (Compound 10)

[0350] 4-[(4-methoxyphenoxy)methyl]-1-[2-(N-methylamino)ethyl]-1H-1,2,3-triazole

[0351]

[0352] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl ether (5.0 mmol, 815 mg) and 2-(N-methylamino)ethyl-1-ammonium chloride (7.0 mmol, 928 mg). Yield 917 mg (70%). Pale yellow solid (Mp: 34° C.). 1 HNMR (400MHz, CD 3 OD)δ8.07(s,1H),6.96(d,J=9.1Hz,2H),6.92–6.83(m,2H),5.13(s,2H),4.55(t,J=6.2Hz,2H),3.76(s,3H),3.08(t,J=6.2Hz,2H),2.41(s,3H). 13 C NMR (126 MHz, CDCl 3 ): δ153.9,148.4,144.1,142.2,123.5,108.1,106.3,101.4,98.7,63.2,58.9,48.4,45.6. IR(cm –1 ):2942,2835,2799,1738,1505,1462,1364,1217,1108,1033,1009,824,733,521. ESI-MS:HRMS:(M+H)C 13 H 18 N 44 O 2 , m / z calculated value 262.1430, found value 262.1432.

[0353] Example 11: (Compound 11)

[0354] 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0355]

[0356] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl ether (20.0 mmol, 2.64 g), 2-chloroethyl-1-ammonium chloride (30.0 mmol, 3.47 g). Yield 3.02 g (61%). Light brown solid (Mp: 66.5-68.0 °C). 1H NMR (400MHz, CD 3 OD) δ 8.05 (s, 1H), 6.95 (d, J = 9.1Hz, 2H), 6.86 (d, J = 9.2Hz, 2H), 5.11 (s, 2H), 4.46 (t, J = 6.1Hz, 2H), 3.75 (s, 3H), 3.12 (t, J = 6.2Hz, 2H).

[0357] Example 12: (Compound 12)

[0358] 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0359]

[0360] Following the procedure of Example 1, starting from 3-methoxyphenyl propargyl ether (10.0 mmol, 1.62 g), 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g). Yield 1.54 g (62%). Light brown solid. 1 H NMR (400MHz, CD 3 OD)δ8.06(s,1H),7.18(t,J=8.1Hz,2H),6.68–6.51(m,3H),5.15(s,2H),4.46(t,J=6.2Hz,2H),3.76(s,3H),3.12(t,J=6.1Hz,2H).

[0361] Example 13: (Compound 13)

[0362] 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole

[0363]

[0364] Following the procedure of Example 1, starting from 3,4-methylenedioxyphenyl propargyl ether (10 mmol, 1.92 g) and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g). Yield 1.75 g (67%). Orange solid (Mp: 56° C.). 1 H NMR (400MHz, CD 3OD)δ8.0(s,1H),6.71(d,J=8.5Hz,1H),6.59(d,J=2.6Hz,1H),6.46(dd,J=8.5Hz,2.5Hz, 1H), 5.89 (s, 2H), 5.09 (s, 2H), 4.84 (s, 1H), 4.46 (t, J = 6.1Hz, 2H), 3.13 (t, J = 6.1Hz, 3H). 13 C NMR (126 MHz, CDCl 3 ): δ153.8,148.4,144.1,142.2,123.5,108.0,106.2,101.3,98.5,63.0,53.5,42.0. IR(cm –1 ):3365,2943,2922,1619,1483,1389,1359,1266,1237,1181,1133,1099,1057,1035,998,937,838,810,780,737,610,511,437. ESI-MS:HRMS:(M+H)C 13 H 18 N 4 O 2 , m / z calculated value 262.1430, found value 262.1432.

[0365] Example 14: (Compound 14)

[0366] 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole

[0367]

[0368] Following the procedure of Example 1, starting from phenyl propargyl ether (10 mmol, 1.32 g) and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g). Yield 1.13 g (52%). Pale yellow solid (Mp: 34° C.). 1 H NMR (400MHz, CD 3 OD)δ8.09(s,1H),7.37 -7.02(m,5H),5.19(s,2H),4.48(t,J=6.1,2H),3.14(s,2H). 13 C NMR (126 MHz, CDCl 3 ): δ158.3,144.3,129.7,123.6,121.4,114.9,62.1,53.4,41.9. IR(cm –1):3338,2873,1738,1636,1599,1586,1561,1484,1427,1384,1338,1226,1173,1079,1052,1007,843,818,748,690,511. ESI-MS:HRMS:(M+H)C 11 H 14 N 4 O, m / z calculated value 218.1168, found value 218.1168.

[0369] Example 15: (Compound 15)

[0370] 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole

[0371]

[0372] Following the procedure of Example 1, starting from 4-methoxyphenyl 1,1-dimethyl-2-propynyl ether (10 mmol, 1.90 g) and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g) prepared in Example 9. Yield 2.00 g (72%). Brown oil. 1 HNMR (400MHz, CD 3 OD)δ7.87(s,1H),6.76–6.67(m,2H),6.67–6.59(m,2H),4.43(t,J=6.2Hz,2H),3.72(s,3H),3.09(t,J=6.2Hz,2H),1.73(s,6H). 13 C NMR (126 MHz, CDCl 3 ): δ156.1,153.1,148.8,124.6,122.4,114.3,77.0,56.0,53.6,42.4,28.1. IR(cm –1 ):3366,2981,2935,1502,1463,1441,1381,1365,1290,1214,1134,1032,940,924,875,844,799,732. ESI-MS:HRMS:(M+H)C 14 H 20 N 4 O 2 , m / z calculated value 276.1586, found value 276.1589.

[0373] Example 16: (Compound 16)

[0374] 4-[(4-methoxyphenoxy)methyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazole

[0375]

[0376] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl ether (5 mmol, 811 mg) and 1-(2-chloroethyl)pyrrolidine hydrochloride (7.5 mmol, 1.38 g). Yield 1.47 g (97%). White solid (Mp: 57° C.). 1 H NMR (400 MHz, CDCl 3 )δ7.75(s,1H),6.93(d,J=9.Hz,2H),6.84(d,J=9.1Hz,2H),5.17(s,2H),4.47(t,J=6.2H z, 2H), 3.77 (s, 3H), 3.67 (t, J = 4.6Hz, 4H), 2.83 (t, J = 6.2Hz, 2H), 2.49 (t, J = 4.5Hz, 4H). 13 CNMR (126MHz, CDCl 3 ): δ154.4,152.5,144.5,123.4,116.0,114.8,67.0,63.0,58.0,55.9,53.7,47.6. IR(cm –1 ):3134,2958,2780,2102,1737,1507,1459,1436,1350,1284,1213,1108,1028,933,819,791,734,666,518. ESI-MS:HRMS:(M+H)C 16 H 22 N 4 O 2 , m / z calculated value 302.1743, found value 302.1741.

[0377] Example 17: (Compound 17)

[0378] 4-[(4-methoxyphenoxy)methyl]-1-[2-(morpholin-4-yl)ethyl]-1H,1,2,3-triazole

[0379]

[0380] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl ether (5 mmol, 811 mg) and 1-(2-chloroethyl)morpholine hydrochloride (7.5 mmol, 1.38 g). Yield 1.24 g (78%). White solid (Mp: 78° C.). 1H NMR (400 MHz, CDCl 3 )δ7.75(s,1H),7.00–6.89(m,2H),6.84(dd,J=8.6,1.5,2H),5.17(d,J=1.6,2H),4.47(td,J=6.2 ,1.5,3H),3.77(d,J=1.3,3H),3.72–3.63(m,4H),2.83(td,J=6.2,1.7,2H),2.49(t,J=4.5,4H). 13 C NMR (126 MHz, CDCl 3 ): δ154.4,152.5,144.5,123.4,116.1,114.8,67.0,63.0,58.0,55.9,53.7,47.6. IR(cm –1 ):3074,2862,1738,1508,1456,1377,1218,1148,1113,1033,916,869,820,798,716,553,518. ESI-MS:HRMS:(M+H)C 16 H 22 N 4 O 3 , m / z calculated value 318.1692, found value 318.1697.

[0381] Example 18: (Compound 18)

[0382] 4-[(4-methoxyphenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0383]

[0384] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl ether (5 mmol, 811 mg) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g). Yield 1.43 g (90%). Slightly yellow oil. 1 H NMR (400 MHz, CDCl 3 )δ7.78(s,1H),7.01–6.90(m,2H),6.88–6.80(m,2H),5.17(s,2H),4.45(t,J=6.4Hz,2H),3.77(s,3H ), 2.76 (t, J = 6.4Hz, 2H), 2.42 (t, J = 5.4Hz, 4H), 1.57 (dq, J = 16.7, 5.6Hz, 4H), 1.45 (q, J = 5.9Hz, 2H). 13C NMR (126 MHz, CDCl 3 ): δ154.1,152.3,144.1,123.3,115.8,114.6,62.7,58.1,55.6,54.4,47.8,25.9,24.1. IR(cm –1 ):3087,2932,2777,2098,1738,1509,1467,1440,1305,1229,1146,1107,1051,1032,853,818,787,709,548,512. ESI-MS:HRMS:(M+H)C 17 H 24 N 4 O 2 , m / z calculated value 316.1899, found value 316.1901.

[0385] Example 19: (Compound 19)

[0386] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0387]

[0388] Following the procedure of Example 1, starting from 3-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g). Yield 1.58 g (89%). Oil. 1 HNMR (400MHz, CDCl 3 )δ7.83(s,1H),7.39(t,J=8.0Hz,2H),7.25–7.15(m,2H),5.25(s,2H),4.46(t,J=6.3Hz,2 H), 2.75 (t, J = 6.3Hz, 2H), 2.41 (t, J = 5.2Hz, 4H), 1.54 (p, J = 5.5Hz, 4H), 1.48–1.37 (m, 2H).

[0389] Example 20: (Compound 20)

[0390] 1-[2-(Piperidin-1-yl)ethyl]-4-[(4-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0391]

[0392] Following the procedure of Example 1, starting from 4-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g). Yield 1.62 g (92%). Oil. 1 HNMR (400MHz, CDCl 3 )δ7.83(s,1H),7.56(d,J=8.5Hz,2H),7.09(d,J=8.5Hz,2H),5.28(s,2H),4.49(t,J=6.3Hz, 2H), 2.78(t,J=6.3Hz,2H), 2.43(t,J=5.4Hz,4H), 1.56(p,J=5.5Hz,4H), 1.52–1.41(m,2H).

[0393] Example 21: (Compound 21)

[0394] 1-[2-(Piperidin-1-yl)ethyl]-4-[(2-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0395]

[0396] Following the procedure of Example 1, starting from 2-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g). Yield 1.58 g (90%). Oil. 1 HNMR (400MHz, CDCl 3 )δ7.84(s,1H),7.59–7.54(m,1H),7.52–7.44(m,1H),7.17(d,J=8.3Hz,1H),7.01(t,J=7.6Hz,1H),5.33(s,2H) ,4.44(t,J=6.2Hz,2H),2.73(t,J=6.2Hz,2H),2.40(t,J=5.4Hz,4H),1.53(p,J=5.5Hz,4H),1.47–1.35(m,2H).

