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

Abstract

A method for treating and / or preventing diseases involving the retinal pigment epithelium, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, the corresponding enantiomer, or, if applicable, the corresponding diastereomer, wherein: X is NH or O, R 11 R 12 and R 13 Independently selected groups consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methyl, and difluoromethoxy groups; Group A consisting of residues of formulas (II)-(VII) or (VIII), where "*" indicates a point connected 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 VI R6 is independently selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethoxy, and R6 is selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, trifluoromethyl and 2,2,2-trifluoroethyl.

Description

[0001] This invention relates to novel compounds and their use as therapeutically active substances in the treatment and / or prevention of diseases involving the retinal pigment epithelium, particularly in the treatment and / or prevention of diseases leading to atrophy, degeneration, or death of the retinal pigment epithelium, which may also lead to atrophy or loss of photoreceptors and / or retinal neovascularization.

[0002] A significant family of diseases involving degeneration and death of the retinal pigment epithelium (RPE) is macular degeneration. Macular degeneration is characterized by progressive loss of central vision associated with abnormalities in the Bruch's membrane, choroid, neuroretina, and / or retinal pigment epithelium. The macula describes the central region of the retina, with an approximate diameter of 0.3 to 0.5 cm. Due to its high density of cone cells, the macula provides detailed vision for activities such as reading, driving, or recognizing faces.

[0003] Age-related macular degeneration (AMD) is the most common form of macular degeneration, 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 a leading cause of irreversible vision loss affecting approximately 2% of individuals in the developed world. The prevalence of AMD increases with age, and its etiology is multifactorial.

[0004] The key contributors to the disease and its progression are the loss of functional RPE cells and changes in their basement membrane (Bruch's membrane). The RPE is a continuous monolayer of cells located between the photoreceptors and the choroid, supplying blood to the retina. As RPE cells nourish the highly metabolic photoreceptors by providing energy and growth factors, removing waste, and recycling essential compounds for the visual cycle, the loss of the RPE ultimately leads to photoreceptor failure and loss.

[0005] AMD has two main clinical manifestations described as the dry or atrophic form (hereinafter referred to as dry AMD) and the wet or neovascular form (hereinafter referred to as wet AMD). Dry AMD is associated with atrophic cell death in the central retina or macula. Approximately 10-20% of these patients with dry AMD further develop into the second form, known as wet or neovascular AMD. In these late stages of AMD, the atrophy of the RPE (geographic atrophy) and / or the development of new blood vessels originating from the choroidal vessels (neovascularization) further lead to photoreceptor death and central vision loss. This loss of central vision, which is crucial for reading, facial recognition, and performing many daily tasks, essentially isolates the patient from the world.

[0006] There are currently no approved treatments for dry AMD or its advanced form (called geographic atrophy (GA)), and many patients with neovascularized AMD, despite current treatment with anti-VEGF agents (e.g. Treatment is available, but remains legally ineffective. Pharmacological approaches to treating vision loss in dry AMD caused by RPE damage differ, but they all involve controlling the mechanisms believed to initially cause the damage (e.g., the complement system), rather than reversing the damage caused by the loss of RPE cells. Alternative approaches under investigation involve the transplantation of induced pluripotent stem cells or mature RPE cells.

[0007] Drusen are tiny yellow or white accumulations of extracellular material that build up between the Bruch's membrane and the retinal pigment epithelium of the eye. The presence of drusen is a hallmark of age-related macular degeneration (AMD). Recent studies of drusen in the etiology of early and late forms of AMD suggest the role of inflammation and other immune-mediated processes, particularly complement activation. EP2302 076 discloses the accumulation of factor H protein (HF1) (a major inhibitor of the complement bypass pathway) within drusen, locally synthesized by the retinal pigment epithelium, and thus provides a drug for effectively reducing the amount of variant factor H or the expression level of the gene encoding factor H in patients with AMD, said drug reducing the amount of variant factor H or the expression level of the gene encoding factor H.

[0008] US 9'815'819B2 relates to compounds whose regulation and preferred inhibition or activation of the complement bypass pathway are methods of treating or preventing AMD.

[0009] WO 2015 / 138628 relates to an AAV vector construct that can be used to deliver anti-inflammatory peptides to the retina of AMD patients and optimizes this delivery.

[0010] AU 2019 / 226198 discloses a method for producing substantially purified cultures of RPE cells suitable for transplantation.

[0011] CN 103656742 relates to a method for preparing a functionalized retinal pigment epithelial cell graft for transplantation into the retina of AMD patients.

[0012] RU 2628697 discloses a process for generating a cell layer from retinal pigment epithelial cells in a convenient and stable manner, which does not use an artificial membrane and has a high transplantation rate when transplanted into the eye.

[0013] PCT / US19 / 68768 describes the use of small molecules to trigger endogenous regeneration of photoreceptors in retinal stem cells and progenitor cells derived from retinal dystrophy (i.e., retinitis). In contrast, this invention relates to the treatment and / or prevention of RPE-related eye diseases by stimulating pigment formation and / or growth in mammalian RPE cells.

[0014] In the case of wet AMD, significant progress has been made in developing drugs that antagonize the effects of vascular endothelial growth factor (anti-VEGF). However, these treatments do not address damage to the RPE layer, but only inhibit angiogenesis. Moreover, they are not curative, but merely effectively maintain the current state of the disease.

[0015] Therefore, the problem of the present invention is to provide a therapeutic agent for treating and / or preventing diseases associated with RPE, and particularly for treating AMD.

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

[0017] It has been shown that the novel compounds of formula (I) stimulate pigment formation and / or growth in mammalian RPE cells. This stimulation of pigment formation and / or growth in endogenous RPE cells allows for controlled repair and regeneration of the retina. Therefore, new healthy RPE cells can be endogenously generated through the compounds of the present invention, thereby preventing vision loss and / or restoring vision. Consequently, the compounds of formula (I) can be used as therapeutically active substances for treating and / or preventing diseases that lead to atrophy, death, or degeneration of the retinal pigment epithelium, i.e., as pharmaceuticals.

[0018] In this context, the term "RPE cell" encompasses any form of proliferative and non-proliferative retinal pigment epithelial cells that support or contribute to the further differentiation of the eye into a functional tissue. RPE cells are smooth, pigmented, and hexagonal in shape. Healthy and fully differentiated RPE cells construct melanosomes, which contain the light-absorbing pigment melanin. Therefore, compounds that promote the differentiation of healthy and functional RPE cells result in the presence of pigmentation.

[0019] The term "growth of mammalian RPE cells" refers to the controlled promotion of RPE cell proliferation and the corresponding increase in the number of RPE cells.

