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

Abstract

The present application relates to a novel compound and its use as therapeutically active substance in the treatment and / or prevention of diseases which involve the retinal pigment epithelium, in particular diseases which lead to atrophy, degeneration or death of the retinal pigment epithelium, which can also lead to atrophy or loss of photoreceptors and / or retinal neovascularization.

Description

[0001] The present application relates to novel compounds and their use as therapeutically active substances in the treatment and / or prevention of diseases involving the retinal pigment epithelium, in particular in the treatment and / or prevention of diseases leading to atrophy, degeneration or death of retinal pigment epithelial cells, which can also lead to photoreceptor atrophy or loss and / or retinal neovascularization.

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

[0003] The so-called age-related macular degeneration (AMD) is the most common form of macular degeneration and is associated with a progressive loss of central part of the visual field, changes in color vision and abnormal dark adaptation and sensitivity. AMD is the leading cause of irreversible vision loss in developed countries, affecting about 2% of the population. The prevalence of AMD increases with age and its etiology is multifactorial.

[0004] Among the key factors leading to this 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 (blood supply of the retina). As RPE cells exert a trophic effect on the highly metabolizing 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 exhaustion and loss.

[0005] The two main clinical presentations of AMD are described as dry or atrophic form (hereinafter dry AMD) and wet or neovascular form (hereinafter wet AMD). Dry AMD is associated with atrophic cell death of the central retina or macula. About 10-20% of these dry AMD patients further develop into the second form, called wet or neovascular AMD. In these late stages of AMD, atrophy of the RPE (geographic atrophy) and / or development of new blood vessels originating from the choroidal blood vessels (neovascularization) further lead 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 surrounding world.

[0006] There is currently no approved treatment for dry AMD or its late form called geographic atrophy (GA), although anti-VEGF drugs (such as Lucentis®) are currently used in the treatment of wet AMD. ) are treated, but many neovascular AMD patients are legally blind. Pharmacological approaches to treat dry AMD vision loss resulting from underlying RPE damage vary, but they all target control of the mechanisms believed to initially cause the damage (e.g., the complement system) rather than reversing the damage caused by RPE cell loss. Alternative approaches under investigation involve transplantation of induced pluripotent stem cells or mature RPE cells.

[0007] Drusen are small yellow or white extracellular deposits of material formed between the Bruch’s membrane and retinal pigment epithelial cells of the eye. The presence of drusen is a hallmark of age-related macular degeneration. Recent studies on drusen suggest that inflammation and other immune-mediated processes, particularly complement activation, play a role in the etiology of early and late AMD. EP 2 302 076 discloses that the major inhibitor of the complement alternative pathway, the H factor protein (HFl), accumulates within drusen and is locally synthesized by retinal pigment epithelial cells, thus providing for the administration of a drug that reduces the amount of variant factor H or the expression of the gene encoding factor H in an amount effective to reduce the symptoms of AMD in a patient.

[0008] US 9'815'819 B2 relates to compounds that modulate and preferably inhibit the activation of the complement alternative pathway as a method of treating or preventing AMD.

[0009] WO 2015 / 138628 relates to AAV vector constructs that can and are optimized for delivery of anti-inflammatory peptides to the retina of AMD patients.

[0010] AU 2019 / 226198 discloses a method of producing a substantially purified RPE cell culture 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 an AMD patient.

[0012] RU 2628697 discloses a procedure for producing a cell layer from retinal pigment epithelial cells in a convenient and stable manner without the use of artificial membranes and with a high implantation rate upon intraocular transplantation.

[0013] PCT / US19 / 68768 describes the use of small molecules in retinal dystrophies (i.e. retinitis pigmentosa) for triggering endogenous regeneration of photoreceptors from retinal stem and progenitor cells. In contrast, the present invention relates to the treatment and / or prevention of RPE-related eye diseases by stimulating pigmentation and / or growth of mammalian RPE cells.

[0014] In the case of wet AMD, great progress has been made in the development of drugs that can antagonize the effect of vascular endothelial growth factor (anti-VEGF). However, these treatments do not address the damage to the RPE layer, but only inhibit the formation of new blood vessels. In addition, they are not curative, but only effective in maintaining the current state of the disease.

[0015] The problem of the present application is therefore to provide therapeutic agents 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 compounds of the formula (I). Further preferred embodiments are the subject of the dependent claims.

[0017] It has been shown that the new compounds of the formula (I) stimulate pigmentation and / or growth of mammalian RPE cells. This stimulation of pigmentation and / or endogenous RPE cell growth allows a controlled repair and regeneration of the retina. Thus, vision loss and / or restoration of vision can be prevented by the endogenous production of new healthy RPE cells by the compounds according to the application. The compounds of the formula I can therefore be used as therapeutically active substances for the treatment and / or prevention of diseases that lead to atrophy, death or degeneration of the retinal pigment epithelium, i.e. as medicaments.

[0018] The term "RPE cells" includes herein proliferative and non-proliferative retinal pigment epithelial cells in any form, which can support or produce further differentiated ocular functional tissue. RPE cells are smooth, pigmented and hexagonal. Healthy and fully differentiated RPE cells build melanosome, which contain the light-absorbing pigment melanin. Compounds that promote the differentiation of healthy and functional RPE cells thus lead to the presence of pigmentation.

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

[0020] The term "prevention" means preventing or reducing signs and symptoms associated with RPE-related diseases, in particular macular degeneration, leading to vision loss in subjects at risk of developing the disease. In these subjects, the predisposing factors can be present, but the signs and / or symptoms of the disease do not appear or take a longer time to develop. In addition, it also includes preventing further deterioration of the symptoms after the disease has occurred.

[0021] The present application therefore relates to a method for the treatment and / or prevention of diseases involving the retinal pigment epithelium, which comprises the administration of a compound of the formula (I)

[0022]

[0023] or a pharmaceutically acceptable salt, a racemic mixture, the corresponding enantiomer or, if applicable, the corresponding diastereomer thereof,

[0024] wherein:

[0025] R1, R 11 and R 12 are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, trifluoromethyl, methyl, dimethylaminoethoxy and difluoromethoxy, wherein at least one of R1, R 11 and R 12 is not hydrogen,

[0026] B is selected from the group consisting of residues of formula (II), (III), (IV), (V), (VI), (VII)

[0027]

[0028] wherein,

[0029] "*" denotes the point of attachment to the rest of the molecule, and

[0030] 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 are independently selected from the group consisting of hydrogen, straight-chain or branched alkyl having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl and difluoromethoxy.

[0031] The term "pharmaceutically acceptable salts" represents the therapeutically active, non-toxic acid forms that the compounds of the present application are able to form.

[0032] In one embodiment of the present application, the asymmetric center of the residues of formula (II), (III), (IV), (V), (VI) and (VII) at the ring position * has the configuration described below, i.e. the compounds of formula (Ii)

[0033]

[0034] and B is selected from the residues of formulae (II), (III), (IV), (V), (VII)

[0035]

[0036] 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 are as defined above.

[0037] In another embodiment of the application, the configuration of the asymmetric centers at the ring positions * of the residues of formulae (II), (III), (IV), (V), (VI) and (VII) is as shown below, i.e. the compounds of formula (III)

[0038]

[0039] and B is selected from the residues of formulae (II), (III), (IV), (V), (VI) and (VII)

[0040]

[0041] 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 , R3V R4 V R5 V as defined above.

[0042] Thus, residue B can be unsubstituted, mono-substituted or poly-substituted. The term "unsubstituted" means that all residues of B are hydrogen. The term "mono-substituted" means that one residue of B is other than hydrogen, and the term "poly-substituted" means that at least two residues of B are other than hydrogen.

[0043] Preferably, residue B is unsubstituted or mono-substituted.

[0044] Preferably, in the mono-substituted residue B of the compound of formula (I), residue R3, R4, R5, R3 I R4 I R3 II R4 II R3 III R4 III R3 IV R4 IV R3 V R4 V are independently selected from hydrogen, chloro, fluoro, methoxy and ethoxy.

[0045] In one embodiment, in the unsubstituted residue B of the compound of formula (I), residues R2, R3, R5, R2 I R3 I R5 I R2 II R3 II R5 II R2 III R3 III R5 III R2 IV R3 IV R5 IV R2 V R3 V R5 V are hydrogen, and R4, R4 I R4 II R4 III R4 IV R4 V are selected from fluoro, chloro, methoxy and ethoxy.

[0046] In another embodiment, in the mono-substituted residue B of the compound of formula (I), residues R2, R4, R5, R2 I R4 I R5 I R2 II R4 II R5 II R2 III R4III R5 III R2 IV R4 IV R5 IV R2 V R4 V R5 V is hydrogen and R3, R3 I R3 II R3 III R3 IV R3 V is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy.

[0047] In another embodiment, in the compounds according to the application, R1is chlorine or methoxy, R 11 and R 12 are both hydrogen and the residue B is unsubstituted or mono-substituted, preferably mono-substituted. Said compounds exhibit a pronounced biological activity.

[0048] In another aspect of the application, in the compounds according to the application, R 12 is methyl, difluoromethoxy or dimethylaminoethoxy, R1and R 11 are both hydrogen and the residue B is unsubstituted or mono-substituted.

[0049] In another aspect of the application, in the compounds according to the application, R1is methyl or trifluoromethyl, R 12 and R 11 are both hydrogen and the residue B is unsubstituted or mono-substituted.

[0050] In another aspect of the application, in the compounds according to the application, R1and R 11 are each, independently of the other, chlorine, fluorine or methoxy, R 12 is hydrogen and the residue B is unsubstituted or mono-substituted.

[0051] One embodiment of the application relates to compounds of the formula (Ia)

[0052]

[0053] or a pharmaceutically acceptable salt, a racemic mixture, a corresponding enantiomer or, if appropriate, a corresponding diastereomer thereof,

[0054] wherein:

[0055] R1, R 11 , R 12 , R2, R3, R4and R5are as defined above. Preferably, the group B in formula Ia is unsubstituted or mono-substituted. Most preferably, R1is chlorine, R 11 and R 12is hydrogen and residue B is unsubstituted.

[0056] or preferably, R1is chloro, R 11 and R 12 are hydrogen, residue B is monosubstituted, wherein R2and R5are hydrogen, one of R3or R4is hydrogen and the other residue is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy, i.e. residue B is monosubstituted and R3or R4is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy.

[0057] Another embodiment of the present application relates to compounds of formula (Ib)

[0058]

[0059] or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, if appropriate, corresponding diastereomer thereof,

[0060] wherein:

[0061] R1, R 11 , R 12 , R2 I , R3 I , R4 I and R5 I are defined as above. Preferably, residue B in formula Ib is unsubstituted or monosubstituted. Most preferably, R1is chloro, R 11 and R 12 are hydrogen and residue B is unsubstituted.

[0062] or preferably, R1is chloro, R 11 and R 12 are hydrogen, residue B is monosubstituted, wherein R2 I and R5 I are hydrogen, one of R3 I or R4 I is hydrogen and the other residue is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy, i.e. residue B is monosubstituted and R3 I or R4 I is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy.

