Triazoles for use in the treatment of eye diseases

Abstract

The present invention relates to substituted 1,2,3-triazoles of formula (I) useful for the treatment of eye diseases, in particular eye diseases associated with retinal degeneration. The present invention also relates to a pharmaceutical composition for treating retinal diseases by topical administration. JPEG2025520705000084.jpg24137

Description

Technical Field

[0001] The present invention relates to substituted 1,2,3-triazoles useful for the treatment of eye diseases, particularly eye diseases associated with retinal degenerations 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 at the back of the eye. The cornea and lens focus light onto the retina. The retina contains millions of light-sensitive cells (rods and cones) and other nerve cells that receive and organize visual information. The retina sends this information to the brain through the optic nerve, enabling us to see. The central region of the retina, called the macula, contains a high density of color-sensitive photoreceptor (light-sensitive) cells. These cells, called cones, create sharp visual images and are responsible for central vision and color vision. The peripheral region of the retina surrounding the macula contains photoreceptor cells called rods, which respond to lower light levels but are not color-sensitive. Rods are responsible for peripheral vision and night vision.

[0003] Retinal diseases are diverse, and most of them cause visual symptoms. Some retinal diseases are more frequent with aging or diabetes. Others are genetic, such as retinitis pigmentosa, or have genetic risk factors. Genetic diseases of the retina often lead to degenerations that cause irreversible vision loss at a very early stage of life, such as retinitis pigmentosa and Stargardt's disease.

[0004] Retinitis pigmentosa (RP) is a term used for a genetically heterogeneous group of hereditary retinal degenerations. Symptoms include the onset of night blindness, constriction of the visual field, and slowly progressive loss of central vision. RP can be: (i) asymptomatic, i.e., occurring alone without other clinical findings, (ii) symptomatic, with other sensory disorders, developmental abnormalities, or complex clinical findings, or (iii) secondary to other systemic diseases. RP associated with deafness (congenital or progressive) is called Usher syndrome. Alport syndrome is associated with glomerular basement membrane abnormalities leading to RP and nephrotic syndrome. This is inherited as X-linked dominant.

[0005] RP associated with ophthalmoplegia, dysphagia, and cardiac conduction disorders is seen in the mitochondrial DNA disease Kearns–Sayre syndrome (also known as red ragged fiber myopathy). RP associated with mental retardation, peripheral neuropathy, epidermal hyperkeratotic spiky erythrocytes, ataxia, steatorrhea, and absence of VLDL is seen in abetalipoproteinemia. RP is clinically seen in association with several other rare hereditary diseases as part of the McLeod syndrome. This is an X-linked recessive phenotype characterized by a complete absence of the XK cell surface protein and thus a marked reduction in the expression of all Kell erythrocyte antigens. RP associated with hypogonadism and developmental delay in an autosomal recessive inheritance pattern is seen together with Bardet–Biedl syndrome.

[0006] Some of the major diseases affecting the macula, such as age-related macular degeneration and diabetic retinopathy, lead to visual impairment. Further examples of retinal diseases are cone dystrophy, rod and cone degeneration, Leber congenital amaurosis, punctate retinitis, coloboma, choroid and retinal gyral atrophy, generalized choroid dystrophy, juvenile retinal detachment, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinochoroidopathy, Best vitelliform macular dystrophy, Usher syndrome, Bardet–Biedl syndrome, Sorsby pseudoinflammatory macular dystrophy, and dominant drusen.

[0007] Currently, there is no treatment for retinitis pigmentosa, but the effectiveness 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. ES 2673942 (A1) discloses the use of acylated resveratrol derivatives. The compound is administered subretinally or forms a complex with cyclodextrin. Metformin is currently being clinically tested for the treatment of age-related macular degeneration (https: / / curativebiotech.com / pipeline).

[0008] Substituted 1,2,3-triazoles are described in WO 2017 / 203083 (A1) for the regulation of intracellular calcium homeostasis for use in the prevention or treatment of skeletal muscle disorders, heart diseases and neurodegenerative diseases. However, this document does not describe the usefulness of these compounds in the treatment of eye diseases.

[0009] Substituted 1,2,3-triazoles having a 4-(aryloxy)methyl group are suitable for designing bioactive compounds disclosed by Grimster, et al. J. Am. Chem. Soc., 2012, 134(15), 6732 for nicotinic acetylcholine receptor modulators and by Li et al. J. Med. Chem. 2017, 60(7), 2697 for free fatty acid receptor GRP40 agonists. These triazoles have also been used as non-degrading bio-ligands disclosed by Hatit et al. Nature Commun. 2018, 9(1), 4021.

[0010] Substituted 4-[(arylthio)alkyl]-1H-1,2,3-triazoles for the regulation of intracellular calcium homeostasis for use in the prevention or treatment of skeletal disorders, heart diseases and neurodegenerative diseases are described in WO 2017 / 203083 (A1) and Aizpurua et al., Eur. J. Med. Chem., 2021, 213. However, these documents do not describe the usefulness of these compounds in the treatment of eye diseases either.

[0011] There is still a need in the art for a sufficient treatment of retinal diseases, particularly eye diseases such as retinitis pigmentosa, and more particularly for a treatment including a non-invasive administration protocol.

Summary of the Invention

[0012] As shown in the examples, the inventors have unexpectedly found that substituted 1,2,3-triazoles are useful for the treatment of eye diseases, in particular retinal diseases such as retinitis pigmentosa. After topical ocular administration, as also shown in the examples, the substituted 1,2,3-triazoles reach the posterior part of the eye. Thus, these substituted 1,2,3-triazoles can be applied topically and still reach their target sites. Topical administration is advantageous as it avoids the use of invasive administration routes such as intravitreal injection and systemic administration routes such as oral administration, reducing side effects and improving patient compliance and comfort.

[0013] Accordingly, in a first aspect, the present invention provides a compound of formula (I) for use in the prevention and / or treatment of eye diseases:

[0014]

Chemical formula

[0015] wherein in said formula (I), 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 form a methylenedioxy or ethylenedioxy biradical; 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 linear C1-C4 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl, ethyl, and F; R 2 is a linear C1-C4 alkylene biradical which may be 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 is 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; Relates to a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

[0016] A second aspect is 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 the prevention and / or treatment of eye diseases, preferably, the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and mixtures thereof, relating to a pharmaceutical composition.

[0017] A third aspect is a compound of formula (II):

[0018]

Chemical formula

[0019] wherein in said formula (II), 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 are a methylenedioxy or ethylenedioxy biradical; 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 independently selected from the group consisting of H and CH3; R 3 is 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)NH, and -N(C1-C4 alkyl)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)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, provided that the compound is not 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole, relates to a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof.

[0020] A fourth aspect relates to a compound of formula (II) as defined in the third aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotopically labeled derivative thereof for use in medicine.

[0021] A fifth aspect relates to a pharmaceutical composition comprising a compound of formula (II) as described in 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 mixtures thereof.

[0022] The present invention also relates to a compound of formula (II) as described in 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 as described in the fifth aspect for use in the prevention and / or treatment of eye diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0023]

Figure 1A

Figure 1B

Figure 1C

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 3

Figure 4A

Figure 4B

Figure 4C

Figure 4D

Figure 5

Figure 6A

Figure 6B

Mode for Carrying Out the Invention

[0024] In the context of the present invention, the following terms have the meanings indicated below: The term "alkylene biradical" represents a biradical formed by a straight-chain hydrocarbon chain consisting of carbon and hydrogen atoms that has no unsaturation and is bonded at its ends to the remainder of the molecule by single bonds, such as, for example, methylene, ethylene, propylene, butylene, and others. The term "C1-C4 alkylene biradical" represents a biradical having 1 to 4 carbon atoms. The alkylene biradical can be substituted as defined by the R1 and R2 substituents in the compound of formula (I).

[0025] The term "alkyl" represents a radical formed by a straight-chain or branched-chain hydrocarbon chain consisting of carbon and hydrogen atoms, which does not include saturation and is bonded to the remainder of the molecule by a single bond, and examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and others. The term "C1-C4 alkyl" represents a radical having 1 to 4 carbon atoms. The term "C1-C6 alkyl" represents a radical having 1 to 6 carbon atoms.

[0026] The term "halogen" represents F, Cl, Br, and I.

[0027] The phrase "isotopically labeled derivative" represents a compound of formula (I) in which at least one of its atoms is isotopically enriched. For example, a compound of formula (I) in which hydrogen is substituted by deuterium or tritium, carbon is substituted by 13 C or 14 C, or nitrogen is substituted by 15 N-rich atoms is within the scope of the present invention. Specifically, the isotopically labeled derivative represents a compound of formula (I) in which the hydrogen atom at position R 3 is substituted by deuterium or tritium.

[0028] The term "pharmaceutically acceptable salt or solvate" refers to any pharmaceutically acceptable salt or solvate that, when administered to a recipient, can provide the compounds of formula (I) described herein. The salts can be prepared using methods known in the art.

[0029] For example, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the previously described compounds containing basic or acidic units using conventional chemical methods. Such salts are generally prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid, for example, in water, an organic solvent, or a mixture of both. Non-aqueous media such as ether, ethyl acetate, ethanol, isopropyl, or acetonitrile are generally preferred. Examples of acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as sodium salt, potassium salt, calcium salt, ammonium salt, magnesium salt, aluminum salt, and lithium salt, and organic alkali salts such as ethylenediamine salt, ethanolamine salt, N,N-dialkyleneethanolamine salt, glucamine salt, and basic amino acid salt.

[0030] A solvate represents a compound 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, and the like. In certain embodiments, the solvate is a hydrate.

[0031] The compound of formula (I) or a salt or solvate thereof is preferably in a pharmaceutically acceptable form or a substantially pure form. A pharmaceutically acceptable form is understood to have, inter alia, a pharmaceutically acceptable level of purity and to contain no substances which are considered toxic at normal dosage levels, except for normal pharmaceutical additives such as diluents and excipients. For drugs, the purity level is preferably greater than 50%, more preferably greater than 70%, still more preferably greater than 90%. In a preferred embodiment, this is greater than 95% of the compound of formula (I) or a salt or solvate thereof.

[0032] The compound of the present invention represented by the above formula (I) can include any stereoisomers that depend on the presence of chiral centers including enantiomers and diastereomers. Individual isomers, enantiomers or diastereomers and mixtures thereof are within the scope of the present invention.

[0033] As used herein, the term "tautomer" represents structural isomers of compounds in which the position of a proton adjacent to a double bond and a single bond is different, such as keto-enol tautomers, amide-imide tautomers, amine-imine tautomers, enamine-imine, lactam-lactim tautomers, etc.

[0034] The term "N-oxide" represents a derivative of a compound of formula (I) in which the nitrogen atom of the amine group is oxidized, i.e., -N + O - Specifically, N-oxides represent N-oxides of nitrogen atoms present in the amine substituents defined for W, such as tertiary amines, preferably -N(O)(C1-C4 alkyl)2, 1-pyrrolidinyl N-oxide optionally substituted by C1-C4 alkyl, 1-piperidinyl N-oxide optionally substituted by C1-C4 alkyl, 4-morpholinyl N-oxide optionally substituted by C1-C4 alkyl, and 4-piperazinyl N-oxide optionally substituted by C1-C4 alkyl.

[0035] As used herein, the terms "treat", "treatment", or "treating" preferably refer to reducing the likelihood of a particular disease or disorder, reducing the occurrence of a particular disease or disorder, and / or reducing the severity of a particular disease or disorder to the extent that the subject no longer suffers from discomfort and / or functional changes as a result. This term also refers to alleviating or reducing at least one clinical symptom and / or inhibiting or delaying the progression of the disease state and / or preventing or delaying the onset of the disease or illness.

[0036] As used herein, the terms "prevent", "preventing", or "prevention" refer to avoiding the occurrence of a particular disease or injury. Prevention can be complete (e.g., no disease at all). Prevention can also be partial, such that, for example, the occurrence of a disease in a subject is less than it would be without administration of the combination or composition of the invention. Prevention also refers to a decrease in susceptibility to a clinical condition. Prevention includes a decrease in the risk of contracting a disease.

[0037] In a first aspect, the present invention relates to a compound of formula (I) for use in the prevention and / or treatment of an eye disease:

[0038]

Chemical formula

[0039] wherein in said formula (I), 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 are a methylenedioxy or ethylenedioxy radical; 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 1is a linear C1-C4 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl, ethyl and F; R 2 is a linear C1-C4 alkylene biradical which may be 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 is 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, relates to a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

[0040] This aspect is for use in the prevention and / or treatment of eye diseases, of a compound of formula (I):

[0041]

Chemical formula

[0042] wherein, in said formula (I), 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 are methylenedioxy or ethylenedioxy biradical; 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 linear C1-C4 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl, ethyl, and F; R 2 is a linear C1-C4 alkylene biradical which may be 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 is 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; It can be formulated as the use of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

[0043] This aspect relates to a compound of formula (I):

[0044] [Chemical formula] (I)

[0045] wherein in said formula (I), 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 are methylenedioxy or ethylenedioxy biradical; 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 linear C1-C4 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl, ethyl and F; R 2 is a linear C1-C4 alkylene biradical which may be 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 is 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, It can also be formulated as a method for preventing and / or treating eye diseases comprising administering a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

[0046] 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.

[0047] Preferably, in the compound of formula (I) for use according to the present invention, m is selected from the group consisting of 0, 1 and 2, and more preferably, m is 1.

[0048] Preferably, in the compound of formula (I) for use according to the present invention, n is 0 or 1, and more preferably, n is 0.

[0049] Preferably, in the compound of formula (I) for use according to the present invention, m is 1; n is 0; and X is para to Z.

[0050] Preferably, in the compound of formula (I) for use according to the present invention, X and Y (when present, i.e., when m and / or n is other than 0) are independently selected from the group consisting of C1-C6 alkyl, OH, O(C1-C4 alkyl), CF3, CN, F, Cl, Br and I; or X and Y together are a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (I) for use according to the present invention, X and Y (when present, i.e., when m and / or n is other than 0) are independently selected from the group consisting of methyl, isopropyl, OH, methoxy, CF3, and Br; or X and Y together are a methylenedioxy biradical. Even more preferably, X is methoxy. Even more preferably still, X is methoxy, m is 1, and Y is absent (i.e., n is 0).

[0051] Preferably, in the compound of formula (I) for use according to the present invention, X (when present, i.e., when m is other than 0) is independently selected from the group consisting of C1-C6 alkyl, OH, O(C1-C4 alkyl), CF3, CN, F, Cl, Br and I; or X and Y together are a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (I) for use according to the present invention, X (when present, i.e., when m is other than 0) is independently selected from the group consisting of methyl, isopropyl, OH, methoxy, CF3, and Br; or X and Y together are a methylenedioxy biradical. Even more preferably, X is methoxy. Even more preferably still, X is methoxy and m is 1.

[0052] Preferably, in the compound of formula (I) for use according to the present invention, when Y is present (i.e., when n is other than 0), Y is independently selected from the group consisting of C1-C6 alkyl and O(C1-C4 alkyl); or X and Y together form a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (I) for use according to the present invention, when Y is present (i.e., when n is other than 0), Y is independently selected from the group consisting of methyl and methoxy; or X and Y together form a methylenedioxy biradical. Even more preferably, Y is absent (i.e., n is 0).