[0020] The term "prevention" refers to the prevention or reduction of signs and symptoms associated with RPE-related diseases, particularly macular degeneration (AMD) that causes vision loss in subjects at risk of developing the disease. In these subjects, precipitating factors may be retained, but the signs and / or symptoms of the disease may not occur or take a significantly longer time to develop. Furthermore, it includes preventing further deterioration of symptoms once the disease has occurred.

[0021] Therefore, this invention relates to compounds of formula (I).

[0022]

[0023] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0024] in:

[0025] X is NH or O.

[0026] R 11 R 12 and R 13 The group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methyl, and difluoromethoxy is selected independently.

[0027] Group A consists of residues of the free form (II), (III), (IV), (V), (VI), (VII), or (VIII).

[0028]

[0029] in,

[0030] The asterisk (*) indicates a point that connects to the rest of the molecule, and

[0031] 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 The residue R6 is independently selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethoxy, and in the residue of formula (VI), R6 is selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, trifluoromethyl and 2,2,2-trifluoroethyl.

[0032] The term "pharmaceutically acceptable salt" refers to a therapeutically active, non-toxic acidic salt form that the compounds according to the invention can form.

[0033] In one embodiment of the invention, the asymmetric center at the ring position* of the residues of formulas (II), (III), (IV), and (V), or the asymmetric center on the side chain of formula (VI), has the following configuration, namely, the compound of formula (Ii).

[0034]

[0035] Furthermore, group A consists of residues of free formula (II), (III), (IV), (V), or (VI).

[0036]

[0037] Furthermore, in the case of residues of formula (VII), the chiral center in the compound according to the invention preferably has the following configuration:

[0038]

[0039] And 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 R6 has the same definition as above.

[0040] In another embodiment of the invention, the asymmetric center at the ring position* of the residues of formula (II), (III), (IV) or (V) or the asymmetric center on the side chain of formula VI is in the configuration described below, i.e., the compound of formula (II)

[0041]

[0042] Furthermore, group A consists of residues of free formula (II), (III), (IV), (V), or (VI).

[0043]

[0044] Furthermore, in the case of residues of formula (VII), the chiral center in the compound according to the invention preferably has the following configuration:

[0045]

[0046] And 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 R6 has the same definition as above.

[0047] Preferably, in the compound of formula (I), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one residue in the group consisting of chlorine and fluorine is selected, while the other residues are hydrogen. This means that, for example, R 11 It is fluorine and R 12 and R 13 They're all hydrogen.

[0048] 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 II R5 IIR2 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 R6 has the same definition as above.

[0049] In another embodiment of the 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 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 R6 has the same definition as above.

[0050] Residue A is preferably unsubstituted or monosubstituted. The term unsubstituted means all R2, R3, R4, R5, and R6. I R3 I R4 I R5 I R2 II R3 II R4 II R5 II R2 III R3 III R4 III R5 III R2IV R3 IV R4 IV R5 IV R2 V R3 V R4 V R5 V R2 VI R3 VI R4 VI and R5 VI It is hydrogen. When residue A is monosubstituted, 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 One of the residues is preferably selected from the group consisting of fluorine and chlorine, and the other residues are hydrogen. The term monosubstituted does not refer to R6 in the residues of formula (VI). Therefore, in the residues of formula (VI), the term monosubstituted refers to R2. IV R3 IV R4 IV R5 IV One of them is different from hydrogen and R6 is hydrogen, a straight-chain or branched alkyl group having 1 to 3 carbon atoms, trifluoromethyl or 2,2,2-trifluoroethyl.

[0051] In the residues of formula (VI), R6 is preferably hydrogen or a straight-chain or branched alkyl group having 1 to 3 carbon atoms, and most preferably methyl.

[0052] One embodiment of the present invention relates to a compound of formula (Ia).

[0053]

[0054] Or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer, or (if applicable) corresponding diastereomer, wherein:

[0055] X, R 11 R 12 R 13 R1, R2, R3, R4, and R5 have the same definitions as above.

[0056] Preferably, in the compound of formula (Ia), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0057] In one embodiment of the invention, in the compound of formula (Ia), X is O and R2, R3, R4, R5 have the same definitions as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0058] In another embodiment of the invention, in the compound of formula (Ia), X is NH and R2, R3, R4, R5 have the same definitions as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0059] Another embodiment of the present invention relates to a compound of formula (Ib).

[0060]

[0061] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0062] in:

[0063] X, R 11 R 12 R 13 R2 I R3 I R4 I and R5 I It has the same definition as above.

[0064] Preferably, in the compound of formula (Ib), residue R 11 R 12 and R 13It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0065] In one embodiment of the invention, in the compound of formula (Ib), X is O and R2 I R3 I R4 I R5 I It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0066] In another embodiment of the invention, in the compound of formula (Ib), X is NH and R2 I R3 I R4 I R5 I It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0067] Another embodiment of the present invention relates to a compound of formula (Ic).

[0068]

[0069] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0070] in:

[0071] X, R 11 R 12 R 13 R2 II R3 II R4 II and R5 II It has the same definition as above.

[0072] Preferably, in the compound of formula (Ic), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0073] In one embodiment of the invention, in the compound of formula (Ic), X is O and R2 II R3 II R4 II R5 II It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0074] In another embodiment of the invention, in the compound of formula (Ic), X is NH and R2 II R3 II R4 II R5 II It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0075] Another embodiment of the present invention relates to a compound of formula (Id).

[0076]

[0077] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0078] in:

[0079] X, R 11 R 12 R 13 R2 III R3 III R4 III R5 III It has the same definition as above.

[0080] Preferably, in the compound of formula (Id), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0081] In one embodiment of the invention, in the compound of formula (Id), X is O and R2 III R3 III R4 III R5III It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0082] In another embodiment of the invention, in the compound of formula (Id), X is NH and R2 III R3 III R4 III R5 III It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0083] Another embodiment of the present invention relates to compounds of formula (Ie).

[0084]

[0085] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0086] in:

[0087] X, R 11 R 12 R 13 R2 IV R3 IV R4 IV R5 IV R6 has the same definition as above.

[0088] Preferably, in the compound of formula (Ie), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0089] In one embodiment of the invention, in the compound of formula (Ie), X is O and R2 IV R3 IV R4 IV R5 IV R6 has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0090] In another embodiment of the invention, in the compound of formula (Ie), X is NH and R2 IV R3 IVR4 IV R5 IV R6 has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0091] Another embodiment of the present invention relates to compounds of formula (If).

[0092]

[0093] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0094] in:

[0095] X, R 11 R 12 R 13 R2 V R3 V R4 V and R5 V It has the same definition as above.

[0096] Preferably, in the compound of formula (If), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0097] In one embodiment of the invention, in the compound of formula (If), X is O and R2 V R3 V R4 V R5 V It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0098] In another embodiment of the invention, in the compound of formula (If), X is NH and R2 V R3 V R4 V R5 V It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0099] Another embodiment of the present invention relates to a compound of formula (Ig).

