Novel compounds as therapeutically active substances in the treatment and / or prevention of diseases involving the retinal pigment epithelium and their use

Abstract

The present invention relates to a method for treating and / or preventing diseases involving the retinal pigment epithelium, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, a racemic mixture, a corresponding enantiomer, or, where appropriate, a corresponding diastereomer: [Formula 1] TIFF2023549640000109.tif27151[In the formula, X is either NH or O; R 11 , R 12 and R 13 are independently selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, and a difluoromethoxy group; A is selected from the group consisting of residues of formula (II), (III), (IV), (V), (VI), (VII) or (VIII): [Case 2] TIFF2023549640000110.tif76151 (in the formula, "*" indicates the point of attachment to the rest of the molecule; R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R2 VI , R3 VI , R4 VI and R5 VIare independently selected from the group consisting of a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, an ethoxy group, a propoxy group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, and a difluoromethoxy group; In the residue of formula (VI), R6 is selected from the group consisting of a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group.

Description

[Technical Field]

[0001] The present invention relates to novel compounds and their uses as therapeutic active substances in the treatment and / or prevention of diseases involving the retinal pigment epithelium, particularly diseases leading to atrophy, degeneration, or death of the retinal pigment epithelium, which may also cause atrophy or loss of photoreceptors and / or retinal neovascularization. [Background technology]

[0002] Macular degeneration is a group of serious diseases involving the degeneration and death of the retinal pigment epithelium (RPE). Macular degeneration is characterized by progressive loss of central vision associated with abnormalities of Bruch's membrane, choroid, neuroretina, and / or retinal pigment epithelium. The macula is the central part of the retina and has a diameter of approximately 0.3–0.5 cm. The macula has a high density of cone photoreceptor cells, which provides detailed vision for activities such as reading, driving, or facial recognition.

[0003] Age-related macular degeneration (AMD), also known as age-related macular degeneration, is the most common form of macular degeneration and is associated with progressive loss of visual acuity in the central visual field, changes in color vision, and abnormalities in dark adaptation and sensitivity. AMD is the leading cause of irreversible vision loss, affecting approximately 2% of individuals in developed countries. The prevalence of AMD increases with age, and its etiology is multifactorial.

[0004] The primary causes of this disease and its progression are the loss of functional RPE cells and alterations in Bruch's membrane, their basement membrane. The RPE is a continuous monolayer of cells located between the light-sensitive photoreceptors and the choroid, which supplies blood to the retina. Because RPE cells nourish highly metabolized photoreceptors by providing energy and growth factors, removing waste, and recycling essential compounds for the visual cycle, the loss of RPE ultimately leads to photoreceptor dysfunction and loss.

[0005] The two main clinical manifestations of AMD are described as dry or atrophic (hereinafter referred to as dry AMD) and wet or neovascular (hereinafter referred to as wet AMD). Dry AMD is associated with atrophic cell death of the central retina or macula. Approximately 10 to 20% of these dry AMD patients further progress to a second form known as wet or neovascular AMD. In these progressive stages of AMD, atrophy of the retinal vascular area (RPE) (geographic atrophy) and / or growth of new blood vessels originating from choroidal vessels (angiogenesis) further leads to photoreceptor death and loss of central vision. This loss of central vision, which is essential for reading, facial recognition, and performing many daily tasks, essentially isolates the patient from the world around them.

[0006] There are currently no approved treatments for its progressive form, known as dry AMD or geographic atrophy (GA), and many patients with neovascular AMD are legally blind despite the latest treatments using anti-VEGF agents such as Lucentis (Registered Trademark). While there are various pharmacological approaches to treat vision loss in dry AMD caused by underlying RPE damage, they all aim to control the mechanisms thought to cause the damage in the first place (e.g., the complement system) rather than reversing the damage caused by the loss of RPE cells. Alternative approaches under investigation include transplantation of induced pluripotent stem cells or mature RPE cells.

[0007] Drusens are small, yellowish or white deposits of extracellular material that accumulate between the Bruch's membrane and the retinal pigment epithelium of the eye. The presence of drusens is characteristic of age-related macular degeneration (AMD). Recent research on drusens suggests that inflammation and other immune processes are involved in the pathogenesis of early and late-stage AMD. This suggests a role in intervening processes, particularly in complement activation. European Patent No. 2 302 076 (EP 2 302 076) discloses the administration of a drug that reduces the amount of mutant H factor or the expression of the gene encoding H factor, in an amount effective in alleviating the AMD symptoms of a patient, because factor H protein (HF1), a major inhibitor of the complement accessory pathway, accumulates in drusen and is locally synthesized by the retinal pigment epithelium.

[0008] U.S. Patent No. 9,815,819 relates to compounds that modulate, and preferably inhibit, the activation of complement accessory pathways as a method for treating or preventing AMD.

[0009] International Publication No. 2015 / 138628 (WO 2015 / 138628) relates to an AAV vector construct optimized for delivering anti-inflammatory peptides to the retina of AMD patients.

[0010] Australian Patent No. 2019 / 226198 (AU 2019 / 226198) discloses a method for producing a substantially purified culture of RPE cells suitable for transplantation.

[0011] Chinese Patent No. 103656742 (CN 103656742) relates to a method for preparing functionalized retinal pigment epithelial cell grafts for implantation into the retina of AMD patients.

[0012] Russian Patent No. 2628697 (RU 2628697) discloses a procedure for producing a cell layer from retinal pigment epithelial cells in a simple and stable manner that does not use an artificial membrane and results in a high engraftment rate during intraocular transplantation.

[0013] PCT / US19 / 68768 describes the application of small molecules that induce endogenous regeneration of photoreceptors derived from retinal stem cells and progenitor cells in retinal dystrophy, i.e., retinitis pigmentosa. In contrast, the present invention relates to the treatment and / or prevention of RPE-related eye diseases by stimulating pigment deposition and / or proliferation of mammalian RPE cells.

[0014] In the case of wet AMD, significant progress has been made in the development of anti-VEGF (anti-vascular endothelial growth factor) drugs. However, these therapies do not address damage to the RPE layer and only suppress angiogenesis. Furthermore, they are not curative and are only effective in maintaining the current state of the disease. [Overview of the project] [Means for solving the problem]

[0015] Therefore, the object of the present invention is to provide a therapeutic agent for the treatment and / or prevention of RPE-related diseases, and in particular for the treatment of AMD.

[0016] This problem is solved by the compound represented by formula (I). More preferred embodiments are the subject of the dependent claims. [Effects of the Invention]

[0017] A novel compound represented by formula (I) has been shown to stimulate pigment deposition and / or proliferation of mammalian RPE cells. This stimulation of endogenous RPE cell pigment deposition and / or proliferation enables controlled repair and regeneration of the retina. Therefore, by intrinsically generating new normal RPE cells with the compound of the present invention, it is possible to prevent vision loss and / or restore vision. Thus, the compound represented by formula (I) can prevent atrophy, death, or It is useful as a therapeutic agent, i.e., as a drug, in the treatment and / or prevention of diseases that lead to degeneration. [Brief explanation of the drawing]

[0018] [Figure 1] Figure 1 shows a schematic diagram of an RPE compound screening regimen. [Modes for carrying out the invention]

[0019] In this context, the term “RPE cells” encompasses any form of proliferative and non-proliferative retinal pigment epithelial cells that support or give rise to further differentiated functional tissues of the eye. RPE cells are smooth, pigmented, and hexagonal in shape. Normal and fully differentiated RPE cells construct melanosomes containing the light-absorbing pigment melanin. Therefore, compounds that promote the differentiation of normal and functional RPE cells lead to the presence of pigmentation.

[0020] The term "mammalian RPE cell proliferation" refers to the controlled promotion of RPE cell proliferation and the corresponding increase in the number of RPE cells.