[0053] Preferably, in the compound of formula (I) for use according to the present invention, when X is present (i.e., when m is other than 0), X is independently selected from the group consisting of C1-C6 alkyl, OH, O(C1-C4 alkyl), CF3, CN, F, Cl, Br and I; when Y is present (i.e., when n is other than 0), Y is independently selected from the group consisting of C1-C6 alkyl and O(C1-C4 alkyl); or X and Y together form a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (I) for use according to the present invention, when X is present (i.e., when m is other than 0), X is independently selected from the group consisting of methyl, isopropyl, OH, methoxy, CF3, and Br; when Y is present (i.e., when n is other than 0), Y is independently selected from the group consisting of methyl and methoxy; or X and Y together form a methylenedioxy biradical. Even more preferably, X is methoxy. Even more preferably, X is methoxy, m is 1, and Y is absent (i.e., n is 0).

[0054] 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-, and more preferably, Z is -S-.

[0055] Preferably, in the compound of formula (I) for use according to the present invention, R1 is a linear C1-C4 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl and ethyl. More preferably, R 1 is a C1-C2 alkylene biradical which may be substituted by two methyl substituents. Even more preferably, R 1 is selected from the group consisting of -CH2- and -C(CH3)2-. Even more preferably, R 1 is -CH2-.

[0056] Preferably, in the compound of formula (I) for use according to the present invention, R 2 is a linear C1-C4 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl and benzyl. More preferably, R 2 is a linear C2-C3 alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl and benzyl. Even more preferably, R 2 is selected from the group consisting of -CH2-CH2-, -CH(Bn)-CH2-, -CH2-CH2-CH2- and -C(CH3)2-CH2-. Even more preferably, R 2 is selected from the group consisting of -CH2-CH2- and -CH2-CH2-CH2-. Even more preferably, R 2 is -CH2-CH2-.

[0057] Preferably, in the compound of formula (I) for use according to the present invention, R 3 is H.

[0058] Preferably, in the compound of formula (I) for use according to the present invention, 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-C4 alkyl)C(=NH)NHC(=NH)NH2. More preferably, W is selected from the group consisting of -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, 1-pyrrolidinyl optionally substituted by C1-C4 alkyl, 1-piperidinyl optionally substituted by C1-C4 alkyl, 4-morpholinyl optionally substituted by C1-C4 alkyl, -NHC(=NH)NH2, and -NHC(=NH)NHC(=NH)NH2. Even more preferably, W is selected from the group consisting of -NH2, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, -NHC(=NH)NH2, and -NHC(=NH)NHC(=NH)NH2. Even more preferably, W is -N(CH3)2.

[0059] 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 O(C1-C4 alkyl), C1-C6 alkyl) and CF3; R 1 is -CH2-; R 2 is selected from the group consisting of -CH2-CH2- and -CH2-CH2-CH2-; R 3is H; and W is selected from the group consisting of -N(C1-C4 alkyl)2, 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, 4-piperazinyl optionally substituted with C1-C4 alkyl, and -NHC(=NH)NHC(=NH)NH2.

[0060] In one embodiment, in the compound of formula (I) for use according to the invention, m is 1; n is 0; X is selected from the group consisting of methoxy, isopropyl and CF3; R 1 is -CH2-; R 2 is 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(CH3)2, 1-piperidinyl, 4-morpholinyl, and -NHC(=NH)NHC(=NH)NH2.

[0061] In one embodiment, in the compound of formula (I) for use according to the invention, Z is O or S; m is 1; n is 0; X is methoxy; R 1 is -CH2-; R 2 is -CH2-CH2-; R 3 is H; and W is -N(CH3)2.

[0062] In one embodiment, in the compound of formula (I) for use according to the invention, Z is O or S; m is 1; n is 0; X is methoxy; R 1 is -CH2-; R 2 is -CH2-CH2-; R 3 is H; W is -N(CH3)2; and X is para to Z.

[0063] In another embodiment, in the compound of formula (I) for use according to the invention, Z is -S-; R 1 is -CH2-; and R 3 is H.

[0064] In a preferred embodiment, the compound of formula (I) for use according to the invention 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; (Guanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(3',4'-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Biguanidyl)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-oxideaminoethyl]-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-(Guanidyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(Biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[3-(Biguanidinyl)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-tritium-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-oxide aminoethyl]-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.

[0065] More preferably, the compound of formula (I) for use according to the present invention 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-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole, 1-[2-(guanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl)]-1H-1,2,3-triazole and 1-[2-(biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0066] Even more preferably, the compound of formula (I) for use according to the present invention is 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0067] In a preferred embodiment, the eye disease is a retinal disease. Preferably, the retinal disease is retinitis pigmentosa (autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other symptoms, etc.), diabetic retinopathy, cone dystrophy, rod and cone dystrophy, Leber congenital amaurosis, punctate retinitis, choroideremia, choroid and retinal gyral atrophy, generalized choroid dystrophy, juvenile retinal detachment, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinochoroidopathy, Stargardt disease, Best vitelliform macular dystrophy, Usher syndrome, Bardet-Biedl syndrome, Sorsby pseudo-inflammatory macular dystrophy, age-related macular degeneration, autosomal dominant congenital stationary night blindness, color vision abnormalities, and dominant drusen, and is selected from the group consisting of. Even more preferably, the eye disease is retinitis pigmentosa (autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other symptoms, etc.), Stargardt disease, Leber congenital amaurosis, age-related macular degeneration, and diabetic retinopathy, and is selected from the group consisting of. Even more preferably, the eye disease is retinitis pigmentosa (autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other symptoms, etc.).

[0068] In another preferred embodiment, the retinal disease is selected from retinitis pigmentosa, autosomal dominant congenital stationary night blindness, and color vision abnormalities.

[0069] 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, and more preferably, a human.

[0070] For administration to a mammalian subject in need of treatment, such as a human, the compounds and pharmaceutical compositions described herein may be administered by any suitable route, including topically, intravitreally, orally (e.g., by mouth, sublingually, etc.), parenterally (e.g., subcutaneously, intramuscularly, intravenously, intramuscularly, etc.), rectally, nasally, and others. Thus, in one embodiment, the compounds and pharmaceutical compositions described herein are administered topically, intravitreally (e.g., subretinally or intravitreally), orally (including sublingual administration), parenterally (e.g., intravenously, intramuscularly, intraperitoneally, subcutaneously), transdermally, intranasally, or rectally. In a preferred embodiment, the compounds and pharmaceutical compositions as defined herein are topically administered to the corneal surface, preferably in the form of droplets, gels, creams, sprays, contact lenses, or intravitreal rings.

[0071] The pharmaceutical composition comprises a compound described herein and one or more pharmaceutically acceptable excipients or vehicles.

[0072] The pharmaceutically acceptable vehicle must be acceptable in the sense of being compatible with the other ingredients of the composition and not deleterious to its recipient. The pharmaceutically acceptable vehicle can be selected from organic and inorganic substances that are used in pharmaceutical formulations and incorporated as analgesics, pH regulators, binders, disintegrants, diluents, emulsifiers, fillers, fluidizing agents, solubilizers, stabilizers, suspending agents, isotonic agents, and thickening agents. Pharmaceutical additives such as antioxidants, fragrances, dyes, fragrance enhancers, preservatives, and sweeteners can be further added.

[0073] The compounds and pharmaceutical compositions described herein may be administered in the form of different formulations. Examples are oral formulations, i.e., tablets, capsules, syrups, or suspensions. Further, the pharmaceutical compositions of the present invention include topical compositions, i.e., creams, ointments or pastes, or transdermal formulations such as patches or liniments. The pharmaceutical compositions of the present invention may be formulated for rectal administration, i.e., rectal gels or rectal capsules.

[0074] Dosage forms suitable for oral administration may be tablets, capsules, syrups or solutions, and may include conventional excipients known in the art, such as binders, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example, lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet molding lubricants, for example, magnesium stearate; disintegrants, for example, starch, polyvinylpyrrolidone, sodium starch glycolate or crystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.

[0075] The pharmaceutical composition may also be adapted for parenteral administration, such as sterile solutions, suspensions or freeze-dried products in suitable unit dosage forms. Suitable excipients such as bulking agents, buffering agents or surfactants can be used.

[0076] In a preferred embodiment, the pharmaceutical composition comprises a pharmaceutically acceptable excipient selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and mixtures thereof.

[0077] 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-(guanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl)]-1H-1,2,3-triazole and 1-[2-(biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole, and a pharmaceutically acceptable excipient selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and mixtures thereof.

[0078] Even more preferably, the pharmaceutical composition comprises 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole and hyaluronic acid.

[0079] An "effective" amount or "therapeutically effective amount" of a compound means an amount of the drug or agent that is non-toxic but sufficient to provide the desired effect. The amount that is "effective" will vary depending on the individual's age and general condition, the particular active agent or agent, and the like. Thus, it is not always possible to specify the exact "effective amount". However, the appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. The compounds are usually administered once or more than once a day, for example, once, twice, three times or four times a day, usually at a total daily dose in the range of 0.001 to 500 mg / day, preferably at a dose of 0.001 to 10 mg / day.

[0080] In another aspect, the present invention is a compound of formula (II) which is a subgroup of the compounds of formula (I):

[0081]

Chemical formula

[0082] wherein in the above formula (II), 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 form a methylenedioxy or ethylenedioxy biradical; 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 independently selected from the group consisting of H and CH3; R 3 is 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 1, 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-C4 alkyl)C(=NH)NHC(=NH)NH2; and 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 -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, provided that the compound is not 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole, relates to a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

[0083] When m has a value other than 0, an X substituent is present. Similarly, when n has a value other than 0, a Y substituent is present.

[0084] In a preferred embodiment, in the compound of formula (II), 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 present, X is 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 present, Y is in the ortho position relative to Z and is CF3; or X and Y together are a methylenedioxy or ethylenedioxy biradical; Each R is independently selected from the group consisting of H and CH3; R 3 is selected from the group consisting of H and I; p is selected from the group consisting of 2 and 4; 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-C4 alkyl)C(=NH)NHC(=NH)NH2.

[0085] In the above embodiments, when Z is -S-, -S(=O)- or -S(=O)2-, 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 are a methylenedioxy or ethylenedioxy biradical; m and n are independently selected from the group consisting of 0, 1, 2, 3, and 4; Each R is independently selected from the group consisting of H and CH3; R 3 is selected from the group consisting of H and I; p is selected from the group consisting of 2, 3 and 4; 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-C4 alkyl)C(=NH)NHC(=NH)NH2.

[0086] In a preferred embodiment of the compound of formula (II), m is 1; n is 0; X is para to Z; X is O(C1-C4 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)NH2; when Z is -O-, W is -N(C1-C4 alkyl)2.

[0087] In a preferred embodiment of the compound of formula (II), m is 1; n is 0; X is para to Z; X is O(C1-C4 alkyl); Z is -O-; R is H; p is 2; R 3 is H; and W is -N(C1-C4 alkyl)2.

[0088] When m has a value other than 0, an X substituent is present. Similarly, when n has a value other than 0, a Y substituent is present.

[0089] Preferably, in the compound of formula (II) according to the present invention, m is selected from the group consisting of 0, 1 and 2, and more preferably, m is 1.

[0090] Preferably, in the compound of formula (II) according to the present invention, n is 0 or 1, and more preferably, n is 0.

[0091] Preferably, in the compound of formula (II) according to the present invention, m is 1; n is 0; and X is para to Z.

[0092] Preferably, in the compound of formula (II) according to the present invention, X and Y (when present, i.e., when m and / or n is other than 0) are independently selected from the group consisting of O(C1-C4 alkyl), OH and CF3; or X and Y together form a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (II) according to the present invention, X and Y (when present, i.e., when m and / or n is other than 0) are independently selected from the group consisting of methoxy, OH and CF3; or X and Y together form a methylenedioxy biradical. Even more preferably, X is methoxy. Even more preferably, X is methoxy, m is 1, and Y is absent (i.e., n is 0).

[0093] In certain embodiments, X, when present, is in the meta or para position relative to Z and is independently selected from the group consisting of (C1-C4 alkyl), OH and CF3; Y, when present, is in the ortho position relative to Z and is CF3.

[0094] Preferably, in the compound of formula (II) according to the present invention, X (when present, i.e., when m is other than 0) is independently selected from the group consisting of O(C1-C4 alkyl), OH and CF3; or X and Y together form a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (II) according to the present invention, X (when present, i.e., when m is other than 0) is independently selected from the group consisting of methoxy, OH and CF3; or X and Y together form a methylenedioxy biradical. Even more preferably, X is methoxy. Even more preferably, X is methoxy and m is 1.

[0095] Preferably, in the compound of formula (II) for use according to the present invention, when Y is present (i.e., when n is other than 0), Y is independently O(C1-C4 alkyl); or X and Y together form a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (II) according to the present invention, when Y is present (i.e., when n is other than 0), Y is independently methoxy; or X and Y together form a methylenedioxy biradical. Even more preferably, Y is absent (i.e., n is 0).

[0096] Preferably, in the compound of formula (II) according to the present invention, when X is present (i.e., when m is other than 0), X is independently selected from the group consisting of O(C1-C4 alkyl), OH and CF3; when Y is present (i.e., when n is other than 0), Y is independently O(C1-C4 alkyl); or X and Y together form a methylenedioxy or ethylenedioxy biradical. More preferably, in the compound of formula (II) according to the present invention, when X is present (i.e., when m is other than 0), X is independently selected from the group consisting of methoxy, OH and CF3; when Y is present (i.e., when n is other than 0), Y is independently methoxy; or X and Y together form a methylenedioxy biradical. Even more preferably, X is methoxy. Even more preferably, X is methoxy, m is 1, and Y is absent (i.e., n is 0).

[0097] Preferably, in the compound of formula (II) according to the present invention, when X is present (i.e., when m is other than 0), X is in the meta or para position, even more preferably the para position, relative to Z.

[0098] Preferably, in the compound of formula (II) according to the present invention, when Y is present (i.e., when n is 0), Y is in the ortho position relative to Z.

[0099] 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-.

[0100] Preferably, in the compound of formula (II) according to the present invention, each R is independently selected from H and CH3; more preferably, R is H.

[0101] Preferably, in the compound of formula (II) according to the present invention, p is selected from 2 and 4. More preferably, p is 2.

[0102] Preferably, in the compound of formula (II) according to the present invention, R 3 is H.

[0103] Preferably, in the compound of formula (II) according to the present invention, when Z is -S-, -S(=O)- or -S(=O)2, W is selected from the group consisting of -NHC(=NH)NH2 and -NHC(=NH)NHC(=NH)NH2. Even more preferably, when Z is -S-, -S(=O)- or -S(=O)2, W is -NHC(=NH)NHC(=NH)NH2.