[0063] Another embodiment of the present application relates to compounds of formula (Ic)

[0064]

[0065] or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, if appropriate, corresponding diastereomer thereof,

[0066] wherein:

[0067] R1, R 11 , R 12 , R2 I , R3 I , R4 I and R5 I are defined as above. Preferably, residue B in formula Ib is unsubstituted or monosubstituted. Most preferably, R1is chloro, R 11 and R 12 are hydrogen and residue B is unsubstituted.11 、R 12 、R2 II 、R3 II 、R4 II and R5 II As defined above. Preferably, the residue B in formula Ic is unsubstituted or monosubstituted. Most preferably, R1 is chlorine, R 11 and R 12 is hydrogen, and the residue B is unsubstituted.

[0068] Or preferably, R1 is chlorine, R 11 and R 12 is hydrogen, the residue B is monosubstituted, wherein R2 II and R5 II is hydrogen, R3 II or R4 II One of the residues is hydrogen and the other residue is selected from fluorine, chlorine, methoxy and ethoxy, i.e. residue B is monosubstituted, R3 II or R4 II is selected from fluorine, chlorine, methoxy and ethoxy.

[0069] Another embodiment of the present invention relates to compounds of formula (Id)

[0070]

[0071] or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, if applicable, corresponding diastereomer thereof,

[0072] in:

[0073] R1, R 11 、R 12 、R2 III 、R3 III 、R4 II and R5 III As defined above. Preferably, the residue B in formula Id is unsubstituted or monosubstituted. Most preferably, R1 is chlorine, R 11 and R 12 is hydrogen, and the residue B is unsubstituted.

[0074] Or preferably, R1 is chlorine, R 11 and R 12 is hydrogen, the residue B is monosubstituted, wherein R2 III and R5 III is hydrogen, and R3 III or R4 III One of the residues is hydrogen and the other residue is selected from fluorine, chlorine, methoxy and ethoxy, i.e. residue B is monosubstituted, R3 III or R4 IIIis selected from fluorine, chlorine, methoxy and ethoxy.

[0075] Another embodiment of the present invention relates to compounds of formula (Ie)

[0076]

[0077] or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, if applicable, corresponding diastereomer thereof,

[0078] in:

[0079] R1, R 11 、R 12 、R2 IV 、R3 IV 、R4 IV and R5 IV As defined above. Preferably, the residue B in formula 1e is unsubstituted or monosubstituted. Most preferably, R1 is chlorine, R 11 and R 12 is hydrogen, and the residue B is unsubstituted.

[0080] Or preferably, R1 is chlorine, R 11 and R 12 is hydrogen, the residue B is monosubstituted, wherein R2 IV and R5 IV is hydrogen, and R3 IV or R4 IV One of the residues is hydrogen and the other residue is selected from fluorine, chlorine, methoxy and ethoxy, i.e. the residue B is monosubstituted, R3 IV or R4 IV is selected from fluorine, chlorine, methoxy and ethoxy.

[0081] Another embodiment of the present invention relates to compounds of formula (If)

[0082]

[0083] or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, if applicable, corresponding diastereomer thereof,

[0084] in:

[0085] R1, R 11 、R 12 、R2 V 、R3 V 、R4 V and R5 V As defined above. Preferably, the residue B in formula If is unsubstituted or monosubstituted. Most preferably, R1 is chlorine, R 11 and R12 is hydrogen and residue B is unsubstituted.

[0086] or preferably, R1is chloro, R 11 and R 12 are hydrogen and residue B is monosubstituted, wherein R2 V and R5 V are hydrogen and R3 V or R4 V is hydrogen and the other residue is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy, i.e. residue B is monosubstituted, R3 V or R4 V is selected from the group consisting of fluorine, chlorine, methoxy and ethoxy.

[0087] preferably, compounds of formula (Ia)

[0088]

[0089] selected from the group of compounds of formula (I), wherein R1, R 11 , R 12 , R2, R3, R4and R5are as indicated in table 1 :

[0090]

[0091]

[0092]

[0093]

[0094] preferably, compounds of formula (Ib)

[0095]

[0096] selected from the group of compounds of formula (I), wherein R1, R 11 , R 12 , R2 I , R3 I , R4 I and R5 I are as indicated in table 2:

[0097]

[0098]

[0099]

[0100]

[0101] preferably, compounds of formula (Ic)

[0102]

[0103] a compound selected from the group consisting of compounds of formula (I) wherein R1, R 11 , R 12 , R2 II , R3 II , R4 II and R5 II are as shown in Table 3:

[0104]

[0105]

[0106]

[0107]

[0108] Preferably, the compound of formula (Id) is

[0109]

[0110] a compound selected from the group consisting of compounds of formula (I) wherein A, R1, R 12 , R2 III , R3 III , R4 III and R5 III are as shown in Table 4:

[0111]

[0112]

[0113]

[0114]

[0115] Preferably, the compound of formula (Ie) is

[0116]

[0117] a compound selected from the group consisting of compounds of formula (I) wherein R1, R 11 , R 12 , R2 IV , R3 IV , R4 IV and R5 IV are as shown in Table 5:

[0118]

[0119]

[0120]

[0121]

[0122] Preferably, the compounds of formula (If)

[0123]

[0124] selected from the compounds of formula (I), wherein R1, R 11 , R 12 , R2 V , R3 V , R4 V and R5 V are as indicated in Table 6:

[0125]

[0126]

[0127]

[0128]

[0129] Particularly good results can be obtained by the following compounds of the present application:

[0130]

[0131]

[0132] C = control experiment (absence of a compound according to the application).

[0133] In particular, compounds (1) and (7) show excellent results in terms of pigmentation of RPE cells.

[0134] Further preferred compounds providing good activity are described in Table 8. The expression "enantiomer with shorter retention time from chiral HPLC resolution" means that this enantiomer comes out first in chiral HPLC when applying the conditions described in the respective chiral separation methods A, B, C, D, E, F, G, H, I and K below. In the context of the present application, the enantiomer with shorter retention time is also referred to as "first enantiomer", while the enantiomer with longer retention time is also referred to as "second enantiomer".

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143] As already mentioned, the compounds according to the present application and the compositions according to the present application stimulate the proliferation and / or differentiation of RPE cells. Thus, the compounds according to the present application are useful for the treatment and / or prevention of RPE-related diseases, in particular RPE diseases from the family of macular degeneration leading to vision loss. Most preferably, the disease is a disease leading to atrophy, degeneration or death of retinal pigment epithelial cells, which can further lead to retinal neovascularization and / or photoreceptor death.

[0144] The compounds and compositions according to the present application are particularly useful for the treatment and / or prevention of a disease selected from the family of macular degeneration consisting of early age-related macular degeneration (AMD), dry AMD and geographic atrophy (GA), as well as for the treatment of wet AMD by inducing proliferation and / or differentiation of RPE cells. Thus, due to the compounds and compositions of the present application, it is possible to reverse the disease-induced damage of RPE cells by restoring or regenerating endogenous RPE cells, rather than merely treating the vision loss caused by RPE cell dysfunction and / or damage.

[0145] The compounds of formula (I) of the present application are particularly useful for preventing the onset of dry age-related macular degeneration (dry AMD) and / or wet age-related macular degeneration (wet AMD), to prevent early AMD to the advanced form of AMD including wet AMD or geographic atrophy (GA), to slow down and / or prevent the progression of GA, to prevent or reduce vision loss due to pre-existing early or advanced dry or wet AMD. It can also be used in combination with anti-VEGF therapy for the treatment of neovascular AMD patients or for the prevention of neovascular AMD.

[0146] The compounds and compositions according to the present application are also useful for the treatment and / or prevention of a disease selected from Best disease, autosomal recessive bestrophinopathy (ARB), gyrate atrophy, North Carolina macular dystrophy, central areolar choroidal dystrophy (CACD), Sorsby's macular dystrophy, familial dominant drusen, corneal or basal laminar drusen, retinopathy of prematurity, myopic degeneration, polypoidal choroidal vasculopathy (PCV), central severe retinopathy, angiod streaks, retinal detachment, serrata ablation, Vogt-Koyanagi-Harada (VKH), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), persistent placoid maculopathy (PPM), persistent placoid retinochoroidopathy (RPC), serpiginous choroiditis, serpentiform choroiditis (multifocal serpiginous choroiditis), multiple evanescent white dot syndrome (MEWDS) or birdshot retinochoroidopathy (uveo retinitis).

[0147] The compounds and compositions according to the present application are particularly useful for the treatment and / or prevention of a disease selected from retinal diseases leading to choroidal neovascularization or vascular leakage. Said retinal diseases are preferably selected from toxoplasmosis, onchocerciasis, rubella, Behcet's disease, choroidal angioma, trauma, choroidal rupture and idiopathic retinitis-vasculitis-artery occlusions and neuroretinitis (IRVAN).

[0148] The compounds and compositions according to the present application are particularly useful for the treatment and / or prevention of a disease selected from retinal diseases causing retinal inflammation and degeneration, such as sympathetic ophthalmia, postoperative inflammation or non-arteritic ischemic optic neuropathy, and retinal degeneration associated with systemic diseases, such as diabetes, sickle cell disease or radiation retinopathy.

[0149] In other embodiments, the present application relates to a pharmaceutical composition for use in the treatment and / or prevention of a disease involving the retinal pigment epithelium, said pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or adjuvant; and a compound of formula (I)

[0150]

[0151] or a pharmaceutically acceptable salt, a racemic mixture, a corresponding enantiomer or, if appropriate, a corresponding diastereomer thereof,

[0152] wherein:

[0153] R1, R 11 and R 12 are independently selected from hydrogen, fluorine, chlorine, methoxy, trifluoromethyl, methyl and difluoromethoxy, wherein R1, R 11 and R 12at least one of R1, R2, R3, R4and R5is not hydrogen,

[0154] B is selected from the residues of formulae (II), (III), (IV), (V), (VI), (VII),

[0155]

[0156] wherein

[0157] "*" denotes the point of attachment to the remainder of the molecule, and

[0158] 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 are independently selected from the group consisting of hydrogen, linear or branched alkyl having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl and difluoromethoxy,

[0159] as therapeutic active substances and pharmaceutically acceptable carriers and / or adjuvants for the treatment and / or prevention of diseases involving the retinal pigment epithelium.