[0021] The term "prevention" refers to the prevention or mitigation of signs and symptoms associated with RPE-related diseases, particularly macular degeneration leading to vision loss in patients at risk of developing the disease. In these patients, predisposition may persist, but signs and / or symptoms of the disease may not develop or may take significantly longer to develop. Furthermore, once the disease has developed, it also includes preventing further worsening of symptoms.

[0022] As described above, the present invention relates to a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding tautomer, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] [In the formula, X is either NH or O. R 11 , R 12 and R 13 These are independently selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, and a difluoromethoxy group. A is selected from the group consisting of residues of formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

Chemical formula

[0023] The term "pharmaceutically acceptable salt" refers to a therapeutically active non-toxic acid salt form that can be formed by the compounds according to the invention.

[0024] In one embodiment of the present invention, the ring-position chiral center* of the residues of formulas (II), (III), (IV), and (V), or the chiral center on the side chain of formula (VI), has the following stereochemistry and is a compound of formula (Ii): [ka] [In the formula, A is selected from the group consisting of residues of formula (II), (III), (IV), (V), or (VI): [ka] In the case of the residue of formula (VII), the chiral center** in the compound according to the present invention preferably has the following stereochemistry: [ka] And then, X, R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V And R6 has the same definition as above.

[0025] In another embodiment of the present invention, the ring-position chiral center* of a residue of formula (II), (III), (IV), or (V) or the chiral center on the side chain of formula (VI) has the following stereochemistry and is a compound of formula (III): [ka] [In the formula, A is selected from the group consisting of residues of formula (II), (III), (IV), (V), or (VI): [ka] In the case of the residue of formula (VII), the chiral center** in the compound according to the present invention preferably has the following stereochemistry: [ka] And then, X, R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R2 VI , R3 VI , R4 VI , R5 VI And R6 has the same definition as above.

[0026] Preferably, in the compound represented by formula (I), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine atoms, and the other residues are hydrogen atoms. For example, R 11 is a fluorine atom, R 12 and R13 means that both are hydrogen atoms.

[0027] In one embodiment of the present invention, in the compound of formula (I), X is O, and R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4< extraordinari II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R2 VI , R3 VI , R4 VI , R5 VI and R6 have the same definitions as above.

[0028] In another embodiment of the present invention, in the compound of formula (I), X is NH, and R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 I I , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R@2 VI , R3 VI , R4 VI , R5VI And R6 has the same definition as above.

[0029] Residue A is preferably unsubstituted or monosubstituted.

[0030] The term non-substitution refers to R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R2 VI , R3 VI , R4 VI and R5 VI This means that all of them are hydrogen. If residue A is monosubstituted, then R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3 IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R2 VI , R3 VI , R4 VI and R5 VIOne of these residues is preferably selected from the group consisting of fluorine and chlorine atoms, and the other residues are hydrogen atoms. The term monosubstituted does not mean R6 in the residue of formula (VI). Therefore, in the residue of formula (VI), the term monosubstituted means R2 IV , R3 IV , R4 IV , R5 IV Unlike one of the hydrogen atoms, R6 means that it can be a hydrogen atom, a linear or branched alkyl group with 1 to 3 carbon atoms, a trifluoromethyl group, or a 2,2,2-trifluoroethyl group.

[0031] In the residue of formula (VI), R6 is preferably a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, and most preferably a methyl group.

[0032] One embodiment of the present invention relates to a compound represented by formula (Ia), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] (In the formula, X, R 11 , R 12 ,R 13 (R2, R3, R4, and R5 have the same definitions as above.)

[0033] Preferably, in the compound represented by formula (Ia), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0034] In one embodiment of the present invention, in the compound of formula (Ia), X is O, R2, R3, R4, and R5 are defined as above, and residue A is preferably unsubstituted or monosubstituted.

[0035] In another embodiment of the present invention, in the compound of formula (Ia), X is NH, R2, R3, R4, and R5 are defined as above, and residue A is preferably unsubstituted or monosubstituted.

[0036] Another embodiment of the present invention relates to a compound represented by formula (Ib), or a pharmaceutically acceptable compound thereof. With respect to salts, racemic mixtures, corresponding enantiomers, or, where applicable, corresponding diastereomers: [ka] (In the formula, X, R 11 , R 12 ,R 13 , R2 I , R3 I , R4 I and R5 I (This is the same definition as above.)

[0037] Preferably, in the compound represented by formula (Ib), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0038] In one embodiment of the present invention, in the compound of formula (Ib), X is O, and R2 I , R3 I , R4 I , R5 IThe definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0039] In another embodiment of the present invention, in a compound of formula (Ib), X is NH and R2 I , R3 I , R4 I , R5 I The definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0040] Another embodiment of the present invention relates to a compound represented by formula (Ic), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] (In the formula, X, R 11 , R 12 ,R 13 , R2 II , R3 II , R4 II and R5 II (This is the same definition as above.)

[0041] Preferably, in the compound represented by formula (Ic), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0042] In one embodiment of the present invention, in a compound of formula (Ic), X is O, and R2 II , R3 II , R4 II , R5 IIThe definition is the same as above, and residue A is preferably unsubstituted or It is a single substitution.

[0043] In another embodiment of the present invention, in a compound of formula (Ic), X is NH and R2 II , R3 II , R4 II , R5 II The definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0044] Another embodiment of the present invention relates to a compound represented by formula (Id), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] (In the formula, X, R 11 , R 12 ,R 13 , R2 III , R3 III , R4 III , R5 III (This is the same definition as above.)

[0045] Preferably, in the compound represented by formula (Id), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0046] In one embodiment of the present invention, in the compound of formula (Id), X is O, and R2 III , R3 III , R4 III and R5 IIIThe definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0047] In another embodiment of the present invention, in a compound of formula (Id), X is NH and R2 III , R3 III , R4 III , R5 III The definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0048] Another embodiment of the present invention relates to a compound represented by formula (Ie), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] (In the formula, X, R 11 , R 12 ,R 13 , R2 IV , R3 IV , R4 IV , R5 IV And R6 has the same definition as above.

[0049] Preferably, in the compound represented by formula (Ie), residue R 11 , R 12 and R 13 Independent The atoms are selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, R 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0050] In one embodiment of the present invention, in a compound of formula (Ie), X is O, and R2 IV , R3 IV , R4 IV , R5 IVAnd R6 are defined as above, and residue A is preferably unsubstituted or monosubstituted.

[0051] In another embodiment of the present invention, in a compound of formula (Ie), X is NH and R2 IV , R3 IV , R4 IV , R5 IV And R6 are defined as above, and residue A is preferably unsubstituted or monosubstituted.

[0052] Another embodiment of the present invention relates to a compound represented by formula (If), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] (In the formula, X, R 11 , R 12 ,R 13 , R2 V , R3 V , R4 V and R5 V (This is the same definition as above.)

[0053] Preferably, in the compound represented by formula (If), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0054] In one embodiment of the present invention, in the compound of formula (If), X is O, and R2 V , R3 V , R4 V , R5 VThe definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0055] In another embodiment of the present invention, in a compound of formula (If), X is NH and R2 V , R3 V , R4 V , R5 V The definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0056] Another embodiment of the present invention relates to a compound represented by formula (Ig), or a pharmaceutically acceptable salt thereof, a racemic mixture, a corresponding enantiomer, or, where applicable, a corresponding diastereomer: [ka] (In the formula, X, R 11 , R 12 ,R 13 , R2 VI , R3 VI , R4 VI and R5 VI (This is the same definition as above.)