[0104] Preferably, in the compound of formula (II) according to the present invention, when Z is -O-, W is selected from the group consisting of -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, 1-pyrrolidinyl optionally substituted by C1-C4 alkyl, 1-piperidinyl optionally substituted by C1-C4 alkyl, and 4-morpholinyl optionally substituted by C1-C4 alkyl. Even more preferably, when Z is -O-, W is selected from the group consisting of -NH2, -NH(CH3), -N(CH3)2, 1-pyrrolidinyl, 1-piperidinyl, and 4-morpholinyl. Even more preferably, when Z is -O-, W is -N(CH3)2.

[0105] In certain embodiments, 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 O(C1-C4 alkyl), OH and CF3; R is H; p is 2; R 3 is H; Z is -O- or -S-, and when Z is -O-, W is selected from the group consisting of -N(C1-C4 alkyl)2, 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl optionally substituted by C1-C4 alkyl, and when Z is -S-, W is -NHC(=NH)NHC(=NH)NH2.

[0106] In certain embodiments, 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 CF3; 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 the group consisting of -N(C1-C4 alkyl)2, 1-piperidinyl, 4-morpholinyl, 1-pyrrolidinyl, and when Z is -S-, W is -NHC(=NH)NHC(=NH)NH2.

[0107] In another particular 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(CH3)2.

[0108] In another particular 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(CH3)2; and X is para to Z.

[0109] In preferred embodiments, the compound of formula (II) 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; (Guanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(guanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(guanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(guanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(guanidyl)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 1-[2-(biguanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(biguanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Biguanidyl)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-oxideaminoethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[2-(Biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole; 1-[3-(Biguanidinyl)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0110] More preferably, the compound of formula (II) is selected from the group consisting of 1-[2-(biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole and 1-[2-(biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0111] Even more preferably, the compound of formula (II) is 1-[2-(biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole.

[0112] As shown and described in the examples relating to the compounds of formula (I), the compounds of formula (II) are also suitable for the treatment and / or prevention of eye diseases.

[0113] Accordingly, 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 isotope-labelled derivative thereof, for use in medicine.

[0114] 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 isotope-labelled derivative thereof, for use in the prevention and / or treatment of eye diseases.

[0115] 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-labelled derivative thereof, in the manufacture of a medicament for the prevention and / or treatment of eye diseases.

[0116] This aspect can also be expressed as a method for the prevention and / or treatment of eye diseases comprising the administration of a compound of formula (II) as defined above or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labelled derivative thereof.

[0117] Preferably, the eye disease is a retinal disease. More preferably, the retinal disease is retinitis pigmentosa (autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other symptoms, etc.), diabetic retinopathy, cone dystrophy, rod and cone degeneration, Leber congenital amaurosis, punctate retinitis, coloboma, choroid and retinal gyral atrophy, systemic choroid dystrophy, juvenile retinal detachment, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinal choroidopathy, Stargardt disease, Best vitelliform macular dystrophy, Usher syndrome, Bardet-Biedl syndrome, Solus pseudo-inflammatory macular dystrophy, age-related macular degeneration, autosomal dominant congenital stationary night blindness, color vision abnormality, and dominant drusen. More preferably, the eye disease is selected from the group consisting of retinitis pigmentosa (autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other symptoms, etc.), Stargardt disease, Leber congenital amaurosis, age-related macular degeneration, and diabetic retinopathy. Even more preferably, the eye disease is retinitis pigmentosa (autosomal dominant retinitis pigmentosa, autosomal recessive retinitis pigmentosa, X-linked retinitis pigmentosa, sporadic retinitis pigmentosa, retinitis pigmentosa associated with other symptoms, etc.).

[0118] In another preferred embodiment, the retinal disease is selected from retinitis pigmentosa, autosomal dominant congenital stationary night blindness, and color vision abnormality.

[0119] A further 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 isotope-labeled derivative thereof, and a pharmaceutically acceptable excipient.

[0120] The pharmaceutically acceptable excipient, route of administration, and dosage form are as defined previously. Preferably, the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer, and mixtures thereof.

[0121] The 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 SO2.

[0122] When Z is O, the following general synthetic route can be used: a) React ω-chloroalkylamine with sodium azide in water at 80 °C to produce a solution of the corresponding ω-azidoalkylamine hydrochloride; b) 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), mix an aqueous solution of the said ω-azidoalkylamine intermediate with a terminal aryloxyalkyl alkyne; c) Stir the reaction mixture at room temperature until completion (usually overnight) and proceed with the work-up. These routes are exemplified in Example 1, Example 9 and Example 33.

[0123] When W is a guanidine derivative, the following general synthetic route may be used: a) Prepare 1-(ω-aminoalkyl)-1H-1,2,3-triazole as outlined above; b) In an aprotic solvent (e.g., dichloromethane) at 0 °C, react a primary amine with a stoichiometric amount of di-tert-butoxycarbonylthiourea S=C(NHBoc)2, molecular iodine and triethylamine until completion (usually 2 hours); when W is an N-alkylated guanidine, use Boc-protected N-alkylthiourea S=C(NHBoc)[N(C1-C4 alkyl)Boc] or S=C[N(C1-C4 alkyl)Boc]2; c) Deprotect the resulting intermediate 1-[ω-(di-tert-butoxycarbonylguanidino)alkyl]-1H-1,2,3-triazole using a suitable acid (e.g., HCl in anhydrous 1,4-dioxane, trifluoroacetic acid). This synthetic route is detailed in Example 22.

[0124] When W is a biguanide derivative, the following general synthetic route may be used: a) Prepare 1-(ω-aminoalkyl)-1H-1,2,3-triazole as outlined above; b) In an aprotic solvent (e.g., acetonitrile) at 150 °C, using an ACE pressure tube until completion (usually 15 minutes), react a primary amine with a stoichiometric amount of cyanoguanidine and chlorotrimethylsilane; When W is an N-alkylated biguanide of the type -N(C1-C4 alkyl)C(=NH)NHC(=NH)NH2, substitute the primary amine with 1-[ω-(N-alkylamino)alkyl]-1H-1,2,3-triazole as embodied in Example 10; c) Cool the mixture, add isopropanol, and crystallize the hydrochloride salt. This synthetic route is detailed in Example 27.

Examples

[0125] The following examples are specific embodiments of the present invention. A) Synthesis of the compound of formula (I) when Z is -O- Example 1: (Compound 1) 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0126]

Chemical formula

[0127] 2-Chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g) and sodium azide (13 mmol, 0.84 g) in water (10 mL) were heated at 80 °C overnight. To the resulting solution of 2-azidoethyl-N,N-dimethylamine hydrochloride, 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) were added 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 minutes 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). The aqueous phase was basified with 20% Na2CO3 and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel, CH2Cl2 / MeOH 95:5). Yield 2.62 g (95%). White solid (melting point: 68 °C). 1 H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.05 - 6.89 (m, 2H), 6.89 - 6.69 (m, 2H), 5.16 (s, 2H), 4.45 (t, J = 6.3 Hz, 2H), 3.77 (s, 3H), 2.77 (t, J = 6.3 Hz, 2H), 2.28 (s, 6H). 13 C NMR (126 MHz, CDCl3): δ 154.0, 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 / z calculated (M+H) C 14 H 20N4O2276.1586, measured 276.1591.

[0128] Example 2: (Compound 2) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole

[0129]

Chem.

[0130] Starting from 3,4-methylenedioxyphenyl propargyl ether (10 mmol, 1.76 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g), the procedure of Example 1 was followed. Yield 2.34 g (80%). White solid (melting point: 44 °C). 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.45 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 5.94 (s, 2H), 5.15 (s, 2H), 4.50 (t, J = 6.3 Hz, 2H), 2.83 (t, J = 6.3 Hz, 2H), 2.33 (s, 6H). 13 C NMR (75 MHz, CDCl3) δ 154.4, 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 / z calculated (M+H) C 14 H 18 N4O3290.1379, measured 290.1384.

[0131] Example 3: (Compound 3) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0132]

Chem.

[0133] Starting from 3-methoxyphenyl propargyl ether (10.0 mmol, 1.78 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.62 g), the procedure of Example 1 was followed. Yield 2.24 g (81%). An oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.21 (t, J = 8.2 Hz, 2H), 6.65 - 6.53 (m, 3H), 5.21 (s, 2H), 4.47 (t, J = 6.3 Hz, 2H), 3.80 (s, 3H), 2.79 (t, J = 6.3 Hz, 2H), 2.30 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 161.1, 159.7, 144.2, 130.2, 123.6, 107.1, 107.0, 101.5, 62.3, 59.0, 55.5, 48.4, 45.6.

[0134] Example 4: (Compound 4) 4-[(3,5-Dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole

[0135]

Chem.

[0136] Starting from 3,5-dimethoxyphenyl prop-2-ynyl ether (10.0 mmol, 1.92 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g), the procedure of Example 1 was followed. Yield 1.80 g (59%). White solid (melting point: 43 °C). 1 H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 6.20 (d, J = 2.1 Hz, 2H), 6.13 (t, J = 2.2 Hz, 1H), 5.18 (s, 2H), 4.47 (t, J = 6.3 Hz, 2H), 3.78 (s, 6H), 2.79 (t, J = 6.3 Hz, 2H), 2.31 (s, 6H). 13 C NMR (126 MHz, CDCl3): δ 161.7, 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 / z calculated (M+H) C 15 H 22 N4O3 306.1692, found 306.1698.

[0137] Example 5: (Compound 5) 1-[2-(N,N-Dimethylamino)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole

[0138]

Chemical Structure

[0139] Starting from phenyl prop-2-ynyl ether (10.0 mmol, 1.32 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g), the procedure of Example 1 was followed. Yield 1.88 g (76%). White solid (melting point: 34 °C). 11H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.35 - 7.25 (m, 2H), 7.05 - 6.89 (m, 2H), 5.22 (s, 2H), 4.45 (t, J = 6.3 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 2.29 (s, 6H).

[0140] Example 6: (Compound 6) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0141]

Chem.

[0142] Starting from 3-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 2-chloroethyl-N,N-dimethylammonium chloride (6 mmol, 0.86 g), the procedure of Example 1 was followed. Yield 1.41 g (90%). Pale yellow oil. 1 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.24 - 7.07 (m, 3H), 5.20 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.24 (s, 6H).

[0143] Example 7: (Compound 7) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(3,4,5-trimethoxyphenoxy)methyl]-1H-1,2,3-triazole

[0144]

Chem.

[0145] Starting from 3,4,5-trimethoxyphenyl propynyl ether (5 mmol, 1.11 g) and 2-chloroethyl-N,N-dimethylammonium chloride (6 mmol, 0.86 g), the procedure of Example 1 was followed. Yield 1.44 g (86%). Pale yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.72 (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, CDCl3): δ 155.0, 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 / z calculated (M+H) C 16 H 24 N4O4 336.1798, found 336.1801.

[0146] Example 8: (Compound 8) 4-[(3,4-Dimethoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole

[0147]

Chemical Structure

[0148] Starting from 3,4-dimethoxyphenyl propynyl ether (10.0 mmol, 1.92 g) and 2-chloroethyl-N,N-dimethylammonium chloride (12 mmol, 1.72 g), the procedure of Example 1 was followed. Yield 1.89 g (62%). White solid (melting point: 39 °C). 11H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.65 (s, 1H), 6.57 (d, J = 8.5 Hz, 1H), 5.18 (s, 2H), 4.44 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 3.86 (s, 3H), 2.81 (t, J = 6.3 Hz, 2H), 2.30 (s, 6H).

[0149] Example 9: (Compound 9) 1-[2-(N,N-Dimethylamino)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole

[0150] [Chemical formula]

[0151] A solution of 2-methyl-3-butyn-2-ol (57.2 mmol, 5.59 mL) and DBU (74.6 mmol, 11.13 mL) in anhydrous acetonitrile (50 mL) cooled to 0 °C under a nitrogen atmosphere was added dropwise with trifluoroacetic anhydride (57.2 mmol, 7.99 mL), and the reaction mixture was stirred at 0 °C for 30 minutes. This solution was added via a cannula to a stirred solution of 4-methoxyphenol (49.7 mmol, 6.17 g), DBU (64.6 mmol, 9.64 mL), and CuCl2 (0.05 mmol, 6.7 mg) in anhydrous acetonitrile (50 mL) cooled to -5 °C. When 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 successively with water (25 mL), 1 M HCl (25 mL), and brine (25 mL). Then, the organic phase was dried (Na2SO4) and evaporated under reduced pressure to obtain 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%). Black-brown oil. 11H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 9.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H), 2.57 (s, 1H), 1.62 (s, 6H). 13 13C NMR (126 MHz, CDCl3): δ 155.9, 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. The alkyne was reacted with 2-azidoethyl-N,N-dimethylammonium chloride according to the procedure of Example 1. Yield 2.71 g (89%). White solid (melting point: 37 °C). 1 1H NMR (400 MHz, CDCl3) δ 7.47 (s, 1H), 6.59 - 6.51 (m, 4H), 4.30 (t, J = 6.4 Hz, 2H), 3.60 (s, 3H), 2.62 (t, J = 6.4 Hz, 2H), 1.92 (s, 6H), 1.60 (s, 6H).

[0152] Example 10: (Compound 10) 4-[(4-Methoxyphenoxy)methyl]-1-[2-(N-methylamino)ethyl]-1H-1,2,3-triazole

[0153]

Chemical Structure

[0154] Starting from 4-methoxyphenyl propargyl ether (5.0 mmol, 815 mg) and 2-(N-methylamino)ethyl-1-ammonium chloride (7.0 mmol, 928 mg), the procedure of Example 1 was followed. Yield 917 mg (70%). Pale yellow solid (melting point: 34 °C). 11H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 6.96 (d, J = 9.1 Hz, 2H), 6.92 - 6.83 (m, 2H), 5.13 (s, 2H), 4.55 (t, J = 6.2 Hz, 2H), 3.76 (s, 3H), 3.08 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H). 13 13C NMR (126 MHz, CDCl3:) δ 153.9, 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 / z calculated (M+H) C 13 H 18 N 44 O2262.1430, found 262.1432.

[0155] Example 11: (Compound 11) 1-(2-Aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0156]

Chemical Structure

[0157] Starting from 4-methoxyphenyl propargyl ether (20.0 mmol, 2.64 g) and 2-chloroethyl-1-ammonium chloride (30.0 mmol, 3.47 g), the procedure of Example 1 was followed. Yield 3.02 g (61%). Light brown solid (melting point: 66.5 - 68.0 °C). 11H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 6.95 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 5.11 (s, 2H), 4.46 (t, J = 6.1 Hz, 2H), 3.75 (s, 3H), 3.12 (t, J = 6.2 Hz, 2H).

[0158] Example 12: (Compound 12) 1-(2-Aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0159]

Chemical Structure

[0160] Starting from 3-methoxyphenyl propargyl ether (10.0 mmol, 1.62 g) and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g), the procedure of Example 1 was followed. Yield 1.54 g (62%). Light brown solid. 1 1H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.18 (t, J = 8.1 Hz, 2H), 6.68 - 6.51 (m, 3H), 5.15 (s, 2H), 4.46 (t, J = 6.2 Hz, 2H), 3.76 (s, 3H), 3.12 (t, J = 6.1 Hz, 2H).