[0160] In other embodiments, the present application relates to a pharmaceutical composition for the treatment and / or prevention of diseases involving the retinal pigment epithelium, said pharmaceutical composition comprising a pharmaceutically acceptable carrier and / or adjuvant; and a compound of formula (I)

[0161]

[0162] or a pharmaceutically acceptable salt, a racemic mixture, a corresponding enantiomer or, if appropriate, a corresponding diastereomer thereof,

[0163] wherein:

[0164] R1, R 11 and R 12independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, trifluoromethyl, methyl and difluoromethoxy, wherein R1, R 11 and at least one of R 12 is not hydrogen,

[0165] B is selected from the group consisting of residues of formula (II), (III), (IV), (V), (VI), (VII),

[0166]

[0167] wherein,

[0168] "*" denotes the point of attachment to the remainder of the molecule, and

[0169] 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 are independently selected from the group consisting of hydrogen, linear or branched alkyl having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl and difluoromethoxy,

[0170] with the proviso that if

[0171] a) R 11 is hydrogen, and

[0172] b) one of R1and R 12 is selected from the group consisting of fluorine, chlorine and methoxy, trifluoromethyl, methyl and difluoromethoxy, and the other of R1and R 12 is hydrogen, then

[0173] B is a residue of formula (IV) or (VII)

[0174] as a therapeutically active substance.

[0175] The compound or composition according to the present application 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, cows, and pigs, preferably humans.

[0176] The pharmaceutical composition according to the present application can comprise one or more additional therapeutic agents.

[0177] In a preferred embodiment of the present application, the pharmaceutical composition comprises a pharmaceutically acceptable carrier and / or adjuvant; and a compound of formula (I), preferably a compound of formula (la), (lb), (lc), (Id), (le) or (If), as defined above. Most preferably, it comprises a compound of formula (la), (lb), (lc), (Id), (le) or (If) as disclosed in Tables 1, 2, 3, 4, 5, 6, 7 and 8 above.

[0178] Preferably, such pharmaceutical compositions provide controlled release properties. The term "controlled release pharmaceutical composition" herein means any composition or dosage form which comprises a compound of the present application and which is formulated so that, after administration of the dosage form, the duration of the pharmacological response provided is longer than would normally be experienced after administration of a corresponding immediate release composition comprising the same amount of the same drug. Controlled release can extend over several months, depending on the matrix used. Preferably, release of the compound according to the present application occurs over a period of up to 12 months, most preferably over a period of up to 6 months. Such controlled release formulations improve patient comfort and significantly reduce costs.

[0179] The matrix material for the pharmaceutical composition according to the present application can comprise a hydrophobic release controlling agent. It preferably, but not exclusively, comprises polyvinyl acetate dispersions, 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(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), waxes such as beeswax, carnauba wax, paraffin wax, microcrystalline wax and ceresine; fatty alcohols such as cetyl stearyl alcohol, stearyl alcohol, cetyl alcohol, myristyl alcohol and fatty acid esters such as glyceryl monostearate; glyceryl monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate or hydrogenated vegetable oil.

[0180] The compounds of the present application can be delivered to the eye by a variety of routes, including but not limited to topical application to the eye or by intraocular injection into, for example, the vitreous, subretinal (interphotoreceptor) or subconjunctival space; topical insertion or injection into the tissue surrounding the eye; systemic administration by oral route or by subcutaneous, intravenous or intramuscular injection; or by catheter or implant. Most preferably, the compounds of the present application are delivered by intraocular injection. Examples of topical ophthalmic compositions are eye drops, ointments, gels, solutions and suspensions.

[0181] The compounds of the present application can be administered prior to the onset of the disorder to prevent its occurrence, such as during ophthalmic surgery, immediately after the onset of the pathological disorder or during the acute or chronic occurrence of the disorder.

[0182] Depending on the intended mode of administration, the compounds of the present application can be incorporated in any pharmaceutically acceptable dosage form, such as liquids, tablets, suppositories, pills, capsules, powders, etc., preferably in a dosage form suitable for single administration of an accurate dose, or in a sustained release dosage form suitable for continuous controlled administration. Most preferred are liquids.

[0183] Liquid pharmaceutically acceptable dosage forms can be, for example, solutions, suspensions or emulsions, preferably suspensions comprising the compounds of the present application and optionally pharmaceutical adjuvants in a carrier, such as water, saline, aqueous dextrose, glycerol, hyaluronic acid, ethanol, DMSO, etc., to form solutions or suspensions. If desired, the pharmaceutical composition to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, etc. Typical examples of such adjuvants are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate and triethanolamine oleate.

[0184] The present application also relates to a method of treating and / or preventing a RPE-related disease, comprising administering a compound of formula (I), preferably a compound of (la), (lb), (lc), (Id), (le) and (If) or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, where appropriate, corresponding diastereomer thereof, to a patient suffering from a retinal disease, so as to be delivered to the eye of the patient in an amount effective to treat the retinal disease. The compounds of formula (la), (lb), (lc), (Id), (le) and (If) are defined in detail above.

[0185] In other embodiments, the present application relates to novel compounds of formula (I)

[0186]

[0187] or a pharmaceutically acceptable salt, racemic mixture, corresponding enantiomer or, where appropriate, corresponding diastereomer thereof, as a therapeutically active substance,

[0188] wherein

[0189] R1, R 11 and R 12 are independently selected from the group consisting of hydrogen, fluorine, chlorine, methoxy, trifluoromethyl, methyl and difluoromethoxy, wherein at least one of R1, R 11 and R 12 is not hydrogen,

[0190] B is selected from the group consisting of residues of formula (II), (III), (IV), (V), (VI), (VII),

[0191]

[0192] wherein

[0193] "*" denotes the point of attachment to the remainder of the molecule, and

[0194] 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 are independently selected from the group consisting of hydrogen, straight-chain or branched alkyl having 1 to 3 carbon atoms, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, trifluoromethyl and difluoromethoxy.

[0195] In other embodiments of the present application, the present application relates to novel compounds of formula (I), wherein the asymmetric center of the residues of formula (II), (III), (IV), (V), (VI) and (VII) at the ring position * has the configuration as shown below,

[0196]

[0197] and B is selected from the group consisting of residues of formula (II), (III), (IV), (V), (VII),

[0198]

[0199] 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 are as defined above,

[0200] with the proviso that if

[0201] a) R 11 is hydrogen, and

[0202] b) one of R1and R 12 is selected from the group consisting of fluorine, chlorine and methoxy, trifluoromethyl, methyl and difluoromethoxy, and the other of R1and R 12 is hydrogen, then

[0203] B is a residue of formula (IV) or (VII).

[0204] In one embodiment of the application, compounds of formula (la)

[0205]

[0206] are selected from the group consisting of compounds of formula (la) as shown in Table 11, wherein R1, R 11 , R 12 , R2, R3, R4and R5:

[0207]

[0208]

[0209]

[0210] In other embodiments of the application, compounds of formula (lb)

[0211]

[0212] selected from the compounds of formula (Ia) as indicated in Table 12, wherein R1, R 11 , R 12 , R2 I , R3 I , R4 I and R5 I :

[0213]

[0214]

[0215]

[0216] In other embodiments of the application, compounds of formula (Ic) are contemplated

[0217]

[0218] selected from the compounds of formula (Ia) as indicated in Table 13, wherein R1, R 11 , R 12 , R2 II , R3 II , R4 II and R5 II :

[0219]

[0220]

[0221]

[0222] In other embodiments of the application, compounds of formula (Id) are contemplated

[0223]

[0224] selected from the compounds of formula (Ia) as indicated in Table 14, wherein R1, R 11 , R 12 , R2 III , R3 III , R4 III and R5 III :

[0225]

[0226]

[0227]

[0228] In other embodiments of the application, compounds of formula (Ie) are contemplated

[0229]

[0230] a compound of formula (Ie) selected from the group consisting of compounds of formula (Ie) as depicted in Table 15, wherein R1, R 11 , R 12 , R2 IV , R3 IV , R4 IV and R5 IV :

[0231]

[0232]

[0233] In other embodiments of the present application, compounds of formula (If) are involved

[0234]

[0235] a compound of formula (If) selected from the group consisting of compounds of formula (If) as depicted in Table 16, wherein R1, R 11 , R 12 , R2 V , R3 V , R4 V and R5 V :

[0236]

[0237]

[0238]

[0239] As already mentioned, it can be shown that the compounds according to the present application and the compositions according to the present application stimulate the proliferation and / or differentiation of RPE cells. Thus, they are suitable for the treatment and / or prevention of RPE-related diseases, in particular RPE diseases from the family of macular degenerations leading to loss of vision.

[0240] Particularly good results can be obtained by the following compounds of the present application:

[0241]

[0242]

[0243]

[0244] In a preferred embodiment of the application, the pharmaceutical composition comprises a pharmaceutically acceptable carrier and / or adjuvant; and a compound of formula (I), preferably a compound of formula (la), (lb), (lc), (Id), (le) or (If), as defined above. Most preferably, it comprises a compound of formula (la), (lb), (lc), (Id), (le) or (If) as disclosed in Tables 11, 12, 13, 14, 15, 16 and 17 above.

[0245] Experimental section

[0246] Cell culture

[0247] 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 that were isolated and reprogrammed into iPSCs, then differentiated and sorted according to cell markers to collect RPE progenitor cells. Vials were shipped frozen on dry ice and stored at -80°C.

[0248] For phenotypic screening, iPSC-fRPE cells were thawed and cultured in Matrigel-coated flasks with N1 VA medium, which protects the 1X MEM solution supplemented with 2.2 g / L sodium bicarbonate, 0.25 mg / ml taurine, 0.02 pg / ml hydrocortisone, 0.013 pg / ml triiodothyronine, 0.1 pg / ml lipoic acid, 1% MEM non-essential amino acids, 1% penicillin / streptomycin, 2% Neurocult SM1 supplement, and 1% N1 supplement. For the initial cultures, 2 mM Thiazovivin was added to the medium for the first 24 hours of incubation, after which the medium was changed to fresh N1 VA medium and incubated for an additional three days at 37°C and 5% C02.

[0249] Compound screening

[0250] iPSC-fRPE cells were seeded in Matrigel-coated 96-well plates at a density of 10,000 cells per well with N1 VA media and cultured for 24 hours prior to treatment with test compounds in 0.1% DMSO at a final concentration of 5 mM. 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 (STEMCELL) as a positive control. To identify hits that promote RPE pigmentation, cells were maintained for 32 days and treated with media containing test or control compounds according to the media exchange schedule (Figure 1). Pigmentation extent was quantified by measuring absorbance at 510 nm using a Cytation5 imaging reader (BIOTEK). Compounds that normalized absorbance endpoint increased over three standard deviations from the average DMSO reading per plate were considered hits. Pigmentation values were finally reported relative to the plate internal DMSO control.

[0251] Preparation of compounds of the application

[0252] Compounds of formula (I) can be prepared by the methods described below, as well as by synthetic methods known in the art of organic chemistry or modifications familiar to one of ordinary skill in the art. The starting materials used herein are commercially available or can be prepared by routine methods known in the art, such as those described in standard reference books, such as "Compendium of Organic Synthetic Methods, Volumes I-XIN" (published with Wiley-Interscience, ISSN: 1934-4783). Preferred methods include, but are not limited to, those described below.

[0253] These schemes are representative methods and supporting examples that can be used to synthesize compounds of the application. They do not limit the scope of the application in any way.