[0057] Preferably, in the compound represented by formula (Ig), residue R 11 , R 12 and R 13 R is independently selected from the group consisting of hydrogen atoms, chlorine atoms, and fluorine atoms. Most preferably, 11 , R 12 and R 13 All of them are hydrogen atoms, or R 11 , R 12 and R 13 One of the residues is selected from the group consisting of chlorine and fluorine atoms, while the other residues are hydrogen atoms.

[0058] In one embodiment of the present invention, in the compound of formula (Ig), X is O, and R2 VI , R3 VI , R4 VI and R5 VIThe definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0059] In another embodiment of the present invention, in a compound of formula (Ig), X is NH and R2 VI , R3 VI , R4 VI and R5 VI The definition is the same as above, and residue A is preferably unsubstituted or monosubstituted.

[0060] Preferably, the compound represented by formula (Ia) is R 11 , R 12 , R 13 Selected from the group consisting of compounds represented by formula (I), where R2, R3, R4, and R5 are as shown in Table 1: [ka] [Table 1] TIFF0007863099000018.tif231149TIFF0007863099000019.tif231149TIFF00078630990 00020.tif231149TIFF0007863099000021.tif231149TIFF0007863099000022.tif110149

[0061] Preferably, the compound represented by formula (Ib) is R 11 , R 12 , R 13 , R2 I , R3 I , R4 I and R5 I The following are selected from the group consisting of compounds represented by formula (I), as shown in Table 2: [ka] [Table 2] TIFF0007863099000025.tif230151TIFF0007863099000026.tif230151TIFF00078630990 00027.tif230151TIFF0007863099000028.tif230151TIFF0007863099000029.tif110151

[0062] Preferably, the compound represented by formula (Ic) is X, R 11 , R 12 , R 13 , R2 II , R3 II , R4 II and R5 II The following are selected from the group consisting of compounds represented by formula (I), as shown in Table 3: [ka] [Table 3] TIFF0007863099000032.tif230150TIFF0007863099000033.tif230150TIFF00078630990 00034.tif230150TIFF0007863099000035.tif230150TIFF0007863099000036.tif109150

[0063] Preferably, the compound represented by formula (Id) is R 11 , R 12 , R 13 , R2 III , R3 III , R4 III , R5 III The following are selected from the group consisting of compounds represented by formula (I), as shown in Table 4: [ka] [Table 4] TIFF0007863099000039.tif230150TIFF0007863099000040.tif230150TIFF00078630990 00041.tif230150TIFF0007863099000042.tif230150TIFF0007863099000043.tif110150

[0064] Preferably, the compound represented by formula (Ie) is R 11 , R 12 , R 13 , R2 IV , R3 IV , R4 IV , R5 IV The following compounds are selected from the group consisting of compounds represented by formula (I), where R6 is as shown in Table 5: [ka] [Table 5] TIFF0007863099000046.tif231150TIFF0007863099000047.tif230150TIFF00078630990 00048.tif230150TIFF0007863099000049.tif230150TIFF0007863099000050.tif109149

[0065] Preferably, the compound represented by formula (If) is R 11 , R 12 , R 13 , R2 V , R3 V , R4 V and R5 V The following are selected from the group consisting of compounds represented by formula (I), as shown in Table 6: [ka] [Table 6] TIFF0007863099000053.tif230150TIFF0007863099000054.tif230150TIFF00078630990 00055.tif230150TIFF0007863099000056.tif230150TIFF0007863099000057.tif110150

[0066] Preferably, the achiral compound represented by formula (Ig) is R 11 , R 12 , R 13 , R2 VI , R3 VI , R4 VI and R5 VI The following are selected from the group consisting of compounds represented by formula (I), as shown in Table 7: [ka] [Table 7] TIFF0007863099000060.tif231150TIFF0007863099000061.tif230150TIFF00078630990 00062.tif231150TIFF0007863099000063.tif230150TIFF0007863099000064.tif110150

[0067] Particularly favorable results can be obtained with the following compounds according to the present invention. [Table 8] TIFF0007863099000066.tif196148TIFF0007863099000067.tif109148

[0068] The expression "enantiomer with a retention time shorter than the chiral HPLC resolution" means that the enantiomer appears first in chiral HPLC when the conditions described in the corresponding chiral separation method below are applied. In the context of this invention, the enantiomer with a short retention time is also referred to as the "first enantiomer," and the one with a long retention time is also referred to as the "second enantiomer."

[0069] As described above, the compounds and compositions according to the present invention promote the proliferation and / or differentiation of RPE cells. Therefore, the compounds according to the present invention may be used for the treatment and / or prevention of RPE-related diseases, particularly RPE diseases from the macular degeneration group that lead to vision loss. Most preferably, the diseases are those that lead to atrophy, degeneration, or death of the retinal pigment epithelium, which may further result in retinal neovascularization and / or photoreceptor death.

[0070] The compounds and compositions according to the present invention are particularly useful in the treatment and / or prevention of diseases selected from the group of macular degenerations consisting of early age-related macular degeneration (AMD), dry AMD, geographic atrophy (GA), and wet AMD, by inducing the proliferation and / or differentiation of RPE cells. Therefore, the compounds and compositions of the present invention can not only treat vision loss caused by RPE cell dysfunction and / or damage, but also reverse disease-induced RPE cell damage by repairing or regenerating endogenous RPE cells.

[0071] The compound represented by formula (I) of the present invention may be used, in particular, to prevent the onset of dry age-related macular degeneration (dry AMD) and / or wet age-related macular degeneration (wet AMD), to prevent early AMD from progressing to wet AMD or progressive AMD such as geographic atrophy (GA), to slow and / or prevent the progression of GA, to prevent or reduce vision loss from AMD, and to improve vision loss due to existing early or progressive dry or wet AMD. It may also be used in combination with anti-VEGF therapy for the treatment of neovascular AMD patients or for the prevention of neovascular AMD.

[0072] The compounds and compositions according to the present invention also treat congenital choroidal agenesis, Best's disease, autosomal recessive bestrofinopathy (ARB), cerebral gynostosis, North Carolina macular dystrophy, central annular choroidal dystrophy (CACD), Sausby's macular dystrophy, familial dominant drusen, cuticle or basement membrane drusen, retinopathy of prematurity, myopic degeneration, polypoid choroidal vasculopathy (PCV), central serous retinopathy, retinal pigment streaks, and retina. It is useful for the treatment and / or prevention of diseases selected from the group consisting of retinal detachment, retinal detachment (tear), Vogt-Koyanagi-Harada disease (VKH), acute posterior multiple macular pigment epitheliopathy (APMPPE), persistent placoid maculopathy (PPM), reactive placoid chorioretinopathy (RPC), serpentine choroiditis, multifocal serpidinoid choroiditis, multiple disappearing white dot syndrome (MEWDS), or birdshot uveitis (white exudate chorioretinitis).

[0073] The compounds and compositions according to the present invention are particularly useful for the treatment of congenital choroidal agenesis. Congenital choroidal agenesis is a hereditary visual impairment that usually affects males and results in symptoms such as difficulty seeing in dim light, progressive loss of peripheral vision, and subsequent tunnel vision. Congenital choroidal agenesis can involve extensive loss of all retinal layers in the eye. This disorder usually begins in childhood with depletion (atrophy) of the pigmented retinal epithelium, retina, and choroid. The disease can be treated using the compounds according to the present invention.

[0074] The compounds and compositions according to the present invention are particularly useful in the treatment and / or prevention of diseases selected from the group consisting of retinal diseases resulting in choroidal neovascularization or vascular leakage. The retinal diseases are preferably selected from the group consisting of toxoplasmosis, toxocariasis, rubella, Behçet's disease, choroidal hemangioma, trauma, choroidal rupture, and idiopathic retinitis-vasculitis-aneurysm and optic retinitis (IRVAN).