[0161] Example 13: (Compound 13) 1-(2-Aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole

[0162]

Chemical Structure

[0163] Starting from 3,4-methylenedioxyphenyl propargyl ether (10 mmol, 1.92 g) and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g), the procedure of Example 1 was followed. Yield 1.75 g (67%). Orange solid (melting point: 56 °C). 1 H NMR (400 MHz, CD3OD) δ 8.0 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 6.46 (dd, J = 8.5 Hz, 2.5 Hz, 1H), 5.89 (s, 2H), 5.09 (s, 2H), 4.84 (s, 1H), 4.46 (t, J = 6.1 Hz, 2H), 3.13 (t, J = 6.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3): δ 153.8, 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 / z calculated (M+H) C 13 H 18 N4O2 262.1430, found 262.1432.

[0164] Example 14: (Compound 14) 1-(2-Aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole

[0165]

Chemical Structure

[0166] Starting from phenyl propargyl ether (10 mmol, 1.32 g) and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g), the procedure of Example 1 was followed. Yield 1.13 g (52%). Pale yellow solid (melting point: 34 °C). 1 H NMR (400 MHz, CD3OD) δ 8.09 (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, CDCl3): δ 158.3, 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 / z calculated (M+H) C 11 H 14 N4O 218.1168, found 218.1168.

[0167] Example 15: (Compound 15) 1-(2-Aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole

[0168]

Chemical Structure

[0169] Starting from 4-methoxyphenyl 1,1-dimethyl-2-propynyl ether (10 mmol, 1.90 g) prepared in Example 9 and 2-chloroethyl-1-ammonium chloride (15.0 mmol, 1.78 g), the procedure of Example 1 was followed. Yield 2.00 g (72%). Brown oil. 11H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 6.76 - 6.67 (m, 2H), 6.67 - 6.59 (m, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.72 (s, 3H), 3.09 (t, J = 6.2 Hz, 2H), 1.73 (s, 6H). 13 13C NMR (126 MHz, CDCl3): δ 156.1, 153.1, 148.8, 124.6, 122.4, 114.3, 77.0, 56.0, 53.6, 42.4, 28.1. IR (cm -1 -1): 3366, 2981, 2935, 1502, 1463, 1441, 1381, 1365, 1290, 1214, 1134, 1032, 940, 924, 875, 844, 799, 732. ESI-MS: HRMS: m / z calculated (M+H) C 14 13 20 H15N4O2 276.1586, found 276.1589.

[0170] Example 16: (Compound 16) 4-[(4-Methoxyphenoxy)methyl]-1-[2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazole

[0171]

Chemical Structure

[0172] Starting from 4-methoxyphenyl propargyl ether (5 mmol, 811 mg) and 1-(2-chloroethyl)pyrrolidine hydrochloride (7.5 mmol, 1.38 g), the procedure of Example 1 was followed. Yield 1.47 g (97%). White solid (melting point: 57 °C). 11H NMR (400 MHz, CDCl3) δ 7.75 (s, 1H), 6.93 (d, J = 9. Hz, 2H), 6.84 (d, J = 9.1 Hz, 2H), 5.17 (s, 2H), 4.47 (t, J = 6.2 Hz, 2H), 3.77 (s, 3H), 3.67 (t, J = 4.6 Hz, 4H), 2.83 (t, J = 6.2 Hz, 2H), 2.49 (t, J = 4.5 Hz, 4H). 13 13C NMR (126 MHz, CDCl3): δ 154.4, 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 / z calculated (M+H) C 16 H 22 N4O2 302.1743, found 302.1741.

[0173] Example 17: (Compound 17) 4-[(4-Methoxyphenoxy)methyl]-1-[2-(morpholin-4-yl)ethyl]-1H,1,2,3-triazole

[0174]

Chemical Structure

[0175] Starting from 4-methoxyphenyl propargyl ether (5 mmol, 811 mg) and 1-(2-chloroethyl)morpholine hydrochloride (7.5 mmol, 1.38 g), the procedure of Example 1 was followed. Yield 1.24 g (78%). White solid (melting point: 78 °C). 11H NMR (400 MHz, CDCl3) δ 7.75 (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 13C NMR (126 MHz, CDCl3): δ 154.4, 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 / z calculated (M+H) C 16 H 22 N4O3 318.1692, found 318.1697.

[0176] Example 18: (Compound 18) 4-[(4-Methoxyphenoxy)methyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0177]

Chem.

[0178] Starting from 4-methoxyphenyl propargyl ether (5 mmol, 811 mg) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g), the procedure of Example 1 was followed. Yield 1.43 g (90%). Yellowish oil. 11H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.01 - 6.90 (m, 2H), 6.88 - 6.80 (m, 2H), 5.17 (s, 2H), 4.45 (t, J = 6.4 Hz, 2H), 3.77 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H), 2.42 (t, J = 5.4 Hz, 4H), 1.57 (dq, J = 16.7, 5.6 Hz, 4H), 1.45 (q, J = 5.9 Hz, 2H). 13 13C NMR (126 MHz, CDCl3): δ 154.1, 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 -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 / z calculated (M+H) C 17 17 24 23N4O2 316.1899, found 316.1901.

[0179] Example 19: (Compound 19) 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0180]

Chemical Structure

[0181] Starting from 3-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g), the procedure of Example 1 was followed. Yield 1.58 g (89%). An oily substance. 11H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.39 (t, J = 8.0 Hz, 2H), 7.25 - 7.15 (m, 2H), 5.25 (s, 2H), 4.46 (t, J = 6.3 Hz, 2H), 2.75 (t, J = 6.3 Hz, 2H), 2.41 (t, J = 5.2 Hz, 4H), 1.54 (p, J = 5.5 Hz, 4H), 1.48 - 1.37 (m, 2H).

[0182] Example 20: (Compound 20) 1-[2-(Piperidin-1-yl)ethyl]-4-[(4-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0183]

Chem.

[0184] Starting from 4-trifluoromethylphenyl propargyl ether (5 mmol, 1.00 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g), the procedure of Example 1 was followed. Yield 1.62 g (92%). An oily substance. 1 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 5.28 (s, 2H), 4.49 (t, J = 6.3 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 2.43 (t, J = 5.4 Hz, 4H), 1.56 (p, J = 5.5 Hz, 4H), 1.52 - 1.41 (m, 2H).

[0185] Example 21: (Compound 21) 1-[2-(Piperidin-1-yl)ethyl]-4-[(2-trifluoromethylphenoxy)methyl]-1H-1,2,3-triazole

[0186] [Chem.]

[0187] Starting from 2-(trifluoromethyl)phenyl propargyl ether (5 mmol, 1.00 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g), the procedure of Example 1 was followed. Yield 1.58 g (90%). An oily substance. 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.59 - 7.54 (m, 1H), 7.52 - 7.44 (m, 1H), 7.17 (d, J = 8.3 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 5.33 (s, 2H), 4.44 (t, J = 6.2 Hz, 2H), 2.73 (t, J = 6.2 Hz, 2H), 2.40 (t, J = 5.4 Hz, 4H), 1.53 (p, J = 5.5 Hz, 4H), 1.47 - 1.35 (m, 2H).

[0188] Example 22: (Compound 22) (Guanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0189] [Chem.]

[0190] 1-[(2-Aminoethyl)-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg), di-tert-butoxycarbonylthiourea (1.2 mmol, 332 mg), I2 (1.2 mmol, 305 mg) and triethylamine (1.2 mmol, 121 mg) prepared in Example 11 were dissolved in CH2Cl2 (10 mL), and the mixture was stirred at 0 °C for 2 h. Volatiles were evaporated under reduced pressure, a saturated solution of NH4Cl (10 mL) was added, and the aqueous solution was extracted with CH2Cl2 (3 × 10 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (CH2Cl2 / MeOH 98:02; CH2Cl2 / MeOH 95:05) to give the intermediate 1-[(2-N,N'-di-tert-butoxycarbonylguanidino)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole. Yield 251 mg (51%). Pale yellow solid. 1 H NMR (300 MHz, CDCl3) δ 11.43 (s, 1H), 8.57 (t, J = 5.8 Hz, 1H), 7.71 (s, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.82 (d, J = 9.2 Hz, 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, CDCl3) δ 162.8, 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 / z calculated (M+H) C 23 H34 N6O6 490.2542, measured 490.2540. To a solution of the intermediate dicarbamate compound (0.5 mmol, 245 mg) in CH2Cl2 (5 mL) was added anhydrous HCl (4.0 M dioxane solution, 1.1 mmol, 0.27 mL), and the reaction mixture was stirred at 0 - 5 °C for 4 h. At the completion point, the volatile substances were evaporated under reduced pressure, and the residue was washed with anhydrous Et2O to obtain the hydrochloride salt of the product. Yield 147 mg (90%). Pale yellow solid. 1 1H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 6.84 (d, J = 9.1 Hz, 2H), 6.75 (d, J = 9.1 Hz, 2H), 5.02 (s, 2H), 4.52 (t, J = 6.5, 2H), 3.68 (t, J = 6.1, 2H), 3.65 (s, 3H). 13 13C NMR (75 MHz, CD3OD) δ 158.8, 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 / z calculated (M+H) C 13 H 18 N6O2 290.1491, measured 290.1496.

[0191] Example 23: (Compound 23) 1-[2-(Guanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0192]

Chemical Structure

[0193] Starting from 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg) prepared according to Example 12, following the procedure of Example 22, 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 H NMR (400 MHz, CDCl3) δ 11.42 (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, CDCl3) δ 162.9, 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 / z calculated (M+H) C 23 H 34 N6O6 490.2540, found 490.2542. The dicarbamate (0.5 mmol, 245 mg) was deprotected to give the product. Yield 49 mg (97%). Pale yellow solid. 1 H NMR (400 MHz, CD3OD) δ 8.01 (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 13C NMR (75 MHz, CD3OD) δ 162.3, 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 / z calculated (M+H) C 13 H 18 N6O2 290.2542, found 290.254.

[0194] Example 24: (Compound 24) 1-[2-(Guanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole

[0195]

Chemical Structure

[0196] Starting from 1-(2-aminoethyl)-4-[(3,4-methylenedioxy)phenoxymethyl]-1H-1,2,3-triazole (1 mmol, 262 mg) prepared according to Example 13, the procedure of Example 22 was followed. Yield 288 mg (57%). Pale yellow solid. 1 1H NMR (400 MHz, CDCl3) δ 11.43 (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 = 6.1 Hz, 2H), 1.51 (s, 9H), 1.48 (s, 9H). 1313C NMR (126 MHz, CDCl3) δ 162.8, 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 / z calculated (M+H) C 23 H 32 N6O7 504.2332, found 504.2331. The dicarbamate (0.5 mmol, 252 mg) was deprotected to give the product. Yield 162 mg (95%). Pale yellow solid. 1 1H NMR (400 MHz, CD3OD) δ 7.99 (s, 1H), 6.60 (d, J = 8.5 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 6.34 (dd, J = 8.4, 2.6 Hz, 1H), 5.78 (s, 2H), 4.99 (s, 2H), 4.53 (t, J = 5.8, 2H), 3.69 (t, J = 5.8, 2H). 13 13C NMR (75 MHz, CD3OD) δ 158.7, 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 / z calculated (M+H) C 13 H 16 N6O3 304.1355, found 304.1360.

[0197] Example 25: (Compound 25) 1-[2-(Guanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole

[0198]

Chemical Structure

[0199] Starting from 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole (0.80 mmol, 176 mg) prepared according to Example 14, the procedure of Example 22 was followed. Yield 266 mg (71%). White solid. 1 H NMR (400 MHz, CDCl3) δ 11.45 (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 = 5.9 Hz, 2H), 3.98 (q, J = 5.9 Hz, 2H), 1.54 (s, 9H), 1.51 (s, 9H). The dicarbamate (0.40 mmol, 109 mg) was deprotected to obtain the product. Yield 175 mg (95%). White solid. 1 H NMR (400 MHz, CD3OD) δ 8.11 (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).

[0200] Example 26: (Compound 26) 1-[2-(Guanidyl)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole

[0201]

Chemical Structure

[0202] 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, the procedure of Example 22 was followed. Yield 108 mg (34%). An oily substance. 1 H NMR (400 MHz, CD3OD) δ 7.01 (s, 1H), 7.22 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.57 (t, J = 6.3 Hz, 2H), 3.74 (s, 3H), 3.62 (t, J = 6.3 Hz, 2H), 1.70 (s, 6H).

[0203] Example 27: (Compound 27) 1-[2-(Biguanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0204]

Chemical formula

[0205] 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 tube was stirred in a silicone oil bath heated to 150 °C for 15 minutes. Then, the ACE tube was cooled to 50 °C in 10 minutes, isopropanol (3 mmol, 0.23 mL) was added, and the mixture was heated to 125 °C again for 1 minute by using another silicone oil bath. Then, the reaction mixture was cooled to room temperature, and the obtained hydrochloride solid product was filtered and further purified by column chromatography if necessary. Yield: 218 mg (57%). An oily substance. 11H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 4.80 (d, J = 5.4 Hz, 2H), 4.19 (s, 2H), 3.80 (s, 3H), 3.54 (d, J = 5.3 Hz, 2H). 13 13C NMR (101 MHz, CD3OD) δ 164.6, 161.2, 159.0, 145.9, 135.3, 126.5, 125.7, 115.8, 55.9, 49.3, 40.0, 30.6.

[0206] Example 28: (Compound 28) 1-[2-(Biguanidyl)ethyl]-4-[(3-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0207]

Chem.

[0208] Starting from 1-(2-aminoethyl)-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole (1 mmol, 248 mg), the procedure of Example 27 was followed. Yield: 236 mg (71%). An oily substance. 1 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7.35 - 7.18 (m, 1H), 6.67 - 6.55 (m, 2H), 5.19 (s, 2H), 4.80 (t, J = 5.4 Hz, 2H), 3.94 (d, J = 5.3 Hz, 2H), 3.79 (s, 3H).

[0209] Example 29: (Compound 29) 1-[2-(Biguanidyl)ethyl]-4-[(3-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0210]

Chem.

[0211] Starting from 1-(2-aminoethyl)-4-[(3,4-(methylenedioxy)phenoxymethyl]-1H-1,2,3-triazole (1 mmol, 262 mg), the procedure of Example 27 was followed. Yield: 152 mg (44%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.35 (dd, J = 8.4, 2.5 Hz, 1H), 5.79 (s, 2H), 4.94 (s, 2H), 4.55 (t, J = 5.7, 2H), 3.65 (t, J = 5.7, 2H).

[0212] Example 30: (Compound 30) 1-[2-(Biguanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole

[0213]

Chemical formula

[0214] Starting from 1-(2-aminoethyl)-4-(phenoxymethyl)-1H-1,2,3-triazole (1.00 mmol, 218 mg), the procedure of Example 27 was followed. Yield: 148 mg (49%). An oil. 1 H NMR (400 MHz, CD3OD) δ 8.06 (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).