[0254] General methods - synthesis

[0255] Method 1:

[0256] Scheme 1:

[0257]

[0258] wherein R1, R 11 , R 12 , R2, R3, R4 and R5 are as described in formula I.

[0259] Compounds of general formula la (Scheme 1) can be prepared by reacting a compound of general formula VIII with a carboxylic acid of general formula IX using methods known to chemists in the art.

[0260] Method 2

[0261] Scheme 2:

[0262]

[0263] wherein R1, R 11 , R 12 , R2 I , R3 I , R4 I and R5 I are as described in Formula I.

[0264] Compounds of general Formula Ib (Scheme 2) can be prepared by reacting a compound of general Formula VIII with a carboxylic acid of general Formula X using methods known to chemists in the art.

[0265] Method 3:

[0266] Scheme 3:

[0267]

[0268] wherein R1, R 11 , R 12 , R2 II , R3 II , R4 II and R5 II are as described in Formula I.

[0269] Compounds of general Formula Ic (Scheme 3) can be prepared by reacting a compound of general Formula VIII with a carboxylic acid of general Formula XI using methods known to chemists in the art.

[0270] Method 4:

[0271] Scheme 4:

[0272]

[0273] wherein R1, R 11 , R 12 , R2 III , R3 III , R4 III and R5 III are as described in Formula I.

[0274] Compounds of general Formula Id (Scheme 4) can be prepared by reacting a compound of general Formula VIII with a carboxylic acid of general Formula XII using methods known to chemists in the art.

[0275] Method 5:

[0276] Scheme 5:

[0277]

[0278] wherein R1, R 11 , R 12 , R2 IV , R3 IV , R4 IV and R5 IV are as described in Formula I.

[0279] Compounds of general formula Id (Scheme 5) can be prepared by reacting a compound of general formula VIII with a carboxylic acid of general formula XIII using methods known to chemists in the art.

[0280] Method 6:

[0281] Scheme 6:

[0282]

[0283] wherein R1, R 11 , R 12 , R2 V , R3 V , R4 V and R5 V are as described in Formula I.

[0284] Compounds of general formula Ie (Scheme 6) can be prepared by reacting a compound of general formula VIII with a carboxylic acid of general formula XIV using methods known to chemists in the art.

[0285] Method 7:

[0286] Scheme 7:

[0287]

[0288] wherein R1, R 12 and R 11 are as described in Formula I.

[0289] Compounds of general formula VIII (Scheme 7) can be prepared by reducing the nitro group in a compound of general formula XVII using methods known to chemists in the art. Compounds of general formula XVII can be prepared from an aldehyde of general formula XV by reacting in the presence of a reagent such as p-toluenesulfonylmethyl isocyanide (XVI) in the presence of a base such as potassium carbonate.

[0290] Method 8:

[0291] Scheme 8:

[0292]

[0293] wherein R1, R 11 and R 12 R1, R 20 and R 21 are each hydroxyl or together with the boron atom form a 4,4,5,5-tetramethyl-1,3,2-dioxaborolane group.

[0294] Compounds of general formula I (Scheme 8) can be prepared from compounds of general formula XIX and XX in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) and a base such as potassium carbonate or reaction conditions known to chemists skilled in the art of organic synthesis. Compounds of general formula XIX can be prepared by reacting compounds of general formula XVIII with carboxylic acids of general formula IX-XIV using methods known to chemists skilled in the art.

[0295] Analytical methods

[0296] 1H NMR spectra were recorded in DMSO-d6 / CD3OD / CDCl3 solutions in 5 mm outer diameter tubes [Wilmad NMR tubes (Sigma-Aldrich), 5 mm thin walled, 7" long] at 300.0 K and collected on a Bruker Avance NMR S-400 at 400 MHz for 1 hour. Chemical shifts (δ) are expressed in ppm relative to CDCl3 (CDCl3 = 7.26 ppm), DMSO-d6 (DMSO-d6 = 2.5 ppm), CD3OD (CD3OD = 3.3 ppm). Chemical shifts in CDCl3, DMSO-d6 and CD3OD are relative to tetramethylsilane (TMS, = 0.00 ppm) and expressed in ppm.

[0297] Analytical HPLC

[0298] Analytical HPLC Method A: Chromegabond WR C18 (3 cm x 3.2 mm, 3 μ) column at a flow rate of 1.5 mL / min. As mobile phase, 0.02% TFA in water (mobile phase C) and 0.02% TFA in CH3CN (mobile phase D) were used, starting with 90% C and 10% D, changing to 10% C and 90% D in 3 minutes, then to 90% C and 10% D in 4.0 minutes and staying constant until 5.1 minutes.

[0299] Analytical HPLC Method B: Restek Ultra AQ C18 (30 x 2.1 mm, 3 u) column at a flow rate of 1.5 mL / min. As mobile phase, 0.05% HCOOH in water (mobile phase A) and CH3CN (mobile phase B) were used, starting with 98% A and 2% B for 0.75 min, then changing to 90% A and 10% B in 1.5 min, further to 2% A and 98% B in 3.0 min, keeping this mobile phase composition for 4.0 min, and finally back to the initial conditions at 5.0 min.

[0300] Analytical HPLC Method C: Column - YMC TRIART C18 (33 x 2.1 mm, 3 u), (mobile phase: 95% [0.01% HCOOH in water] and 5% [0.01% HCOOH in CH3CN] for 0.50 min, then changing to 99% [0.01% HCOOH in water] and 1% [0.01% HCOOH in CH3CN] in 3.0 min, keeping this mobile phase composition for 4.0 min, and finally back to the initial conditions in 4.10 min, keeping this mobile phase composition for 4.50 min). Flow = 1.0 ml / min.

[0301] Preparative HPLC

[0302] Preparative HPLC Method A: Waters Sunfire C18 OBD preparative column, 100 A, 5 pm, 19 mm x 100 mm with SunFire C18 Prep Guard Cartridge, 100 A, 10 pm, 19 mm x 10 mm was used. Deionized water (phase A) and HPLC grade methanol (phase B) were used as eluents.

[0303] Preparative HPLC Method B: Waters automated purification instrument equipped with YMC Triart C18 (250 x 21.2 mm, 5 pm) column was run at room temperature at a flow rate of 16 mL / min. The sample was eluted with 20 mM ammonium bicarbonate in water (mobile phase A) and acetonitrile (mobile phase B), with a gradient curve starting with 70% A and 30% B, then 45% A and 55% B in 3 min, 20% A and 80% B in 20 min, then 5% A and 95% B in 21 min, and kept constant for 2 min. Concentration of the pure fractions gave the final product.

[0304] Chiral separation method

[0305] Chiral analysis method

[0306] Chiral separation method A: Separation was performed using Agilent Prep-HPLC, column: Regis Reflect C-Amylose A, containing amylose tris(3,5-dimethylphenylcarbamate) (250x30mm, 5μ), flow rate: 35g / min, mobile phase: 35% CO2 + 65% (0.1% NH3 in methanol), ABPR: 100 bar, temperature: 35°C.

[0307] Chiral separation method B: Separation was accomplished using Agilent Prep-HPLC, column: Daicel Chiralpak IG (250 x 20 mm) containing tris(3-chloro-5-methylphenylcarbamate)-substituted amylose immobilized on 5 μm silica; flow rate: 25 g / min, mobile phase: 45% CO2 + 55% (0.1% NH3 in methanol), ABPR: 120 bar, temperature: 35°C.

[0308] Chiral separation method C: The separation was accomplished using the following: Column: Regis Reflect C-Amylose A, containing amylose tris(3,5-dimethylphenylcarbamate) (250x30mm, 5μ), Mobile phase: 40% CO2 + 60% (0.1% ammonia in methanol), Flow rate: 25.0 g / min, Run time: 10 minutes, Wavelength: 220 nm, ABPR: 110 bar, Temperature: 35°C.

[0309] Chiral separation method D: Separation was accomplished using Agilent Prep-HPLC, column: Chiralpak IG (250x30mm, 5μ), flow rate: 35g / min, mobile phase: 35% CO2 + 65% (0.1% NH3 in methanol), ABPR: 100 bar, temperature: 35°C.

[0310] Chiral separation method E: Separation was accomplished using Agilent Prep-HPLC, column: Chiralpak IG (250x30mm, 5μ), flow rate: 25g / min, mobile phase: 60% CO2 + 40% (0.1% NH3 in methanol), ABPR: 100 bar, temperature: 35°C.

[0311] Chiral separation method F: Separation was accomplished using Agilent Prep-HPLC, column: Chiralpak IG (250x30mm, 5μ), flow rate: 25g / min, mobile phase: 45% CO2 + 55% (0.1% NH3 in methanol), ABPR: 120 bar, temperature: 35°C.

[0312] Chiral separation method G: Separation was done using a column: Chiralpak AD-H (4.6 x 250 mm, 5 µ); mobile phase: 100% EtOH; flow rate: 0.5 ml / min; column temperature: 24 °C; wavelength: 286 nm.

[0313] Chiral preparation method

[0314] Chiral separation method H: Performed using a Daicel Chiralpak AD-H (250 x 20 mm x 5 µm) column coated with amylose-tris(3,5-dimethylphenylcarbamate); mobile phase: hexane-IPA-MeOH, 70-15-15; flow rate: 12 mL / min; column temperature: 24 °C; wavelength: 210 nm, 225 nm, 254 nm.

[0315] Chiral separation method I: Performed using a Daicel Chiralpak AD-H (250 x 20 mm x 5 µm) column coated with amylose-tris(3,5-dimethylphenylcarbamate); mobile phase: hexane-IPA-MeOH, 70-15-15; flow rate: 12 mL / min; column temperature: 24 °C; wavelength: 215 nm, 280 nm.

[0316] Chiral separation method K: Performed using a Daicel Chiralpak AD-H (250 x 20 mm x 5 µm) column coated with amylose-tris(3,5-dimethylphenylcarbamate); mobile phase: EtOH, flow rate: 10 mL / min; column temperature: 24 °C; wavelength: 286 nm.

[0317] General synthesis procedure

[0318] Coupling procedure A: The carboxylic acid (1.1 mmol) and a DMSO solution of N-hydroxylbenzotriazole (100 g / L, 2 mL, 1.5 mmol) were placed in a vial followed by the addition of the aniline derivative (1 mmol). If the amine was used as a hydrochloride salt, then also Et3N (1 mmol) was added. The reaction mixture was stirred on a shaker for 30 min and EDC (1.2 mmol) was added. After charging all reagents, the vial was sealed and stirred in a shaker for 1 h. If a clear solution was formed, the vial was left at room temperature for 24 h. Otherwise, the reaction mixture was kept in an ultrasonic bath for 24 h (intensive heating should be avoided). If the reaction mixture was observed to become strongly thickened so that stirring was ineffective, 0.2 mL of DMSO could be added in one portion. The crude reaction mixture was analyzed by LC-MS and then subjected to chromatographic purification. Purification was performed using an Agilent 1260 Infinity system equipped with a DAD and mass detector.