[0100]

[0101] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0102] in:

[0103] X, R 11 R 12 R 13 R2 VI R3 VI R4 VI and R5 VI It has the same definition as above.

[0104] Preferably, in the compound of formula (Ig), residue R 11 R 12 and R 13 It is independently selected from the group consisting of hydrogen, chlorine, and fluorine. Most preferably, R... 11 R 12 and R 13 It's all hydrogen, or R 11 R 12 and R 13 Only one of the residues is selected from the group consisting of chlorine and fluorine, while the other residues are hydrogen.

[0105] In one embodiment of the invention, in the compound of formula (Ig), X is O and R2 VI R3 VI R4 VI and R5 VI It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0106] In another embodiment of the invention, in the compound of formula (Ig), X is NH and R2 VI R3 VI R4 VI and R5 VI It has the same definition as above, and wherein residue A is preferably unsubstituted or monosubstituted.

[0107] Preferably, the compound of formula (Ia)

[0108]

[0109] Select the group consisting of compounds of free formula (I), where R 11 R 12 R 13 R1, R2, R3, R4, and R5 are shown in Table 1:

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] Preferably, the compound of formula (Ib)

[0116]

[0117] Select the group consisting of compounds of free formula (I), where R 11 R 12 R 13 R2 I R3 I R4 I and R5 I As shown in Table 2:

[0118]

[0119]

[0120]

[0121]

[0122]

[0123] Preferably, the compound of formula (Ic)

[0124] Choose the group consisting of compounds of free formula (I), where X and R 11 R 12 R 13 R2 II R3 II R4 II and R5 II As shown in Table 3:

[0125]

[0126]

[0127]

[0128]

[0129]

[0130] Preferably, the compound of formula (Id)

[0131]

[0132] Select the group consisting of compounds of free formula (I), where R 11 R 12 R 13 R2 III R3 III R4 III R5 III As shown in Table 4:

[0133]

[0134]

[0135]

[0136]

[0137]

[0138] Preferably, the compound of formula (Ie)

[0139]

[0140] Compounds selected from formula (I), wherein R 11 R 12 R 13 R2 IV R3 IV R4 IV R5 IV R6 is shown in Table 5:

[0141]

[0142]

[0143]

[0144]

[0145]

[0146] Preferably, the compound of formula (If)

[0147]

[0148] Select the group consisting of compounds of free formula (I), where R 11 R 12 R 13 R2 V R3 V R4 V and R5 V As shown in Table 6:

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] Preferably, the achiral compound of formula (Ig)

[0155]

[0156] Select the group consisting of compounds of free formula (I), where R 11 R 12 R 13 R2 VI R3 VI R4 VI and R5 VI like

[0157] As shown in Table 7:

[0158]

[0159]

[0160]

[0161]

[0162]

[0163] Particularly good results can be obtained by using the following compounds according to the present invention:

[0164]

[0165]

[0166] C* = Control experiment (no compound according to the invention exists)

[0167] The phrase "enantiomers with shorter retention times separated by chiral HPLC" means that the enantiomers first appear in chiral HPLC under the conditions described in the corresponding chiral separation method. In the context of this invention, enantiomers with shorter retention times are also referred to as "first enantiomers," and enantiomers with longer retention times are also referred to as "second enantiomers."

[0168] As mentioned, the compounds and compositions according to the invention stimulate the proliferation and / or differentiation of RPE cells. Therefore, the compounds according to the invention can be used to treat and / or prevent RPE-related diseases, particularly RPE diseases from the macular degeneration family, which cause vision loss. Most preferably, the disease is one that causes atrophy, degeneration, or death of the retinal pigment epithelium, which may further lead to retinal neovascularization and / or photoreceptor death.

[0169] The compounds and compositions according to the invention are particularly useful in treating and / or preventing macular degeneration selected from the group 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, due to the compounds and compositions of the invention, disease-induced RPE cell damage can be reversed by restoring or regenerating endogenous RPE cells, rather than merely treating vision loss caused by RPE cell dysfunction and / or damage.

[0170] The compounds of formula (I) of the present invention are particularly useful for preventing the onset of dry age-related macular degeneration (dry AMD) and / or wet age-related macular degeneration (wet AMD), preventing early AMD from developing into later forms of AMD (including wet AMD or geographic atrophy (GA)), slowing and / or preventing the progression of GA, preventing or reducing vision loss caused by AMD, and improving vision loss due to pre-existing early or late dry or wet AMD. It can also be used in combination with anti-VEGF therapy for the treatment of patients with neovascular AMD or for the prevention of neovascular AMD.

[0171] The compounds and compositions according to the invention can also be used to treat and / or prevent diseases selected from the group consisting of: choroideremia, Best disease, autosomal recessive bestrophinopathy (ARB), gyrate atrophy, North Carolina macular dystrophy, central areolar choroidal dystrophy (CACD), Sorsby macular dystrophy, familial dominant drusen, cuticular or basal laminar drusen, retinopathy of prematurity, myopic degeneration, polypoidal choroidal vasculopathy (PCV), central serious retinopathy, and angioid striation. streaks, retinal detachment, retinal dialysis, Vogt-Koyangia-Harada disease (VKH), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), persistent placoid maculopathy (PPM), relentless placoid chorioretinopathy (RPC), serpiginous choroiditis, serpiginous-like choroiditis (multifocal serpiginoid choroiditis), and multiple evanescence white dot syndrome.MEWDS (Mean Flow Disorders) or Birdshot Uveitis (Vitiligo Chorioretinitis).

[0172] The compounds and compositions according to the invention are particularly useful for treating choroidal agenesis. Choroidal agenesis is a genetic disorder that typically affects males, causing symptoms such as difficulty seeing in the dark leading to progressive loss of peripheral vision, followed by narrowing of the visual field. Choroidal agenesis can involve significant loss of all retinal layers in the eye. This condition usually begins in childhood with the consumption (atrophy) of the pigmented retinal epithelium, retina, and choroid. The disease can be treated using the compounds according to the invention.

[0173] The compounds and compositions according to the invention are particularly useful in the treatment and / or prevention of retinal diseases selected from the group consisting of retinal diseases leading to choroidal neovascularization or vascular leakage. The retinal diseases are preferably selected from the group consisting of: toxoplasmosis, toxocariasis, rubella, Behçet's disease, etc. Disease, choroidal hemangioma, trauma, choroidal rupture, and idiopathic retinitis–vasculitis-aneurysms and neuroretinitis (IRVAN).

[0174] The compounds and compositions according to the invention are particularly useful for treating and / or preventing diseases selected from the group consisting of retinal diseases that cause retinal inflammation and degeneration, such as sympathetic ophthalmia, post-operative inflammation, or non-arteritic ischemic optic neuropathy, as well as retinal degeneration associated with systemic diseases such as diabetes, sickle cell disease, or radiation retinopathy.