[0215] Example 31: (Compound 31) 1-[2-(Biguanidyl)ethyl]-4-[(3-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0216] [Chemical formula]

[0217] Starting from 1-(2-aminoethyl)-4-[1-(4-methoxyphenoxy)-1-(methyl)ethyl]-1H-1,2,3-triazole (1 mmol, 276 mg), the procedure of Example 27 was followed. Yield 100 mg (28%). An oily substance. 1 H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.55 (t, J = 6.3 Hz, 2H), 3.79 (s, 3H), 3.66 (t, J = 6.3 Hz, 2H), 1.76 (s, 6H).

[0218] Example 32: (Compound 32) 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-hydroxyphenoxy)methyl]-1H-1,2,3-triazole

[0219] [Chemical formula]

[0220] A solution of 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazole (1 mmol, 278 mg), thiophenol (1 mmol, 0.103 mL) and K2CO3 (catalyst, 7 mg) in N-methylpyrrolidone (1 mL) was heated to 200 °C for 2 hours under nitrogen. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH (7M NH3) 95:5). Yield 160 mg (61%). 11H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.05 - 6.95 (m, 2H), 6.89 - 6.78 (m, 2H), 5.08 (s, 2H), 4.47 (t, J = 6.4 Hz, 2H), 2.71 (t, J = 6.4 Hz, 2H), 2.30 (s, 6H).

[0221] Example 33: (Compound 33) 5-Iodo-4-[(4-methoxyphenoxy)methyl]-1-[2-(N,N-dimethylamino)ethyl]-1H-1,2,3-triazole

[0222]

Chemical formula

[0223] To a solution of 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) in anhydrous CH3CN (8 mL) maintained under a nitrogen atmosphere, 2-azido-N,N-dimethylethyl-1-amine (3.3 mmol, 376 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours. Then, the solvent was evaporated under reduced pressure, and the residue was suspended in a saturated aqueous solution of NaCl (10 mL), and the aqueous suspension was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with a saturated aqueous solution of NaCl (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was purified by column chromatography. (CH2Cl2 / MeOH 20:1). Yield 0.85 g (70%) as a brown solid. 1 1H NMR (400 MHz, CDCl3) δ 7.05 - 6.93 (m, 2H), 6.89 - 6.79 (m, 2H), 5.07 (s, 2H), 4.48 (t, J = 7.2 Hz, 2H), 3.76 (s, 3H), 2.82 (t, J = 7.2 Hz, 2H), 2.32 (s, 6H). 1313C NMR (101 MHz, CDCl3): δ 154.1, 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 / z calculated (M+H) C 14 H 19 IN4O2402.0553, found 402.0562.

[0224] Example 34: (Compound 34) 1-[2-(N,N-Dimethyl)-N-oxide aminoethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole

[0225]

Chemical Structure

[0226] A solution of 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazole (1 mmol, 276 mg) and 33% aqueous hydrogen peroxide solution (1 mL) in MeOH (4 mL) was stirred at room temperature overnight. The solvent was evaporated to below 25 °C using an efficient vacuum pump. Yield: 289 mg (98%). Colorless oil. 1 1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 6.94 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.2 Hz, 2H), 5.13 (s, 2H), 5.03 (t, J = 6.5 Hz, 2H), 3.96 (t, J = 6.5 Hz, 2H), 3.75 (s, 3H), 3.23 (s, 6H).

[0227] B) Synthesis of the compound of formula (I) when Z is -S- Example 35: (Compound 35) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0228]

Chemical Structure

[0229] Starting from 4-methoxyphenyl propargyl sulfide (30 mmol, 5.35 g) and 2-chloroethyl-N,N-dimethylammonium chloride (36 mmol, 5.18 g), the procedure of Example 1 was followed. Yield 7.53 g (86%). White solid (melting point: 35 - 40 °C). 1 H NMR (400 MHz, CD3OD) δ 7.67 (s, 1H), 7.29 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 6.9 Hz, 2H), 4.44 (t, J = 6.5 Hz, 2H), 4.09 (s, 2H), 3.77 (s, 3H), 2.75 (t, J = 6.5 Hz, 2H), 2.27 (s, 6H). 13 C NMR (101 MHz, CDCl3): 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 / z (M+H) C 14 H 21 N4OS 293.1436, found: 293.1440.

[0230] Example 36: (Compound 36) 1-[3-(N,N-Dimethylamino)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0231]

Chemical Structure

[0232] Starting from 4-methoxyphenyl propargyl sulfide (10 mmol, 1.91 g) and 3-chloropropyl-N,N-dimethylammonium hydrochloride (12 mmol, 1.89 g), the procedure of Example 1 was followed. Yield 2.31 g (70%). An oily substance. 1 H NMR (400 MHz, CD3OD) δ 7.64 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.37 (t, J = 6.9 Hz, 2H), 4.09 (s, 2H), 3.78 (s, 3H), 2.25 (t, J = 5.4 Hz, 2H), 2.22 (s, 6H), 2.01 (q, J = 8.1, 6.5 Hz, 2H). 13 C NMR (101 MHz, CD3OD) δ 164.9, 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.

[0233] Example 37: (Compound 37) 1-[2-(N,N-Diethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0234]

Chemical formula

[0235] Starting from 4-methoxyphenyl propargyl sulfide (15 mmol, 2.67 g) and 2-chloroethyl-N,N-dimethylammonium hydrochloride (18.0 mmol, 3.10 g), the procedure of Example 1 was followed. Yield 2.74 g (57%). A brown oily substance. 11H NMR (400 MHz, CD3OD) δ 7.66 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.37 (t, J = 6.5 Hz, 2H), 4.09 (s, 2H), 3.74 (s, 3H), 2.83 (t, J = 6.5 Hz, 2H), 2.50 (q, J = 7.1 Hz, 4H), 0.95 (t, J = s, 6H). 13 13C NMR (101 MHz, CD3OD): δ 161.7, 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.

[0236] Example 38: (Compound 38) 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-(trifluoromethyl)phenyl)thiomethyl]-1H-1,2,3-triazole

[0237]

Chemical Structure

[0238] Starting from 3-(trifluoromethyl)phenyl propargyl sulfide (5 mmol, 1.08 g) and 1-(2-chloroethyl)piperidine hydrochloride (7.5 mmol, 1.35 g), the procedure of Example 1 was followed. Yield 1.67 g (90%). Yellowish odorless oil. 11H NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.65 - 7.57 (m, 2H), 7.53 - 7.45 (m, 2H), 4.47 (td, J = 6.6, 1.3 Hz, 2H), 4.33 (s, 2H), 2.75 (td, J = 6.6, 1.8 Hz, 2H), 2.47 - 2.36 (m, 4H), 1.52 (q, J = 5.3 Hz, 4H), 1.48 - 1.36 (m, 2H).

[0239] Example 39: (Compound 39) 4-[(4-Methoxyphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0240]

Chemical Structure

[0241] Starting from 4-methoxyphenyl propargyl sulfide (10 mmol, 1.78 g) and 1-(2-chloroethyl)piperidine hydrochloride (12 mmol, 2.16 g), the procedure of Example 1 was followed. Yield 2.59 g (78%). An oily substance. 1 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.32 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.39 (t, J = 6.4 Hz, 2H), 4.14 (s, 2H), 3.79 (s, 3H), 2.71 (t, J = 6.4 Hz, 2H), 2.48 - 2.33 (m, 4H), 1.63 - 1.50 (m, 4H), 1.50 - 1.37 (m, 2H).

[0242] Example 40: (Compound 40) 4-[(4-tert-Butylphenyl)thiomethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0243] [Chem.]

[0244] Starting from 4-tert-butylphenyl propargyl sulfide (5 mmol, 1.02 g) and 1-(2-chloroethyl)piperidine hydrochloride (7 mmol, 1.26 g), the procedure of Example 1 was followed. Yield 1.13 g (63%). An oily substance. 1 H NMR (400 MHz, CD3OD) δ 7.79 (s, 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.47 (t, J = 6.5 Hz, 2H), 4.20 (s, 3H), 2.76 (t, J = 6.5 Hz, 2H), 2.49 - 2.36 (m, 4H), 1.62 - 1.53 (m, 4H), 1.51 - 1.40 (m, 2H), 1.32 (s, 9H).

[0245] Example 41: (Compound 41) 4-[(4-Isopropylphenyl)thiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0246] [Chem.]

[0247] Starting from 4-isopropylphenyl propargyl sulfide (7 mmol, 1.33 g) and 4-(2-chloroethyl)morpholine hydrochloride (9 mmol, 1.67 g), the procedure of Example 1 was followed. Yield 2.16 g (89%). A white solid (melting point: 66 - 68 °C). 11H NMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 4.42 (t, J = 6.2 Hz, 2H), 4.25 (s, 2H), 3.71 - 3.58 (m, 4H), 2.89 (hept, J = 6.9 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.50 - 2.38 (m, 4H), 1.25 (d, J = 6.9 Hz, 6H).

[0248] Example 42: (Compound 42) 1-[2-(4-Morpholinyl)ethyl]-4-(phenylthiomethyl)-1H,1,2,3-triazole

[0249]

Chem.

[0250] Starting from phenyl propargyl ether (4.69 mmol, 697 mg) and 4-(2-chloroethyl)morpholine hydrochloride (5.7 mmol, 1.05 g), the procedure of Example 1 was followed. Yield 985 mg (69%). White solid (melting point: 57 - 59 °C). 1 1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.40 - 7.12 (m, 5H), 4.39 (t, J = 6.1 Hz, 2H), 4.26 (s, 2H), 3.69 - 3.58 (m, 4H), 2.75 (t, J = 6.1 Hz, 2H), 2.47 - 2.39 (m, 4H).

[0251] Example 43: (Compound 43) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(4-hydroxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0252]

Chem.

[0253] Starting from 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1 mmol, 292 mg), the procedure of Example 32 was followed. Yield (57%). White solid. Melting point: 102 °C. 1 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 4.47 - 4.37 (m, 2H), 4.05 (s, 2H), 2.76 (t, J = 6.4 Hz, 2H), 2.28 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ 157.1, 145.2, 134.5, 122.9, 122.9, 116.3, 58.4, 48.1, 45.2, 30.7.

[0254] Example 44: (Compound 44) 1-[1-(R)-benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0255]

Chemical formula

[0256] To a solution of (R)-(+)-2-amino-3-phenyl-1-propanol (19.9 mmol, 3.00 g) in anhydrous CH2Cl2 (20 mL) under a nitrogen atmosphere, triethylamine (20.8 mmol, 2.88 mL) and di-tert-butyl dicarbonate (20.75 mmol, 4.53 g) were added at 0 °C. Then, the reaction mixture was stirred at room temperature overnight and washed successively with saturated NH4Cl solution (3 × 15 mL) and brine (2 × 15 mL). Yield: 4.44 g (89%). 11H NMR (400 MHz, CDCl3) δ 7.36 - 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). 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 was added with methanesulfonyl chloride (53.0 mmol, 7.35 mL), and the mixture was stirred at the same temperature for 1 hour. The resulting suspension was basified with NaHCO3 (20 mL of saturated solution), and the product was extracted with CH2Cl2 (3 × 15 mL). The crude mesylated product (17.67 mmol) was immediately dissolved in anhydrous CH3CN (7 mL) under a nitrogen atmosphere, 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 evaporation of the solvent under vacuum, the crude reaction product was dissolved in CH2Cl2 (20 mL) and extracted with 10% citric acid (3 × 10 mL). The aqueous phase was basified with NaHCO3, and the product was extracted with CH2Cl2 (3 × 15 mL). Then, the product was purified by column chromatography (EtOAc / hexane 1:1). Yield: 3.35 g (59%). 11H NMR (300 MHz, CDCl3) δ 7.37 - 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). (R)-1-(2-tert-Butoxycarbonylamino-3-phenylpropyl)piperidine (7.85 mmol, 2.5 g) was dissolved in a mixture of CH2Cl2 (2 mL) and trifluoroacetic acid (4 mL) and stirred at room temperature for 1.5 h. The solvent was then evaporated under vacuum, 1M NaOH (5 mL) was added, and the product was extracted with CH2Cl2 (3 × 4 mL). A solution of CuSO4·H2O (0.078 mmol, 19 mg) in H2O (0.5 mL) and KHCO3 (15.7 mmol, 1.57 g) was added to a solution of (R)-1-(2-amino-3-phenylpropyl)piperidine (7.85 mmol) in MeOH (5 mL) under a nitrogen atmosphere. Then, a freshly prepared solution of trifluoromethanesulfonyl azide (17 mmol) in CH2Cl2 (25 mL) was added, and the reaction mixture was stirred at room temperature for 3 h. The organic solvent was evaporated under reduced pressure, the aqueous solution was basified with NaHCO3 (saturated solution 10 mL), and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried (NaSO4) and evaporated to purify the (R)-1-(2-azido-3-phenylpropyl)piperidine product by column chromatography (CH2Cl2 / MeOH 95:5). Yield: 480 mg (25% overall). 11H NMR (400 MHz, CDCl3) δ 7.39 - 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). According to the procedure of Example 1, a 1,2,3-triazole ring was synthesized starting from 4-methoxyphenyl propyl sulfide (2.2 mmol, 392 mg) and (R)-1-(2-azido-3-phenylpropyl)piperidine (2 mmol, 489 mg). Yield 584 mg (66%). An oily substance. 1 1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.26 - 7.17 (m, 5H), 6.99 (dd, J = 7.4, 2.1 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.90 - 4.84 (m, 1H), 4.03 (s, 2H), 3.78 (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).

[0257] Example 45: (Compound 45) 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole

[0258]

Chemical Structure

[0259] Starting from 3-trifluoromethylphenyl propargyl sulfide (2.2 mmol, 476 mg) and (R)-1-(2-azido-3-phenylpropyl)piperidine (2 mmol, 489 mg), the procedure of Example 1 was followed. Yield 749 mg (74%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.68 (s, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.25 - 7.20 (m, 2H), 7.17 - 7.14 (m, 3H), 6.95 (dd, J = 6.8, 2.9 Hz, 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, 5.4 Hz, 2H), 2.29 (dd, J = 11.1, 5.4 Hz, 2H), 1.44 (t, J = 5.6 Hz, 4H), 1.39 - 1.33 (m, 2H).

[0260] Example 46: (Compound 46) 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(4-tert-butylphenyl)thiomethyl]-1H-1,2,3-triazole

[0261]

Chemical formula

[0262] Starting from 4-tert-butylphenyl propargyl sulfide (2.2 mmol, 449 mg) and (R)-1-(2-azido-3-phenylpropyl)piperidine (2 mmol, 489 mg), the procedure of Example 1 was followed. Yield 592 mg (60%). An oil. 11H NMR (400 MHz, CD3OD) δ 7.60 (s, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.17 - 7.13 (m, 3H), 6.95 (dd, J = 6.7, 2.9 Hz, 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, 5.8 Hz, 2H), 2.24 (dd, J = 11.0, 5.4 Hz, 2H), 1.46 (t, J = 5.5 Hz, 4H), 1.41 - 1.34 (m, 2H), 1.30 (s, 9H).