[0319] Synthesis of intermediates

[0320] Preparation of 5-(2-methoxy-4-nitrophenyl)oxazole

[0321]

[0322] To a stirred solution of 2-methoxy-4-nitrobenzaldehyde (3.00 g, 16.6 mmol) in methanol (20 mL) was added 1-(isocyanomethane)sulfonyl-4-methylbenzene (3.80 g, 19.9 mmol), followed by K2CO3 (8.00 g, 58.0 mmol) and the reaction mixture was heated to 80 ° C for 2 hours. After the reaction was complete, the reaction mass was poured into a saturated NaHCO3 solution (20 mL) and extracted into ethyl acetate (3x100 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude product, which was purified by flash silica gel chromatography (eluted with 30% ethyl acetate in hexane) to give 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole (2.1 g, 57%). LCMS: 221 (M+H).

[0323] Preparation of 3-methoxy-4-(1,3-oxazol-5-yl)aniline

[0324]

[0325] To a stirred solution of 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole (1.00 g, 4.52 mmol) in ethanol (20 mL) was added tin chloride ( II ) (5.14 g, 27.1 mmol) and concentrated HCl (6 mL) solution was added dropwise at 0°C, followed by stirring at room temperature for 6 hours. After completion of the reaction, the reaction mixture was diluted with saturated NaHCO3 solution (20 mL) and extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude 3-methoxy-4-(1,3-oxazol-5-yl)aniline (700 mg, 81%). LCMS: 191 (M+H).

[0326] Preparation of 5-(2-chloro-4-nitrophenyl)-1,3-oxazole

[0327]

[0328] To a stirred solution of 2-chloro-4-nitrobenzaldehyde (3 g, 16.16 mmol) and 1-(isocyanomethane)sulfonyl-4-methylbenzene (4.1 g, 21.0 mmol) in MeOH (30 mL) was added KCO (8.9 g, 64.66 mmol) and the reaction mixture was heated to 80°C for 2 hours. After completion of the reaction, the reaction mass was poured into a saturated NaHCO solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give the crude product, which was purified by flash silica gel chromatography (eluting with 30% ethyl acetate in hexanes) to give 5-(2-chloro-4-nitrophenyl)-1,3-oxazole (2.1 g, 57%). LCMS: 225.2 (M+H).

[0329] Preparation of 3-chloro-4-(1,3-oxazol-5-yl)aniline

[0330]

[0331] To a stirred solution of 5-(2-chloro-4-nitrophenyl)-1,3-oxazole (3 g, 13.4 mmol) in EtOH (40 mL) was added tin chloride ( II ) dihydrate (12.08 g, 53.57 mmol) was added dropwise to a concentrated HCl solution (5 mL) at 0°C, and the reaction mixture was stirred at 80°C for 30 minutes. After completion of the reaction, the reaction mass was neutralized with 2N NaOH solution and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed thoroughly with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 3-chloro-4-(1,3-oxazol-5-yl)aniline (1.5 g, 57%). LCMS: 195 (M+H).

[0332] Preparation of 5-(2-fluoro-4-nitrophenyl)-1,3-oxazole

[0333]

[0334] To a stirred solution of 2-fluoro-4-nitrobenzaldehyde (5 g, 29.56 mmol) and l-(isocyano- methan)sulfonyl-4-methylbenzene (7.5 g, 38.43 mmol) in MeOH (35 mL) was added K2CO3(16.3 g, 118.27 mmol) and the reaction mixture was heated to 80 °C for 2 h. After completion of the reaction, the reaction mass was poured into saturated NaHCO3solution (50 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under vacuum to get the crude product which was purified by flash silica gel chromatography eluting in 30% ethyl acetate in hexane to get 5-(2-fluoro-4-nitrophenyl)-l,3-oxazole (2.5 g, 40%). LCMS: 209.2 (M+H).

[0335] Preparation of 3-fluoro-4-(l,3-oxazol-5-yl)aniline

[0336]

[0337] To a stirred solution of 5-(2-fluoro-4-nitrophenyl)-l,3-oxazole (700 mg, 3.36 mmol) in EtOH (35 mL) was added tin (II) chloride dihydrate (3.03 g, 13.46 mmol) and a solution of concentrated HCl (2 mL) was added dropwise at 0 °C and the reaction mixture was stirred at 80 °C for 30 min. After completion of the reaction, the reaction mass was neutralized with 2 N NaOH solution and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed thoroughly with water, dried over anhydrous sodium sulfate and concentrated under vacuum to get 3-fluoro-4-(l,3-oxazol-5-yl)aniline (350 mg, 53%). LCMS: 179 (M+H).

[0338] Preparation of 5-(2-methyl-4-nitrophenyl)oxazole

[0339]

[0340] To a stirred solution of 2-methyl-4-nitrobenzaldehyde (1.02 g, 6.05 mmol) and 1-(isocyanomethane)sulfonyl-4-methylbenzene (1.36 g, 7.05 mmol) in MeOH (25 mL) was added potassium carbonate (1.67 g, 12.1 mmol) and the reaction mixture was heated to reflux for 2 h. After TLC indicated complete consumption of the starting material, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous NaHCO₃ (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (30 mL), brine (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography to afford 5-(2-methyl-4-nitrophenyl)oxazole (1.2 g, 91%).

[0341] Preparation of 3-methyl-4-(oxazol-5-yl)aniline

[0342]

[0343] To a stirred solution of 5-(2-methyl-4-nitrophenyl)oxazole (1.1 g, 5.39 mmol) in ethanol (20 mL) was added tin chloride ( II ) dihydrate (4.08 g, 21.5 mmol). The mixture was cooled to 0 ° C and concentrated. HCl (3.0 mL) was added dropwise. The reaction mixture was then stirred at 80 ° C for 0.5 hours. After TLC showed that the reaction was complete, the reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 aqueous solution (30 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with water (20 mL), brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 3-methyl-4-(oxazol-5-yl)aniline (610 mg, 65%).

[0344] Preparation of 5-(3-methyl-4-nitrophenyl)oxazole

[0345]

[0346] To 3-methyl-4-nitrobenzaldehyde (2.01g, 12.1mmol) and 1-(isocyanomethane) sulfonyl-4-methylbenzene (2.6g, 13.3mmol) in MeOH (50mL) stirred solution was added KCO (3.34g, 24.2mmol) and the reaction mixture was heated to reflux for 2 hours. After TLC showed that the raw material was completely consumed, the reaction was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was treated with saturated NaHCO aqueous solution (40mL) and extracted with ethyl acetate (3x40mL). The organic layers were combined, washed with water (30mL) and brine (20mL), through NaSO dried, and concentrated under reduced pressure. Silica was used to obtain 5-(3-methyl-4-nitrophenyl) oxazole (1.9g, 76%) by column chromatography purification of crude product.

[0347] Preparation of 2-methyl-4-(oxazol-5-yl)aniline

[0348]

[0349] To a stirred solution of 5-(3-methyl-4-nitrophenyl)oxazole (1.8g, 5.39mmol) in methanol (20mL) was added Raney nickel (2.0g) at room temperature. The reaction mixture was stirred for 18 hours under H2 atmosphere. After the complete consumption of raw material, the reaction mixture was filtered through a diatomaceous earth bed and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2-methyl-4-(oxazole-5-yl)aniline (1.3g, 84%).

[0350] LCMS: 174.7 (M+H)

[0351] Preparation of 5-(4-nitro-2-(trifluoromethyl)phenyl)oxazole

[0352]

[0353] To a stirred solution of 4-nitro-2-(trifluoromethyl)benzaldehyde (2.0 g, 9.13 mmol) and 1-(isocyanomethane)sulfonyl-4-methylbenzene (2.05 g, 10.5 mmol) in MeOH (50 mL) was added KCO (2.52 g, 18.26 mmol) and the reaction mixture was heated at reflux for 2 hours. After TLC indicated complete consumption of the starting material, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous NaHCO (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (30 mL), brine (20 mL), dried over NaSO, and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography to afford 5-(4-nitro-2-(trifluoromethyl)phenyl)oxazole (1.66 g, 72%).

[0354] Preparation of 4-(oxazol-5-yl)-3-(trifluoromethyl)aniline

[0355]

[0356] To a stirred solution of 5-(4-nitro-2-(trifluoromethyl)phenyl)oxazole (1.545 g, 5.99 mmol) in ethanol (30 mL) was added tin chloride ( II ) dihydrate (5.40 g, 23.95 mmol). The mixture was cooled to 0 ° C and concentrated HCl (3.5 mL) was added dropwise. The reaction mixture was then stirred at 80 ° C for 2.0 hours. After TLC showed that the reaction was complete, the reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 aqueous solution (70 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with water (40 mL), brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 4-(oxazol-5-yl)-3-(trifluoromethyl)aniline (1.13 mg, 83%).

[0357] Preparation of chroman-3-carbonyl chloride

[0358]

[0359] To a solution of chroman-3-carboxylic acid (750 mg, 4.21 mmol) in anhydrous dichloromethane (10 mL) was added thionyl chloride (0.45 mL, 6.32 mmol) at 0°C, followed by DMF (catalytic). After addition, the reaction mixture was warmed to room temperature and heated to reflux for 2.0 hours. The reaction mass was cooled to room temperature, the solvent was evaporated under reduced pressure, and dried in vacuo.

[0360] Preparation of N-(4-bromo-2-(difluoromethoxy)phenyl)chroman-3-carboxamide

[0361]

[0362] A solution of chroman-3-carbonyl chloride in anhydrous dichloromethane (10 mL) was added to a solution of a mixture of 4-bromo-2-(difluoromethoxy)aniline (600 mg, 2.521 mmol) and triethylamine (1.1 mL, 7.563 mmol) in anhydrous dichloromethane (10 mL) at 0°C. After addition, the reaction was slowly warmed to room temperature over 3 hours. The reaction was diluted with dichloromethane (5 mL), washed with water (10 mL) and brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography to obtain N-(4-bromo-2-(difluoromethoxy)phenyl)chroman-3-carboxamide (520 mg, 62%).

[0363] 5-(3-methoxy-4-nitrophenyl)oxazole

[0364]

[0365] To a stirred solution of 3-methoxy-4-nitrobenzaldehyde (2.5 g, 13.80 mmol) and tosylmethyl isocyanide (3.1 g, 15.87 mmol) in MeOH (60 mL) was added K2CO3(3.8 g, 27.60 mmol) and the reaction mixture was heated to reflux for 2 h. After consumption of starting material was checked by TLC, the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, the residue was treated with saturated aqueous NaHCO3(40 mL) and extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with water (40 mL), brine (30 mL), dried over Na2SO4and concentrated under reduced pressure to get crude product which was triturated with dichloromethane / hexane to get 5-(3-methoxy-4-nitrophenyl)oxazole (2.4 g, 78%).