[0175] In another embodiment, the present invention relates to pharmaceutical compositions for treating and / or preventing diseases involving the retinal pigment epithelium, said pharmaceutical compositions comprising a pharmaceutically acceptable carrier and / or adjuvant; and a compound of formula (I) as a therapeutically active substance.

[0176]

[0177] Or its pharmaceutically acceptable salts, racemic mixtures, corresponding tautomers, corresponding enantiomers, or (if applicable) corresponding diastereomers,

[0178] in:

[0179] X is NH or O.

[0180] R 11 R 12 and R 13 The group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methyl, and difluoromethoxy is selected independently.

[0181] Group A consists of residues of the free form (II), (III), (IV), (V), (VI), (VII), or (VIII).

[0182]

[0183] in,

[0184] The asterisk (*) indicates a point that connects to the rest of the molecule, and

[0185] 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 VIThe residue R6 is independently selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethoxy, and in the residue of formula (VI), R6 is selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, trifluoromethyl and 2,2,2-trifluoroethyl.

[0186] The compounds or compositions according to the invention may be administered to a patient, alone or in combination with one or more other therapeutic agents. As used herein, "patient" includes mammals such as humans, non-human primates, rats, mice, rabbits, hares, dogs, cats, horses, cattle, and pigs, preferably humans.

[0187] The pharmaceutical compositions according to the present invention may contain one or more additional therapeutic agents.

[0188] In a preferred embodiment of the invention, the pharmaceutical composition comprises a pharmaceutically acceptable carrier and / or adjuvant; and a compound of formula (I) above, preferably a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig). Most preferably, it comprises a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig) as disclosed in Tables 1, 2, 3, 4, 5, 6, or 7 above. The compounds disclosed in Table 8 are particularly preferred.

[0189] Preferably, this pharmaceutical composition provides controlled-release properties. As used herein, the term "controlled-release pharmaceutical composition" refers to any composition or dosage form that contains the compounds of the present invention and is formulated to provide a longer-lasting pharmacological response after administration of this dosage form than is typically experienced after administration of a corresponding immediate-release composition containing the same amount of the same drug. Depending on the matrix used, controlled release can be extended to several months. Preferably, the release of the compounds according to the invention occurs over a period of up to 12 months, most preferably up to 6 months, ideally up to 3 months, and can be, for example, 1 to 4 weeks. This controlled-release formulation results in increased patient comfort and significantly lower costs.

[0190] The matrix material used in the pharmaceutical composition according to the invention may contain a hydrophobic release controller. It is preferably selected from, but not limited to, polysorbate, polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose acetate propionate, 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(methyl methacrylate), etc. Phenyl acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), waxes (such as beeswax, carnauba wax, paraffin wax, microcrystalline wax and ceresin); fatty alcohols (such as cetearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol), and fatty acid esters, such as glyceryl monostearate; glyceryl monooleate, acetylated monoglycerides, glyceryl tristearate, glyceryl tripalmitate, cetyl wax, glyceryl palmitate, glyceryl behenate or hydrogenated vegetable oils.

[0191] The compounds of the present invention can be delivered to the eye via a variety of routes, including but not limited to topical application to the eye or intraocular injection into, for example, the vitreous, suprachoroidal, subretinal (between photoreceptors), or subconjunctival spaces; local insertion or injection into tissues surrounding the eye; systemic administration via oral route or via subcutaneous, intravenous, or intramuscular injection; or via catheters or implants. Most preferably, the compounds of the present invention are delivered via intravitreal or suprachoroidal injection. Intravitreal application results in high concentrations of the compounds in the eye with minimal systemic exposure. Suprachoroidal injection allows for higher local concentrations of the compounds of the present invention in posterior tissues, which allows for lower doses or less frequent administration. Examples of topical ophthalmic compositions are eye drops, ointments, gels, solutions, and suspensions.

[0192] The compounds of the present invention can be administered before the onset of a condition to prevent its occurrence, such as during eye surgery, immediately after the onset of a pathological condition, or during an acute or persistent condition.

[0193] Depending on the intended method of administration, the compounds according to the invention can be incorporated in any pharmaceutically acceptable dosage form, such as liquids, including solutions, suspensions and emulsions, tablets, suppositories, pills, capsules, powders, etc., preferably dosage forms suitable for a single, precise dose, or sustained-release dosage forms for continuous, controlled administration. Liquids are most preferred.

[0194] Liquid pharmaceutically applicable dosage forms may include, for example, solutions, suspensions, or emulsions, preferably suspensions containing the compounds of the present invention and optional pharmaceutical adjuvants in a carrier, such as water, saline, hydrated dextran, glycerol, hyaluronic acid, ethanol, DMSO, etc., thereby forming a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc. Typical examples of such excipients are sodium acetate, sodium hyaluronate, sorbitol monolaurate, triethanolamine, and triethanolamine oleate.

[0195] The present invention also relates to methods for treating and / or preventing diseases associated with retinal retinal disease, the methods comprising administering a compound of formula (I) (preferably (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig)) or a pharmaceutically acceptable salt thereof, a racemic mixture thereof, the corresponding enantiomer, or (if applicable) the corresponding diastereomer to a patient suffering from retinal disease, so as to deliver to the patient's eye in an amount effective for treating retinal disease. Compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) are described in detail above.

[0196] Experimental Section

[0197] Cell culture

[0198] Induced pluripotent stem cell-derived fetal RPE (iPSC-fRPE) cells obtained from the University of California, Santa Barbara, were generated from human fetal RPE cells, which were isolated and reprogrammed into iPSCs, then differentiated and classified for cell labeling to collect RPE progenitor cells. The virus was transported frozen on dry ice and stored at -80°C.

[0199] For phenotypic screening, iPSC-fRPE cells were thawed and cultured in Matrigel-coated flasks in N1VA medium supplemented with 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% Neuroult SM1 supplement, and 1% N1 supplement. For the initial culture, Thiazovin was added to the medium at 2 μM for the first 24 hours of incubation, followed by replacement of the medium with fresh N1VA medium for an additional three days of incubation at 37°C and 5% CO2.

[0200] iPSC-fRPE cells were plated in Matrigel-coated 96-well plates at a density of 10,000 cells / well using N1VA medium and cultured for 24 h before being treated with the test compound at a final concentration of 5 μM in 0.1% DMSO. 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 (STEMCELL) as a positive control.

[0201] To identify compounds that promote RPE pigment formation, cells were maintained for 32 days and treated with medium containing either the test or control compound, according to the medium replacement protocol. The degree of pigment formation was quantified by measuring absorbance at 510 nm using a Cytation5 imaging reader (BIOTEK). Pigment formation values ​​were ultimately reported relative to the DMSO control within the plate.