[0263] Example 47: (Compound 47) 1-[3-(N,N-Diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0264]

Chemical formula

[0265] Methyl α-bromoisobutyrate (15 mmol, 1.94 mL) was added to a solution of sodium azide (45 mmol, 2.92 g) and iodine (0.75 mmol, 112 mg) in DMSO. The reaction mixture was stirred at 50 °C for 2 h. The product was extracted with diethyl ether (3 × 10 mL). Yield: 1.78 g (83%). Brown oil. 1 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 1.51 (s, 6H). Starting from 4-methoxyphenyl propynyl sulfide (11 mmol, 1.96 g) and methyl 2-azido-2-methylpropanoate (13.2 mmol, 1.89 g), the procedure of Example 1 was followed. Yield 3.39 g (96%). Brown oil. 11H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.31 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.14 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H), 1.90 (s, 6H). To a solution of 1-(1-methoxycarbonyl-1-methylethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (5.29 mmol, 1.70 g) in H2O / THF (17:17 mL) was added LiOH·H2O (10.58 mmol, 443 mg), and the reaction mixture was stirred at room temperature overnight. THF was evaporated under vacuum, and after acidifying the aqueous phase, the product was extracted with EtOAc (3 × 10 mL). Yield: 1.21 g (74%). Brown oil. 1 1H NMR (400 MHz, CD3OD) δ 7.70 (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). Under N2, to a solution of 1-(1-carboxy-1-methylethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (3.04 mmol, 935 mg) in anhydrous CH2Cl2 (9 mL) were added N,N-dimethylformamide (0.304 mmol, 23 μL) and oxalyl chloride (3.65 mmol, 309 μL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Then, N,N-diethylamine (6.08 mmol, 629 μL) was added dropwise, and the new reaction mixture was stirred at room temperature overnight. The product was purified by column chromatography (CH2Cl2 / MeOH 98:2). Yield: 825 mg (75%). 11H NMR (400 MHz, CDCl3) δ 7.32 (s, 1H), 7.29 (d, J = 2.7 Hz, 2H), 6.82 (d, J = 8.8 Hz, 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).

[0266] A solution of LiAlH4 (1.10 mmol, 41.87 mg) in anhydrous Et2O (5 mL) was added to a suspension of 1-[1-(N,N-diethylaminocarbonyl)-1-methylethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.55 mmol, 200 mg) in anhydrous Et2O (5 mL) under N2. The reaction mixture was stirred at room temperature overnight. Carefully, H2O (1 mL) was added, the solution was filtered, dried over MgSO4, and the solvent was evaporated. The product was purified by column chromatography (CH2Cl2 / MeOH 98:2). Yield: 162 mg (84%). 1 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 7.34 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.16 (s, 2H), 3.80 (s, 3H), 2.68 (s, 2H), 2.22 (q, J = 7.1 Hz, 4H), 1.60 (s, 6H), 0.82 (t, J = 7.1 Hz, 6H).

[0267] Example 48: (Compound 48) 1-[2-(Guanidyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0268] [Chemical formula]

[0269] Starting from 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)thiomethyl]-1H-1,2,3-triazole (0.76 mmol, 200 mg), the procedure of Example 22 was followed. 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, CDCl3) δ 11.45 (s, 1H), 8.52 (t, J = 5.9 Hz, 1H), 7.36 (s, 1H), 7.31 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.56 - 4.48 (m, 2H), 4.12 (s, 2H), 3.87 (q, J = 5.9 Hz, 2H), 3.79 (s, 3H), 1.52 (s, 9H), 1.48 (s, 9H). The title product was obtained by deprotecting the intermediate (0.25 mmol, 125 mg) in CH2Cl2 (3.75 mL) using trifluoroacetic acid (1.25 mL). Yield 73 mg (96%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.82 (s, 1H), 7.32 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.58 (t, J = 5.8 Hz, 2H), 4.11 (s, 2H), 3.79 (s, 3H), 3.75 (t, J = 5.8 Hz, 2H).

[0270] Example 49: (Compound 49) 1-[2-(Biguanidinyl)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0271]

Chemical formula

[0272] Starting from 1-(2-aminoethyl)-4-[(4-methoxyphenoxy)thiomethyl]-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), the procedure of Example 27 was followed. Yield: 83 mg (57%). An oil. 1 H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.35 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 4.80 (d, J = 5.4 Hz, 2H), 4.19 (s, 2H), 3.80 (s, 3H), 3.54 (d, J = 5.3 Hz, 2H). 13 C NMR (101 MHz, CD3OD) δ 164.6, 161.2, 159.0, 145.9, 135.3, 126.5, 125.7, 115.8, 55.9, 49.3, 40.0, 30.6.

[0273] Example 50: (Compound 50) 1-[3-(Biguanidinyl)propyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0274]

Chemical formula

[0275] Starting from 1-(3-aminopropyl)-4-[(4-(methoxy)phenylthio)methyl]-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), the procedure of Example 27 was followed. Yield: 64.6 mg (45%). An oil. 11H NMR (400 MHz, CD3OD) δ 8.33 (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, 6.2 Hz, 2H), 2.35 (p, J = 7.1 Hz, 2H). 13 13C NMR (101 MHz, CD3OD) δ 164.6, 161.6, 159.0, 144.4, 136.0, 127.9, 124.5, 116.1, 55.9, 50.6, 37.7, 29.6, 28.5.

[0276] Example 51: (Compound 51) 1-[2-(N,N-Dimethylamino)ethyl]-5-iodo-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0277]

Chemical Structure

[0278] Starting from 4-methoxyphenyl propargyl sulfide (3.84 mmol, 648 mg) and 2-azido-N,N-dimethylethyl-1-amine (4.22 mmol, 482 mg), the procedure of Example 33 was followed. Yield 0.92 g (62%). Brown solid (melting point: 45 °C). 1 1H NMR (400 MHz, CD3OD) δ 7.26 (d, 2H), 6.84 (d, 2H), 4.50 (t, J = 6.9 Hz, 2H), 4.01 (s, 2H), 3.79 (s, 3H), 2.80 (t, J = 6.9 Hz, 2H), 2.32 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ 159.3, 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。

[0279] Example 52: (Compound 52) 1-[2-(N,N-Dimethylamino)ethyl]-5-tritium-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole

[0280]

Chemical formula

[0281] Tritium was obtained from RC Tritec AG. The tritium reaction was carried out 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 in absolute ethanol, palladium calcium carbonate and Et3N (10 μL) were degassed by three freeze-pump-thaw cycles. The flask was filled with tritium gas released from the uranium bed by heating the flask using a blowtorch and stirred at room temperature for 4 hours. Thereafter, the flask was frozen and excess tritium was blown off together with the solvent under a nitrogen stream. The flask was removed 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, which was purified by preparative HPLC using an Xbridge Prep C-18 column (5 μm OBD 19×100 mm) as the stationary phase and an aqueous solution of 0.1% ammonium formate (AFM) / MeCN as the mobile phase. Chromatographic analysis was performed under AFM aqueous solution / MeCN gradient conditions from 75:25 to 25:75 over a total chromatographic time of 30 minutes (flow rate = 10 mL / min). The purified fractions were dried under vacuum, redissolved in 10 mL of ethanol and stored at -20 °C. Total manufacturing time: 6 hours. Isotope incorporation: 87.1%. Molar activity at the end of synthesis: 933.2 KBq / nmol. Radiochemical purity determined by radio-HPLC >95%.

[0282] C) Synthesis of the compound of formula (I) when Z is -S(=O)- Example 53: (Compound 53) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0283]

Chemical Structure

[0284] A solution of 1-[2-(N,N-diethylamino)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 CH2Cl2 (38 mL) was added phthaloyl peroxide (16.42 mmol, 2.69 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was basified by the addition of 7N NH3 in MeOH and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel; eluent: CH2Cl2 / MeOH (7N NH3) mixture). Yield 3.13 g (66%). White solid. 1 H NMR (400 MHz, CD3OD) δ 7.81 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H), 4.51 (t, J = 6.3 Hz, 2H), 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, CD3OD) δ 164.1, 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.

[0285] Example 54: (Compound 54) 1-[3-(N,N-dimethylamino)propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0286]

Chemical Structure

[0287] Starting from 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 CH2Cl2 (3 mL), the procedure of Example 53 was followed. Yield 161 mg (77%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.87 (s, 1H), 7.51 (d, J = 2.1 Hz, 2H), 7.12 (d, J = 4.7 Hz, 2H), 4.54 (t, J = 6.8 Hz, 2H), 4.29 (dd, 2H), 3.88 (s, 3H), 3.13 (t, 2H), 2.88 (s, 6H), 2.36 (p, J = 10.4, 5.0 Hz, 2H). 13 C NMR (101 MHz, CD3OD) δ 164.2, 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.

[0288] Example 55: (Compound 55) 1-[2-(N,N-diethylamino)ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0289]

Chemical Structure

[0290] Starting from 1-[2-(N,N-dimethylamino)propyl]-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 CH2Cl2 (2 mL), the procedure of Example 53 was followed. Yield 78 mg (67%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.9 Hz, 2H), 4.45 (t, J = 6.6 Hz, 2H), 4.30 (dd, J = 12.6, 1.8 Hz, 2H), 3.85 (s, 3H), 2.89 (t, J = 6.6 Hz, 2H), 2.57 (q, J = 7.2 Hz, 4H), 1.00 (t, J = 7.2 Hz, 6H). 13 C NMR (101 MHz, CD3OD) δ 164.1, 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.

[0291] Example 56: (Compound 56) 1-[2-(Piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0292]

Chemical Structure

[0293] Starting from 1-[2-(piperidinyl)ethyl]-4-[(3-trifluoromethoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.74 mmol, 300 mg), TFA (0.74 mmol, 56 μL) and phthaloyl peroxide (1.11 mmol, 181 mg) in CH2Cl2 (2 mL), the procedure of Example 53 was followed. Yield 176 mg (62%). An oil. 1 H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.76 - 7.58 (m, 4H), 4.46 (td, J = 6.5, 2.0 Hz, 2H), 4.23 (dd, J = 12.9, 2.3 Hz, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.46 (t, J = 5.5 Hz, 4H), 1.59 (p, J = 5.6 Hz, 4H), 1.49 - 1.40 (m, 2H).

[0294] Example 57: (Compound 57) 4-[(4-Isopropylphenyl)sulfinylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0295]

Chemical Structure

[0296] Starting from 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 phthaloyl peroxide (1.62 mmol, 265 mg) in CH2Cl2 (5 mL), the procedure of Example 53 was followed. Yield 340 mg (64%). A white solid (melting point: 131 °C). 11H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 4.55 - 4.33 (m, 2H), 4.13 (dd, J = 12.6, 1.8 Hz,), 3.65 (t, J = 4.6 Hz, 4H), 2.92 (hept, J = 6.9 Hz, 1H), 2.77 (t, J = 6.3 Hz, 2H), 2.51 - 2.39 (m, 4H), 1.23 (d, J = 6.9 Hz, 6H).

[0297] Example 58: (Compound 58) 4-[(2,6-Dimethylphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0298]

Chemical Structure

[0299] 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 phthaloyl peroxide (1.81 mmol, 296 mg) in CH2Cl2 (5 mL), the procedure of Example 53 was followed. Yield 364 mg (64%). White solid (melting point: 84 - 85 °C). 1 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.32 - 7.21 (m, 1H), 7.04 (d, J = 7.6 Hz, 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 = 5.5 Hz, 4H), 1.51 - 1.40 (m, 2H).

[0300] Example 59: (Compound 59) 1-[2-(4-Morpholinyl)ethyl]-4-(phenylsulfinylmethyl)-1H,1,2,3-triazole

[0301]

Chem.

[0302] Starting from 1-[2-(4-morpholinyl)ethyl]-4-(phenylthiomethyl)-1H,1,2,3-triazole (0.86 mmol, 260 g), TFA (0.86 mmol, 66 μL) and phthaloyl peroxide (0.95 mmol, 155 mg) in CH2Cl2 (3 mL), the procedure of Example 53 was followed. Yield 167 g (61%). White solid (mp: 134 °C). 1 H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.54 - 7.38 (m, 5H), 4.47 - 4.31 (m, 2H), 4.13 (dd, J = 13.1, 1.9 Hz, 2H), 3.62 (t, J = 4.6 Hz, 4H), 2.73 (t, J = 6.2 Hz, 2H), 2.48 - 2.36 (m, 4H).

[0303] Example 60: (Compound 60) 4-[(4-Methoxyphenyl)sulfinylmethyl]-1-[2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazole

[0304]

Chem.

[0305] Starting from 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 phthaloyl peroxide (2.26 mmol, 370 mg) in CH2Cl2 (4 mL), the procedure of Example 53 was followed. Yield 325 g (62%). Oil. 11H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.38 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 4.49 - 4.27 (m, 2H), 4.10 (dd, J = 12.9, 1.7 Hz, 2H), 3.78 (s, 3H), 2.70 (t, J = 6.5 Hz, 2H), 2.49 - 2.30 (m, 4H), 1.52 (p, J = 5.6 Hz, 4H), 1.39 (q, J = 5.9 Hz, 2H).

[0306] Example 61: (Compound 61) 1-[1-(R)-Benzyl-2-(piperidin-1-yl)ethyl]-4-[(3-trifluoromethylphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0307] [Chemical formula]

[0308] Starting from 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 phthaloyl peroxide (0.24 mmol, 40 mg) in CH2Cl2 (0.5 mL), the procedure of Example 53 was followed. Yield 50 mg (65%). An oily substance. 11H NMR (400 MHz, CDCl3) δ 7.93 - 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, 4.7 Hz, 1H), 4.31 - 4.07 (m, 3H), 3.25 (dtt, J = 23.2, 9.1, 5.0 Hz, 2H), 2.92 - 2.78 (m, 2H), 2.43 (dt, J = 11.1, 5.2 Hz, 2H), 2.34 (dq, J = 10.4, 5.0 Hz, 2H), 1.53 (dd, J = 8.8, 3.2 Hz, 4H), 1.41 (d, J = 6.2 Hz, 2H).

[0309] Example 62: (Compound 62) 1-[3-(N,N-Diethylamino)-2-methyl-propyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0310]

Chem.

[0311] Starting from 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 CH2Cl2 (1 mL), the procedure of Example 53 was followed. Yield 57 mg (75%). An oily substance. 11H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 4.19 (dd, J = 13.5, 1.0 Hz, 2H), 3.87 (s, 3H), 2.73 (s, 2H), 2.28 (q, J = 7.4 Hz, 2H), 1.65 (s, 3H), 1.64 (s, 3H), 0.86 (t, J = 7.1 Hz, 5H).

[0312] Example 63: (Compound 63) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(4-hydroxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0313] [Chemical formula]

[0314] Starting from 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 CH2Cl2 (0.7 mL), the procedure of Example 53 was followed. Yield 59 mg (78%). White solid. 1 1H NMR (400 MHz, CD3OD) δ 7.89 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 4.78 (t, J = 6.4 Hz, 2H), 4.28 (dd, J = 12.5, 2.0 Hz, 2H), 3.44 (t, J = 6.5 Hz, 2H), 2.74 (s, 6H).