[0366] 2-nitro-5-(oxazol-5-yl)phenol

[0367]

[0368] To a stirred solution of 5-(3-methoxy-4-nitrophenyl)oxazole (2.0 g, 9.09 mmol) in dry dichloromethane (50 mL) was added BBr3(1 M in dichloromethane, 22.7 mL, 22.72 mmol) at 0 °C under N2. The resulting mixture was allowed to warm to room temperature and stirred for 2 h. After consumption of starting material was checked by TLC, the reaction mixture was quenched with ice cold water (30 mL) and stirred at room temperature for 30 min. The reaction mixture was filtered and the solid was washed with dichloromethane (2 x 25 mL). The filtrate was washed with water (30 mL), brine (20 mL), dried over Na2SO4and concentrated under reduced pressure. The crude was purified using silica gel by column chromatography to get 2-nitro-5-(oxazol-5-yl)phenol (1.7 g, 90%) as a solid.

[0369]

[0370] A mixture of 2-nitro-5-(oxazol-5-yl)phenol (1.65g, 8.01mmol), dimethylaminoethyl chloride hydrochloride (1.9g, 13.2mmol), K2CO3 (6.6g, 47.7mmol), potassium iodide (215mg, 1.29mmol) and DMF (35mL) was heated at 100°C for 2 hours. The reaction was monitored by TLC (part of the raw materials were unreacted), and the reaction mixture was cooled to room temperature and concentrated. The residue was diluted with saturated NH4Cl aqueous solution (20mL), extracted with ethyl acetate (3x50mL), and the organic layer was washed with water (50mL), brine (40mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain N,N-dimethyl-2-(2-nitro-5-(oxazol-5-yl)phenoxy)ethylamine as a solid.

[0371] Preparation of 2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)aniline

[0372]

[0373] To a stirred solution of N,N-dimethyl-2-(2-nitro-5-(oxazol-5-yl)phenoxy)ethanamine (725 mg, 2.62 mmol) in ethanol (20 mL) was added tin chloride ( II ) dihydrate (2.95 g, 13.08 mmol) was added and the reaction mixture was heated to 65-70°C for 1.5 hours. After the starting material was consumed as detected by TLC, the reaction mixture was cooled to room temperature, basified with saturated aqueous Na2CO3 solution (45 mL), diluted with dichloromethane (60 mL), and the aqueous phase was extracted with dichloromethane (3 x 30 mL). The organic layers were combined, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)aniline (575 mg, 86%).

[0374] Preparation of 5-(4-nitro-2-(trifluoromethyl)phenyl)oxazole

[0375]

[0376] To a stirred solution of 4-nitro-2-(trifluoromethyl)benzaldehyde (2.0 g, 9.13 mmol) and tosylmethyl isocyanide (2.05 g, 10.5 mmol) in MeOH (50 mL) was added KCO (2.52 g, 18.26 mmol) and the reaction mixture was heated to reflux for 2 hours. After TLC showed that the starting material was consumed, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous NaHCO (20 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water (30 mL), brine (20 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to afford 5-(4-nitro-2-(trifluoromethyl)phenyl)oxazole (1.66 g, 72%) as a solid.

[0377] Preparation of 4-(oxazol-5-yl)-3-(trifluoromethyl)aniline

[0378]

[0379] To a stirred solution of 5-(4-nitro-2-(trifluoromethyl)phenyl)oxazole (1.545 g, 5.99 mmol) in ethanol (30 mL) was added tin chloride ( II ) dihydrate (5.40 g, 23.95 mmol). The mixture was cooled to 0 ° C and concentrated HCl (3.5 mL) was added dropwise. The reaction mixture was then stirred at 80 ° C for 2.0 hours. After TLC showed that the reaction was complete, the reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 aqueous solution (70 mL), and extracted with ethyl acetate (3×50 mL). The organic layers were combined, washed with water (40 mL), brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 4-(oxazol-5-yl)-3-(trifluoromethyl)aniline (1.13 g, 83%).

[0380] Preparation of N-(4-bromo-3-chloro-5-fluorophenyl)chroman-3-carboxamide

[0381]

[0382] A solution of chroman-3-carbonyl chloride in anhydrous dichloromethane (10 mL) was added to a mixture of 4-bromo-3-chloro-5-fluoroaniline (300 mg, 1.34 mmol) and triethylamine (0.56 mL, 4.00 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. After addition, the reaction was slowly allowed to warm to room temperature over 3 h. The reaction was diluted with dichloromethane (10 mL), washed with water (10 mL) and brine (15 mL), dried over Na2S04, concentrated under reduced pressure to obtain the crude. The crude was purified by column chromatography to obtain N-(4-bromo-3-chloro-5-fluorophenyl)chroman-3-carboxamide (280 mg, 49%) as a solid.

[0383] Preparation of N-(4-bromo-3-chloro-2-fluorophenyl)chroman-3-carboxamide

[0384]

[0385] A solution of chroman-3-carbonyl chloride in anhydrous dichloromethane (10 mL) was added to a mixture of 4-bromo-3-chloro-5-fluoroaniline (300 mg, 1.34 mmol) and triethylamine (0.56 mL, 4.00 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. After addition, the reaction was slowly allowed to warm to room temperature over 3 h. The reaction mixture was monitored by TLC. After maximum conversion, the reaction mixture was diluted with dichloromethane (5 mL), washed with water (10 mL) and brine (15 mL), dried over sodium sulfate, concentrated under reduced pressure to obtain crude N-(4-bromo-3-chloro-2-fluorophenyl)chroman-3-carboxamide. The crude was purified by column chromatography to obtain N-(4-bromo-3-chloro-2-fluorophenyl)chroman-3-carboxamide (320 mg, 31.2%) as a solid.

[0386] Compound (1): First (-)-N-(3-chloro-4-(l,3-oxazol-5-yl)phenyl)chroman-3- carboxamide

[0387]

[0388] To a stirred solution of 3-chloro-4-(oxazol-5-yl)aniline (100 mg, 0.51 mmol) and indol-3-carboxylic acid (109 mg, 0.61 mmol) in DMF (1 mL) was added DIPEA (0.26 mL) and HATU (392 mg, 1.03 mmol) at room temperature and the reaction stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-chloro-4-(1,3-oxazol-5-yl)phenyl)indol-3- carboxamide (34 mg, 18%). The racemic product was separated by chiral chromatography using chiral separation method C to yield compound (1) which was characterised by retention time = 4.76 min (eluted first from the column).

[0389] Analytical HPLC Method A. Rt: 1.73 min; MS: 355 (M+H).

[0390] [α]D 25 = -7.57 (589 nm, c = 0.49, DMSO).

[0391] Compound (2): Second (+)-N-(3-chloro-4-(1,3-oxazol-5-yl)phenyl)indol-3- carboxamide

[0392]

[0393] To a stirred solution of 3-chloro-4-(oxazol-5-yl)aniline (100 mg, 0.51 mmol) and indol-3-carboxylic acid (109 mg, 0.61 mmol) in DMF (1 mL) was added DIPEA (0.26 mL) and HATU (392 mg, 1.03 mmol) at room temperature and the reaction stirred at room temperature for 16 h. Upon completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-chloro-4-(1,3-oxazol-5-yl)phenyl)indol-3- carboxamide (34 mg, 18%). The racemic product was separated by chiral chromatography using chiral separation method C to yield compound (2) which was characterised by retention time = 6.04 min (second from column eluted).

[0394] Analytical HPLC Method A. Rt: 1.73 min; MS: 355 (M+H).

[0395] [α]D 25 = +5.83 (589 nm, c = 0.55, DMSO).

[0396] Compound (3): N-(3-chloro-4-(oxazol-5-yl)phenyl)isoindol-3-carboxamide

[0397]

[0398] The title compound was prepared from isochromane-3-carboxylic acid and 3-chloro-4-(oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A (33% yield).

[0399] MS: 355.0 (M+H).

[0400] 1 H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), 8.53 (s, 1H), 8.11 (d, J = 1.7Hz, 1H), 7.84 (dd, J = 8.7, 1.9Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.25–7.18 (m, 3H), 7.16–7.09 (m, 1H), 5.04–4.85 (m, 2H), 4.48–4.37 (m, 1H), 3.19–2.95 (m, 2H).

[0401] Compound (4): N-(3-chloro-4-(oxazol-5-yl)phenyl)chromane-4-carboxamide

[0402]

[0403] The title compound was prepared from 3,4-dihydro-2H-1-chromene-4-carboxylic acid and 3-chloro-4-(oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A (12% yield).

[0404] MS: 355.0 (M+H).

[0405] Compound (5): N-(3-chloro-4-(oxazol-5-yl)phenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide

[0406]

[0407] A mixture of 3-chloro-4-(oxazol-5-yl)aniline (110 mg, 0.567 mmol), 2,3-dihydro-1H-indene-1-carboxylic acid (105 mg, 0.595 mmol), and N-hydroxybenzotriazole (85 mg, 0.624 mmol) was dissolved in 1 ml of anhydrous dimethylacetamide and cooled to -10°C. 106 mg (0.68 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was then added, and the mixture was stirred at room temperature for 16 hours. 30 ml of water was added, and the resulting precipitate was filtered, washed three times with 10 ml of water, once with 3 ml of isopropanol, and twice with 10 ml of hexane. It was then dried in air at 50°C. 110 mg (55% yield) was obtained.

[0408] MS: 353.0 (M+H).

[0409] 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.52 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.70 (s, 1H), 7.65 (dd, J = 8.7, 2.0 Hz, 1H), 7.18 - 7.00 (m, 4H), 2.94 (d, J = 7.8 Hz, 2H), 2.89 - 2.72 (m, 3H), 2.18 - 2.01 (m, 1H), 1.87 - 1.69 (m, 1H).

[0410] Compound (6): N-(3-chloro-4-(oxazol-5-yl)phenyl)-2,3-dihydro-lH-indene-l- carboxamide

[0411]

[0412] The title compound was prepared from 2,3-dihydro-lH-indene-l-carboxylic acid and 3-chloro-4-(oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A (yield 9%).

[0413] MS: 339.0 (M+H).

[0414] Compound (7): N-(3-chloro-4-(oxazol-5-yl)phenyl)-2,3-dihydro-lH-indene-2- carboxamide

[0415]

[0416] The title compound was prepared from 2,3-dihydro-lH-indene-2-carboxylic acid and 3-chloro-4-(oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A (yield 14%).

[0417] MS: 339.2 (M+H).

[0418] Compound (8): N-(3-chloro-4-(oxazol-5-yl)phenyl)-6-methoxychroman-3- carboxamide

[0419]

[0420] To a stirred solution of 3-chloro-4-(oxazol-5-yl)aniline (200 mg, 1.03 mmol) and 6-methoxy-3,4-dihydro-2H-1-chromene-3-carboxylic acid (278.76 mg, 1.34 mmol) in DMF (2 mL) was added DIPEA (0.52 mL) and HATU (784 mg, 2.06 mmol) at room temperature, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-chloro-4-(oxazol-5-yl)phenyl)-6-methoxychroman-3-carboxamide (143 mg, 36%).