[0202] To assess RPE cell proliferation, duplicates of compound-treated RPE cells were fixed on day 5 and stained with Hoechst 33342 to determine the viable cell count using fluorescence microscopy. The cell count was reported relative to the in-plate DMSO control.

[0203]

[0204] The schematic process of the RPE compound screening scheme is shown above.

[0205] Preparation of the compounds of the present invention

[0206] Compounds of formula (I) can be prepared by the methods described below, combined with synthetic methods known in the field of organic chemistry, or by modifications familiar 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 references, e.g., "Compendium of Organic Synthetic Methods, Vol. I-XlN" (Wiley-Interscience, ISSN: 1934-4783). Preferred methods include, but are not limited to, those described below.

[0207] These schemes represent methods that can be used to synthesize the compounds of this invention and supporting examples. They do not, in any way, limit the scope of this invention.

[0208] General Methods - Synthesis

[0209] Method 1:

[0210] Option 1:

[0211]

[0212] Where R 11 R 12 R 13 And A as described in formula (I). R7 is a hydroxyl group or R7 together with a boron atom forms a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane group.

[0213] Compounds of general formula (I) (Scheme 1) can be prepared from compounds of 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-Miyamura coupling reaction conditions known to chemists skilled in the field of organic synthesis. Compounds of general formula (XII) can be prepared by reacting a compound of general formula (X) with a carboxylic acid of general formula (XI) using a procedure known to those skilled in the art. The crude intermediate can eventually be dehydrated, for example, using conditions of heating in a solvent such as acetic acid.

[0214] Method 2:

[0215] Option 2:

[0216]

[0217] Where R 11 R 12 R 13 And A as described in formula (I).

[0218] The compound of general formula (I) (Scheme 2) can be prepared by reacting the compound of general formula (XIV) with the carboxylic acid of general formula (XI) using a procedure known to chemists skilled in the art. The crude intermediate can eventually be dehydrated, for example, by heating in a solvent such as acetic acid.

[0219] Method 3:

[0220] Option 3:

[0221]

[0222] Where R 11 R 12 R 13 As described in formula (I).

[0223] Compounds of general formula (XIV) (Scheme 3) can be prepared by reducing the nitro group in compounds of general formula (XVIII) using procedures known to chemists skilled in the art. Compounds of general formula (XVIII) can be prepared from aldehydes of general formula (XVI) by reacting them with a reagent such as 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (XVII) in the presence of a base such as potassium carbonate. Compounds of general formula (XVI) can be prepared by bubbling ammonia in a solvent such as dichloromethane at room temperature in a solution of compounds of general formula (XV).

[0224] Method 4:

[0225] Option 4:

[0226]

[0227] Where R 11 R 12 R 13 And A as described in formula (I).

[0228] The compound of general formula (I) (Scheme 2) can be prepared by reacting the compound of general formula (XIV) with the aldehyde of general formula (XIX) at high temperature in a solvent such as 1,4-dioxane and in the presence of an acid such as p-toluenesulfonic acid.

[0229] Method 5:

[0230] Option 5:

[0231]

[0232] Where R 11 R 12 R 13 And A as described in formula (I). R7 is a hydroxyl group or R7 together with a boron atom forms a 4,4,5,5-tetramethyl-1,3,2-dioxanepentaboryl group.

[0233] Compounds of general formula (I) (Scheme 1) can be prepared from compounds of general formulas (XXII) and (XIII) in the presence of a palladium catalyst such as tetra(triphenylphosphine)palladium(O) and a base such as potassium carbonate, or under other Suzuki-Miyamura coupling reaction conditions known to chemists skilled in the field of organic synthesis. Compounds of general formula (XXII) can be prepared by treating compounds of general formula (XXI) in the presence of a dehydrating agent such as phosphoryl chloride. Compounds of general formula (XXI) can be prepared by converting compounds of general formula (XI) to the corresponding acyl chlorides using a reagent such as thionyl chloride and reacting them with compounds of general formula (XX).

[0234] Analytical methods

[0235] 1 1H NMR spectra were recorded at 300.0 K in DMSO-d6 / CD3OD / CDCl3 solution in a 5 mm OD tube [Wilmad NMR tube (Sigma-Aldrich), 5 mm thin-walled, 7” length] and at 400 MHz on a Bruker Avance NMRS-400. 1 H was collected. Chemical shifts (δ) relative to CDCl3 (CDCl3 = 7.26 ppm), DMSO-d6 (DMSO-d6 = 2.5 ppm), and CD3OD (CD3OD = 3.3 ppm) are expressed in ppm. Chemical shifts in CDCl3, DMSO-d6, and CD3OD are relative to tetramethylsilane (TMS, = 0.00 ppm) and expressed in ppm.

[0236] Analytical HPLC

[0237] Analytical HPLC Method A:

[0238] A Zorbax SB-C18 column (1.8μm 4.6*15mm, Rapid Resolution cartridge PN 821975-932) was run at a flow rate of 3 ml / min in an Agilent 1100 Series LC / MSD system equipped with DAD / ELSD and Agilent LC / MSD VL (G1956A), SL (G1956B) mass spectrometers. Mobile phase A: acetonitrile, 0.1% formic acid; mobile phase B: water (0.1% formic acid); with the following gradients: 0 min - 100% B; 0.01 min - 100% B; 1.5 min - 0% B; 1.8 min - 0% B; 1.81 min - 100% B.

[0239] Analytical HPLC Method B:

[0240] The UPLC column was a YMC Triart C18 (33 x 2.1 mm, 3 μm) column, 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 aqueous solution] and 2% [acetonitrile] for 0.75 min, then to 90% [10 mM ammonium acetate aqueous solution] and 10% [acetonitrile] for 1.0 min, and further to 2% [10 mM ammonium acetate aqueous solution] and 98% [acetonitrile] for 2.0 min.

[0241] Chiral analytical HPLC

[0242] Chiral analysis HPLC method A: Chiral chromatography using a Chiralpak IA (250*4.6, 5μm) column; hexane-IPA-MeOH, 90-5-5 as the mobile phase; flow rate 0.6 mL / min.

[0243] Preparative HPLC

[0244] Preparative HPLC Method A: Agilent 1260 Infinity system equipped with DAD and mass detector; Waters Sunfire C18 OBD Prep column, 100A, 5μm, 19mm*100mm, with SunFire C18 Prep GuardCartridge, 100A, 10μm, 19mm*10mm; 30-85% H2O-methanol, 0-5min, flow rate 30mL / min.

[0245] Chiral separation methods

[0246] Chiral separation method A: Chiral chromatography, using a Chiralpak IA-II (250*20, 5mkm) column; hexane-IPA-MeOH, 80-10-10 as the mobile phase; flow rate 12mL / min.