[0397] Example 22: (Compound 22)

[0398] (Guanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0399]

[0400] 1-[(2-aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg), di-tert-butoxycarbonylthiourea (1.2 mmol, 332 mg), and I 2 (1.2mmol, 305mg) and triethylamine (1.2mmol, 121mg) were dissolved in CH 2 Cl 2 (10 mL) and the mixture was stirred at 0°C for two hours. The volatiles were evaporated under reduced pressure and saturated NH 4 Cl solution (10 mL) and CH 2 Cl 2 The aqueous solution was extracted with 10 mL (3 × 10 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated under reduced pressure. The crude product was purified by column chromatography (CH 2 Cl 2 / MeOH 98:02; CH 2 Cl 2 / MeOH 95:05) to obtain the intermediate 1-[2-(N,N'-di-tert-butoxycarbonylguanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole. Yield: 251 mg (51%). Light yellow solid. 1 H NMR (300 MHz, CDCl 3 )δ11.43(s,1H),8.57(t,J=5.8Hz,1H),7.71(s,1H),6.92(d,J=9.2Hz,2H),6.82(d,J=9.2Hz,2H ),5.16(s,2H),4.59(d,J=6.5,2H),3.93(q,J=5.9,2H),3.76(s,3H),1.51(s,9H),1.47(s,9H). 13 C NMR (126 MHz, CDCl 3 )δ162.8,156.2,154.0,152.8,152.2,144.5,123.2,115.7,114.5,83.5,79.6,62.6,55.5,49.1,40.5,28.1,27.9. IR(cm –1 ):3326,2979,2932,1721,1637,1614,1567,1506,1413,1366,1324,1226,1133,1097,1038,911,823,731. ESI-MS:HRMS:(M+H)C 23 H 34 N6 O 6 , m / z calculated value 490.2542, found value 490.2540. The intermediate diurethane compound (0.5 mmol, 245 mg) was reacted in CH 2 Cl 2 To the solution in 4% paraformaldehyde (5 mL) was added anhydrous HCl (4.0 M in dioxane, 1.1 mmol, 0.27 mL) and the reaction mixture was stirred at 0-5 °C for 4 h. After completion, the volatiles were evaporated under reduced pressure and washed with anhydrous Et 2 The residue was washed with 2% O to obtain the hydrochloride of the product. Yield: 147 mg (90%). Pale yellow solid. 1 H NMR (400MHz, CD 3 OD)δ7.99(s,1H),6.84(d,J=9.1Hz,2H),6.75(d,J=9.1Hz,2H),5.02(s,2H),4.52(t,J=6.5,2H),3.68(t,J=6.1,2H),3.65(s,3H). 13 C NMR (75MHz, CD 3 OD)δ158.8,155.8,153.7,145.6,125.8,117.0,115.7,63.0,56.1,50.1,42.1. IR(cm –1 ):3304,2955,1670,1619,1619,1506,1464,1440,1199,1181,1132,1034,827,799,721. ESI-MS:HRMS:(M+H)C 13 H 18 N 6 O 2 , m / z calculated value 290.1491, found value 290.1496.

[0401] Example 23: (Compound 23)

[0402] 1-[2-(Guandino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0403]

[0404] Following the procedure of Example 22, starting from 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg) prepared according to Example 12, the intermediate 1-[2-(N,N'-di-tert-butoxycarbonylguanidino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole was obtained. Yield 305 mg (62%). Pale yellow solid. 1 HNMR (400MHz, CDCl 3 )δ11.42(s,1H),8.57(s,1H),7.73(s,1H),7.32–7.15(m,1H),6.65–6.50(m,3H),5.18( s, 2H), 4.58 (t, J = 5.9, 2H), 3.94 (t, J = 5.9, 2H), 3.77 (s, 3H), 1.49 (s, 9H), 1.46 (s, 9H). 13 C NMR (126 MHz, CDCl 3 )δ162.9,160.6,159.3,156.1,152.7,144.0,129.8,123.3,106.8,106.6,101.1,83.4,79.5,61.8,55.1,49.1,40.4,28.1,27.8. IR(cm –1 ):3326,3146,2978,2935,1721,1638,1612,1492,1413,1366,1325,1133,1097,1043,1018,731. ESI-MS:HRMS:(M+H)C 23 H 34 N 6 O 6 , m / z calculated 490.2540, found 490.2542. Deprotection of dicarbamate (0.5 mmol, 245 mg) provided the product. Yield 49 mg (97%). Light yellow solid. 1 H NMR (400MHz, CD 3 OD)δ8.01(s,1H),7.08(t,J=8.1,1H),6.58–6.39(m,3H),5.06(s,2H),4.53(dt,J=6.5,2H),3.69(t,J=6.0,2H),3.66(s,3H). 13 C NMR (75MHz, CD 3OD)δ162.3,160.8,158.8,145.3,131.0,125.9,107.9,107.8,102.3,62.3,55.7,50.1,42.1. IR(cm –1 ):3331,2942,2376,1671,1593,1492,1454,1436,1284,1263,1197,1135,1043,974,834,799,764,721. ESI-MS:HRMS:(M+H)C 13 H 18 N 6 O 2 , m / z calculated value 290.2542, found value 290.254.

[0405] Example 24: (Compound 24)

[0406] 1-[2-(Guandino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole

[0407]

[0408] Following the procedure of Example 22, starting from 1-(2-aminoethyl)-4-[3,4-(methylenedioxy)phenoxymethyl]-1H-1,2,3-triazole (1 mmol, 262 mg) prepared according to Example 13. Yield 288 mg (57%). Pale yellow solid. 1 HNMR (400MHz, CDCl 3 )δ11.43(s,1H),8.60(s,1H),7.71(s,1H),6.70(d,J=8.5,1H),6.56(d,J=2.3,1H),6.42(ddd,J=8.4,2.6 ,0.9,2H),5.92(s,2H),5.13(s,2H),4.60(t,J=5.9,2H),3.95(q,J=6.1Hz,2H),1.51(s,9H),1.48(s,9H). 13 C NMR (126 MHz, CDCl 3 )δ162.8,156.1,153.4,152.7,148.0,144.0,141.8,123.3,107.7,105.85,101.0,98.3,83.4,79.5,62.7,49.0,40.4,28.0,27.8. IR(cm –1):3327,3138,2978,2933,1720,1613,1563,1486,1413,1366,1324,1228,1177,1131,1097,1034,1016,916,809,775,730,611. ESI-MS:HRMS:(M+H)C 23 H 32 N 6 O 7 , m / z calculated 504.2332, found 504.2331. Deprotection of dicarbamate (0.5 mmol, 252 mg) provided the product. Yield 162 mg (95%). Light yellow solid. 1 H NMR (400MHz, CD 3 OD)δ7.99(s,1H),6.60(d,J=8.5Hz,1H),6.47(d,J=2.5Hz,1H),6.34(dd,J=8.4 ,2.6Hz,1H),5.78(s,2H),4.99(s,2H),4.53(t,J=5.8,2H),3.69(t,J=5.8,2H). 13 C NMR (75MHz, CD 3 OD)δ158.7,154.9,149.6,145.2,143.4,125.8,108.8,107.2,102.4,99.3,63.2,63.2,50.1,42.0. IR(cm –1 ):3336,2896,2377,1670,1612,1502,1486,1363,1178,1131,1035,925,834,799,721. ESI-MS:HRMS:(M+H)C 13 H 16 N 6 O 3 , m / z calculated value 304.1355, found value 304.1360.

[0409] Example 25: (Compound 25)

[0410] 1-[2-(Guandino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole

[0411]

[0412] Following the procedure of Example 22, starting from 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole (0.80 mmol, 176 mg) prepared according to Example 14. Yield 266 mg (71%). White solid.1 H NMR (400 MHz, CDCl 3 )δ11.45(s,1H),8.64(s,1H),7.74(s,1H),7.43–7.22(m,2H),7.11–6.92(m,3H),5.25(s,2H),4.62(t,J=5.9Hz,2H),3.98(q,J=5.9Hz,2H),1.54(s,9H),1.51(s,9H). Deprotection of dicarbamate (0.40mmol, 109mg) provided the product. Yield 175mg (95%). White solid. 1 H NMR (400MHz, CD 3 OD)δ8.11(s,1H),7.38-6.91(m,5H),5.20(s,2H),4.72(t,J=6.5,2H),3.88(t,J=6.1,2H).

[0413] Example 26: (Compound 26)

[0414] 1-[2-(Guandino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole

[0415]

[0416] The procedure of Example 22 was followed, starting from 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole (1 mmol, 276 mg) prepared according to Example 15. Yield 108 mg (34%). Oil. 1 HNMR (400MHz, CD 3 OD) δ 7.01 (s, 1H), 7.22 (d, J = 8.7Hz, 2H), 6.88 (d, J = 8.6Hz, 2H), 4.57 (t, J = 6.3Hz, 2H), 3.74 (s, 3H), 3.62 (t, J = 6.3Hz, 2H), 1.70 (s, 6H).

[0417] Example 27: (Compound 27)

[0418] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0419]

[0420] A mixture of 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg), cyanoguanidine (1 mmol, 84 mg), acetonitrile (1.35 mL) and chlorotrimethylsilane (1.1 mmol, 0.14 mL) placed in an ACE pressure tube was stirred in a silicone oil bath heated to 150°C for 15 minutes. Then, the ACE tube was cooled to 50°C for 10 minutes, isopropanol (3 mmol, 0.23 mL) was added, and the mixture was heated to 125°C for one minute again by using another silicone oil bath. Finally, the reaction mixture was cooled to room temperature, the resulting hydrochloride solid product was filtered out, and the product was further purified by column chromatography if necessary. Yield: 218 mg, (57%). Oil. 1 H NMR (400MHz, CD 3 OD) δ 8.07 (s, 1H), 7.35 (d, J = 8.3Hz, 2H), 6.90 (d, J = 8.2Hz, 2H), 4.80 (d, J = 5.4Hz, 2H), 4.19 (s, 2H), 3.80 (s, 3H), 3.54 (d, J = 5.3Hz, 2H). 13 CNMR(101MHz,CD 3 OD)δ164.6,161.2,159.0,145.9,135.3,126.5,125.7,115.8,55.9,49.3,40.0,30.6.

[0421] Example 28: (Compound 28)

[0422] 1-[2-(Biguanidino)ethyl]-4-[(3-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0423]

[0424] Following the procedure of Example 27, starting from 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg). Yield: 236 mg, (71%). Oil. 1 H NMR (400MHz, CD 3 OD)δ8.53(s,1H),7.35–7.18(m,1H),6.67–6.55(m,2H),5.19(s,2H),4.80(t,J=5.4Hz,2H),3.94(d,J=5.3Hz,2H),3.79(s,3H).

[0425] Example 29: (Compound 29)

[0426] 1-[2-(Biguanidino)ethyl]-4-[(3-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0427]

[0428] Following the procedure of Example 27, starting from 1-(2-aminoethyl)-4-[3,4-(methylenedioxy)phenoxymethyl]-1H-1,2,3-triazole (1 mmol, 262 mg). Yield: 152 mg, (44%). Oil. 1 HNMR (400MHz, CD 3 OD)δ7.81(s,1H),6.62(d,J=8.4Hz,1H),6.48(d,J=2.5Hz,1H),6.35(dd,J=8.4 ,2.5Hz,1H),5.79(s,2H),4.94(s,2H),4.55(t,J=5.7,2H),3.65(t,J=5.7,2H).

[0429] Example 30: (Compound 30)

[0430] 1-[2-(Biguanidino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole

[0431]

[0432] Following the procedure of Example 27, starting from 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole (1.00 mmol, 218 mg). Yield: 148 mg, (49%). Oil. 1 H NMR (400MHz, CD 3 OD)δ8.06(s,1H),7.39-6.89(m,5H),5.21(s,2H),4.72(t,J=6.4,2H),3.90(t,J=6.4,2H).

[0433] Example 31: (Compound 31)

[0434] 1-[2-(Biguanidino)ethyl]-4-[(3-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0435]

[0436] Following the procedure of Example 27, starting from 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole (1 mmol, 276 mg). Yield 100 mg (28%). Oil. 1 HNMR (400MHz, CD 3 OD) δ 7.94 (s, 1H), 7.24 (d, J = 8.7Hz, 2H), 6.82 (d, J = 8.7Hz, 2H), 4.55 (t, J = 6.3Hz, 2H), 3.79 (s, 3H), 3.66 (t, J = 6.3Hz, 2H), 1.76 (s, 6H).