[0421] Analytical HPLC Method A. Rt: 1.73 min; MS: 385.2 (M+H).

[0422] Compound (9): N-(3-fluoro-4-(oxazol-5-yl)phenyl)chromane-4-carboxamide

[0423]

[0424] To a stirred solution of 3-fluoro-4-(1,3-oxazol-5-yl)aniline (150 mg, 0.84 mmol) and 3,4-dihydro-2H-1-chromene-4-carboxylic acid (195.21 mg, 1.09 mmol) in DMF (2 mL) was added DIPEA (0.44 mL) and HATU (640 mg, 1.68 mmol) at room temperature, and the reaction was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-fluoro-4-(oxazol-5-yl)phenyl)chromene-4-carboxamide (102 mg, 35%).

[0425] Analytical HPLC Method A. Rt: 1.50 min; MS: 339.2 (M+H).

[0426] Compound (10): N-(3-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide

[0427]

[0428] To a stirred solution of 3-fluoro-4-(l,3-oxazol-5-yl)aniline (100 mg, 0.56 mmol) and 3,4-dihydro-2H-l-benzopyran-3-carboxylic acid (130.7 mg, 0.73 mmol) in DMF (1 mL) was added DIPEA (0.29 mL) and HATU (427 mg, 1.12 mmol) at room temperature and the reaction was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-fluoro-4-(oxazol-5-yl)phenyl)oxazinan-3-carboxamide (70 mg, 36%).

[0429] Analytical HPLC Method A. Rt: 1.62 min; MS: 339.2 (M+H).

[0430] Compound (11): N-(3-fluoro-4-(oxazol-5-yl)phenyl)-6-methoxyoxazinan-3- carboxamide

[0431]

[0432] To a stirred solution of 3-fluoro-4-(l,3-oxazol-5-yl)aniline (150 mg, 0.84 mmol) and 6-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid (227.86 mg, 1.09 mmol) in DMF (1.5 mL) was added DIPEA (0.44 mL) and HATU (640.5 mg, 1.68 mmol) at room temperature and the reaction was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-fluoro-4-(oxazol-5-yl)phenyl)-6-methoxyoxazinan-3-carboxamide (121 mg, 38%),

[0433] Analytical HPLC Method A. Rt: 1.64 min; MS: 369.3 (M+H),

[0434] Compound (12): N-(3-methoxy-4-(oxazol-5-yl)phenyl)oxazinan-4-carboxamide

[0435]

[0436] To a stirred solution of 3-methoxy-4-(oxazol-5-yl)aniline (75 mg, 0.395 mmol) and 3,4-dihydro-2H-l-benzopyran-4-carboxylic acid (105.3 mg, 0.592 mmol) in DMF (3 mL) was added DIPEA (0.15 mL) and HATU (226 mg, 0.592 mmol) at room temperature and the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-methoxy-4-(oxazol-5-yl)phenyl)chromane-4-carboxamide (60.07 mg, 44%).

[0437] Analytical HPLC Method A. Rt: 1.42 min; MS: 351.2 (M+H).

[0438] Compound (13): N-(3-methoxy-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide

[0439]

[0440] To a stirred solution of 3-methoxy-4-(oxazol-5-yl)aniline (75 mg, 0.395 mmol) and 3,4-dihydro-2H-l-benzopyran-3-carboxylic acid (105.3 mg, 0.592 mmol) in DMF (3 mL) was added DIPEA (0.15 mL) and HATU (226 mg, 0.592 mmol) at room temperature and the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain N-(3-methoxy-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide (77.6 mg, 56%).

[0441] Analytical HPLC Method A. Rt: 1.59 min; MS: 351.2 (M+H).

[0442] Compound (14): 6-methoxy-N-(3-methoxy-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0443]

[0444] To a stirred solution of 3-methoxy-4-(oxazol-5-yl)aniline (75 mg, 0.395 mmol) and 6-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid (123.1 mg, 0.592 mmol) in DMF (3 mL) was added DIPEA (0.15 mL) and HATU (226 mg, 0.592 mmol) at room temperature and the reaction was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was purified by preparative HPLC to obtain 6-methoxy-N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (72.3 mg, 48%).

[0445] Analytical HPLC Method A. Rt: 1.55 min; MS: 381.2 (M+H).

[0446] Compound (15): First N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3- carboxamide

[0447]

[0448] Racemic N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (Compound (13)) was subjected to chiral separation using Chiral Separation Method K. First N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide was identified using Chiral Separation Method G, Rt: 9.09 min.

[0449] MS: 351.25 (M+H).

[0450] Compound (16): Second N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3- carboxamide

[0451]

[0452] Racemic N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (Compound (13)) was subjected to chiral separation using Chiral Separation Method K. First N-(3-methoxy-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide was identified using Chiral Separation Method G, Rt: 10.85 min.

[0453] MS: 351.25 (M+H).

[0454] Compound (17): N-(3-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide

[0455]

[0456] A solution of chroman-3-carbonyl chloride freshly prepared in anhydrous dichloromethane (10 mL) was added to a mixture of 3-methyl-4-(oxazol-5-yl)aniline (500 mg, 2.87 mmol) and triethylamine (1.25 mL, 8.61 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. After the addition was complete, the reaction was slowly warmed to room temperature over 3 hours. The reaction was monitored by TLC, after maximum conversion (part of the starting material was still unreacted), it was diluted with dichloromethane (5 mL), washed with water (10 mL) and brine (15 mL), dried over Na2S04and concentrated under reduced pressure. The crude product was purified by column chromatography and then triturated with MTBE to obtain N-(3-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (240 mg, 25%).

[0457] Analytical HPLC Method B. Rt: 2.47 min, LCMS: 335.08 (M+H).

[0458] Compound (18): First N-(3-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide

[0459]

[0460] The title compound (65.6 mg) was obtained by chiral separation of racemic N-(3-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (compound (17)) using Chiral Separation Method A, characterized by retention time = 5.41. (The first compound to elute from the column)

[0461] Compound (19): Second N-(3-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide

[0462]

[0463] The title compound (75.6 mg) was obtained by chiral separation of racemic N-(3-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (compound (17)) using Chiral Separation Method A, characterized by retention time = 11.73 min. (The second compound to elute from the column)

[0464] Compound (20): N-(2-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide

[0465]

[0466] A freshly prepared solution of chroman-3-carbonyl chloride in anhydrous dichloromethane (10 mL) was added to a mixture of 3-methyl-4-(oxazol-5-yl)aniline (500 mg, 2.87 mmol) and triethylamine (1.25 mL, 8.61 mmol) in anhydrous dichloromethane (10 mL) at 0°C. After the addition was complete, the reaction was slowly warmed to room temperature over 3 hours. The reaction was monitored by TLC and after maximum conversion (some starting material remained unreacted), it was diluted with dichloromethane (5 mL), washed with water (10 mL) and brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography and then triturated with MTBE to obtain N-(2-methyl-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide (210 mg, 22%).

[0467] Analytical HPLC method B. Rt: 2.56 min, LCMS: 335.1

[0468] Compound (21): First N-(2-methyl-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide

[0469]

[0470] Compound (20) was chirally separated using chiral separation method A to obtain (69.9 mg) characterized by a retention time of 5.41 min. (First eluting compound)

[0471] Compound (22): Second N-(2-methyl-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide

[0472]

[0473] Compound (20) was chirally separated using chiral separation method A to obtain (73.2 mg) characterized by retention time = 11.73 min. (Second eluting compound)

[0474] Compound (23): N-(2-(difluoromethoxy)-4-(oxazol-5-yl)phenyl)chroman-3-carboxamide

[0475]

[0476] To a stirred solution of N-(4-bromo-2-(difluoromethoxy)phenyl)chromane-3- carboxamide (400 mg, 1.01 mmol) in 1,4-dioxane / water (20 mL, 2:1) under argon was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (255 mg, 1.31 mmol) and Na2C03(213 mg, 2.02 mmol). The reaction mixture was degassed with argon for 20 minutes. Pd(PPh3)4(58 mg, 0.05 mmol) was then added and the mixture was degassed with argon for 5 minutes. The reaction mixture was sealed and stirred at 80 °C for 10 hours. After maximum consumption of starting material, the reaction mixture was cooled to room temperature, diluted with water (5.0 mL) and extracted with EtOAc (2 x 50 mL). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2S04and evaporated under reduced pressure. The crude product was purified by column chromatography to give racemic N-(2-(difluoromethoxy)-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide (152 mg, 39%).

[0477] Analytical HPLC Method B. Rt: 2.50 min, LCMS: 387 (M+H).

[0478] Compound (24): First N-(2-(difluoromethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0479]

[0480] Chiral separation of racemic N-(2-(difluoromethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide compound (23) using Chiral separation method C gave compound (24) (44.9 mg) characterized by retention time = 6.64 min. (first eluting compound)

[0481] Compound (25): Second N-(2-(difluoromethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0482]

[0483] Chiral separation of racemic N-(2-(difluoromethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide compound (23) using Chiral separation method C gave compound (25) (47.0 mg) characterized by retention time = 8.67 min. (second eluting compound)

[0484] Compound (26): First N-(3-chloro-4-(oxazol-5-yl)phenyl)-6-fluorochroman-3-carboxamide

[0485]

[0486] The racemic compound was prepared from 6-fluorochroman-3-carboxylic acid and 3-chloro-4-(oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A.

[0487] MS: 373.0 (M+H).

[0488] Chiral separation of the racemic N-(3-chloro-4-(oxazol-5-yl)phenyl)-6- fluorochroman-3-carboxamide compound was accomplished using chiral separation method H to obtain compound (26) characterized by a retention time = 10.9 min. (first eluting compound)

[0489] Compound (27): second N-(3-chloro-4-(oxazol-5-yl)phenyl)-6-fluorochroman-3- carboxamide

[0490]

[0491] Chiral separation of the racemic N-(3-chloro-4-(oxazol-5-yl)phenyl)-6- fluorochroman-3-carboxamide compound was accomplished using chiral separation method H to obtain compound 26 characterized by a retention time = 18.9 min. (second eluting compound)

[0492] Compound (28): racemic N-(3-chloro-4-(oxazol-5-yl)phenyl)-7-fluorochroman-3- carboxamide

[0493]

[0494] The racemic compound was prepared from 7-fluorochroman-3-carboxylic acid (1.1 mmol) and 3-chloro-4-(oxazol-5-yl)aniline using coupling procedure A. The racemic product was purified by preparative HPLC method (511 mg, 71% yield).

[0495] MS: 373.0 (M+H).