[0315] Example 64: (Compound 64) 1-(2-Aminoethyl)-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0316] [Chemical formula]

[0317] Under N2, to a solution of 1-(2-aminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (2.33 mmol, 700 mg) in anhydrous CH2Cl2 (14 mL) were 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 N-Boc intermediate product was purified by column chromatography (silica gel; eluent: CH2Cl2 / MeOH 95:5). Yield: 460 mg (54%). 1 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.8 Hz, 2H), 7.28 (s, 1H), 6.83 (d, J = 8.7 Hz, 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, 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.27 mmol, 100 mg) was oxidized using phthaloyl peroxide (0.41 mmol, 67.5 mg) in CH2Cl2 (1.8 mL). Yield: 56 mg (78%). 11H NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.43 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 4.45 (t, J = 5.7 Hz, 2H), 4.23 - 4.08 (m, 2H), 3.84 (s, 3H), 3.65 - 3.55 (m, 2H), 1.43 (s, 9H). A solution of 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole (0.15 mmol, 56 mg) in anhydrous CH2Cl2 (2.4 mL) was added trifluoroacetic acid (0.82 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The crude product was purified by column chromatography (silica gel; eluent: CH2Cl2 / MeOH (7N NH3) 95:5). Yield 39 mg (94%). An oil. 1 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.49 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4.37 - 4.25 (m, 2H), 3.88 (s, 3H), 3.09 (t, J = 6.1 Hz, 2H).

[0318] Example 65: (Compound 65) 1-[2-(N-Methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0319]

Chemical Structure

[0320] Starting from 1-[2-(N-methylamino)-ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1.39 mmol, 388 mg), according to the procedure of Example 64, the intermediate 1-[2-(N-tert-butoxycarbonyl-N-methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole was obtained. Yield: 164 mg (98%). 1 H NMR (400 MHz, CDCl3) δ 7.49 (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, 2.0 Hz, 2H), 2.74 - 2.60 (m, 3H), 1.38 (s, 9H). This compound (0.41 mmol, 164 mg) was N-deprotected using trifluoroacetic acid (2.30 mL) in anhydrous CH2Cl2 (6.5 mL) to give the product. Yield 115 (95%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.77 (s, 1H), 7.50 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 4.50 (t, J = 6.2 Hz, 2H), 4.41 - 4.25 (m, 2H), 3.88 (s, 3H), 3.03 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H).

[0321] Example 66: (Compound 66) 1-[2-(N,N-dimethyl)-N-oxideaminoethyl]-4-[(4-methoxyphenyl)sulfinylmethyl]-1H-1,2,3-triazole

[0322]

Chemical Structure

[0323] 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), the procedure of Example 34 was followed. Yield 314 mg (97%). An oil. 1 H NMR (400 MHz, MeOD) δ 7.95 (d, J = 1.4 Hz, 1H), 7.49 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 5.02 (t, J = 6.4 Hz, 2H), 4.34 (q, J = 13.9 Hz, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.87 (s, 3H), 3.28 (s, 6H).

[0324] D) Synthesis of the compounds of formula (I) when Z is -S(=O)2- Example 67: (Compound 67) 1-[2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0325]

Chemical formula

[0326] To a solution of 1-[(2-(N,N-dimethylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.86 mmol, 250 mg) in H2O / MeCN 50:50 (5 mL) was added Oxone (1.28 mmol, 788 mg), and the reaction mixture was stirred at room temperature for 1 hour. Immediately upon basification by addition of solid Na2CO3, the product was extracted with EtOAc (3 × 5 mL), the combined organic layers were dried (Na2SO4), and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel; eluent: EtOAc / hexane or CH2Cl2 / MeOH mixture). Yield 167 mg (60%). An oil. 11H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.61 (d, J = 7.7 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 4.51, (s, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.84 (s, 3H), 2.73 (t, J = 6.2 Hz, 2H), 2.27 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ 163.8, 135.6, 130.4, 129.2, 125.0, 114.2, 58.5, 55.5, 54.1, 48.2, 45.2.

[0327] Example 68: (Compound 68) 1-[2-(N,N-Diethylamino)ethyl]-4-[(4-bromophenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0328]

Chemical Structure

[0329] Starting from 4-[(4-bromophenyl)thiomethyl]-1-[(2-N,N-diethylamino)ethyl]-1H-1,2,3-triazole (2.00 mmol, 739 mg) and oxone (3.00 mmol, 1.84 g), the procedure of Example 67 was followed. Yield 545 mg (68%). White solid (melting point: 88 °C). 1 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 4.56 (s, 2H), 4.43 (t, J = 6.1 Hz, 2H), 2.89 (d, J = 6.1 Hz, 2H), 2.58 (q, J = 7.1 Hz, 4H), 1.00 (t, J = 7.1 Hz, 6H).

[0330] Example 69: (Compound 69) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(3,4-dimethoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0331]

Chem.

[0332] Starting from 4-[(3,4-dimethoxyphenyl)thiomethyl]-1-[(2-N,N-dimethylamino)ethyl]-1H-1,2,3-triazole (2.00 mmol, 645 mg) and oxone (3.00 mmol, 1.84 g), the procedure of Example 67 was followed. Yield 545 mg (77%). White solid (melting point: 152 °C). 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.31 (dd, J = 8.5, 2.1 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 4.54 (s, 2H), 4.46 (t, J = 6.2 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 2.76 (t, J = 6.2 Hz, 2H), 2.29 (s, 6H).

[0333] Example 70: (Compound 70) 4-[(4-Isopropylphenyl)sulfonylmethyl]-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0334]

Chem.

[0335] Starting from 4-[(4-isopropylphenyl)thiomethyl]-1-[(4-morpholinyl)ethyl]-1H,2,3-triazole (2.00 mmol, 693 mg) and oxone (3.00 mmol, 1.84 g), the procedure of Example 67 was followed. Yield 401 mg (53%). Oil. 11H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 4.53 (s, 2H), 4.46 (t, J = 6.1 Hz, 2H), 3.74 - 3.61 (m, 4H), 2.95 (hept, J = 6.9 Hz, 1H), 2.80 (t, J = 6.2 Hz, 2H), 2.53 - 2.43 (m, 4H), 1.24 (d, J = 6.9 Hz, 6H).

[0336] Example 71: (Compound 71) 4-(Phenylsulfonylmethyl)-1-[2-(4-morpholinyl)ethyl]-1H,1,2,3-triazole

[0337]

Chemical Structure

[0338] Starting from 4-(phenylthiomethyl]-1-[2-(4-morpholinyl)ethyl]-1H,2,3-triazole (0.85 mmol, 260 mg) and oxone (1.28 mmol, 788 mg) in H2O (4 mL), the procedure of Example 67 was followed. Yield 108 mg (38%). An oily substance. 1 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.77 - 7.72 (m, 2H), 7.66 (td, J = 7.2, 1.3 Hz, 1H), 7.56 - 7.50 (m, 2H), 4.58 (s, 2H), 4.50 (t, J = 6.1 Hz, 2H), 3.77 - 3.71 (m, 4H), 2.84 (t, J = 6.1 Hz, 2H), 2.54 - 2.51 (m, 4H).

[0339] Example 72: (Compound 72) 1-[2-(N,N-Dimethylamino)ethyl]-4-[(3-trifluoromethylphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0340]

Chem.

[0341] Starting from 1-[2-(N,N-dimethylamino)ethyl]-4-[(3-trifluoromethylphenyl)thiomethyl]-1H-1,2,3-triazole (0.76 mmol, 250 mg) and oxone (1.13 mmol, 698 mg), the procedure of Example 67 was followed. Yield: 85 mg (31%). 1 1H NMR (400 MHz, CD3OD) δ 8.10 - 7.97 (m, 4H), 7.82 (t, J = 7.9 Hz, 1H), 4.77 (s, 2H), 4.53 (t, J = 6.5 Hz, 2H), 2.81 (t, J = 6.5 Hz, 2H), 2.29 (s, 6H).

[0342] Example 73: (Compound 73) 1-(2-Aminoethyl)-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0343]

Chem.

[0344] According to the procedure of Example 67, 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (0.27 mmol, 100 mg) was oxidized to the corresponding sulfone using oxone (0.41 mmol, 253 mg). Yield: 105 mg (97%). 11H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.66 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 4.54 (s, 2H), 4.51 (t, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.65 (q, J = 5.9 Hz, 2H), 1.47 (s, 9H). A solution of 1-(2-tert-butoxycarbonylaminoethyl)-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole (0.27 mmol, 105 mg) in anhydrous CH2Cl2 (5 mL) was added with trifluoroacetic acid (1.6 mL) at 0 °C. Then, the reaction mixture was stirred at room temperature for 3 hours, the solvent was evaporated, and the product was purified by column chromatography (silica gel; eluent: CH2Cl2 / MeOH (7N NH3) 95:5). Yield 78 mg (97%). An oily substance. 1 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 4.64 (s, 2H), 4.45 (t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.09 (t, J = 6.2 Hz, 2H).

[0345] Example 74: (Compound 74) 1-[2-(N-Methylamino)-ethyl]-4-[(4-methoxyphenyl)sulfonylmethyl]-1H-1,2,3-triazole

[0346]

Chemical Structure

[0347] Starting from 1-[2-(N-methylamino)ethyl]-4-[(4-methoxyphenyl)thiomethyl]-1H-1,2,3-triazole (1.39 mmol, 388 mg), the procedure of Example 73 was followed. The N-Boc product was purified by column chromatography (silica gel; eluent: CH2Cl2 / MeOH 95:5). Yield: 500 mg (95%). 1 H NMR (400 MHz, CDCl3) δ 7.32 (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 sulfide (0.36 mmol, 135 mg) was oxidized to the corresponding sulfone using oxone (0.54 mmol, 329 mg). Yield: 127 mg (87%). 1 H NMR (400 MHz, CDCl3) δ 7.75 (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 product was obtained by N-deprotection of the N-Boc-N-methylamino intermediate according to the procedure of Example 73. Yield 106 mg (95%). An oil. 1 H NMR (400 MHz, CD3OD) δ 7.95 (s, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 4.85 (s, 2H), 4.63 (s, 2H), 4.52 (t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 3.04 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H).

[0348] Example 75.4 Retinal in vivo distribution assay after topical ocular administration in mammalian species.

[0349] To test the bioavailability of Compounds 1, 24, 35, 53, 66 and 67 to the retina, the inventors used the following species: mouse, rat, rabbit and pig. The animals were treated under anesthesia. In vivo autoradiography imaging was performed on Sprague-Dawley rats (n = 4 for each time point) under carrier-added conditions (about 7 mBq / eye) at 1, 8 and 24 hours after instillation of Compound 3 H]-35 (5 μL / eye) as a 20 mM solution of phosphate-buffered saline (PBS). After enucleation, the eyes were incubated first in 4% aqueous paraformaldehyde solution for 4 hours, then in 10% and 20% aqueous sucrose solutions for 2 hours each, and then in 30% aqueous sucrose solution for 1 week. All incubations were at 4°C. The samples were fixed in OCT (optimal cutting temperature polymer), and 20-μm sections of the eyes were cut at -24°C using a Leica cryostat (Leica CM3050 S, Germany). The slices (20-μm thick) were placed on glass slides (Superfrost Plus, Labolan). Autoradiography was performed for 1 hour on a Beta Imager 2000 system (Biospace Lab, France) on four consecutive slices of the central part of the organ where all parts were visible (Figure 1A).

[0350] A PBS solution containing 0.2% hyaluronic acid (HA) and the selected compound of the present invention was administered by eye drops: 17 μg / eye (3 μL of 20 mM solution per eye) in mice; 65 μg / eye (10 μL of 17 mM solution per eye) in rats; and 559 μg / eye (50 μL of 40 mM solution per eye) in pigs. The animals were sacrificed 4 hours (in mice, rabbits and pigs) or 24 hours (in rats) after treatment to determine the availability of the compound in the retina. The retina was mechanically homogenized in physiological serum (9% NaCl) and processed for analysis of the availability of the compound by HPLC-MS. Figure 1B shows a higher delivery percentage of compound 35 to the mouse retina when formulated with hyaluronic acid. Figure 1C shows the in vivo distribution results of compound 5 in the retina after topical ocular administration in mice, rats, rabbits and pigs.

[0351] Example 76. In vivo efficacy assay in the rd10 mouse model of retinitis pigmentosa as measured by electrophysiological analysis.

[0352] The rd10 mice were treated by eye drops with phosphate buffered saline (PBS) containing the compounds of the present invention (1, 35, 50, 56 and 70) for 11 days (P14 - P24). The animals were dark adapted for 8 hours at P25 and the full-field flash electroretinogram (ERG) responses were recorded against the retina illuminated by an LED-driven whole-field dome. A series of light flashes with increasing intensities from 0.001 to 10 cd·sec / m 2 were averaged in both scotopic (dark adapted) and photopic (light adapted) conditions. The photopic cone response was measured against a background white light (30 cd / m 2) were recorded 5 minutes after light adaptation using it. The light intensity was controlled for each animal group (Mavo-Monitor, USA; Gossen, Germany). The stimulation protocol was designed according to the International Society for Clinical Electrophysiology of Vision. Briefly, mice were anesthetized by intraperitoneal injection of saline containing ketamine (95 mg / kg) and xylazine (5 mg / kg) and maintained on a 37 °C heating pad. 1% tropicamide eye drops were applied to induce mydriasis. ERG responses were recorded from both eyes in response to full-field stimulation under a light flash. For weak flashes for all light intensities used, a total of 4 - 64 consecutive stimuli with intervals between light flashes were averaged under scotopic conditions for 10 seconds for weak flashes and 60 seconds or less for the highest intensity. For photopic conditions, a 1-second light flash interval was used. The ERG signal was amplified and filtered with a band of 0.3 - 1000 Hz (CP511 AC amplifier; Grass Instruments, Quincy, Massachusetts, USA). The electrical signal was digitized at 20 kHz using a PowerLab data acquisition board (AD Instruments, Chalgrove, UK).

[0353] ERG was performed using a ground electrode placed on the tail and an electrode fixed to the corneal lens (Burian-Allen electrode; Hansen Ophthalmic Development Laboratory, Coralville, Iowa, USA) and a reference electrode fixed to the mouth. The rod-mediated response was recorded from light flashes in the range of 0.001 - 10 cd·s / m 2 using dark-adapted mice. The rod-mediated and cone-mediated mixed signals were recorded in response to light flashes of -1.5 - 1.5 log cd·s / m 2 The oscillatory potential (OP) was isolated using an 11 cd·s / m white flash while recording frequencies in the range of 100 - 10,000 Hz. For recording the cone-mediated response, the inventors used 30 cd·s / m 2 2A light flash in the range of 0.5 to 2 log cd·sec / m against the rod-saturated background was applied. Using data provided by the researcher without using information on the experimental conditions of the mice, the amplitudes of the a-wave and b-wave were averaged. 2 Using data provided by the researcher without using information on the experimental conditions of the mice, the amplitudes of the a-wave and b-wave were averaged.