[0437] Example 32: (Compound 32)

[0438] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenoxy)methyl]-1H-1,2,3-triazole

[0439]

[0440] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 278 mg), thiophenol (1 mmol, 0.103 mL) and K 2 CO 3 A solution of (catalytic, 7 mg) in N-methylpyrrolidone (1 mL) was heated to 200° C. under nitrogen for 2 hours. The solvent was evaporated in vacuo and the product was purified by column chromatography (silica gel; CH 2 Cl 2 / MeOH (7M NH 3 )95:5) to purify the residue. Yield: 160 mg (61%). 1 H NMR (400 MHz, CDCl 3 )δ7.49(s,1H),7.05-6.95(m,2H),6.89-6.78(m,2H),5.08(s,2H),4.47(t,J=6.4Hz,2H),2.71(t,J=6.4Hz,2H),2.30(s,6H).

[0441] Example 33: (Compound 33)

[0442] 5-Iodo-4-[(4-methoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole

[0443]

[0444] 4-Methoxyphenyl propargyl ether (3 mmol, 486 mg), CuI (3.4 mmol, 649 mg), NBS (3.6 mmol, 3.6 mg), and DIPEA (3.4 mmol, 591 μL) were added to a dry CH 3 2-Azido-N,N-dimethylethyl-1-amine (3.3 mmol, 376 mg) was added to a solution in CN (8 mL), and the reaction mixture was stirred at room temperature for 2 h. Then, the solvent was evaporated under reduced pressure, and the residue was suspended in saturated aqueous NaCl solution (10 mL) and washed with CH 2 Cl 2 The aqueous suspension was extracted with 10 mL of saturated NaCl solution (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL) and purified by MgSO 4 The product was purified by column chromatography. (CH 2 Cl 2 / MeOH 20:1). Yield 0.85 g (70%), brown solid. 1 H NMR (400 MHz, CDCl 3 )δ7.05–6.93(m,2H),6.89–6.79(m,2H),5.07(s,2H),4.48(t,J=7.2Hz,2H),3.76(s,3H),2.82(t,J=7.2Hz,2H),2.32(s,6H). 13 C NMR (101 MHz, CDCl 3 ): δ154.1,152.2,147.2,116.1,114.4,81.3,62.4,58.2,55.5,48.5,45.4,45.2. IR(cm –1 ):2994,2937,2827,2795,2768,1712,1506,1461,1452,1287,1215,1130,1081,1035,1005,926,860,821,804,707,523. ESI-MS:HRMS:(M+H)C 14 H 19 IN 4 O 2 , m / z calculated value 402.0553, found value 402.0562.

[0445] Example 34: (Compound 34)

[0446] 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0447]

[0448] A solution of 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 276 mg) and 33% aqueous hydrogen peroxide (1 mL) in MeOH (4 mL) was stirred at room temperature overnight. The solvent was evaporated to below 25°C using a high-efficiency vacuum pump. Yield: 289 mg (98%). Colorless oil. 1 H NMR (400MHz, CD 3 OD)δ8.18(s,1H),6.94(d,J=9.1Hz,2H),6.86(d,J=9.2Hz,2H),5.13(s,2H ), 5.03 (t, J = 6.5Hz, 2H), 3.96 (t, J = 6.5Hz, 2H), 3.75 (s, 3H), 3.23 (s, 6H).

[0449] B) Synthesis A compound of formula (I), wherein Z is -S-

[0450] Example 35: (Compound 35)

[0451] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0452]

[0453] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl sulfide (30 mmol, 5.35 g) and 2-chloroethyl-N,N-dimethylammonium hydrochloride (36 mmol, 5.18 g), yield 7.53 g (86%). White solid (Mp: 35-40° C.). 1 HNMR (400MHz, CD 3 OD)δ7.67(s,1H),7.29(d,J=8.7Hz,2H),6.85(d,J=6.9Hz,2H),4.44(t,J= 6.5Hz, 2H), 4.09 (s, 2H), 3.77 (s, 3H), 2.75 (t, J = 6.5Hz, 2H), 2.27 (s, 6H). 13 C RMN(101MHz,CDCl 3 ):159.2,144.8,133.7,125.5,122.6,114.5,58.6,55.3,48.0,45.3,30.9. ESI-MS:HRMS:(M+H)C 14 H 21 N4 OS, m / z 293.1436; found: 293,1440.

[0454] Example 36: (Compound 36)

[0455] 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0456]

[0457] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl sulfide (10 mmol, 1.91 g) and 3-chloropropyl-N,N-dimethylammonium hydrochloride (12 mmol, 1.89 g). Yield 2.31 g (70%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.64(s,1H),7.30(d,J=8.8Hz,2H),6.86(d,J=8.7Hz,2H),4.37(t,J=6.9Hz,2H),4 .09(s,2H),3.78(s,3H),2.25(t,J=5.4Hz,2H),2.22(s,6H),2.01(q,J=8.1,6.5Hz,2H). 13 CNMR(101MHz,CD 3 OD)δ164.9,138.3,134.5,128.6,127.8,116.8,57.1,54.5,54.4,50.4,49.0,12.9. IR(cm –1 ):2942,2818,2767,1591,1492,1459,1283,1242,1174,1027,824,637,522.

[0458] Example 37: (Compound 37)

[0459] 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0460]

[0461] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl sulfide (15 mmol, 2.67 g) and 2-chloroethyl-N,N-diethylammonium hydrochloride (18.0 mmol, 3.10 g). Yield 2.74 g (57%). Brown oil. 1 H NMR (400MHz, CD 3OD)δ7.66(s,1H),7.29(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),4.37(t,J=6.5Hz,2H),4 .09(s,2H),3.74(s,3H),2.83(t,J=6.5Hz,2H),2.50(q,J=7.1Hz,4H),0.95(t,J=s,6H). 13 C NMR (101 MHz, CD 3 OD): δ161.7,146.6,135.8,127.5,125.8,116.6,56.7,54.4,50.3,49.0,32.1,13.0. IR(cm -1 ):2967,2810,1738,1591,1492,1460,1283,1241,1174,1027,823,637,522.

[0462] Example 38: (Compound 38)

[0463] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-(trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole

[0464]

[0465] Following the procedure of Example 1, starting from 3-trifluoromethylphenyl propargyl sulfide (5 mmol, 1.08 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g). Yield 1.67 g (90%). Slightly yellow oil. 1 H NMR (400MHz, CD 3 OD)δ7.89(s,1H),7.65–7.57(m,2H),7.53–7.45(m,2H),4.47(td,J=6.6,1.3Hz,2H),4.33(s, 2H), 2.75 (td, J=6.6, 1.8Hz, 2H), 2.47–2.36 (m, 4H), 1.52 (q, J=5.3Hz, 4H), 1.48–1.36 (m, 2H).

[0466] Example 39: (Compound 39)

[0467] 4-[(4-methoxyphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0468]

[0469] Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl sulfide (10 mmol, 1.78 g) and 1-(2-chloroethyl)piperidine hydrochloride (12 mmol, 2.16 g). Yield 2.59 g (78%). Oil. 1 HNMR (400MHz, CDCl 3 )δ7.45(s,1H),7.32(d,J=8.7Hz,2H),6.82(d,J=8.7Hz,2H),4.39(t,J=6.4Hz,2H),4.14(s,2H ), 3.79 (s, 3H), 2.71 (t, J = 6.4Hz, 2H), 2.48–2.33 (m, 4H), 1.63–1.50 (m, 4H), 1.50–1.37 (m, 2H).

[0470] Example 40: (Compound 40)

[0471] 4-[(4-tert-Butylphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0472]

[0473] Following the procedure of Example 1, starting from 4-tert-butylphenyl propargyl sulfide (5 mmol, 1.02 g) and 1-(2-chloroethyl)piperidine hydrochloride (7 mmol, 1.26 g). Yield 1.13 g (63%). Oil. 1 HNMR (400MHz, CD 3 OD)δ7.79(s,1H),7.35(d,J=8.6Hz,2H),7.29(d,J=8.4Hz,2H),4.47(t,J=6.5Hz,2H),4.20(s,3 H), 2.76 (t, J = 6.5Hz, 2H), 2.49–2.36 (m, 4H), 1.62–1.53 (m, 4H), 1.51–1.40 (m, 2H), 1.32 (s, 9H).

[0474] Example 41: (Compound 41)

[0475] 4-[(4-Isopropylphenyl)thiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0476]

[0477] Following the procedure of Example 1, starting from 4-isopropylphenyl propargyl sulfide (7 mmol, 1.33 g) and 4-(2-chloroethyl)morpholine hydrochloride (9 mmol, 1.67 g). Yield 2.16 g (89%). White solid (Mp: 66-68° C.). 1 H NMR (400 MHz, CDCl 3 )δ7.53(s,1H),7.30(d,J=8.3Hz,2H),7.16(d,J=8.2Hz,2H),4.42(t,J=6.2Hz,2H),4.25(s,2H),3.71– 3.58(m,4H),2.89(hept,J=6.9Hz,1H),2.78(t,J=6.2Hz,2H),2.50–2.38(m,4H),1.25(d,J=6.9Hz,6H).

[0478] Example 42: (Compound 42)

[0479] 1-[2-(4-morpholinyl)ethyl]-4-(phenylthiomethyl)-1H,1,2,3-triazole

[0480]

[0481] Following the procedure of Example 1, starting from phenyl propargyl ether (4.69 mmol, 697 mg) and 4-(2-chloroethyl)morpholine hydrochloride (5.7 mmol, 1.05 g). Yield 985 mg (69%). White solid (Mp: 57-59° C.). 1 H NMR (400 MHz, CDCl 3 )δ7.51(s,1H),7.40–7.12(m,5H),4.39(t,J=6.1Hz,2H),4.26(s,2H),3.69–3.58(m,4H),2.75(t,J=6.1Hz,2H),2.47–2.39(m,4H).

[0482] Example 43: (Compound 43)

[0483] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0484]

[0485] Following the procedure of Example 32, starting from 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1 mmol, 292 mg). Yield (57%). White solid Mp: 102°C.1 H NMR (400 MHz, CDCl 3 )δ7.49(s,1H),7.16(d,J=8.5Hz,2H),6.67(d,J=8.5Hz,2H),4.47–4.37(m,2H),4.05(s,2H),2.76(t,J=6.4Hz,2H),2.28(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ157.1,145.2,134.5,122.9,122.9,116.3,58.4,48.1,45.2,30.7.