[0247] Chiral separation method B: SFC chiral chromatography (Reflect C-Amylose A (250x30 mm) 5μ column, CO2- (0.1% ammonia in MeOH solution), 35%-65%, as mobile phase, P=110 bar, flow rate 35 g / min, T=35℃.

[0248] General Synthesis Program

[0249] Synthesis Program A:

[0250]

[0251] Ethylbis(propyl-2-yl)amine (1.44 mmol, 1.18 equivalent) and HATU (1.34 mmol) were added to a solution of carboxylic acid (1.22 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 20 minutes, followed by the addition of 4-(1,3-oxazol-5-yl)phenyl-1,2-diamine (1.34 mmol). The reaction mixture was stirred overnight at room temperature. The suspension was then concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with aqueous NaHCO3 solution (2 x 20 mL) and brine (2 x 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 overnight at 60 °C. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), alkalized with aqueous NaHCO3 solution, washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residues were purified by prep-HPLC using a SunFireC18 100*19mm 5μm column (20-50% water-MeCN as eluent) at a flow rate of 30 ml / min.

[0252] Synthesis Program B:

[0253]

[0254] An aldehyde (1.43 mmol) and 4-(1,3-oxazol-5-yl)phenyl-1,2-diamine (1.43 mmol) were mixed in 1,4-dioxane (5 mL). The resulting mixture was stirred for 5 minutes, and then 4-methylbenzene-1-sulfonic acid (0.29 mmol) was added. The reaction mixture was stirred overnight at 100 °C. The mixture was then cooled to room temperature, evaporated to dryness, and purified by rapid chromatography.

[0255] Synthesis of intermediates

[0256] Preparation of 4-amino-3-nitrobenzaldehyde

[0257]

[0258] A stirred solution of 4-fluoro-3-nitrobenzaldehyde (50.0 g, 295.67 mmol) in dichloromethane (1200 mL) was bubbled with ammonia at 0 °C for 30 min. The mixture was then stirred at room temperature for another 3 hours and concentrated to give 4-amino-3-nitrobenzaldehyde (45.1 g, 271.47 mmol, 91.8% yield).

[0259] Preparation of 2-nitro-4-(1,3-oxazol-5-yl)aniline

[0260]

[0261] A solution of 4-amino-3-nitrobenzaldehyde (45.1 g, 271.47 mmol) in methanol (800 mL) 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 min. The cooled solution was then concentrated and treated with water (750 mL). The mixture was extracted with ethyl acetate (4 x 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 rapid chromatography to give 2-nitro-4-(1,3-oxazol-5-yl)aniline (10.1 g, 49.23 mmol, 18.1% yield).

[0262] Preparation of 4-(1,3-oxazol-5-yl)phenyl-1,2-diamine

[0263]

[0264] Pd(OH)₂ (410.75 mg, 2.92 mmol) (20% w / w) was added to a solution of 2-nitro-5-(1,3-oxazol-5-yl)aniline (3.0 g, 14.62 mmol) in THF (50 mL). The resulting mixture was stirred overnight at room temperature and atmospheric pressure under a hydrogen atmosphere. The catalyst was removed by filtration, and the solvent was evaporated to give 4-(1,3-oxazol-5-yl)phenyl-1,2-diamine (2.1 g, 11.99 mmol, 82% yield).

[0265] Preparation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-[tris(prop-2-yl)silyl]-1,3-oxazole

[0266]

[0267] A solution of 2.5 mol of n-butyllithium (11.0 mmol, 4.4 mL, 1.2 equivalents) was added dropwise at -78 °C under argon to a stirred solution of 2-[tris(prop-2-yl)silyl]-1,3-oxazole (2.07 g, 9.18 mmol) in 60 mL of anhydrous THF. The resulting mixture was stirred at -78 °C for 1 h, and then a solution of tris(prop-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 h, and then at room temperature overnight. Then, 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 h. The suspension was then evaporated and the residue diluted with water. The product was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and evaporated to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2-[tris(propyl-2-yl)methyl]-1,3-oxazole (3.0 g, 85.0% purity, 7.26 mmol, 79% yield).

[0268] Preparation of N-(5-bromo-2-hydroxyphenyl)chromoside-3-carboxamide

[0269]

[0270] Chlorane-3-carboxylic acid (2 g, 11.23 mmol) was dissolved in SOCl2 (2 mL, 28.09 mmol) and stirred at room temperature for 24 h under a nitrogen atmosphere. The reaction mixture was then concentrated under vacuum and diluted with dichloromethane (10 mL) under a nitrogen atmosphere, and the evaporation process was repeated twice. A dichloromethane (6 mL) solution of 2-amino-4-bromophenol (2.3 g, 12.36 mmol) and pyridine (1 mL, 12.36 mmol) were added to a round-bottom flask. The mixture was stirred at room temperature for 15 min. In a second round-bottom flask containing the freshly prepared chromane-3-carbonyl chloride (2), dichloromethane (4 mL) was added at room temperature, followed by the mixture containing the above-mentioned 2-amino-4-bromophenol (1) in dichloromethane. The combined reaction mixture was stirred at room temperature for 18 h. The crude reaction mixture was extracted with dichloromethane and washed with water. The combined organic fraction 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)chromoproton-3-carboxamide (3) (1.3 g, 33%).

[0271] Preparation of 5-bromo-2-((chromo-3-yl)benzo[d]oxazole

[0272]

[0273] POCl3 (8 mL, 86.2 mmol) was added to a stirred solution of N-(5-bromo-2-hydroxyphenyl)chromogen-3-carboxamide (2.5 g, 7.18 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was sealed and refluxed at 110 °C for 2 h. The reaction mixture was then concentrated and purified by rapid chromatography to give 5-bromo-2-(chromogen-3-yl)benzo[d]oxazole (800 mg, 33%).

[0274] Compound (1): “First” (R)-5-(2-(chromo-3-yl)-1H-benzo[d]imidazol-6-yl)oxazole

[0275]

[0276] 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-oxazol-5-yl)phenyl-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), dried over anhydrous sodium sulfate with aqueous NaHCO3 solution (2 x 80 mL) and brine (2 x 50 mL), filtered, and concentrated under reduced pressure. Without further purification, the obtained crude product was dissolved in acetic acid (100 mL), and the mixture was stirred overnight at 60 °C. The resulting solution was evaporated under vacuum, diluted with ethyl acetate (250 mL), alkalized with an aqueous NaHCO3 solution, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using preparative HPLC method A to give 5-(2-(chromo-3-yl)-1H-benzo[d]imidazol-6-yl)oxazole.

[0277] Compound (1) (603.3 mg) was produced by chiral separation method A, characterized by a retention time of 19.7 minutes.