[0075] The compounds and compositions according to the present invention are particularly useful in the treatment and / or prevention of diseases selected from the group consisting of retinal inflammation and degeneration such as sympathetic ophthalmitis, postoperative inflammation, or non-arteritic ischemic optic neuropathy, and retinal diseases that cause retinal degeneration associated with systemic diseases such as diabetes mellitus, sickle cell disease, or radiation retinopathy.

[0076] In further embodiments, the present invention relates to a pharmaceutical composition for use in the treatment and / or prevention of diseases involving the retinal pigment epithelium, the pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or adjuvant; and a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding tautomer, a corresponding enantiomer, or, where applicable, a corresponding diastereomer, as a therapeutic active substance. [ka] [In the formula, X is either NH or O. R 11 , R 12 and R 13 These are independently selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group, a methyl group, and a difluoromethoxy group. A is selected from the group consisting of residues of formulas (II), (III), (IV), (V), (VI), (VII), and (VIII): [ka] (In the formula, “*” indicates a bond point to the rest of the molecule. R2, R3, R4, R5, R2 I , R3 I , R4 I , R5 I , R2 II , R3 II , R4 II , R5 II , R2 III , R3 III , R4 III , R5 III , R2 IV , R3IV , R4 IV , R5 IV , R2 V , R3 V , R4 V , R5 V , R2 VI , R3 VI , R4 VI and R5 VI These are independently selected from the group consisting of a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, a fluorine atom, a chlorine atom, a bromine atom, a methoxy group, an ethoxy group, a propoxy group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, and a difluoromethoxy group. In the residue of formula (VI), R6 is selected from the group consisting of a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group.

[0077] The compounds or compositions according to the present invention can be administered to a patient alone or in combination with one or more additional therapeutic agents. As used herein, “patient” includes mammals such as humans, non-human primates, rats, mice, rabbits, hares, dogs, cats, horses, cattle, and pigs, and is preferably human.

[0078] The pharmaceutical composition according to the present invention may contain one or more additional therapeutic agents.

[0079] In preferred embodiments of the present invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier and / or adjuvant; and a compound represented by formula (I) as defined above, preferably a compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig). Most preferably, it comprises a compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) as disclosed in Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, or Table 7. Compounds disclosed in Table 8 are particularly preferred.

[0080] Preferably, the pharmaceutical composition provides controlled release properties. The term "controlled release pharmaceutical composition" as used herein refers to any composition or dosage form comprising the compound of the present invention and formulated in such a dosage form that the post-administration pharmacological response lasts longer than typically experienced after administration of a corresponding immediate-release (rapid-acting) composition containing the same drug in the same amount. The controlled release can be extended up to several months, depending on the matrix used. Preferably, the release of the compound according to the present invention occurs over a period of up to 12 months, most preferably up to 6 months, ideally up to 3 months, and for example, over 1 to 4 weeks. This is possible. Such controlled-release formulations offer improved patient comfort and significantly reduced costs.

[0081] The matrix substance used in the pharmaceutical composition according to the present invention may include a hydrophobic release control agent. Preferably, but not limited to, polysorbate, polyvinyl acetate dispersion, ethylcellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose propionate acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl methacrylate). Waxes such as poly(isobutyl acrylate), poly(octadecyl acrylate), beeswax, carnauba wax, paraffin wax, microcrystalline wax, and ozokerite; aliphatic alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol, and myristyl alcohol, and fatty acid esters such as glyceryl monostearate; selected from glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl ester wax, glyceryl palmitostearate, glyceryl behenate, or hydrogenated vegetable oils.

[0082] The compounds of the present invention can be delivered to the eye through a variety of routes, including topical application to the eye, or by intraocular injection, for example, into the vitreous, suprachoroidal, subretinal (interphotoreceptor) or subconjunctival space; topical by insertion or injection into the tissues around the eye; systemic via the oral route, or by subcutaneous, intravenous or intramuscular injection; or via a catheter or implant, but not limited to these. Most preferably, the compounds of the present invention are delivered by intravitreal or suprachoroidal injection. Intravitreal administration results in high concentrations of the compound in the eye with minimal systemic exposure. Suprachoroidal injection may allow for higher local concentrations of the compounds of the present invention in the posterior tissues, which allows for lower dosages or less frequent dosing. Examples of topical ophthalmic compositions are eye drops, ointments, gels, solutions and suspensions.

[0083] The compounds of the present invention can be administered prior to the onset of the condition to prevent its occurrence, such as during ophthalmic surgery, immediately after the onset of a pathological condition, or during the occurrence of an acute or long-term condition.

[0084] Depending on the intended method of administration, the compounds according to the present invention can be incorporated into any pharmaceutically acceptable dosage form, such as liquids, for example, solutions, suspensions and emulsions, tablets, suppositories, pills, capsules, powders, etc., preferably into a dosage form suitable for single administration of an exact dosage amount, or into a sustained release dosage form for continuous controlled administration. Most preferably, it is a liquid.

[0085] Pharmaceutically administrable dosage forms of the liquid can be, for example, solutions, suspensions, or emulsions, and preferably, a solution or suspension form which is a suspension containing the compound of the present invention and any pharmaceutical adjuvant such as water, physiological saline, aqueous dextrose, glycerol, hyaluronic acid, ethanol, DMSO, etc. in a carrier. If desired, the pharmaceutical composition to be administered may also contain a small amount of non-toxic auxiliary substances such as wetting agents or emulsifying agents, pH buffering agents, etc. Typical examples of such auxiliaries are sodium acetate, sodium hyaluronate, sorbitan monolaurate, triethanolamine, and triethanolamine oleate.

[0086] The present invention also relates to a method for the treatment and / or prevention of RPE-related diseases, which includes administering a compound represented by formula (I), preferably a compound represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If) or (Ig), or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer, or, where applicable, corresponding diastereomer, to a patient having a retinal disease in an amount effective for the treatment of the retinal disease so as to be delivered to the patient's eye. The compounds represented by formula (Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) are defined in detail above.

Example

[0087] Cell culture Fetal RPE (iPSC-fRPE) cells derived from induced pluripotent stem cells were obtained from the University of California, Santa Barbara. (These cells) were generated from human fetal RPE cells, isolated, reprogrammed into iPSCs, and then differentiated and sorted with cell markers to recover RPE precursors. The vials were frozen with dry ice for transportation and stored at -80°C.

[0088] ​For phenotypic screening, iPSC-fRPE cells were thawed and cultured in Matrigel-coated flasks containing N1VA medium with a 1XMEM solution supplemented with 2.2 g / L sodium bicarbonate, 0.25 mg / mL taurine, 0.02 μg / mL hydrocortisone, 0.013 μg / mL triiodothyronine, 0.1 μg / mL lipoic acid, 1% MEM non-essential amino acids, 1% penicillin / streptomycin, 2% Neurocult SM1 supplement (adjuvant), and 1% N1 supplement (adjuvant). In the initial culture, thiazovibin was added to the medium at a concentration of 2 μM for the first 24 hours of culture, after which the medium was replaced with fresh N1VA medium and cultured for a further 3 days at 37°C and 5% CO2.

[0089] iPSC-fRPE cells were seeded in N1VA medium at a density of 10,000 cells per well in a Matrigel-coated 96-well plate, cultured for 24 hours, and treated with the test compound at a final concentration of 5 μM in 0.1% DMSO. The internal controls for each test plate were (a) 0.1% DMSO as a negative control and (b) 0.1% DMSO + 10 ng / ml human recombinant bFGF (stem cells) as a positive control.

[0090] To identify compounds that promote RPE pigmentation, cells were maintained for 32 days and treated with media containing the test or control compound according to a media change regimen (Figure 1). The degree of pigmentation was quantified by measuring absorbance at 510 nm using a Cytation5 imaging reader (BIOTEK). Finally, pigmentation values ​​were reported compared to the internal DMSO control in the plate.