[0486] Example 44: (Compound 44)

[0487] 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0488]

[0489] (R)-(+)-2-amino-3-phenyl-1-propanol (19.9 mmol, 3.00 g) was added to dry CH 2 Cl 2 Triethylamine (20.8 mmol, 2.88 mL) and di-tert-butyl dicarbonate (20.75 mmol, 4.53 g) were added to the solution in 4% ethanol (20 mL). The reaction mixture was then stirred at room temperature overnight and washed with saturated NH 4 The product was washed with Cl (3 x 15 mL) and brine (2 x 15 mL). Yield: 4.44 g (89%). 1 H NMR (400 MHz, CDCl 3 )δ7.36–7.20 (m, 5H), 3.95–3.83 (m, 1H), 3.69 (dd, J=11.0, 3.8 Hz, 1H), 3.58 (dd, J=11.0, 5.3 Hz, 1H), 2.87 (d, J=7.2 Hz, 2H), 1.44 (s, 9H). Methanesulfonyl chloride (53.0 mmol, 7.35 mL) was added dropwise to a solution of (R)-N-tert-butoxycarbonyl-1-hydroxy-3-phenylpropyl-2-amine (17.67 mmol, 4.44 g) and triethylamine (53.0 mmol, 4.10 mL) in anhydrous THF (20 mL) cooled to 0°C under nitrogen, and the mixture was stirred at the same temperature for one hour. NaHCO 3 (saturated 20 mL) and basified the resulting suspension with CH 2 Cl2 The crude mesylated product (17.67 mmol) was immediately dissolved in dry CH 3 CN (7 mL), and triethylamine (35.34 mmol, 4.90 mL) and piperidine (70.68 mmol, 10.86 mL) were added. The reaction mixture was stirred at room temperature for 48 hours. After evaporating the solvent under vacuum, the crude reaction product was dissolved in CH 2 Cl 2 (20 mL) and extracted with 10% citric acid (3 × 10 mL). 3 Alkalinize the aqueous phase and use CH 2 Cl 2 (3 x 15 mL) to extract the product. Finally, the product was purified by column chromatography (EtOAc / Hex 1:1). Yield: 3.35 g (59%). 1 H NMR (300 MHz, CDCl 3 )δ7.37–7.17 (m, 5H), 4.06–3.89 (m, 1H), 2.97 (dd, J=13.6, 5.4 Hz, 1H), 2.91–2.74 (m, 1H), 2.60–2.34 (m, 5H), 2.27 (dd, J=12.4, 6.2 Hz, 1H), 1.61 (d, J=5.2 Hz, 4H), 1.52–1.37 (m, 11H). A solution of (R)-1-(2-tert-butoxycarbonylamino-3-phenylpropyl)-piperidine (7.85 mmol, 2.5 g) was dissolved in CH 2 Cl 2 (2 mL) and trifluoroacetic acid (4 mL) and stirred at room temperature for 1.5 hours. Then, the solvent was evaporated in vacuo, 1 M NaOH (5 mL) was added, and CH 2 Cl 2 To a solution of (R)-1-(2-amino-3-phenylpropyl)-piperidine (7.85 mmol) in MeOH (5 mL) under nitrogen atmosphere was added CuSO 4 ·H 2 O (0.078 mmol, 19 mg) in H 2 O (0.5 mL) and KHCO 3 (15.7 mmol, 1.57 g). Finally, freshly prepared trifluoromethanesulfonyl azide (17 mmol) was added in CH 2 Cl 2 (25 mL), and the reaction mixture was stirred at room temperature for 3 hours. The organic solvent was evaporated under reduced pressure, and the aqueous solution was washed with NaHCO 3(saturated 10 mL) and basified with CH 2 Cl 2 (3 × 15 mL) extraction. The combined organic phase was dried (NaSO 4 ), evaporated, and purified by column chromatography (CH 2 Cl 2 The (R)-1-(2-azido-3-phenylpropyl)-piperidine product was purified by HPLC-MS / MS (MeOH 95:5). Yield: 480 mg (25%, total). 1 H NMR (400 MHz, CDCl 3 )δ7.39–7.25 (m, 4H), 3.79 (tt, J=8.2, 4.9 Hz, 1H), 2.86 (dd, J=13.9, 5.1 Hz, 1H), 2.74 (dd, J=13.9, 8.1 Hz, 1H), 2.48 (dddt, J=16.8, 11.3, 8.4, 4.5 Hz, 6H), 1.70–1.59 (m, 4H), 1.47 (p, J=6.1 Hz, 2H). The 1,2,3-triazole ring was synthesized according to the procedure of Example 1, starting from 4-methoxyphenyl propargyl sulfide (2.2 mmol, 392 mg) and (R)-1-(2-azido-3-phenylpropyl)-piperidine (2 mmol, 489 mg). Yield 584 mg (66%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.55(s,1H),7.26–7.17(m,5H),6.99(dd,J=7.4,2.1Hz,2H),6.83(d,J=8.8Hz,2H),4.90–4.84(m,1H),4.03(s,2H),3.7 8(s,3H),3.27–3.05(m,2H),2.98–2.74(m,2H),2.52–2.37(m,2H),2.34–2.22(m,2H),1.54–1.47(m,4H),1.47–1.36(m,2H).

[0490] Example 45: (Compound 45)

[0491] 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole

[0492]

[0493] Following the procedure of Example 1, starting from 3-trifluoromethylphenylpropargyl sulfide (2.2 mmol, 476 mg) and (R)-1-(2-azido-3-phenylpropyl)-piperidine (2 mmol, 489 mg). Yield 749 mg (74%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.68(s,1H),7.31(t,J=8.0Hz,2H),7.25–7.20(m,2H),7.17–7.14(m,3H),6.95(dd,J=6.8,2.9Hz,2H),4.90–4.80(m,1H),3.30– 3.18(m,2H),2.93–2.70(m,2H),2.41(dd,J=6.8,5.4Hz,2H),2.29(dd,J=11.1,5.4Hz,2H),1.44(t,J=5.6Hz,4H),1.39–1.33(m,2H).

[0494] Example 46: (Compound 46)

[0495] 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-tert-butylphenyl)thiomethyl]-1H-1,2,3-triazole

[0496]

[0497] Following the procedure of Example 1, starting from 4-tert-butylphenyl propargyl sulfide (2.2 mmol, 449 mg) and (R)-1-(2-azido-3-phenylpropyl)-piperidine (2 mmol, 489 mg). Yield 592 mg (60%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.60(s,1H),7.31(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),7.17–7.13(m,3H),6.95(dd,J=6.7,2.9Hz,2H),4.92–4.82(m,1H),3.25–3.06 (m,2H),2.95–2.75(m,2H),2.41(dd,J=6.8,5.8Hz,2H),2.24(dd,J=11.0,5.4Hz,2H),1.46(t,J=5.5Hz,4H),1.41–1.34(m,2H),1.30(s,9H).

[0498] Example 47: (Compound 47)

[0499] 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0500]

[0501] To a solution of sodium azide (45 mmol, 2.92 g) and sodium iodide (0.75 mmol, 112 mg) in DMSO was added methyl α-bromoisobutyrate (15 mmol, 1.94 mL). The reaction mixture was stirred at 50 °C for 2 hours. The product was extracted with diethyl ether (3 x 10 mL). Yield: 1.78 g (83%). Brown oil. 1 H NMR (400 MHz, CDCl 3 )δ3.82 (s, 3H), 1.51 (s, 6H). Following the procedure of Example 1, starting from 4-methoxyphenyl propargyl sulfide (11 mmol, 1.96 g) and methyl 2-azido-2-methylpropanoate (13.2 mmol, 1.89 g). Yield 3.39 g (96%). Brown oil. 1 H NMR (400 MHz, CDCl 3 )δ7.36(s,1H),7.31(d,J=8.7Hz,2H),6.83(d,J=8.7Hz,2H),4.14(s,2H),3.79(s,3H),3.72(s,3H),1.90(s,6H). 1-(1-methoxycarbonyl-1-methylethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (5.29mmol, 1.70g) was added to 1-(1-methoxycarbonyl-1-methylethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (5.29mmol, 1.70g) in H 2 LiOH·H2O / THF (17:17 mL) was added to the solution 2 O (10.58 mmol, 443 mg), and the reaction mixture was stirred at room temperature overnight. After evaporation of THF in vacuo and acidification of the aqueous phase, the product was extracted with EtOAc (3×10 mL). Yield: 1.21 g (74%). Brown oil. 1 H NMR (400MHz, CD 3 OD) δ7.70 (s, 1H), 7.32–7.25 (m, 2H), 6.94–6.80 (m, 2H), 4.08 (s, 2H), 3.79 (s, 3H), 1.88 (s, 6H). 2 1-(1-carboxy-1-methylethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (3.04 mmol, 935 mg) was added to dry CH 2 Cl 2N,N-dimethylformamide (0.304mmol, 23μL) and oxalyl chloride (3.65mmol, 309μL) were added dropwise to a solution in 1% ethanol (9mL). The reaction mixture was stirred at room temperature for one hour. Then, N,N-diethylamine (6.08mmol, 629μL) was added dropwise, and the new reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by column chromatography (CH 2 Cl 2 / MeOH 98:2) to purify the product. Yield: 825 mg (75%). 1 H NMR (400 MHz, CDCl 3 )δ7.32(s,1H),7.29(d,J=2.7Hz,2H),6.82(d,J=8.8Hz,2H),4.16(s,2H),3.80(s,3H),3 .37–3.25(m,2H),2.76–2.66(m,2H),1.86(s,6H),1.17–1.03(m,3H),0.79–0.69(m,3H).

[0502] To N 2 1-[1-(N,N-diethylaminocarbonyl)-1-methylethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.55 mmol, 200 mg) was added to dry Et 2 O (5 mL), LiAlH 4 (1.10mmol, 41.87mg) in dry Et 2 O (5 mL). The reaction mixture was stirred at room temperature overnight. Carefully, H 2 O (1 mL), and the solution was filtered and purified by MgSO 4 The solvent was dried and evaporated. 2 Cl 2 / MeOH 98:2) to purify the product. Yield: 162 mg (84%). 1 H NMR (400 MHz, CDCl 3 )δ7.42(s,1H),7.34(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),4.16(s,2H),3.80 (s,3H),2.68(s,2H),2.22(q,J=7.1Hz,4H),1.60(s,6H),0.82(t,J=7.1Hz,6H).

[0503] Example 48: (Compound 48)

[0504] 1-[2-(Guandino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0505]

[0506] Following the procedure of Example 22, starting from 1-(2-aminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.76 mmol, 200 mg), intermediate 1-[2-(N,N'-di-tert-butoxycarbonylguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole. Yield 276 mg (72%). 1 H NMR (400 MHz, CDCl 3 )δ11.45(s,1H),8.52(t,J=5.9Hz,1H),7.36(s,1H),7.31(d,J=8.8Hz,2H),6.82(d,J=8.8Hz,2H),4.56–4.48(m,2H),4.12(s,2H),3.87(q,J=5.9Hz,2H),3.79(s,3H),1.52(s,9H),1.48(s,9H). Trifluoroacetic acid (1.25 mL) was used in CH 2 Cl 2 The intermediate (0.25 mmol, 125 mg) was deprotected in 4% paraformaldehyde (3.75 mL) to afford the title product. Yield 73 mg (96%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.82(s,1H),7.32(d,J=8.8Hz,2H),6.88(d,J=8.8Hz,2H),4.58(t,J=5.8Hz,2H),4.11(s,2H),3.79(s,3H),3.75(t,J=5.8Hz,2H).

[0507] Example 49: (Compound 49)

[0508] 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0509]

[0510] Following the procedure of Example 27, starting from 1-(2-aminoethyl)-4-[4-(methyloxy)phenylthiomethyl]-1H-1,2,3-triazole (0.38 mmol, 100 mg), cyanoguanidine (0.38 mmol, 31.8 mg), acetonitrile (0.5 mL), chlorotrimethylsilane (0.42 mmol, 0.05 mL) and isopropanol (1.14 mmol, 0.09 mL). Yield: 83 mg, (57%). Oil. 1 H NMR (400MHz, CD 3 OD) δ 8.07 (s, 1H), 7.35 (d, J = 8.3Hz, 2H), 6.90 (d, J = 8.2Hz, 2H), 4.80 (d, J = 5.4Hz, 2H), 4.19 (s, 2H), 3.80 (s, 3H), 3.54 (d, J = 5.3Hz, 2H). 13 C NMR (101 MHz, CD 3 OD)δ164.6,161.2,159.0,145.9,135.3,126.5,125.7,115.8,55.9,49.3,40.0,30.6.

[0511] Example 50: (Compound 50)

[0512] 1-[3-(Biguanidino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0513]

[0514] Following the procedure of Example 27, starting from 1-(3-aminopropyl)-4-[4-(methyloxy)phenylthiomethyl]-1H-1,2,3-triazole (0.36 mmol, 100 mg), cyanoguanidine (0.36 mmol, 30.2 mg), acetonitrile (0.5 mL), chlorotrimethylsilane (0.40 mmol, 0.05 mL) and isopropanol (1.08 mmol, 0.08 mL). Yield: 64.6 mg, (45%). Oil. 1 H NMR (400MHz, CD 3 OD)δ8.33(s,1H),7.43–7.29(m,2H),6.97–6.84(m,2H),4.24(s,2H),3.81(s,3H),3.04(dd,J=9.2,6.2Hz,2H),2.35(p,J=7.1Hz,2H). 13 C NMR (101 MHz, CD 3OD) δ164.6,161.6,159.0,144.4,136.0,127.9,124.5,116.1,55.9,50.6,37.7,29.6,28.5.