[0278] [α] D 25 = -12.00 (c = 0.25, MeOH).

[0279] [M+H+ m / z:318.2

[0280] 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).

[0281] The structure was confirmed using X-rays.

[0282] Compound (2): "Second" (S)-5-(2-(chromo-3-yl)-1H-benzo[d]imidazol-6-yl)oxazole

[0283]

[0284] 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-oxazol-5-yl)phenyl-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 x 80 mL) and brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Without further purification, the obtained crude product was dissolved in acetic acid (100 mL), and the mixture was stirred overnight at 60 °C. The resulting solution, evaporated under vacuum, was diluted with ethyl acetate (250 mL), alkalized with an 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 produce 5-(2-(chromoalkyl-3-yl)-1H-benzo[d]imidazol-6-yl)oxazole.

[0285] Compound (2) (607.5 mg) was produced by chiral separation method A, characterized by a retention time of 27.4 minutes.

[0286] [α] D25 = +13.56 (c = 0.25, MeOH).

[0287] [M+H + m / z:318.2

[0288] 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).

[0289] Compound (3): 2-(2,3-dihydro-1-benzofuran-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0290]

[0291] 2,3-Dihydro-1-benzofuran-2-carboxylic acid (0.2 g) was combined with synthetic procedure A to give 2-(2,3-dihydro-1-benzofuran-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (63 mg, 14.0% yield).

[0292] Analytical HPLC method A[M+H + m / z: 304.2; Rt = 2.35 minutes.

[0293] Compound (4): 2-(7-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0294]

[0295] 7-Fluoro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (0.2 g) was used in combination with synthetic procedure A to give 2-(7-fluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (68 mg, 15.1% yield).

[0296] Analytical HPLC method A[M+H + m / z: 336.2; Rt = 2.35 minutes.

[0297] Compound (5): 2-(6-chloro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0298]

[0299] 6-Fluoro-3,4-dihydro-2H-1-benzopyran-3-carbonyl chloride (0.17 g) was used in combination with synthetic procedure A to give 2-(6-chloro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (70 mg, 15.8% yield).

[0300] Analytical HPLC method A[M+H + m / z: 352.0; Rt = 2.54.

[0301] Compound (6): 2-(6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0302]

[0303] 6,8-Difluoro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (0.2 g) was combined with synthetic procedure A to give 2-(6,8-difluoro-3,4-dihydro-2H-1-benzopyran-3-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (39 mg, 8.6% yield).

[0304] Analytical HPLC method A[M+H + m / z: 354.2; Rt = 2.47 minutes.

[0305] Compound (7): 2-(2,3-dihydro-1H-inden-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0306]

[0307] 2-Dihydro-1H-indene-2-carboxaldehyde (0.098 g) was combined with synthetic procedure B to obtain 2-(2,3-dihydro-1H-indene-2-yl)-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (30 mg, 10% yield).

[0308] Analytical HPLC method A[M+H + m / z: 302.2; Rt = 1.94 minutes.

[0309] Compound (8): 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0310]

[0311] Step 1: 6-Bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-1H-1,3-benzodiazole

[0312] Ethylbis(propyl-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 to a solution of 3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (3.95 g, 22.17 mmol) in DMF (100 mL). The resulting mixture was stirred for 20 minutes, followed by the addition of 5-bromo-3-fluorophenyl-1,2-diamine (5.0 g, 24.39 mmol). The reaction mixture was stirred overnight at room temperature. The resulting product was concentrated under reduced pressure, diluted with ethyl acetate (250 mL), washed with aqueous NaHCO3 solution (2 x 75 mL) and brine (2 x 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), and alkalized with an aqueous NaHCO3 solution. It was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid chromatography to give 6-bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-1H-1,3-benzodiazole (4.2 g, 12.1 mmol, 54.6% yield).

[0313] Step 2: 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-2-[tris(propyl-2-yl)silyl]-1,3-oxazol-5-yl-1H-1,3-benzodiazole

[0314] Add 5-(4,4,5,5-tetramethyl-1,3,2-dioxane-3-yl)-7-fluoro-1H-1,3-benzodiazole (2.72 g, 7.83 mmol) to a stirred solution of 5-bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-1H-1,3-benzodiazole (2.72 g, 7.83 mmol), tetra(triphenylphosphine)palladium(0) (907.54 mg, 782.63 μmol), and potassium carbonate (3.24 g, 23.48 mmol) to a stirred solution of 5-bromo-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-1H-1,3-benzodiazole (2.72 g, 7.83 mmol) in 40 mL of dry dimethoxyethane and 13.5 mL of water. The reaction mixture was stirred at room temperature for 20 min, then incubated overnight at 80 °C. The mixture was evaporated to dryness and purified by rapid chromatography to give 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-2-[tris(propyl-2-yl)silyl]-1,3-oxazol-5-yl-1H-1,3-benzodiazole (2.9 g, 5.9 mmol, 75.4% yield).

[0315] Step 3: 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-6-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0316] To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-7-fluoro-5-2-[tris(propyl-2-yl)silyl]-1,3-oxazol-5-yl-1H-1,3-benzodiazole (2.9 g, 5.9 mmol) in 1.5 mL of THF, add a solution of tetrabutylammonium fluoride (7.71 g, 29.49 mmol, 8.54 mL, 5.0 equivalents) in THF. The reaction mixture was stirred overnight at room temperature, evaporated, diluted with water, extracted with ethyl acetate, washed with water, dried over sodium sulfate, evaporated, and purified by column chromatography (SiO2, CHCl3-MeCN as mobile phase) to give 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, 65.7% yield).

[0317] Analytical HPLC method A[M+H + m / z: 336.2; Rt = 2.76 minutes.

[0318] Compound (9): 2-(3,4-dihydro-2H-1-benzopyran-3-yl)-4-fluoro-5-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole

[0319]

[0320] Using the same three-step synthetic procedure and molar ratio as compound 12, 4-bromo-3-fluorophenyl-1,2-diamine (1 g) was used to give 6-chloro-2-(3,4-dihydro-2H-1-benzopyran-3-yl)-5-(1,3-oxazol-5-yl)-1H-1,3-benzodiazole (54 mg).

[0321] Analytical HPLC method A[M+H + m / z: 336.0; Rt = 2.66 minutes.

[0322] Compound (10): “Second” 2-(chromo-3-yl)-6-(oxazol-5-yl)benzo[d]oxazol

[0323]

[0324] In a sealed tube at room temperature, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)oxazole (261 mg, 1.33 mmol) and Na2CO3 (258 mg, 2.43 mmol) were added to a stirred solution of 6-bromo-2-(chromoprotan-3-yl)-1H-benzo[d]imidazole (400 mg, 1.21 mmol) in a mixture of 1,4-dioxane and water (4:1) (15 mL). The resulting reaction mixture was degassed at room temperature for 20 min, followed by the addition of a PdCl2(dppf)-dichloromethane complex (99 mg, 0.12 mmol), and stirred at 100 °C for 6 h. The reaction mixture was filtered and purified by rapid chromatography to give racemic 5-(2-(chromoprotan-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole (170 mg, 46%).