[0091] To evaluate RPE cell proliferation, replicated RPE cells treated with a compound were fixed on day 5, stained with Hoechst 33342, and the number of viable cells was measured by fluorescence microscopy. The cell count was reported compared to the DMSO control inside the plate.

[0092] Preparation of the compound of the present invention The compound represented by formula (I) can be prepared by the methods described below, along with known synthetic methods in the field of organic chemistry, or modifications well known to those skilled in the art. The starting materials used herein are commercially available or can be prepared by conventional methods known in the art, such as those described in standard reference books such as "Outline of Organic Synthesis Methods, vol. I-X1N" (published by Wiley-Interscience, ISSN: 1934-4783). Preferred methods, but not limited to, are described below.

[0093] The schemes are representative of useful methods and supporting examples in the synthesis of the compounds of the present invention. In any case, they do not limit the scope of the present invention.

[0094] General methods - synthesis Method 1: Scheme 1: [ka] In the formula, R 11 , R 12 , R 13 And A are as described in formula (I). R7 is either a hydroxyl group or R7 is combined with a boron atom to form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane group.

[0095] The compound represented by general formula (I) (Scheme 1) can be prepared from the compounds represented by general formulas (XII) and (XIII) in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(O) and a base such as potassium carbonate, or under other Suzuki-Miyaura coupling reaction conditions known to chemists in the field of organic synthesis. The compound represented by general formula (XII) can be prepared by reacting the compound represented by general formula (X) with the carboxylic acid represented by general formula (XI) using a procedure known to chemists in the field. The crude intermediate can be dehydrated, for example, by heating in a solvent such as acetic acid.

[0096] Method 2: Scheme 2:

Chem.

[0097] The compound represented by general formula (I) (Scheme 2) can be prepared by reacting the compound represented by general formula (XIV) with the carboxylic acid represented by general formula (XI) using procedures known to those skilled in the art. The crude intermediate can be finally dehydrated using conditions such as heating in a solvent such as acetic acid.

[0098] Method 3: Scheme 3:

Chem.

[0099] The compound represented by general formula (XIV) (Scheme 3) can be prepared by reducing the nitro group of the compound represented by general formula (XVIII) using procedures known to those skilled in the art. The compound represented by general formula (XVIII) can be prepared from the aldehyde represented by general formula (XVI) by reacting it in the presence of a base such as potassium carbonate in the presence of a reagent such as 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (XVII). The compound represented by general formula (XVI) can be prepared by bubbling ammonia at room temperature into a solution in which the compound represented by general formula (XV) is dissolved in a solvent such as dichloromethane.

[0100] Method 4: Scheme 4:

Chem.

[0101] The compound represented by general formula (I) (Scheme 2) can be prepared by reacting the compound represented by general formula (XIV) with the aldehyde represented by general formula (XIX) in a solvent such as 1,4-dioxane, in the presence of an acid such as para-toluenesulfonic acid, at a high temperature.

[0102] Method 5: Scheme 5: [ka] In the formula, R 11 , R 12 , R 13 And A are as described in formula (I). R7 is either a hydroxyl group or R7 is combined with a boron atom to form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane group.

[0103] The compound represented by general formula (I) (Scheme 1) can be prepared from the compounds represented by general formulas (XXII) and (XIII) in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as potassium carbonate, or under other Suzuki-Miyaura coupling reaction conditions known to professional chemists involved in organic synthesis. The compound represented by general formula (XXII) can be prepared by treating the compound represented by general formula (XXI) in the presence of a dehydrating agent such as phosphoryl chloride. The compound represented by general formula (XXI) can be prepared by converting the compound represented by general formula (XI) to the corresponding acyl chloride using a reagent such as thionyl chloride, and then reacting them with the compound represented by general formula (XX).

[0104] Analysis method 1The 1H NMR spectrum was recorded at 300.0K in a 5mm outer diameter (od) tube [Wilmad NMR tube (Sigma-Aldrich), thin wall 5mm, length 7 inches] using DMSO-d6 / CD3OD / CDCl3 solution, and then analyzed using a Bruker Avance NMRS-400. 1 The H sample was collected at 400 MHz. The chemical shift (δ) is a relative value to CDCl3 (CDCl3 = 7.26 ppm), DMSO-d6 (DMSO-d6 = 2.5 ppm), and CD3OD (CD3OD = 3.3 ppm), and is expressed in ppm. The chemical shifts of CDCl3, DMSO-d6, and CD3OD are relative values ​​to tetramethylsilane (TMS = 0.00 ppm) and are expressed in ppm.

[0105] Analytical HPLC Analytical HPLC Method A: A Zorbax SB-C18 column (1.8 μm 4.6*15 mm, Rapid Resolution cartridge PN 821975-932) was used in an Agilent 1100 series LC / MSD system equipped with DAD / ELSD and Agilent LC / MSD VL (G1956A) and SL (G1956B) mass spectrometers, with mobile phase A: acetonitrile, 0.1% formic acid; mobile phase B: water (0.1% formic acid) in the following gradient. The following settings were used: 0 min - 100% B; 0.01 min - 100% B; 1.5 min - 0% B; 1.8 min - 0% B; 1.81 min - 100% B, and the procedure was performed at a flow rate of 3 ml / min.

[0106] Analytical HPLC Method B: A UPLC column, YMC Triart C18 (33 × 2.1 mm, 3 μm), was operated at room temperature at a flow rate of 1.0 mL / min. The sample was eluted with the following mobile phase: 98% [10 mM ammonium acetate in water] and 2% [acetonitrile] were retained for 0.75 minutes, then 90% [10 mM ammonium acetate in water] and 10% [acetonitrile] for 1.0 minute, and finally 2% [10 mM ammonium acetate in water] and 98% [acetonitrile] for 2.0 minutes.

[0107] Chiral analysis HPLC Chiral analysis by HPLC. Method A: Chiral chromatography using a Chiralpak IA (250*4.6, 5 μm) column; hexane-IPA-MeOH, 90-5-5 as mobile phase; flow 0.6 mL / min.

[0108] Preparative HPLC Preparative HPLC Method A: Agilent 1260 Infinity system with DAD and mass detector; Waters SunFire C18 OBD Prep Column, 100A, 5μm, 19mm*100mm; SunFire C18 Prep Guard Cartridge, 100A, 10μm, 19mm*10mm; 30-85% H2O-methanol, 0-5 min, flow rate 30 mL / min).

[0109] Chiral separation method Chiral separation method A: Chiral chromatography using a Chiralpak IA-II (250*20, 5mkm) column; hexane-IPA-MeOH, 80-10-10 as mobile phase; flow rate 12 mL / min.

[0110] Chiral separation method B: SFC chiral chromatography (Reflect C-amylose A (250×30mm) 5μ column, mobile phase CO2- (0.1% ammonia in MeOH), 35%-65%, P=110 bar, flow 35 g / min, T=35℃).

[0111] General synthesis procedure Synthesis procedure A: [ka] To a solution of carboxylic acid (1.22 mmol) in DMF (5 mL), ethylbis(propan-2-yl)amine (1.44 mmol, 1.18 equivalents) and HATU (1.34 mmol) were added. The resulting mixture was stirred at room temperature for 20 minutes, followed by the addition of 4-(1,3-oxazole-5-yl)benzene-1,2-diamine (1.34 mmol). The reaction mixture was stirred at room temperature overnight. The suspension was then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 ml) and washed with aqueous NaHCO3 solution (2 × 20 ml) and brine (2 × 10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in acetic acid (5 ml), and the mixture was stirred at 60°C overnight. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 ml), basicized with aqueous NaHCO3 solution, and salt The solution was washed with water (brine) (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC using a SunFire C18 100*19 mm 5 μm column (with 20-50% water-MeCN as the eluent for 0-5 minutes) and a flow rate of 30 ml / min.