[0515] Example 51: (Compound 51)

[0516] 1-[2-(N,N-dimethylamino)ethyl]-5-iodo-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0517]

[0518] Following the procedure of Example 33, starting from 4-methoxyphenyl propargyl sulfide (3.84 mmol, 648 mg) and 2-azido-N,N-dimethylethyl-1-amine (4.22 mmol, 482 mg). Yield 0.92 g (62%). Brown solid (Mp: 45° C.). 1 HNMR (400MHz, CD 3 OD)δ7.26(d,2H),6.84(d,2H),4.50(t,J=6.9Hz,2H),4.01(s,2H),3.79(s,3H),2.80(t,J=6.9Hz,2H),2.32(s,6H). 13 C NMR (101 MHz, CDCl 3 )δ159.3,148.0,134.7,124.4,114.1,79.6,57.9,54.9,48.2,45.1,31.2. IR(cm -1 ):2946,2830,2779,1709,1589,1491,1461,1439,1283,1241,1173,1121,1101,1021,858,821,788,640,522,449.

[0519] Example 52: (Compound 52)

[0520] 1-[2-(N,N-dimethylamino)ethyl]-5-tritiated-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0521]

[0522] Tritium was obtained from RC Tritec AG. Tritium reactions were performed on an RC Tritec tritium manifold. 1-[2-(N,N-dimethylamino)ethyl]-5-iodo-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole prepared according to Example 51, palladium on calcium carbonate and Et2O3 in absolute ethanol were added. 3 The flask was heated to 40 ℃ and stirred for 4 hours.Then, the flask was frozen and the excess tritium was blown out with the solvent under a nitrogen stream.The flask was taken out from the bath and warmed to room temperature.The reaction mixture was dissolved in methanol and then passed through a syringe filter (0.45 μm PTFE filter).The solvent was evaporated under reduced pressure to obtain a solid, using Xbridge Prep C-18 columns (5 μm OBD 19 × 100 mm) as stationary phase and 0.1% ammonium formate (AFM) / MeCN aqueous solution as mobile phase, the solid was purified by preparative HPLC.Chromatographic operation was carried out under aqAFM / MeCN gradient conditions (75:25 to 25:75), wherein the total chromatographic time was 30 min (flow = 10 mL / min). The purified fractions were dried under vacuum and reconstituted in 10 mL of ethanol and stored at -20°C. Total production time: 6 h. Isotope incorporation: 87.1%. Molar activity at the end of the synthesis: 933.2 KBq / nmol. Radiochemical purity determined by radio-HPLC >95%.

[0523] C) Synthesis A compound of formula (I), wherein Z is -S(=O)-

[0524] Example 53: (Compound 53)

[0525] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0526]

[0527] Phthaloyl peroxide (16.42 mmol, 2.69 g) was added to 1-[(2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (13.7 mmol, 4.0 g) and trifluoroacetic acid (13.7 mmol, 1.10 mL) in CH 2 Cl 2 (38 mL) and the mixture was stirred at room temperature for 30 min. 3 The reaction mixture was basified and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: CH2 Cl 2 / MeOH(7NNH 3 ) mixture) to purify the product. Yield: 3.13 g (66%). White solid. 1 H NMR (400MHz, CD 3 OD)δ7.81(s,1H),7.49(d,J=8.8Hz,2H),7.95(d,J=8.8Hz,2H),4.51(t,J=6.3Hz,2 H), 4.30 (dd, J = 13.7, 1.6 Hz, 2H), 3.86 (s, 3H), 2.82 (t, J = 6.3 Hz, 2H), 2.31 (s, 6H). 13 C NMR (101 MHz, CD 3 OD)δ164.1,137.5,133.5,127.7,126.7,115.9,59.5,56.1,53.6,45.4. IR(cm -1 ):1592,1495,1459,1303,1249,1172,1086,1022,829,524.

[0528] Example 54: (Compound 54)

[0529] 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0530]

[0531] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 1-[(3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.47 mmol, 160 mg), TFA (0.47 mmol, 37 μL) and phthaloyl peroxide (0.70 mmol, 115 mg) in 4% paraformaldehyde (3 mL). Yield 161 mg (77%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.87(s,1H),7.51(d,J=2.1Hz,2H),7.12(d,J=4.7Hz,2H),4.54(t,J=6.8Hz,2H ), 4.29 (dd, 2H), 3.88 (s, 3H), 3.13 (t, 2H), 2.88 (s, 6H), 2.36 (p, J = 10.4, 5.0Hz, 2H). 13 C NMR (101 MHz, CD3 OD)δ164.2,138.1,133.6,132.3,130.9,130.1,129.6,129.1,128.7,127.6,126.7,116.0,56.2,56.1,43.7,26.5. IR(cm -1 ):3386,2682,2478,1719,1592,1496,1304,1253,1175,1087,1023,833,528.

[0532] Example 55: (Compound 55)

[0533] 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0534]

[0535] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 1-[(2-(N,N-diethylamino)ethyl]-4-[(4-(methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.34 mmol, 100 mg), TFA (0.34 mmol, 27 μL) and phthaloyl peroxide (0.50 mmol, 84 mg) in 4% paraformaldehyde (2 mL). Yield 78 mg (67%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.83(s,1H),7.50(d,J=8.8Hz,2H),7.08(d,J=8.9Hz,2H),4.45(t,J=6.6Hz,2H),4.30(dd,J= 12.6, 1.8Hz, 2H), 3.85 (s, 3H), 2.89 (t, J = 6.6Hz, 2H), 2.57 (q, J = 7.2Hz, 4H), 1.00 (t, J = 7.2Hz, 6H). 13 C NMR (101 MHz, CD 3 OD)δ164.1,137.4,133.6,127.7,126.8,115.9,56.1,53.6,53.5,49.4,48.1,11.9. IR(cm -1 ):2967,1592,1495,1460,1303,1250,1086,1024,829,524.

[0536] Example 56: (Compound 56)

[0537] 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0538]

[0539] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 1-[(2-(piperidinyl)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole (0.74 mmol, 300 mg), TFA (0.74 mmol, 56 μL) and phthalyl peroxide (1.11 mmol, 181 mg) in 4% paraformaldehyde (2 mL). Yield 176 mg (62%). Oil. 1 H NMR (400 MHz, CDCl 3 )δ7.78(s,1H),7.76–7.58(m,4H),4.46(td,J=6.5,2.0Hz,2H),4.23(dd,J=12.9,2.3Hz,2 H), 2.77 (t, J = 6.4Hz, 2H), 2.46 (t, J = 5.5Hz, 4H), 1.59 (p, J = 5.6Hz, 4H), 1.49–1.40 (m, 2H).

[0540] Example 57: (Compound 57)

[0541] 4-[(4-Isopropylphenyl)sulfinylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0542]

[0543] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 4-[(4-isopropylphenyl)thiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H-1,2,3-triazole (1.47 mmol, 507 mg), TFA (1.47 mmol, 112 μL) and phthalyl peroxide (1.62 mmol, 265 mg) in (5 mL). Yield 340 mg (64%). White solid (Mp: 131 °C). 1 H NMR (400 MHz, CDCl 3)δ7.70(s,1H),7.43(d,J=8.4Hz,2H),7.31(d,J=8.0Hz,2H),4.55–4.33(m,2H),4.13(dd,J=12.6,1.8Hz,),3. 65(t,J=4.6Hz,4H),2.92(hept,J=6.9Hz,1H),2.77(t,J=6.3Hz,2H),2.51–2.39(m,4H),1.23(d,J=6.9Hz,6H).

[0544] Example 58: (Compound 58)

[0545] 4-[(2,6-Dimethylphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0546]

[0547] According to the procedure of Example 53, from CH 2 Cl 2 Starting from 4-[(2,6-dimethylphenyl)thiomethyl]-1-[(2-(piperidinyl)ethyl]-1H-1,2,3-triazole (1.64 mmol, 543 mg), TFA (1.64 mmol, 126 μL) and phthalyl peroxide (1.81 mmol, 296 mg) in 4% paraformaldehyde (5 mL). Yield 364 mg (64%). White solid (Mp: 84-85 °C). 1 H NMR (400 MHz, CDCl 3 )δ7.54(s,1H),7.32–7.21(m,1H),7.04(d,J=7.6Hz,2H),4.62–4.32(m,4H),2.77–2. 65(m,2H),2.49(s,6H),2.46–2.38(m,4H),1.57(p,J=5.5Hz,4H),1.51–1.40(m,2H).

[0548] Example 59: (Compound 59)

[0549] 1-[2-(4-morpholinyl)ethyl]-4-(phenylsulfinylmethyl)-1H,1,2,3-triazole

[0550]

[0551] According to the procedure of Example 53, from CH 2 Cl 2Start with 1-[2-(4-morpholinyl)ethyl]-4-[phenylthiomethyl]-1H-1,2,3-triazole (0.86 mmol, 260 g), TFA (0.86 mmol, 66 μL) and phthalyl peroxide (0.95 mmol, 155 mg) in 1% ethyl acetate (3 mL). Yield 167 g (61%). White solid (Mp: 134 °C). 1 H NMR (400 MHz, CDCl 3 )δ7.65(s,1H),7.54–7.38(m,5H),4.47–4.31(m,2H),4.13(dd,J=13.1,1. 9Hz, 2H), 3.62 (t, J = 4.6Hz, 4H), 2.73 (t, J = 6.2Hz, 2H), 2.48–2.36 (m, 4H).

[0552] Example 60: (Compound 60)

[0553] 4-[(4-methoxyphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0554]

[0555] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 4-[4-methoxyphenylthiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole (1.50 mmol, 500 g), TFA (1.50 mmol, 115 μL) and phthalyl peroxide (2.26 mmol, 370 mg) in (4 mL). Yield 325 g (62%). Oil. 1 H NMR (400 MHz, CDCl 3 )δ7.64(s,1H),7.38(d,J=8.9Hz,2H),6.92(d,J=9.0Hz,2H),4.49–4.27(m,2H),4.10(dd,J=12.9,1.7Hz, 2H), 3.78 (s, 3H), 2.70 (t, J = 6.5Hz, 2H), 2.49–2.30 (m, 4H), 1.52 (p, J = 5.6Hz, 4H), 1.39 (q, J = 5.9Hz, 2H).

[0556] Example 61: (Compound 61)

[0557] 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0558]

[0559] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole (0.16 mmol, 80 mg), TFA (0.74 mmol, 12 μL) and phthalyl peroxide (0.24 mmol, 40 mg) in (0.5 mL). Yield 50 mg (65%). Oil. 1 H NMR (400 MHz, CDCl 3 )δ7.93–7.67(m,2H),7.63–7.44(m,2H),7.41–7.15(m,4H),7.10–6.94(m, 2H),4.83(ddt,J=12.7,9.5,4.7Hz,1H),4.31–4.07(m,3H),3.25(dtt,J=23 .2,9.1,5.0Hz,2H),2.92–2.78(m,2H),2.43(dt,J=11.1,5.2Hz,2H),2.34( dq,J=10.4,5.0Hz,2H), 1.53(dd,J=8.8,3.2Hz,4H), 1.41(d,J=6.2Hz,2H).