[0354] Figure 2 shows the improvement of retinal function in rd10 mice treated with the compounds of the present invention (1, 35, 50, 56 and 70; 3 μL of 20 mM solution per eye) as measured by ERG activity after stimulation with lights of different intensities (0.001; 0.01; 0.1; 1 and 10 cd·sec / m 2 ) in dark-adapted mice (scotopic viewing conditions). The data correspond to a pool of 3 independent experiments (N = 3) with 4 - 5 mice per experimental group. The data are presented as mean ± standard deviation. An unpaired t-test was used for statistical analysis. All compounds tested showed different degrees of increased ERG activity that can be summarized as follows: - The b-wave amplitude was significantly increased in mice treated with the compound in the scotopic ERG at flash intensities in the range of 0.001 - 10 cd·sec / m 2 - The compounds improved rod function by increasing the ERG amplitude by 42% or less and 44% under scotopic conditions at light intensities of 0.002 and 0.02 cd·sec / m, respectively, compared to the rd10 untreated group (***p = 0.0014; *p = 0.0194). This represents an average recovery score of 32% compared to wild-type mice. - The scotopic oscillatory potential at maximum intensity related to the function of amacrine cells and Müller cells was significantly increased by 81% or less (*p = 0.039) in treated rd10 mice with a 25% recovery score. 2 - Some compounds (e.g., compound 35) significantly improved cone function by 66% in terms of ERG amplitude at a light intensity of 0.2 cd·sec / m (*p = 0.0113 compared to the rd10 control group) and showed a 78% recovery score compared to WT. - The scotopic oscillatory potential at maximum intensity related to the function of amacrine cells and Müller cells was significantly increased by 81% or less (*p = 0.039) in treated rd10 mice with a 25% recovery score. - Some compounds (e.g., compound 35) significantly improved cone function by 66% in terms of ERG amplitude at a light intensity of 0.2 cd·sec / m (*p = 0.0113 compared to the rd10 control group) and showed a 78% recovery score compared to WT. 2 - Some compounds (e.g., compound 35) significantly improved cone function by 66% in terms of ERG amplitude at a light intensity of 0.2 cd·sec / m (*p = 0.0113 compared to the rd10 control group) and showed a 78% recovery score compared to WT.

[0355] Example 77. In vivo efficacy assay in the rd10 mouse model of retinitis pigmentosa when measured by histological analysis.

[0356] In this experiment, rd10 mice were treated by instilling a phosphate-buffered saline (PBS) solution containing the compound of the present invention (1, 35, 53, and 36; 3 μL of a 20 mM solution per eye) for 11 days (P14 - P24). At P25, the eyeballs were enucleated and fixed with 4% paraformaldehyde (PBS solution) for 3 hours. The anterior segment and lens were dissected, and the eyecups were incubated in 30% sucrose (PBS solution) at 4 °C for 12 hours. 12 μM frozen sections were obtained and stained with DAPI. The sections were analyzed by fluorescence microscopy, and several nuclei in the outer nuclear layer containing photoreceptor nuclei were compared.

[0357] Figure 3 shows some improved photoreceptor nuclei in the retinas of rd10 mice treated with four different compounds compared to untreated mice in the central (C), mid-peripheral (M-P), and peripheral (P) retinas.

[0358] Example 78. Morphometric analysis of the retina Detailed morphometric analysis was performed based on immunohistochemistry. For this purpose, rd10 mice were treated by instilling phosphate buffered saline (PBS) containing compound 35 (3 μL of 20 mM solution per eye) for 11 days (P14 - P24). At P25, the eyeballs were enucleated and fixed in 4% paraformaldehyde (PBS solution) for 3 hours. The anterior segment and lens were dissected, and the eye cups were incubated in 30% sucrose (PBS solution) at 4 °C for 12 hours. Frozen sections containing DAPI. The frozen sections of the eyes were stained with DAPI, rhodopsin, and cone arrestin for immunohistochemical analysis. Briefly, the frozen sections were incubated with antibodies against rhodopsin (Millipore, MABN15) and cone arrestin (Millipore, AB15282) at both 1:400 at 4 °C for 8 hours, and buffered with secondary antibodies at both 1:400 and DAPI (Sigma, D89542) 1:1000 for 1 hour. The sections were analyzed by fluorescence microscopy. As shown in Figure 4, significant preservation of photoreceptors in the retina of rd10 mice treated with compound 35 was observed when measured by the number of rod photoreceptor cells (B) and cone photoreceptor cells (C), or rod outer segments and inner segments of photoreceptor cells (D) per square mm.

[0359] Example 79. In vivo efficacy assay in an rd10 mouse model of retinitis pigmentosa when measured by optomotor response based on the water maze.

[0360] The rd10 mice were treated by instilling phosphate buffered saline (PBS) containing Compound 35 of the present invention into the eyes for 16 days (P14 - P29). To test the optokinetic (OKT) response, the inventors conducted an OKT test in combination with the Morris water maze corrected using 9 rd10 mice at p30: 5 treated with Compound 35 and 4 untreated. The animals were acclimated to the experimental conditions for 1 week before the behavioral tests. The mice were trained in a square pool (70×40 cm) filled with water (24 - 26°C) having an opaque overall surface except for the front face where the screen was placed. The screen was vertically divided into two equal parts. The pattern of a moving vertical bar was displayed on one half of the screen and the other half was erased. The direction of the bar was random: 50% of the times moving to the right and 50% of the times moving to the left. The bar speed was constant throughout the process. The mice were trained for 1 week to associate the screen area with the presence of a submerged platform placed to the right adjacent to the screen area that was invisible to the mice under dim light conditions. The platform enabled the mice to escape from the water. As a result of conducting the experimental procedure over 7 days, the animals were able to associate the moving bar with the presence of the platform. Due to 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 adjusted until the mice could no longer see the bar pattern. The contrast sensitivity values were measured and the results of treated and untreated mice were compared. Figure 5 shows that the largest differences were observed at outlier spatial frequencies and there was more difficulty in recognizing the patterns of moving bars (0.01; 0.02; 0.17 and 0.35 cycles / degree).

[0361] Example 80.661 In vitro efficacy of Compound 35 in preventing phototoxicity of 1W cells.

[0362] 661W is a mouse photoreceptor-derived cell line immortalized by the expression of simian virus (SV) T antigen (T-ag) under the control of the human IRBP promoter. Cell and molecular analyses indicate that these cells express cone photoreceptor markers but not rod photoreceptor markers, suggesting that the cells are derived from the cone photoreceptor lineage. For this reason, the 661W cell line contributes significantly to the study of cone photoreceptor cell function and diseases affecting cone photoreceptor cells, including age-related macular degeneration, Stargardt's disease or diabetic retinopathy, including the mechanism of photoreceptor cell death in various retinal dystrophies (Tan et al. Invest Ophthalmol. Vis. Sci., 2004, 45, 764).

[0363] 661W cells were seeded (50,000 cells / well) in 96-well impedance plates pre-coated with ECM 1:100 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), an antibacterial-antifungal solution (Sigma, A5955) and 10% fetal bovine serum (FBS) and grown overnight at 37 °C and 5% CO2. After 8 h, the medium was replaced with DMEM / F-12 without FBS or complement to remove cell debris. When a steady state of impedance recording (4 - 8 h after medium change depending on the culture plate) was reached, compound 35 was added and 2 h later, 9-cis-retinal (Cf = 20 μM) was added. Cells were placed in Maestro Z, exposed to 30,000 white light lux and the impedance was registered. Figure 6 shows that compound 35 protects against the photoinduced phototoxicity of 9-cis-retinal and 661W cells in a dose-responsive manner with an EC50 = 30.5 nM potency.

Claims

1. A compound of formula (I) for use in the prevention and / or treatment of eye diseases: 【Chemical 1】 (I) wherein in said formula (I), X and Y are 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, independently selected from the group consisting of; or X and Y together are methylenedioxy or ethylenedioxyl radical; 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 ２ - and -O-; R １ is a linear C １ to C ４ alkylene biradical which may be substituted by one or two substituents independently selected from the group consisting of methyl, ethyl and F; R ２ is a linear C ３ -C １ to C ４ alkylenebiradical which may be 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 CF R ３ is selected from the group consisting of H and I; and W is -NH ２ , -NH(C １ ~C ４ alkyl), -N(C １ ~C ４ alkyl) ２ , -N(C １ ~C ４ alkyl) ３ , C １ ~C ４ 1-pyrrolidinyl optionally substituted by C １ ~C ４ alkyl, C １ ~C ４ 1-piperidinyl optionally substituted by C １ ~C ４ alkyl, C ２ ~C １ alkyl, 4-morpholinyl optionally substituted by C ４ ~C １ alkyl, 4-piperazinyl optionally substituted by C ４ alkyl, -NH C(=NH)NH １ ~C ４ alkyl), -NH C(=NH)NH C(=NH)NH ２ , -N(C １ ~C ４ alkyl) C(=NH)NH C(=NH)NH ２ , -CO ２ H, and -SO ３ H, selected from the group consisting of a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

2. m is 1; n is 0; X is selected from the group consisting of O(C １ ~C ４ alkyl), C １ ~C ６ alkyl) and CF ３ ; R １ is -CH ２ -; R ２ is selected from the group consisting of -CH ２ -CH ２ - and -CH ２ -CH ２ -CH ２ -; 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, and 4-piperazinyl optionally substituted by C １ ~C ４ alkyl, a compound of formula (I) for use according to claim 1.

3. Z is -S-; R １ is -CH ２ -; and R ３ is H, a compound of formula (I) for use according to claim 1 or 2.

4. m is 1; n is 0; and X is para to Z, a compound of formula (I) for use according to any one of claims 1 to 3.

5. Said compound is 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; (Guanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Guanidyl)ethyl]-4-[1-(4-methoxyphenoxy)-1-(methyl)-ethyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(4-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(3-methoxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole; 1-[2-(Biguanidyl)ethyl]-4-(phenoxymethyl)-1H-1,2,3-triazole; 1-[2-(Biguanidyl)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-oxideaminoethyl]-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 - (guanidyl)ethyl] - 4 - [(4 - methoxyphenyl)thiomethyl] - 1H - 1,2,3 - triazole; 1 - [2 - (biguanidinyl)ethyl] - 4 - [(4 - methoxyphenyl)thiomethyl] - 1H - 1,2,3 - triazole; 1 - [3 - (biguanidinyl)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 - tritium - 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-oxideaminoethyl]-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 A compound of formula (I) for use according to claim 1, selected from the group consisting of:

6. A pharmaceutical composition for use in the prevention and / or treatment of eye diseases, comprising a compound of formula (I) as defined in any one of claims 1 to 5 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, carboxymethylcellulose, carbomer and mixtures thereof.

7. The eye disease is selected from the group consisting of retinal diseases, preferably retinitis pigmentosa, diabetic retinopathy, cone dystrophy, rod and cone dystrophy, Leber congenital amaurosis, punctate retinitis, choroideremia, gyral retinal choroid atrophy, choroid dystrophy, X-linked retinal detachment, Wagner vitreoretinal degeneration, autosomal dominant vitreoretinal choroidopathy, Stargardt disease, Best vitelliform macular dystrophy; dominant vitreoretinal choroidopathy; Usher syndrome, Bardet-Biedl syndrome, Sorsby fundus dystrophy, age-related macular degeneration, autosomal dominant congenital stationary night blindness, color vision abnormalities and macular drusen, a compound of formula (I) or a pharmaceutical composition for use according to any one of claims 1 to 6.

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

9. The retinal disease is selected from retinitis pigmentosa, autosomal dominant congenital stationary night blindness and color vision abnormalities, a compound of formula (I) or a pharmaceutical composition for use according to claim 7.

10. A compound of formula (I) or a pharmaceutical composition for use according to any one of claims 1 to 9, administered locally, intravitreally, orally, parenterally, transdermally, intranasally, or rectally.

11. A compound of formula (I) or a pharmaceutical composition for use according to any one of claims 1 to 10, administered locally on the corneal surface, preferably in the form of a drop, gel, cream, spray or contact lens.

12. The compound of formula (I) is administered at a dose of 0.001 to 10 mg / day, a compound of formula (I) or a pharmaceutical composition for use according to any one of claims 1 to 11.

13. Formula (II): 【Chemical 2】 (II) A compound, wherein in the formula (II), X and Y are 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, independently selected from the group consisting of; or X and Y together are methylenedioxy or ethylenedioxyl radical; 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 CH ３ and is selected from the group consisting of; R ３ is selected from the group consisting of H and I; Z is —S—, —S(═O)— or —S(═O)₂ ２ when, p is selected from the group consisting of 2, 3 and 4, and W is —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)NH(C═NH)NH ２ , and —N(C １ ~C ４ alkyl)C(═NH)NH(C═NH)NH ２ is selected from the group consisting of; and When Z is -O-, p is selected from the group consisting of 2 and 4, and W is -NH ２ , -NH(C １ ~C ４ alkyl), -N(C １ ~C ４ alkyl) ２ , -N(C １ ~C ４ alkyl) ３ , C １ ~C ４ 1-pyrrolidinyl optionally substituted by alkyl, C １ ~C ４ 1-piperidinyl optionally substituted by alkyl, C １ ~C ４ 4-morpholinyl optionally substituted by alkyl, C １ ~C ４ 4-piperazinyl optionally substituted by alkyl, -NH C(=NH)NH ２ , -NH C(=NH)NH(C １ ~C ４ alkyl), -NH C(=N(C １ ~C ４ alkyl)NH(C １ ~C ４ alkyl), -NH C(=NH)NH C(=NH)NH ２ , -N(C １ ~C ４ alkyl)C(=NH)NH C(=NH)NH ２ , -CO ２ H, and -SO ３ H, and is selected from the group consisting of provided that the compound is not 1-(2-aminoethyl)-4-[(3,4-methylenedioxyphenoxy)methyl]-1H-1,2,3-triazole, a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or N-oxide thereof, or an isotope-labeled derivative thereof.

14. 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; X, when present, is in the meta or para position relative to Z and is selected from the group consisting of OH, O(C １ ~C ４ alkyl), OCF ３ and CF ３ ; Y, when present, is ortho to Z and is CF ３ and; or X and Y together are a methylenedioxy or ethylenedioxyl radical; Each R is independently selected from the group consisting of H and CH ３ and; R ３ is selected from the group consisting of H and I; p is selected from the group consisting of 2 and 4; and W is -NH ２ , -NH(C １ ~C ４ alkyl), -N(C １ ~C ４ alkyl) ２ , -N(C １ ~C ４ alkyl) ３ , C １ ~C ４ 1-pyrrolidinyl which may be substituted by C １ ~C ４ alkyl, C １ ~C ４ 1-piperidinyl which may be substituted by C １ ~C ４ 4-morpholinyl which may be substituted by C ２ ~C １ ~C ４ alkyl, -NHC(=NH)NH １ ~C ４ alkyl), -NHC(=NH)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 selected from the group consisting of the compound according to claim 13.

15. m is 1; n is 0; X is para to Z; X is O(C １ ~C ４ 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 NH C(=NH)NH C(=NH)NH ２ ; when Z is -O-, W is -N(C １ ~C ４ alkyl) ２ is, The compound of formula (II) according to claim 13 or 14.

16. The 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 for use in medicine.

17. A pharmaceutical composition comprising the 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, the pharmaceutically acceptable excipient is selected from the group consisting of hyaluronic acid, carboxymethyl cellulose, carbomer and mixtures thereof.

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