[0112] Synthesis procedure B: [ka] Aldehyde (1.43 mmol) and 4-(1,3-oxazole-5-yl)benzene-1,2-diamine (1.43 mmol) were mixed in 1,4-dioxane (5 ml). The resulting mixture was stirred for 5 minutes, followed by the addition of 4-methylbenzene-1-sulfonic acid (0.29 mmol). The reaction mixture was stirred overnight at 100°C. The mixture was then cooled to room temperature, evaporated to dryness, and purified by flash chromatography.

[0113] Synthesis of intermediates Preparation of 4-amino-3-nitrobenzaldehyde [ka] Ammonia was bubbling into a stirred solution of 4-fluoro-3-nitrobenzaldehyde (50.0 g, 295.67 mmol) in dichloromethane (1200 mL) at 0°C for 30 minutes. The mixture was stirred at room temperature for a further 3 hours and then concentrated to obtain 4-amino-3-nitrobenzaldehyde (45.1 g, 271.47 mmol, yield 91.8%).

[0114] Preparation of 2-nitro-4-(1,3-oxazol-5-yl)aniline [ka] A methanol (800 ml) solution of 4-amino-3-nitrobenzaldehyde (45.1 g, 271.47 mmol) was treated with 1-isocyanomethanesulfonyl-4-methylbenzene (79.5 g, 407.2 mmol) and potassium carbonate (39.39 g, 285.04 mmol). The reaction mixture was heated under reflux for 90 minutes. The cooled solution was then concentrated and treated with water (750 ml). The mixture was extracted with ethyl acetate (4 × 250 ml). The combined organic layers were washed with brine and water, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by flash chromatography to obtain 2-nitro-4-(1,3-oxazole-5-yl)aniline (10.1 g, 49.23 mmol, yield 18.1%).

[0115] Preparation of 4-(1,3-oxazol-5-yl)benzene-1,2-diamine [ka] Pd(OH)2 (410.75 mg, 2.92 mmol) (20% w / w) was added to a solution of 2-nitro-5-(1,3-oxazole-5-yl)aniline (3.0 g, 14.62 mmol) in THF (50 mL). The resulting mixture was stirred overnight under a hydrogen atmosphere at room temperature and atmospheric pressure. The catalyst was removed by filtration, and the solvent was evaporated to obtain 4-(1,3-oxazole-5-yl)benzene-1,2-diamine (2.1 g, 11.99 mmol, yield 82%).

[0116] Preparation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(propan-2-yl)silyl]-1,3-oxazole [ka] To a 60 ml stirred solution of 2-[tris(propan-2-yl)silyl]-1,3-oxazole (2.07 g, 9.18 mmol) in dry THF, a 2.5 molar solution of n-butyllithium (11.0 mmol, 4.4 mL, 1.2 equivalents) was added dropwise under argon at -78°C. The resulting mixture was stirred at -78°C for 1 hour, and then a solution of tris(propan-2-yl)borate (3.45 g, 18.37 mmol, 4.21 mL, 2.0 equivalents) in 10 ml of THF was added dropwise at the same temperature. The reaction mixture was stirred at -78°C for 2 hours, and then stirred overnight at room temperature. Next, 2,3-dimethylbutane-2,3-diol (1.09 g, 9.18 mmol) and acetic acid (827.29 mg, 13.78 mmol, 800.0 μl, 1.5 equivalents) were added. The resulting mixture was stirred at room temperature for 2 hours. The suspension was then evaporated, and the residue was diluted with water. The product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated to obtain 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(propan-2-yl)silyl]-1,3-oxazole (3.0 g, purity 85.0%, 7.26 mmol, yield 79%).

[0117] Preparation of N-(5-bromo-2-hydroxyphenyl)chroman-3-carboxamide [ka] Chroman-3-carboxylic acid (2 g, 11.23 mmol) was dissolved in SOCl2 (2 mL, 28.09 mmol) and stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was then concentrated under vacuum, diluted with dichloromethane (10 mL) under a nitrogen atmosphere, and the evaporation process was repeated twice. In a round-bottom flask, 2-amino-4-bromophenol (2.3 g, 12.36 mmol) in dichloromethane (6 mL) was added together with pyridine (1 mL, 12.36 mmol). The mixture was stirred at room temperature for 15 minutes. The newly prepared chroman-3-carboxylic acid was then used. In a second round-bottom flask containing n-3-carbonyl chloride (2), dichloromethane (4 mL) was added at room temperature, followed by the above mixture containing 2-amino-4-bromophenol (1) in the dichloromethane. The combined reaction mixture was stirred at room temperature for 18 hours. The crude reaction mixture was extracted with dichloromethane and washed with water. The combined organic portion was dried over sodium sulfate, filtered, and evaporated under vacuum. The crude product was purified by amine silica gel column chromatography to obtain N-(5-bromo-2-hydroxyphenyl)chroman-3-carboxamide (3) (1.3 g, 33%).

[0118] Preparation of 5-bromo-2-(croman-3-yl)benzo[d]oxazole [ka] To a stirred solution of N-(5-bromo-2-hydroxyphenyl)chroman-3-carboxamide (2.5 g, 7.18 mmol) in 1,4-dioxane (2 mL), POCl3 (8 mL, 86.2 mmol) was added. The reaction mixture was sealed and refluxed at 110 °C for 2 hours. The reaction mixture was then concentrated and purified by flash chromatography to obtain 5-bromo-2-(chroman-3-yl)benzo[d]oxazole (800 mg, 33%).

[0119] Compound (1): "First" (R)-5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole [ka] To a solution of 3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (5.0 g, 28.07 mmol) in DMF (200 mL), DIPEA (4.28 g, 33.13 mmol, 5.77 ml, 1.18 equivalents) and HATU (11.74 g, 30.88 mmol) were added. The resulting mixture was stirred at room temperature for 20 minutes, followed by the addition of 4-(1,3-oxazole-5-yl)benzene-1,2-diamine (5.41 g, 30.88 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, diluted with ethyl acetate (250 mL), washed with aqueous NaHCO3 solution (2 × 80 mL) and brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Without further purification, the resulting crude product was dissolved in acetic acid (100 mL), and the mixture was stirred overnight at 60°C. The resulting solution was evaporated under reduced pressure, diluted with ethyl acetate (250 mL), basicized with aqueous NaHCO3 solution, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using preparative HPLC method A to obtain 5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole. By chiral separation of 5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole using chiral separation method A, compound (1) (603.3 mg) characterized at a retention time of 19.7 minutes was obtained. [α] D 25 = -12.00 (c=0.25, MeOH). [M+H + ]m / z:318.2 1 H NMR(DMSO-d6, 400MHz):δ(ppm)3.23(m,2H),3.59(m,1H),4.27(t,1H),4.59(d,1H),6.80(d,1H),6.88(t,1H) ,7.10(t,1H),7.17(d,1H),7.56(d,1H),7.62(m,2H),7.86(s,1H),8.41(s,1H),12.57(s,1H). The structure was confirmed using X-rays.