[0560] Example 62: (Compound 62)

[0561] 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0562]

[0563] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.21 mmol, 71 mg), TFA (0.21 mmol, 16 μL) and phthaloyl peroxide (0.31 mmol, 50 mg) in (1 mL). Yield 57 mg (75%). Oil. 1 H NMR (400 MHz, CDCl 3)δ7.65(s,1H),7.51(d,J=8.8Hz,1H),7.02(d,J=8.8Hz,1H),4.19(dd,J=13.5,1.0Hz,2H),3.8 7(s,3H),2.73(s,2H),2.28(q,J=7.4Hz,2H),1.65(s,3H),1.64(s,3H),0.86(t,J=7.1Hz,5H).

[0564] Example 63: (Compound 63)

[0565] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0566]

[0567] According to the procedure of Example 53, from CH 2 Cl 2 Starting with 4-[4-hydroxyphenylthiomethyl]-1-[(2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole (0.26 mmol, 71 g), TFA (0.26 mmol, 20 μL) and phthaloyl peroxide (0.31 mmol, 50 mg) in 4% paraformaldehyde (0.7 mL). Yield 59 mg (78%). White solid. 1 H NMR (400MHz, CD 3 OD)δ7.89(s,1H),7.41(d,J=8.7Hz,2H),6.95(d,J=8.6Hz,2H),4.78(t,J=6 .4Hz, 2H), 4.28 (dd, J = 12.5, 2.0Hz, 2H), 3.44 (t, J = 6.5Hz, 2H), 2.74 (s, 6H).

[0568] Example 64: (Compound 64)

[0569] 1-(2-aminoethyl)-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0570]

[0571] To N 2 1-(2-aminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (2.33 mmol, 700 mg) was stirred in dry CH 2 Cl 2To a solution in 4% paraformaldehyde (14 mL) was added di-tert-butyl dicarbonate (2.44 mmol, 533 mg), DIPEA (4.66 mmol, 798 μL) and 4-(N,N-dimethylamino)pyridine (catalyst, 20 mg), and the reaction mixture was stirred at room temperature overnight. The product was purified by column chromatography (silica gel; eluent: CH 2 Cl 2 / MeOH 95:5) to purify the N-Boc intermediate. Yield: 460 mg (54%). 1 H NMR (400 MHz, CDCl 3 )δ7.32(d,J=8.8Hz,2H),7.28(s,1H),6.83(d,J=8.7Hz,2H),4.18-4.07(m,4H),3.80(s,3H),3.62-3.52(m,2H),1.45(s,9H). According to the procedure of Example 53, using CH 2 Cl 2 Phthaloyl peroxide (0.41 mmol, 67.5 mg) in 4-(1.8 mL) was used to oxidize 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.27 mmol, 100 mg). Yield: 56 mg (78%). 1 H NMR (400 MHz, CDCl 3 )δ7.57(s,1H),7.43(d,J=8.8Hz,2H),6.98(d,J=8.8Hz,2H),4.45(t,J=5.7Hz,2H),4.23–4.08(m,2H),3.84(s,3H),3.65–3.55(m,2H),1.43(s,9H). Trifluoroacetic acid (0.82 mL) was added to 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole (0.15 mmol, 56 mg) in dry CH at 0°C. 2 Cl 2 (2.4 mL) and the reaction mixture was stirred at room temperature for 3 hours. The column chromatography (silica gel; eluent: CH 2 Cl 2 / MeOH(7NNH 3 )95:5) Purified product. Yield 39 mg (94%). Oil. 1 H NMR (400MHz, CD 3OD)δ7.76(s,1H),7.49(d,J=8.9Hz,2H),7.10(d,J=8.9Hz,2H),4.43(t,J=6.1Hz,2H),4.37–4.25(m,2H),3.88(s,3H),3.09(t,J=6.1Hz,2H).

[0572] Example 65: (Compound 65)

[0573] 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0574]

[0575] Following the procedure of Example 64, starting from 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1.39 mmol, 388 mg), to provide the intermediate 1-[2-(N-tert-butoxycarbonyl-N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole. Yield: 164 mg (98%). 1 HNMR (400MHz, CDCl 3 )δ7.49(s,1H),7.44–7.38(m,2H),7.00–6.85(m,2H),4.52–4.37(m,2H),4.20–4.04(m,2H),3.80(s,3H),3.62(td,J=6.0,2.0Hz,2H),2.74–2.60(m,3H),1.38(s,9H). Used in dry CH 2 Cl 2 This compound (0.41 mmol, 164 mg) was N-deprotected with trifluoroacetic acid (2.30 mL) in (6.5 mL) to afford the product. Yield 115 (95%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.77(s,1H),7.50(d,J=8.9Hz,2H),7.10(d,J=8.9Hz,2H),4.50(t,J=6. 2Hz, 2H), 4.41–4.25 (m, 2H), 3.88 (s, 3H), 3.03 (t, J = 6.2Hz, 2H), 2.41 (s, 3H).

[0576] Example 66: (Compound 66)

[0577] 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0578]

[0579] Following the procedure of Example 34, starting from 1-[2-(N,N-dimethylamino)-ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1.00 mmol, 292 mg) and 33% hydrogen peroxide (1.5 mL). Yield 314 mg (97%). Oil.

[0580] 1 H NMR(400MHz,MeOD)δ7.95(d,J=1.4Hz,1H),7.49(d,J=8.9Hz,2H),7.09(d,J=8.9Hz,2H),5.0 2(t,J=6.4Hz,2H), 4.34(q,J=13.9Hz,2H), 3.98(t,J=6.4Hz,2H), 3.87(s,3H), 3.28(s,6H).

[0581] D) Synthesis A compound of formula (I), wherein Z is -S(=O) 2 –

[0582] Example 67: (Compound 67)

[0583] 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0584]

[0585] Potassium persulfate (1.28 mmol, 788 mg) was added to 1-[(2-N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.86 mmol, 250 mg) in H 2 O / MeCN 50:50 (5 mL) and the reaction mixture was stirred at room temperature for 1 hour. 2 CO 3 After basification, the product was extracted with EtOAc (3 x 5 mL) and the combined organic layers were dried (Na 2 SO 4 ), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel; eluent: EtOAc / Hex or CH 2 Cl 2 The crude product was purified by evaporation with 4% paraformaldehyde (2% paraformaldehyde / MeOH mixture). Yield: 167 mg (60%). Oil. 1H NMR (400 MHz, CDCl 3 )δ7.88(s,1H),7.61(d,J=7.7Hz,2H),6.92(d,J=8.9Hz,2H),4.51,(s,2H ), 4.43 (t, J = 6.2Hz, 2H), 3.84 (s, 3H), 2.73 (t, J = 6.2Hz, 2H), 2.27 (s, 6H). 13 C NMR (101 MHz, CDCl 3 )δ163.8,135.6,130.4,129.2,125.0,114.2,58.5,55.5,54.1,48.2,45.2.

[0586] Example 68: (Compound 68)

[0587] 1-[2-(N,N-diethylamino)ethyl]-4-[(4-bromophenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0588]

[0589] Following the procedure of Example 67, starting from 4-[(4-bromophenyl)thiomethyl]-1-[(2-N,N-diethylamino)ethyl]-1H-1,2,3-triazole (2.00 mmol, 739 mg) and potassium persulfate (3.00 mmol, 1.84 g). Yield 545 mg (68%). White solid (Mp: 88°C). 1 H NMR (400 MHz, CDCl 3 )δ7.93(s,1H),7.65(d,J=8.6Hz,2H),7.57(d,J=8.6Hz,2H),4.56(s,2H),4.43(t, J=6.1Hz, 2H), 2.89 (d, J=6.1Hz, 2H), 2.58 (q, J=7.1Hz, 4H), 1.00 (t, J=7.1Hz, 6H).

[0590] Example 69: (Compound 69)

[0591] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-dimethoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0592]

[0593] Following the procedure of Example 67, starting from 4-[(3,4-dimethoxyphenyl)thiomethyl]-1-[(2-N,N-dimethylamino)ethyl]-1H-1,2,3-triazole (2.00 mmol, 645 mg) and potassium persulfate (3.00 mmol, 1.84 g). Yield 545 mg (77%). White solid (Mp: 152°C). 1 H NMR (400 MHz, CDCl 3 )δ7.91(s,1H),7.31(dd,J=8.5,2.1Hz,1H),7.17(d,J=2.1Hz,1H),6.91(d,J=8.5Hz,1H),4.5 4(s,2H),4.46(t,J=6.2Hz,2H),3.94(s,3H),3.88(s,3H),2.76(t,J=6.2Hz,2H),2.29(s,6H).

[0594] Example 70: (Compound 70)

[0595] 4-[(4-isopropylphenyl)sulfonylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0596]

[0597] Following the procedure of Example 67, starting from 4-[(4-isopropylphenyl)thiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole (2.00 mmol, 693 mg) and potassium persulfate (3.00 mmol, 1.84 g). Yield 401 mg (53%). Oil. 1 H NMR (400 MHz, CDCl 3 )δ7.93(s,1H),7.63(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),4.53(s,2H),4.46(t,J=6.1Hz,2H),3.74– 3.61(m,4H),2.95(hept,J=6.9Hz,1H),2.80(t,J=6.2Hz,2H),2.53–2.43(m,4H),1.24(d,J=6.9Hz,6H).

[0598] Example 71: (Compound 71)

[0599] 4-(Phenylsulfonylmethyl)-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0600]

[0601] According to the procedure of Example 67, from H 2 Starting with 4-(phenylthiomethyl)-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole (0.85 mmol, 260 mg) and potassium persulfate (1.28 mmol, 788 mg) in 1H 2 O (4 mL). Yield 108 mg (38%). Oil. 1 H NMR (400 MHz, CDCl 3 )δ7.93(s,1H),7.77–7.72(m,2H),7.66(td,J=7.2,1.3Hz,1H),7.56–7.50(m,2H),4.58(s ,2H),4.50(t,J=6.1Hz,2H),3.77–3.71(m,4H),2.84(t,J=6.1Hz,2H),2.54–2.51(m,4H).

[0602] Example 72: (Compound 72)

[0603] 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0604]

[0605] Following the procedure of Example 67, starting from 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole (0.76 mmol, 250 mg) and potassium persulfate (1.13 mmol, 698 mg). Yield 85 mg (31%). 1 H NMR (400MHz, CD 3 OD)δ8.10–7.97(m,4H),7.82(t,J=7.9Hz,1H),4.77(s,2H),4.53(t,J=6.5Hz,2H),2.81(t,J=6.5Hz,2H),2.29(s,6H).

[0606] Example 73: (Compound 73)

[0607] 1-(2-aminoethyl)-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0608]

[0609] 1-(2-tert-Butyloxycarbonylaminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.27 mmol, 100 mg) was oxidized to the corresponding sulfone with potassium hydrogen persulfate (0.41 mmol, 253 mg) according to the procedure of Example 67. Yield: 105 mg (97%). 1 H NMR (400 MHz, CDCl 3 )δ7.78(s,1H),7.66(d,J=8.9Hz,2H),6.98(d,J=8.9Hz,2H),4.54(s,2H),4.51(t,J=5.7Hz,2H),3.89(s,3H),3.65(q,J=5.9Hz,2H),1.47(s,9H). At 0°C, 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole (0.27mmol, 105mg) was added to dry CH 2 Cl 2 Trifluoroacetic acid (1.6 mL) was added to the solution in 1% ethanol (5 mL). The reaction mixture was then stirred at room temperature for 3 hours, the solvent was evaporated, and the mixture was purified by column chromatography (silica gel; eluent: CH 2 Cl 2 / MeOH(7N NH 3 )95:5) Purified product. Yield 78 mg (97%). Oil. 1 H NMR (400MHz, CD 3 OD) δ7.94(s,1H),7.69(d,J=8.9Hz,2H),7.09(d,J=8.9Hz,2H),4.64(s,2H),4.45(t,J=6.2Hz,2H),3.90(s,3H),3.09(t,J=6.2Hz,2H).