[0496] Compound (29): first N-(3-chloro-4-(oxazol-5-yl)phenyl)-7-fluorochroman-3- carboxamide

[0497]

[0498] Chiral separation of the racemic N-(3-chloro-4-(oxazol-5-yl)phenyl)-7- fluorochroman-3-carboxamide compound was accomplished using chiral separation method I to obtain compound 26 (100.3 mg) characterized by a retention time = 11.5 min. (first eluting compound)

[0499] Compound (30): Second N-(3-chloro-4-(oxazol-5-yl)phenyl)-7-fluoroindoline-3- carboxamide

[0500]

[0501] Chiral separation of racemic N-(3-chloro-4-(oxazol-5-yl)phenyl)-7-fluoroindoline-3- carboxamide compound was accomplished using chiral separation method I to obtain compound 26 (87.1 mg) characterized by retention time = 15.8 min. (second eluting compound)

[0502] Compound (31): 6-chloro-N-(3-chloro-4-(oxazol-5-yl)phenyl)indoline-3-carboxamide

[0503]

[0504] The title compound was prepared from 6-chloroindoline-3-carboxylic acid and 3-chloro-4- (oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A (yield 16%).

[0505] MS: 389.0 (M+H).

[0506] Compound (32): N-(3-chloro-4-(oxazol-5-yl)phenyl)-6,8-difluoroindoline-3-carboxamide

[0507]

[0508] The title compound was prepared from 6,8-difluoroindoline-3-carboxylic acid and 3-chloro-4- (oxazol-5-yl)aniline using coupling procedure A and preparative HPLC method A (yield 18%).

[0509] MS: 391.0 (M+H).

[0510] 1 H NMR (500 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.52 (s, 1H), 8.01 - 7.97 (m, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.71 (s, 1H), 7.61 (dd, J = 8.5, 1.6 Hz, 1H), 7.14 - 7.06 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.54 - 4.48 (m, 1H), 4.16 - 4.08 (m, 1H), 3.13 - 3.08 (m, 1H), 3.08 - 3.00 (m, 2H).

[0511] Compound (33): N-(3-chloro-4-(oxazol-5-yl)phenyl)-5-methoxychromane-3- carboxamide

[0512]

[0513] The title compound was prepared from 5-methoxychromane-3-carboxylic acid and 3-chloro-4-(oxazol-5-yl)phenylamine using coupling procedure A and preparative HPLC method A (yield: 16.6%).

[0514] MS: 385.0 (M+H)

[0515] Compound (34): N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0516]

[0517] To a mixture of 2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenylamine (535 mg, 2.16 mmol) and triethylamine (0.9 mL, 6.50 mmol) in anhydrous dichloromethane (10 mL) at 0 °C was added a solution of chromane-3-carbonyl chloride in anhydrous dichloromethane (10 mL). After the addition, the reaction was slowly warmed to room temperature over 3 hours. The reaction was monitored by TLC. After maximum conversion (part of the starting material was still unreacted), the reaction mixture was diluted with dichloromethane (10 mL), washed with water (30 mL) and brine (20 mL), dried over Na2S04and concentrated under reduced pressure. The crude mixture was purified by column chromatography to obtain racemic N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide as a solid (410 mg, 45%).

[0518] Analytical HPLC method C. Rt: 2.03 min; MS: 408.2 (M+H).

[0519] Compound (35): first N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0520]

[0521] Chiral separation method D was used for the chiral separation of racemic N-(2-(2- (dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide (compound (34)). The first N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide was eluted first at 4.16 min (83.8 mg).

[0522] Analytical HPLC Method C. Rt: 2.03 min; MS: 408.2 (M+H).

[0523] Compound (36): Second N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5- yl)phenyl)chromane-3-carboxamide

[0524]

[0525] Racemic N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide (compound (34)) was subjected to chiral separation using chiral separation method D. The second N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5- yl)phenyl)chromane-3-carboxamide eluted first at 7.89 min (56.3 mg).

[0526] Analytical HPLC Method C. Rt: 2.03 min; MS: 408.2 (M+H).

[0527] Compound (37): Racemic N-(4-(oxazol-5-yl)-3-(trifluoromethyl)phenyl)chromane- 3-carboxamide

[0528]

[0529] To a mixture of 4-(oxazol-5-yl)-3-(trifluoromethyl)aniline (600 mg, 2.63 mmol) and triethylamine (1.1 mL, 7.90 mmol) in anhydrous dichloromethane (10 mL) at 0 °C was added a solution of chromane-3-carbonyl chloride in anhydrous dichloromethane (10 mL). After the addition, the reaction was slowly warmed to room temperature over 3 hours. The reaction was monitored by TLC. After maximum conversion (part of the starting material was still unreacted), the reaction mixture was diluted with dichloromethane (5 mL), washed with water (20 mL) and brine (15 mL), dried over Na2S04and concentrated under reduced pressure. The crude was purified by column chromatography to obtain racemic N-(4-(oxazol-5-yl)-3- (trifluoromethyl)phenyl)chromane-3-carboxamide as a solid (350 mg, 35%).

[0530] Analytical HPLC Method C. Rt: 2.79 min; MS: 389.1 (M+H).

[0531] Compound (38): First N-(4-(oxazol-5-yl)-3-(trifluoromethyl)phenyl)chromane-3- carboxamide

[0532]

[0533] Racemic N-(4-(oxazol-5-yl)-3-(trifluoromethyl)phenyl)chromane-3-carboxamide was subjected to chiral separation using Chiral Separation Method E. The first N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide eluted at 2.69 min (70.2 mg).

[0534] Analytical HPLC Method C. Rt: 2.79 min; MS: 389.1 (M+H).

[0535] Compound (39): Second N-(4-(oxazol-5-yl)-3-(trifluoromethyl)phenyl)chromane-3- carboxamide

[0536]

[0537] Racemic N-(4-(oxazol-5-yl)-3-(trifluoromethyl)phenyl)chromane-3-carboxamide was subjected to chiral separation using Chiral Separation Method E. The second N-(2-(2-(dimethylamino)ethoxy)-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide eluted at 3.24 min (71.6 mg).

[0538] Analytical HPLC Method C. Rt: 2.79 min; MS: 389.1 (M+H).

[0539] 化合物(40) : Second N-(3-chloro-5-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide

[0540]

[0541] To a stirred solution of N-(4-bromo-3-chloro-2-fluorophenyl)chromane-3-carboxamide (100 mg, 0.260 mmol) in 1,4-dioxane / water (6 mL, 2: 1) under argon was added 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)oxazole (66 mg, 0.338 mmol) and Na2CO3(55 mg, 0.521 mmol). The reaction mixture was degassed with argon for 20 minutes. Pd(dppf)Cl l2dichloromethane complex (10.6 mg, 0.013 mmol) and degassed with argon for 5 minutes. The reaction mixture was sealed and stirred at 80 °C for 8.0 hours. The reaction mixture was cooled to room temperature, diluted with water (5.0 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were combined, washed with water and brine, dried over anhydrous Na2S04and evaporated under reduced pressure. The crude was purified by column chromatography to obtain racemic N-(3-chloro-5-fluoro-4-(oxazol-5- yl)phenyl)chromane-3-carboxamide as a solid (20 mg, 20%).

[0542] Racemic N-(3-chloro-5-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide was subjected to chiral separation using chiral separation method F. The second N-(3-chloro-5-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide eluted at 5.25 min second (21.6 mg).

[0543] Analytical HPLC method C. Rt: 2.78 min; MS: 373.1 (M+H).

[0544] Compound (41): First N-(3-chloro-5-fluoro-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0545]

[0546] To a stirred solution of N-(4-bromo-3-chloro-2-fluorophenyl)chromane-3- carboxamide (100 mg, 0.260 mmol) in 1,4-dioxane / water (6 mL, 2:1) under argon was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (66 mg, 0.338 mmol) and Na2C03(55 mg, 0.521 mmol). The reaction mixture was degassed with argon for 20 minutes. Pd(dppf)Cl2-dichloromethane complex (10.6 mg, 0.013 mmol) was then added and degassed with argon for 5 minutes. The reaction mixture was sealed and stirred at 80 °C for 8.0 hours. The reaction mixture was cooled to room temperature, diluted with water (5.0 mL) and extracted with EtOAc (2 x 30 mL). The organic layers were combined, washed with water and brine, dried over anhydrous Na2S04and evaporated under reduced pressure. The crude was purified by column chromatography to obtain racemic N-(3-chloro-5-fluoro-4-(oxazol-5- yl)phenyl)chromane-3-carboxamide as a solid (20 mg, 20%).

[0547] Racemic N-(3-chloro-5-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide was subjected to chiral separation using chiral separation method F. The first N-(3-chloro-5-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide eluted first at 4.78 min (21.9 mg).

[0548] Analytical HPLC Method C. Rt: 2.78 min; MS: 373.1 (M+H).

[0549] Compound (42): N-(3-chloro-2-fluoro-4-(oxazol-5-yl)phenyl)chromane-3- carboxamide

[0550]

[0551] To a stirred solution of N-(4-bromo-3-chloro-2-fluorophenyl)chromane-3- carboxamide (100 mg, 0.260 mmol) in 1,4-dioxane / water (6 mL, 2:1) under argon was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (66 mg, 0.338 mmol) and Na2C03(55 mg, 0.521 mmol). The reaction mixture was degassed with argon for 20 minutes. Pd(dppf)C12-dichloromethane complex (10.6 mg, 0.013 mmol) was then added and degassed with argon for 5 minutes. The reaction mixture was sealed and stirred at 80 °C for 8.0 hours. The reaction mixture was cooled to room temperature, diluted with water (5.0 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude was purified by column chromatography to obtain N-(3-chloro-2-fluoro-4-(oxazol-5-yl)phenyl)chromane-3-carboxamide (compound 42) as a solid (19 mg, 19%).

[0552] Analytical HPLC Method C. Rt: 2.75 min; MS: 373.1 (M+H).

Claims

1. Use of a compound in the preparation of a medicament for stimulating pigmentation and / or growth of mammalian retinal pigment epithelial cells, wherein the compound is selected from the group consisting of Compound 1, Compound 2 and Compound 3, or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising: a compound as a therapeutically active substance, and a pharmaceutically acceptable carrier and / or adjuvant, wherein the compound is selected from the group consisting of Compound 1, Compound 2 and Compound 3, or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, wherein The pharmaceutical preparation is suitable for intraocular injection.

4. The pharmaceutical composition according to claim 2, wherein Its pharmaceutical preparations are suitable for topical ophthalmic applications.

5. The pharmaceutical composition of claim 2, comprising a pharmaceutically acceptable salt of a compound selected from the group consisting of Compound 1, Compound 2 and Compound 3.

6. The pharmaceutical composition of claim 2, further comprising one or more additional therapeutic agents.

7. The pharmaceutical composition according to claim 2, wherein The pharmaceutical composition provides controlled release properties.

8. Use of a compound in the preparation of a medicament for treating and / or preventing macular degeneration, wherein the compound is selected from the group consisting of Compound 1, Compound 2 and Compound 3. or a pharmaceutically acceptable salt thereof.

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