[0120] Compound (2): "Second" (S)-5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole [ka] To a solution of 3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (5.0 g, 28.07 mmol) in DMF (200 mL), DIPEA (4.28 g, 33.13 mmol, 5.77 ml, 1.18 equivalents) and HATU (11.74 g, 30.88 mmol) were added. The resulting mixture was stirred at room temperature for 20 minutes, followed by the addition of 4-(1,3-oxazole-5-yl)benzene-1,2-diamine (5.41 g, 30.88 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure, diluted with ethyl acetate (250 mL), washed with aqueous NaHCO3 solution (2 × 80 mL) and brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Without further purification, the resulting crude product was dissolved in acetic acid (100 mL), and the mixture was stirred overnight at 60°C. The resulting solution was evaporated under reduced pressure, diluted with ethyl acetate (250 mL), basicized with aqueous NaHCO3 solution, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using preparative HPLC method A to obtain 5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole. By chiral separation of 5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole using chiral separation method A, compound (2) (607.5 mg) characterized at a retention time of 27.4 minutes was obtained. [α] D 25 = +13.56 (c=0.25, MeOH). [M+H + ]m / z:318.2 1H NMR (DMSO-d6, 400MHz): δ(ppm)3.25(m,2H),3.59(m,1H),4.27(t,1H),4.59(m,1H),6.80(d,1H) ),6.88(t,1H),7.10(t,1H),7.17(d,1H),7.61(m,3H),7.86(d,1H),8.41(s,1H),12.63(s,1H).

[0121] Compound (3): 2-(2,3-dihydro-1-benzofuran-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] 2,3-dihydro-1-benzofuran-2-carboxylic acid (0.2g) was used in combination with synthetic procedure A to produce 2-(2,3-dihydro-1-benzofuran-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (63mg, yield 1 4.0% was obtained. Analytical HPLC Method A. [M+H + ]m / z:304.2;Rt=2.35 min

[0122] Compound (4): 2-(7-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] 7-Fluoro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (0.2 g) was used in combination with synthetic procedure A to obtain 2-(7-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (68 mg, yield 15.1%). Analytical HPLC Method A. [M+H + ]m / z:336.2;Rt=2.35 min

[0123] Compound (5): 2-(6-chloro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] 6-fluoro-3,4-dihydro-2H-1-benzopyran-3-carbonyl chloride (0.17 g) was used in combination with synthetic procedure A to obtain 2-(6-chloro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (70 mg, yield 15.8%). Analytical HPLC Method A. [M+H + ]m / z:352.0;Rt=2.54 mins

[0124] Compound (6): 2-(6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] 6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (0.2 g) was used in combination with synthetic procedure A to obtain 2-(6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (39 mg, yield 8.6%). Analytical HPLC Method A. [M+H + ]m / z:354.2;Rt=2.47 mins

[0125] Compound (7): 2-(2,3-dihydro-1H-inden-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] 2,3-dihydro-1H-inden-2-carbaldehyde (0.098 g) was used in combination with synthetic procedure B to obtain 2-(2,3-dihydro-1H-inden-2-yl)-6-(1,3-oxazole-5-yl)-1H-1,3-benzodiazole (30 mg, yield 10%). Analytical HPLC Method A. [M+H + ]m / z:302.2;Rt=1.94 min

[0126] Compound (8): 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] Step 1: 6-bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-1H-1,3-benzodiazole To a solution of 3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (3.95 g, 22.17 mmol) in DMF (100 mL), ethylbis(propan-2-yl)amine (3.38 g, 26.16 mmol, 4.56 ml, 1.18 equivalents) and HATU (9.27 g, 24.39 mmol) were added. The resulting mixture was stirred for 20 minutes, followed by the addition of 5-bromo-3-fluorobenzene-1,2-diamine (5.0 g, 24.39 mmol). The reaction mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure, diluted with ethyl acetate (250 mL), washed with aqueous NaHCO3 solution (2 × 75 mL) and brine (2 × 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Without further purification, the crude product was dissolved in acetic acid (100 mL), and the mixture was stirred overnight at 60°C. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (250 mL), basicized with aqueous NaHCO3 solution, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain 6-bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-1H-1,3-benzodiazole (4.2 g, 12.1 mmol, yield 54.6%).

[0127] Step 2: 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-2-[tris(propan-2-yl)silyl]-1,3-oxazol-5-yl-1H-1,3-benzodiazole 5-bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-1H-1,3-benzodiazole (2.72 g, 7.83 mmol) is mixed with 40 mL of dry dimethoxyethane and 13.5 mL of water under argon. ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[tris(propan-2-yl)silyl]-1,3-oxazole (5.5 g, 15.65 mmol), tetrakis(triphenylphosphine)palladium (0) (907.54 mg, 782.63 μmol), and potassium carbonate (3.24 g, 23.48 mmol) were added. The reaction mixture was stirred at room temperature for 20 minutes, then at 80°C overnight. The mixture was evaporated to dryness and purified by flash chromatography to obtain 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-2-[tris(propan-2-yl)silyl]-1,3-oxazole-5-yl-1H-1,3-benzodiazole (2.9 g, 5.9 mmol, yield 75.4%).

[0128] Step 3: 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole To a 1.5 mL THF-stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-2-[tris(propan-2-yl)silyl]-1,3-oxazole-5-yl-1H-1,3-benzodiazole (2.9 g, 5.9 mmol) was added a THF solution of tetrabutylammonium fluoride (7.71 g, 29.49 mmol, 8.54 ml, 5.0 equivalents). The reaction mixture was stirred at room temperature overnight, evaporated, and diluted with water. The solution was extracted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated, and purified by column chromatography (SiO2, CHCl3-MeCN as mobile phase) to obtain 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (1.3 g, 3.88 mmol, yield 65.7%). Analytical HPLC Method A. [M+H + ]m / z:336.2;Rt=2.76 mins

[0129] Compound (9): 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-5-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole [ka] 4-bromo-3-fluorobenzene-1,2-diamine (1 g) was used in the same three-step synthesis procedure and molar ratio as compound 12 to obtain 6-chloro-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-5-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (54 mg). Analytical HPLC Method A. [M+H + ]m / z:336.0;Rt=2.66 mins

[0130] Compound (10): "Second" 2-(chroman-3-yl)-6-(oxazol-5-yl)benzo[d]oxazole [ka] To a 15 mL stirred solution of 6-bromo-2-(chroman-3-yl)-1H-benzo[d]imidazole (400 mg, 1.21 mmol) mixed with 1,4-dioxane and water (4:1), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (261 mg, 1.33 mmol) and Na2CO3 (258 mg, 2.43 mmol) were added in a sealed tube at room temperature. The resulting reaction mixture was degassed at room temperature for 20 minutes, followed by the addition of PdCl2(dppf)-dichloromethane complex (99 mg, 0.12 mmol), and the mixture was stirred at 100°C for 6 hours. The reaction mixture was filtered and purified by flash chromatography to obtain racemic 5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole (170 mg, 46%). Chiral separation of 5-(2-(croman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole using chiral separation method B yielded a "second" 2-(croman-3-yl)-6-(oxazole-5-yl)benzo[d]oxazole characterized by a retention time of 11.3 minutes (120 mg). Analytical HPLC Method B. [M+H + ]m / z:319.2;Rt=1.87 mins

[0131] Compound (11): "First" 2-(chroman-3-yl)-6-(oxazol-5-yl)benzo[d]oxazole [ka] To a 15 mL stirred solution of 6-bromo-2-(chroman-3-yl)-1H-benzo[d]imidazole (400 mg, 1.21 mmol) mixed with 1,4-dioxane and water (4:1), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (261 mg, 1.33 mmol) and Na2CO3 (258 mg, 2.43 mmol) were added in a sealed tube at room temperature. The resulting reaction mixture was degassed at room temperature for 20 minutes, followed by the addition of PdCl2(dppf)-dichloromethane complex (99 mg, 0.12 mmol), and the mixture was stirred at 100°C for 6 hours. The reaction mixture was filtered and purified by flash chromatography to obtain racemic 5-(2-(chroman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole (170 mg, 46%).