[0610] Example 74: (Compound 74)

[0611] 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0612]

[0613] Following the procedure of Example 73, starting from 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1.39 mmol, 388 mg), the product was purified by column chromatography (silica gel; eluent: CH 2 Cl 2 / MeOH 95:5) to purify the N-Boc product. Yield: 500 mg (95%). 1 H NMR (400 MHz, CDCl 3 )δ7.32 (d, J=8.7 Hz, 2H), 7.21 (s, 1H), 6.89-6.76 (m, 2H), 4.53-4.37 (m, 2H), 4.13 (s, 2H), 3.79 (s, 3H), 3.64 (t, J=6.1 Hz, 2H), 2.72-2.56 (m, 3H), 1.44 (s, 9H). According to the procedure of Example 64, the N-Boc protected thioether (0.36 mmol, 135 mg) was oxidized to the corresponding sulfone with potassium hydrogen persulfate (0.54 mmol, 329 mg). Yield: 127 mg (87%). 1 H NMR (400 MHz, CDCl 3 )δ7.75 (s, 1H), 7.67 (d, J = 8.9 Hz, 2H), 7.02-6.93 (m, 2H), 4.62-4.48 (m, 4H), 3.89 (s, 3H), 3.71 (t, J = 6.1 Hz, 2H), 2.79-2.64 (m, 3H), 1.47 (s, 9H). The N-Boc-N-methylamino intermediate was N-deprotected according to the procedure of Example 73 to give the product. Yield 106 mg (95%). Oil. 1 H NMR (400MHz, CD 3 OD)δ7.95(s,1H),7.69(d,J=8.9Hz,2H),7.09(d,J=9.0Hz,2H),4.85(s,2H),4.6 3(s,2H),4.52(t,J=6.2Hz,2H),3.90(s,3H),3.04(t,J=6.2Hz,2H),2.41(s,3H).

[0614] Example 75. Determination of retinal biodistribution after topical ocular administration in four mammalian species.

[0615] To test the bioavailability of compounds 1, 24, 35, 53, 66 and 67 to the retina, we used the following species: mice, rats, rabbits and pigs. Animals were treated under anesthesia. Compounds [ 3H]-35 (5 μL / eye) was ocularly instilled into Sprague-Dawley rats (n=4 at each time point) in 20 mM solution of phosphate buffered saline (PBS), and in vivo autoradiography was performed at 1, 8 and 24 hours. After removal, the eyes were first incubated in an aqueous solution of 4% paraformaldehyde for 4 hours, then in an aqueous solution of 10% and 20% sucrose for 2 hours each, and finally in an aqueous solution of 30% sucrose for one week. All incubations were at 4°C. The samples were fixed in OCT (optimal cutting temperature polymer) and the eyes were cut into fine 20-μm sections at -24°C using a Leyca cryostat (Leica CM3050 S, Germany). The sections (20 μm thick) were placed on glass slides (Superfrost Plus, Labolan). Four serial sections of the central part of the organ were autoradiographed for 1 h in a Beta Imager 2000 system (Biospace Lab, France), where all sections were visible ( Figure 1 A).

[0616] The compounds were administered by ocular instillation with PBS solutions containing 0.2% hyaluronic acid (HA) and selected compounds of the invention: 17 μg / eye in mice (3 μL of 20 mM solution per eye); 65 μg / eye in rats (10 μL of 17 mM solution per eye); and 559 μg / eye in pigs (50 μL of 40 mM solution per eye). Animals were sacrificed after 4 hours of treatment (mice, rabbits and pigs) or 24 hours of treatment (rats) to determine the availability of the compounds in the retina. The retinas were mechanically homogenized and processed in physiological serum (9% NaCl) to analyze the availability of the compounds by HPLC-MS. Figure 1 B shows that the percentage of delivery of compound 35 to the mouse retina was higher when formulated with hyaluronic acid. Figure 1 C shows the retinal biodistribution results of the five compounds after topical ocular administration in mice, rats, rabbits and pigs.

[0617] Example 76. In vivo efficacy assay in the rd10 mouse model of retinitis pigmentosa as measured by electrophysiological analysis.

[0618] The rd10 mice were treated by ocular instillation of phosphate buffered saline (PBS) containing compounds of the invention (1, 35, 50, 56 and 70) for 11 days (P14 to P24). The animals were dark adapted for 8 hours at P25, and the retina was illuminated with a full-view dome (Ganzfeld dome) driven by an LED, and the full-view flash electroretinogram (ERG) response was recorded. Under both scotopic (dark adaptation) and photopic (light adaptation) conditions, a range of intensities from 0.001 to 10 cd s / m2 After 5 min of light adaptation, the images were averaged using background white light (30 cd / m 2 ) record photopic cone responses. Control the light intensity of each animal group (Mavo-Monitor USB, Gossen, Germany). The stimulation protocol was designed according to the International Society for Clinical Electrophysiology of Vision. In brief, mice were anesthetized by intraperitoneal administration of a saline solution containing ketamine (95 mg / kg) and xylazine (5 mg / kg) and kept on a 37°C heating pad. Ocular instillation of 1% tropicamide was applied to induce pupil dilation. Under flash, the ERG response of both eyes to the full-field stimulator was recorded. For each light intensity used, a total of 4 to 64 continuous stimuli were averaged, and for dim flashes, the interval between flashes was 10s under dark-vision conditions, and for the highest intensity, the interval between flashes was up to 60s. For photopic conditions, an interval between flashes of one second was used. ERG signals were amplified and bandpass filtered between 0.3 and 1000 Hz (CP511 AC amplifier; Grass Instruments, Quincy, MA, USA). Electrical signals were digitized at 20 kHz using an Electric Laboratories data acquisition board (AD Instruments, Chalgrove, UK).

[0619] ERG was performed using electrodes fixed to the corneal lens (Burian-Allen electrodes; Hansen Ophthalmic Development Laboratory, Coralville, Iowa (IA), USA) and a reference electrode fixed to the mouth, with a ground electrode placed in the tail. Using dark-adapted mice, recordings from 0.001 to 10 cds / m 2 Rod-mediated responses to flashes. Record responses from -1.5 to 1.5 log cd s / m 2 Mixed rod- and cone-mediated signals for flashes. Using 11cd s / m 2 White flashes were used to isolate oscillatory potentials (OPs), where the recording frequency ranged from 100 to 10,000 Hz. To record cone-mediated responses, we used 30 cd s / m 2 The rod saturation background ranged from 0.5 to 2 log cd s / m 2The amplitudes of the a- and b-waves were averaged using data provided by the researchers, with no information on the experimental conditions of the mice.

[0620] Figure 2 The enhanced retinal function of rd10 mice treated with compounds of the invention (1, 35, 50, 56 and 70; 3 μL of 20 mM solution per eye) was shown by subjecting dark-adapted mice (scotopic conditions) to different intensities (0.001; 0.01; 0.1; 1 and 10 cd s / m 2 ) ERG activity after light stimulation. Data correspond to the merger of 3 independent experiments (N=3), with 4-5 mice in each experimental group. Data are expressed as mean + / - standard deviation. Statistical analysis was performed using unpaired t-test. All tested compounds showed varying degrees of increase in ERG activity, which can be summarized as follows:

[0621] - In dark-adapted ERG, the b-wave amplitudes of mice treated with the compound ranged from 0.001 to 10 cd s / m 2 The flash intensity increases significantly.

[0622] -Compared with the rd10 untreated group, the compound showed significant 2 The light intensities improved rod function by increasing ERG amplitude under scotopic conditions by up to 42% and 44%, respectively (***p=0.0014; *p=0.0194). This represented a mean recovery score of 32% compared to wild-type mice.

[0623] - Scotopic oscillatory potentials at maximum intensity, associated with the function of amacrine and Muller cells, were significantly increased up to 81% (*p=0.039) in treated rd 10 mice with a recovery score of 25%.

[0624] - Some compounds (e.g. compound 35) were detected by 2 Increasing ERG amplitude by 66% (*p=0.0113 compared to rd10 control group) at light intensity significantly improved cone function and demonstrated a recovery score of 78% compared to WT.

[0625] Example 77. In vivo efficacy assay in the rd10 mouse model of retinitis pigmentosa as measured by histological analysis.

[0626] In this experiment, rd10 mice were treated by ocular instillation of a phosphate-buffered saline (PBS) solution containing compounds of the invention (1, 35, 53, and 36; 3 μL of a 20 mM solution per eye) for 11 days (from P14 to P24). At P25, the eyeballs were enucleated and fixed with 4% paraformaldehyde (in PBS) for 3 hours. The anterior segment and lens were dissected, and the eye cups were incubated in 30% sucrose (in PBS) at 4°C for 12 h. 12 μM cryosections were obtained and stained with DAPI. The sections were analyzed by fluorescence microscopy, and the number of nuclei in the outer nuclear layer containing the photoreceptor nuclei was compared.

[0627] Figure 3 Shown is an increase in the number of photoreceptor nuclei in the retina of rd10 mice treated with four different compounds compared to untreated mice in the central (C), midperipheral (MP), and peripheral (P) retina.

[0628] Example 78. Morphometric Analysis of the Retina

[0629] Detailed morphometric analysis based on immunohistochemistry was performed. For this purpose, rd10 mice were treated by ocular instillation of phosphate buffered saline (PBS) containing compound 35 (3 μL of 20 mM solution per eye) for 11 days (from P14 to P24). At P25, the eyeballs were removed and fixed with 4% paraformaldehyde (in PBS) for 3 hours. The anterior segment and lens were dissected, and the eye cups were incubated in 30% sucrose (in PBS) at 4 ° C for 12 h. Cryosections were made with DAPI. Eye cryosections were stained with DAPI, rhodopsin and cone arrestin for immunohistochemical analysis. Briefly, cryosections were incubated with antibodies against rhodopsin (Millipore, MABN15) and cone arrestin (Millipore, AB15282) at 1:400 for 8 h at 4 °C, and buffered with secondary antibodies at 1:400 and DAPI (Sigma, D89542) at 1:1000 for 1 h. Sections were analyzed by fluorescence microscopy. Figure 4 As shown, significant preservation of photoreceptors was observed in the retina of rd10 mice treated with compound 35, as measured by the number of rods (B) and cones (C), or rod outer and inner segments (D) per square mm.

[0630] Example 79. In vivo efficacy assay in the rd10 mouse model of retinitis pigmentosa as measured by water maze-based optokinetic responses.

[0631] rd10 mice were treated by ocular instillation of phosphate buffered saline (PBS) containing compound 35 of the present invention for 16 days (from P14 to P29). To study the optokinetic (OKT) response, we used 9 rd10 mice at p30 for the OKT test in combination with a modified Morris water maze: 5 were treated with compound 35 and 4 were untreated. Animals were adapted to the experimental conditions for 1 week before behavioral testing. Mice were trained in a square pool (70×40 cm) filled with water (24–26°C) in which all sides were opaque except for the front side where the screen was placed. The screen was divided vertically into 2 equal parts. A pattern of moving vertical bars was presented on half of the screen, with the other half closed. The direction of the bar was random: 50% of the time it moved to the right and 50% of the time it moved to the left. The bar speed was constant throughout the process. Mice were trained for one week to associate an area of ​​the screen with a moving bar in which there was an underwater platform, invisible to the mice under dim light conditions, placed right next to that area of ​​the screen. The platform caused the mice to escape from the water. The experimental procedure was performed for 7 days so that the animals were able to associate the moving bar with the presence of the platform. For the experimental conditions during training, a bar pattern with maximum contrast (100%) and optimal spatial frequency (0.088 cycles / degree) was used. In the experiment, the contrast and spatial frequency parameters were modified until the mice could not see the bar pattern. Contrast sensitivity values ​​were measured and the results for treated and untreated mice were compared. Figure 5 It is shown that the largest differences are observed in the outliers of spatial frequency where identifying the moving bar pattern is more difficult (0.01; 0.02; 0.17 and 0.35 cycles / degree).

[0632] Example 80. In vitro efficacy of Compound 35 in preventing phototoxicity in 661W cells.