[0325] Chiral separation method B is used to chirally separate 5-(2-(chromoside-3-yl)-1H-benzo[d]imidazol-6-yl)oxazole to produce a "second" 2-(chromoside-3-yl)-6-(oxazol-5-yl)benzo[d]oxazole (120 mg), characterized by a retention time of 11.3 minutes.

[0326] Analytical HPLC method B[M+H + m / z: 319.2; Rt = 1.87 minutes.

[0327] Compound (11): “First” 2-(chromo-3-yl)-6-(oxazol-5-yl)benzo[d]oxazol

[0328]

[0329] In a sealed tube at room temperature, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)oxazole (261 mg, 1.33 mmol) and Na2CO3 (258 mg, 2.43 mmol) were added to a stirred solution of 6-bromo-2-(chromoprotan-3-yl)-1H-benzo[d]imidazole (400 mg, 1.21 mmol) in a mixture of 1,4-dioxane and water (4:1) (15 mL). The resulting reaction mixture was degassed at room temperature for 20 min, followed by the addition of a PdCl2(dppf)-dichloromethane complex (99 mg, 0.12 mmol), and stirred at 100 °C for 6 h. The reaction mixture was filtered and purified by rapid chromatography to give racemic 5-(2-(chromoprotan-3-yl)-1H-benzo[d]imidazole-6-yl)oxazole (170 mg, 46%).

[0330] Chiral separation method B is used to chirally separate 5-(2-(chromoside-3-yl)-1H-benzo[d]imidazol-6-yl)oxazole to produce “first” 2-(chromoside-3-yl)-6-(oxazol-5-yl)benzo[d]oxazole (102 mg), characterized by a retention time of 10.1 minutes.

[0331] Analytical HPLC method B[M+H + m / z: 319.2; Rt = 1.87 minutes.

Claims

1. Compounds of formula (I) (I) Or its pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer, or, if applicable, corresponding diastereomer, wherein: X is NH or O. R 11 R 12 and R 13 The group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methyl, and difluoromethoxy is selected independently. Group A consists of groups with free formulas (II), (III), (IV), (V), (VI), (VII), or (VIII). in, " "Indicates the point where it connects to the rest of the molecule, and 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 Independently selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethoxy, and In formula (VI), R6 is selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, trifluoromethyl and 2,2,2-trifluoroethyl.

2. The compound according to claim 1, wherein, The compounds of formula (I) have ring positions in the groups of formulas (II), (III), (IV) and (V). The asymmetric center located at or on the side chain of a group of formula (VI) has the following configuration, namely the compound of formula (Ii). (Ii) And 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 and R5 IV It has the same definition as in claim 1.

3. The compound according to claim 1, wherein, The asymmetric center in the compound of formula (I) It has the following configuration: R2 V R3 V R4 V R5 V R6 has the same definition as in claim 1.

4. The compound according to claim 1, wherein, The compounds of formula (I) have ring positions in the groups of formulas (II), (III), (IV) and (V). The asymmetric center located at or on the side chain of a group of formula (VI) has the configuration shown below, namely the compound of formula (II). (Iii) And 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 and R5 IV It has the same definition as in claim 1.

5. The compound according to claim 1, wherein, The asymmetric center in the compound of formula (I) It has the following configuration: R2 V R3 V R4 V R5 V R6 has the same definition as in claim 1.

6. The compound according to claim 1, wherein, In the compound of formula (I), R 11 R 12 and R 13 The group consisting of hydrogen, chlorine, and fluorine is selected independently.

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

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

9. The compound according to claim 1, wherein, Group A is unsubstituted.

10. The compound according to claim 1, wherein, Group A is monosubstituted.

11. The compound according to claim 10, wherein, Group A is monosubstituted, and 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 One of the groups is selected from those composed of chlorine and fluorine, and the remaining groups are hydrogen.

12. The compound according to claim 1, wherein, The compounds of formula (I) are selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11: 。 13. Compounds of formula (I) (I) The use of its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or, if applicable, corresponding diastereomers, as active ingredients in the preparation of medicaments for the treatment and / or prevention of diseases involving the retinal pigment epithelium, wherein the diseases involving the retinal pigment epithelium are selected from the group consisting of diseases that cause atrophy, degeneration, or death of the retinal pigment epithelium. in: X is NH or O. R 11 R 12 and R 13 The group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methyl, and difluoromethoxy is selected independently. Group A consists of groups with free formulas (II), (III), (IV), (V), (VI), (VII), or (VIII). in, " "Indicates the point where it connects to the rest of the molecule, and 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 Independently selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethoxy, and In formula (VI), R6 is selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, trifluoromethyl and 2,2,2-trifluoroethyl.

14. The application according to claim 13, wherein, The compounds of formula (I) are selected from the group consisting of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11: 。 15. The application according to claim 13, wherein, The diseases involving the retinal pigment epithelium are selected from early age-related macular degeneration, dry age-related macular degeneration, geographic atrophy (GA), and wet age-related macular degeneration.

16. The application according to claim 15, wherein, The disease involving the retinal pigment epithelium is dry age-related macular degeneration.

17. A pharmaceutical composition comprising: Compound of formula (I) as a therapeutically active substance (I) Or its pharmaceutically acceptable salts, racemic mixtures, corresponding enantiomers, or, if applicable, corresponding diastereomers, and Pharmaceutically acceptable carriers and / or adjuvants in: X is NH or O. R 11 R 12 and R 13 The group consisting of hydrogen, fluorine, chlorine, trifluoromethyl, methyl, and difluoromethoxy is selected independently. Group A consists of groups with free formulas (II), (III), (IV), (V), (VI), (VII), or (VIII). in, " "Indicates the point where it connects to the rest of the molecule, and 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 Independently selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl, 2,2,2-trifluoroethyl, and difluoromethoxy, and In formula (VI), R6 is selected from the group consisting of hydrogen, straight-chain or branched alkyl groups having 1 to 3 carbon atoms, trifluoromethyl, and 2,2,2-trifluoroethyl. The pharmaceutical composition is used to treat and / or prevent diseases involving the retinal pigment epithelium.

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

19. The pharmaceutical composition according to claim 17, wherein, The drug formulation is suitable for intravitreal injection or suprachoroidal injection.

20. The pharmaceutical composition of claim 17, further comprising one or more additional therapeutic agents.

21. The pharmaceutical composition according to claim 17, wherein, The pharmaceutical composition provides controlled release properties.

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