[0132] Chiral separation of 5-(2-(croman-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole using chiral separation method B yielded the "first" 2-(croman-3-yl)-6-(oxazole-5-yl)benzo[d]oxazole characterized by a retention time of 10.1 minutes (102 mg). Analytical HPLC Method B. [M+H + ]m / z:319.2;Rt=1.87 mins [Prior art documents] [Patent Documents]

[0133] [Patent Document 1] European Patent No. 2 302 076 (EP 2 302 076) [Patent Document 2] U.S. Patent No. 9,815,819 [Patent Document 3] International Publication No. 2015 / 138628 (WO 2015 / 138628) [Patent Document 4] Australian Patent No. 2019 / 226198 (AU 2019 / 226198) [Patent Document 5] Chinese Patent No. 103656742 (CN 103656742) [Patent Document 6] Russian Patent No. 2628697 (RU 2628697) [Patent Document 7] PCT / US19 / 68768 specification

Claims

1. Compounds represented by formula (I), or pharmaceutically acceptable salts thereof, racemic mixtures, corresponding enantiomers, or, where applicable, corresponding diastereomers: 【Chemistry 1】 [In the formula, X is either NH or O, R １１ , R １２ and R １３ These are independently selected from the group consisting of hydrogen atoms and fluorine atoms. A is selected from the group consisting of residues of formulas (II), (IV), and (V): 【Chemistry 2】 (In the formula, "*" indicates a bond point to the rest of the molecule. R ２ 、 R ３ 、 R ４ 、 R5, R ２ ＩＩ 、 R ３ ＩＩ 、 R ４ ＩＩ 、 R ５ ＩＩ 、 R ２ ＩＩＩ 、 R ３ ＩＩＩ 、 R ４ ＩＩＩ and R ５ III is independently selected from the group consisting of a hydrogen atom, a fluorine atom, and a chlorine atom.)]]。

2. The compound according to claim 1, wherein the ring-positioned chiral centers of the residues of formulas (II), (IV), and (V) in the compound represented by formula (I) have the stereoconfiguration shown in the compound of formula (Ii) below. 【Transformation 3】 [In the formula, X, R 11 , R 12 , R 13 , R ２ , R ３ , R ４ , R ５ , R ２ ＩＩ , R ３ ＩＩ , R ４ ＩＩ , R ５ ＩＩ , R ２ ＩＩＩ , R ３ ＩＩＩ , R ４ ＩＩＩ and R ５ III has the same definition as above.

3. The compound according to claim 1, wherein the ring-position chiral center* of the residue of formula (II), (IV), or (V) in the compound represented by formula (I) has the stereoconfiguration shown in the compound of formula (III) below. 【Chemistry 4】 [In the formula, X, R 11 , R 12 , R 13 , R ２ , R ３ , R ４ , R ５ , R ２ ＩＩ , R ３ ＩＩ , R ４ ＩＩ , R ５ ＩＩ , R ２ ＩＩＩ , R ３ ＩＩＩ , R ４ ＩＩＩ and R ５ III has the same definition as above.

4. The compound according to claim 1, wherein X is O.

5. The compound according to claim 1, wherein X is NH.

6. The compound according to claim 1, wherein residue A is unsubstituted.

7. The compound according to claim 1, wherein residue A is monosubstituted.

8. Residue A is a single substitution, R ２ , R ３ , R ４ , R ５ , R ２ ＩＩ , R ３ ＩＩ , R ４ ＩＩ , R ５ ＩＩ , R ２ ＩＩＩ , R ３ ＩＩＩ , R ４ ＩＩＩ and R ５ The compound according to claim 7, wherein one of III is selected from the group consisting of chlorine atoms and fluorine atoms, and the remaining residues are hydrogen atoms.

9. The compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11. Table 1

10. Compounds of formula (I) or pharmaceutically acceptable salts thereof, racemic mixtures, and corresponding enantiomers for use in the treatment and / or prevention of diseases involving the retinal pigment epithelium as active ingredients. Alternatively, if applicable, the corresponding diastereomer: 【Transformation 5】 [In the formula, X is either NH or O, R １１ , R １２ and R １３ These are independently selected from the group consisting of hydrogen atoms and fluorine atoms. A is selected from the group consisting of residues of formulas (II), (IV), and (V): 【Transformation 6】 (In the formula, "*" indicates a bond point to the rest of the molecule. R ２ 、R ３ 、R ４ 、R ５ 、R ２ ＩＩ 、R ３ ＩＩ 、R ４ ＩＩ 、R ５ ＩＩ 、R ２ ＩＩＩ 、R ３ ＩＩＩ 、R ４ ＩＩＩ and R ５ III is independently selected from the group consisting of a hydrogen atom, a fluorine atom, and a chlorine atom.)]]

11. The compound according to claim 10, wherein the compound of formula (I) is selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11. Table 2

12. The compound according to claim 10, wherein retinal cells are regenerated through proliferation and / or differentiation of retinal pigment epithelial cells.

13. The compound according to claim 10, wherein the retinal disease is selected from the group consisting of diseases that lead to atrophy, degeneration, or death of the retinal pigment epithelium.

14. The compound according to claim 13, wherein the retinal disease is selected from the group consisting of early age-related macular degeneration, dry age-related macular degeneration, geographic atrophy (GA), and wet age-related macular degeneration.

15. The compound according to claim 14, wherein the retinal disease is age-related macular degeneration in dry skin.

16. The aforementioned retinal diseases include congenital choroidal absence, Best's disease, autosomal recessive bestrofinopathy (ARB), cerebral gynostosis, North Carolina macular dystrophy, central annular choroidal dystrophy (CACD), Sausby's macular dystrophy, familial dominant drusen, cuticle or basement membrane drusen, retinopathy of prematurity, myopic degeneration, polypoidal choroidal vasculopathy (PCV), central serous retinopathy, retinal pigment streaks, retinal detachment, retinal detachment (tear), Vogt-Koyanagi-Harada disease (VKH), acute posterior multiple macular pigment epitheliopathy (APPPE), persistent placoid maculopathy (PPM), retinal retinal detachment (tear), and retinal detachment (tear). A compound according to claim 10, selected from the group consisting of trespracoid chorioretinopathy (RPC), serpentinoid choroiditis, serpentinoid choroiditis (multifocal serpidinoid choroiditis), multiple disappearing white spot syndrome (MEWDS) or birdshot uveitis (white spot chorioretinitis), toxoplasmosis, toxocariasis, rubella, Behçet's disease, choroidal hemangioma, trauma, choroidal rupture, idiopathic retinitis-vasculitis-aneurysm and optic neuroretinitis (IRVAN), sympathetic ophthalmitis, postoperative inflammation, or non-arteritic ischemic optic neuropathy, and retinal degeneration associated with systemic diseases such as diabetes mellitus, sickle cell disease or radiation retinopathy.

17. A pharmaceutical composition for use in the treatment and / or prevention of diseases affecting the retinal pigment epithelium, comprising as a therapeutic active substance a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, a corresponding enantiomer, or, where applicable, a corresponding diastereomer, and a pharmaceutically acceptable carrier and / or adjuvant: 【Transformation 7】 [In the formula, X is either NH or O, R １１ , R １２ and R １３ These are independently selected from the group consisting of hydrogen atoms and fluorine atoms. A is selected from the group consisting of residues of formulas (II), (IV), and (V): 【Transformation 8】 (In the formula, "*" indicates a bond point to the rest of the molecule. R ２ 、R ３ 、R ４ 、R ５ 、R ２ ＩＩ 、R ３ ＩＩ 、R ４ ＩＩ 、R ５ ＩＩ 、R ２ ＩＩＩ 、R ３ ＩＩＩ , R ４ ＩＩＩ and R ５ III is independently selected from the group consisting of hydrogen atoms, fluorine atoms, and chlorine atoms.

18. The pharmaceutical composition according to claim 17, which is suitable for intraocular injection or topical ophthalmic application.

19. Furthermore, the pharmaceutical composition according to claim 17, comprising one or more additional therapeutic agents.

20. The pharmaceutical composition according to claim 17, which provides release control properties.

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