[0633] 661W is a mouse photoreceptor-derived cell line (661W) immortalized by expressing simian virus (SV) T antigen (T-ag) under the control of the human IRBP promoter. Cellular and molecular analysis showed that these cells express cone but not rod photoreceptor markers, indicating that these cells are from the cone photoreceptor lineage. For this reason, the 661W cell line should be significantly beneficial for the study of cone photoreceptor cell function and diseases affecting cone photoreceptor cells, including various retinal dystrophies (including age-related macular degeneration, Starshatz disease or diabetic retinopathy, etc.) Photoreceptor cell death mechanisms (Tan et al. Invest Ophthalmol. Vis. Sci., 2004, 45, 764).

[0634] 661W cells were seeded in 96-well impedance plates (50,000 cells / well), previously coated with ECM 1:100, and cultured at 37 °C and 5% CO 2 Cells were grown O / N in DMEM / F-12 (Thermo Fisher, 11320033) supplemented with 40 μL / L hydrocortisone 21-hemisuccinate (Sigma, H-2270), 40 μL / L progesterone (Sigma, P-8783), 0.032 g / L putrescine (Sigma, P-7505), 40 μL / L β-mercaptoethanol (Sigma, M-6250), antibiotic-antimycotic solution (Sigma, A5955) and 10% fetal bovine serum (FBS). After 8 h, the medium was replaced with DMEM / F-12 without FBS or complement to remove cell debris. When the cells reached a plateau in the impedance recording (4-8 hours after the medium change, depending on the culture plate), compound 35 was added, and 9-cis-retinal (Cf=20 μM) was added two hours later. Cells were placed in a Maestro Z and exposed to 30,000 lux white light.

[0635] To record the impedance. Figure 6 Compound 35 was shown to protect 661W cells from 9-cis-retinal and light-induced phototoxicity in a dose-response manner with a potency of EC50 = 30.5 nM.

Claims

1. Compounds of formula (I): in X and Y are independently selected from the group consisting of C1-C6 alkyl, OH, O(C1-C4 alkyl), OCF3, S(C1-C4 alkyl), NHC(O)(C1-C4 alkyl), CF3, CN, F, Cl, Br and I; or X and Y together represent methylenedioxy or ethylenedioxydiradical; m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4; Z is selected from the group consisting of -S-, -S(=O)-, -S(=O)2- and -O-; R 1 is a straight chain C1-C4 alkylene diradical, optionally substituted by one or two substituents independently selected from the group consisting of methyl, ethyl and F; R 2 is a straight chain C1-C4 alkylene diradical, optionally substituted by one or two substituents independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, allyl, propargyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, 1-naphthyl, 2-naphthyl, benzyl, 4-hydroxybenzyl and CF3; R 3 Selected from the group consisting of H and I; and W is selected from the group consisting of: -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -N(C1-C4 alkyl)3, 1-pyrrolidinyl optionally substituted by C1-C4 alkyl, 1-piperidinyl optionally substituted by C1-C4 alkyl, 4-morpholinyl optionally substituted by C1-C4 alkyl, 4-piperazinyl optionally substituted by C1-C4 alkyl, -NHC(=NH)NH2, -NHC(=NH)NH(C1-C4 alkyl), -NHC(=N(C1-C4 alkyl)NH(C1-C4 alkyl), - NHC(=NH)NHC(=NH)NH2,-N(C1-C4 alkyl)C(=NH)NHC(=NH)NH2,- CO2H and -SO3H; or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof; For use in preventing and / or treating eye diseases.

2. The compound of formula (I) for use according to claim 1, wherein m is 1; n is 0; X is selected from the group consisting of O(C1-C4 alkyl), C1-C6 alkyl and CF3; R 1 is -CH2-; R 2 Selected from the group consisting of -CH2-CH2- and -CH2-CH2-CH2-; R 3 is H; and W is selected from the group consisting of: -N(C1-C4 alkyl)2, 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl and 4-piperazinyl, which are optionally substituted with C1-C4 alkyl.

3. A compound of formula (I) for use according to any one of the preceding claims, wherein Z is -S-; R 1 is -CH2-; and R 3 It's H.

4. A compound of formula (I) for use according to any one of the preceding claims, wherein m is 1; n is 0; and X is located in the para position relative to Z.

5. The compound of formula (I) for use according to claim 1, wherein The compound is selected from the group consisting of: 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 4-[(3,5-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4,5-trimethoxyphenoxy)methyl]-1H-1,2,3-triazole; 4-[(3,4-dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 4-[(4-methoxyphenoxy)methyl]-1-[2-(N-methylamino)ethyl]-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 4-[(4-methoxyphenoxy)methyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazole; 4-[(4-methoxyphenoxy)methyl]-1-[2-(morpholin-4-yl)ethyl]-1H,1,2,3-triazole; 4-[(4-methoxyphenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole; 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Piperidin-1-yl)ethyl]-4-[(4-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Piperidin-1-yl)ethyl]-4-[(2-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole; (Guanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guandino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guandino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guandino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Guandino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenoxy)methyl]-1H-1,2,3-triazole; 5-iodo-4-[(4-methoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-(trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole; 4-[(4-methoxyphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole; 4-[(4-tert-Butylphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole; 4-[(4-isopropylphenyl)thiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole; 1-[2-(4-morpholinyl)ethyl]-4-(phenylthiomethyl)-1H,1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-tert-butylphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(Guandino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(Biguanidino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[3-(Biguanidino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-5-iodo-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-5-tritiated-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 4-[(4-isopropylphenyl)sulfinylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole; 4-[(2,6-dimethylphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole; 1-[2-(4-morpholinyl)ethyl]-4-(phenylsulfinylmethyl)-1H,1,2,3-triazole; 4-[(4-methoxyphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole; 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[3-(N,N-diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethyl)-N-oxyaminoethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole; 1-[2-(N,N-diethylamino)ethyl]-4-[(4-bromophenyl)sulfonylmethyl]-1H-1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(3,4-dimethoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole; 4-[(4-isopropylphenyl)sulfonylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole; 4-(phenylsulfonylmethyl)-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole; 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenyl)sulfonylmethyl]-1H-1,2,3-triazole; 1-(2-aminoethyl)-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole; and 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole.

6. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of the preceding claims or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof, and a pharmaceutically acceptable excipient for use in preventing and / or treating eye diseases, preferably wherein the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethylcellulose, carbomer and mixtures thereof.

7. A compound of formula (I) or a pharmaceutical composition for use according to any one of the preceding claims, wherein: The ocular disease is a retinal disease, preferably selected from the group consisting of: retinitis pigmentosa, diabetic retinopathy, cone dystrophy, rod and cone degeneration, Leber congenital amaurosis, white punctate retinitis, choroideremia, gyratory choroidal and retinal atrophy, choroidal dystrophy, X-linked retinoschisis, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinal choroidopathy, Starshatz disease, Best vitelliform macular dystrophy; dominant vitreoretinal choroidopathy; Usher syndrome, Bard-Biedel syndrome, Thorsby fundus dystrophy, age-related macular degeneration, autosomal dominant congenital stationary night blindness, achromatopsia and macular drusen.

8. The compound of formula (I) or the pharmaceutical composition for use according to claim 7, wherein The retinal disease is selected from the group consisting of retinitis pigmentosa, Starcharts' disease, Leber congenital amaurosis, age-related macular degeneration and diabetic retinopathy.

9. The compound of formula (I) or pharmaceutical composition for use according to claim 7, wherein The retinal disease is selected from the group consisting of retinitis pigmentosa, autosomal dominant congenital stationary night blindness and achromatopsia.

10. A compound of formula (I) or a pharmaceutical composition for use according to any one of the preceding claims, which is administered topically, intraocularly, orally, parenterally, transdermally, intranasally or rectally.

11. A compound of formula (I) or a pharmaceutical composition for use according to any one of the preceding claims for topical administration on the corneal surface, preferably in the form of drops, gel, cream, spray or contact lenses.

12. A compound of formula (I) or a pharmaceutical composition for use according to any one of the preceding claims, wherein: The compound of formula (I) is administered at a dosage of 0.001 to 10 mg / day.

13. Compounds of formula (II): in X and Y are independently selected from the group consisting of C1-C6 alkyl, OH, O(C1-C4 alkyl), OCF3, S(C1-C4 alkyl), NHC(O)(C1-C4 alkyl), CF3, F, Cl, Br and I; or X and Y together represent methylenedioxy or ethylenedioxydiradical; m and n are independently selected from the group consisting of 0, 1, 2, 3 and 4; Z is selected from the group consisting of -S-, -S(=O)-, -S(=O)2- and -O-; Each R is selected from the group consisting of H and CH3; R 3 Selected from the group consisting of H and I; When Z is -S-, -S(=O)- or -S(=O)2-, p is selected from the group consisting of 2, 3 and 4, and W is selected from the group consisting of: -NHC(=NH)NH2, -NHC(=NH)NH(C1-C4 alkyl), -NHC(=N(C1-C4 alkyl)NH(C1-C4 alkyl), - NHC(=NH)NHC(=NH)NH2 and -N(C1-C4alkyl)C(=NH)NHC(=NH)NH2; and when Z is -O-, p is selected from the group consisting of 2 and 4, and W is selected from the group consisting of -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl), -N(C1-C4 alkyl), 1-pyrrolidinyl optionally substituted with C1-C4 alkyl, 1-piperidinyl optionally substituted with C1-C4 alkyl, 4-morpholinyl optionally substituted with C1-C4 alkyl, 4-piperazinyl optionally substituted with C1-C4 alkyl, -NHC(=NH)NH2, -NHC(=NH)NH(C1-C4 alkyl), -NHC(=N(C1-C4 alkyl)NH(C1-C4 alkyl), -NHC(=NH)NHC(=NH)NH2, -N(C1-C4 alkyl)C(=NH)NHC(=NH)NH2, -CO2H, and -SO3H; or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof; The proviso is that the compound is not 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole.

14. The compound according to claim 13, wherein When Z is -O-, m is selected from the group consisting of 0, 1, 2 and 3; n is selected from the group consisting of 0, 1 and 2; When X is present, it is located in the meta or para position relative to Z and is selected from the group consisting of OH, O(C1-C4 alkyl), OCF3 and CF3; When Y is present, it is located in the ortho position relative to Z and is CF3; or X and Y together represent a methylenedioxy or ethylenedioxydiradical; Each R is independently selected from the group consisting of H and CH3; R 3 Selected from the group consisting of H and I; p is selected from the group consisting of 2 and 4; as well as W is selected from the group consisting of: -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -N(C1-C4 alkyl)3, 1-pyrrolidinyl optionally substituted by C1-C4 alkyl, 1-piperidinyl optionally substituted by C1-C4 alkyl, 4-morpholinyl optionally substituted by C1-C4 alkyl, 4-piperazinyl optionally substituted by C1-C4 alkyl, -NHC(=NH)NH2, -NHC(=NH)NH(C1-C4 alkyl), -NHC(=N(C1-C4 alkyl)NH(C1-C4 alkyl), - NHC(=NH)NHC(=NH)NH2 and -N(C1-C4alkyl)C(=NH)NHC(=NH)NH2.

15. A compound of formula (II) according to claim 13 or 14, wherein m is 1; n is 0; X is located in the para position relative to Z; X is O(C1-C4 alkyl); Z is -S- or -O-; R is H; p is selected from the group consisting of 2 and 3; R 3 is H; when Z is -S-, W is NHC(=NH)NHC(=NH)NH2; and when Z is -O-, W is -N(C1-C4alkyl)2.

16. A compound of formula (II) according to any one of claims 13 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof, for use in medicine.

17. A pharmaceutical composition comprising a compound of formula (II) according to any one of claims 13 to 15 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof, and a pharmaceutically acceptable excipient; preferably wherein the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and mixtures thereof.

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