COMPOUNDS FOR THE TREATMENT OF EYE DISORDERS

Abstract

The compounds of Formula I as defined in the present description, or pharmaceutically acceptable salts, solvates, or derivatives thereof, are potent inhibitors of angiogenesis and, consequently, are useful in the treatment and prevention of various disorders related to angiogenesis, such as cancer.

Description

COMPOUNDS FOR THE TREATMENT OF EYE DISORDERS FIELD OF INVENTION The present invention relates to the field of pharmaceuticals and, in particular, to compounds that are inhibitors of angiogenesis. The compounds of the invention may be useful in the treatment of angiogenesis and angiogenesis-related disorders, such as eye disorders (e.g., macular degeneration and diabetic retinopathy). BACKGROUND OF THE INVENTION The inclusion or discussion of a previously published document in this description should not necessarily be taken as an acknowledgment that the document is part of the prior art or is common knowledge. Macular degeneration (MD) is a disease that affects a layer of cells in the eye known as the retinal pigment epithelium (RPE), which lies beneath the retina. The RPE acts as a wall or barrier and is responsible for passing oxygen, sugar, and other essential substances to the retina and moving waste products to the blood vessels underneath (these vessels are called the choroid). The RPE also acts as a barrier between the choroid and the retina. When the RPE cells die, the retinal cells above them also die, leading to age-related macular degeneration. Ref. 330213 patches of missing retina. This is commonly referred to as geographic atrophy or dry AMD, which is a slow-progressing form of the disease that causes a gradual loss of vision. Wet macular degeneration occurs when the RPE cells fail to stop the growth of choroidal blood vessels under the retina. This growth is called choroidal neovascularization or CNV. The rapidly growing vessels are fragile with leaky walls and leak fluid and blood under the retina. This leads to scarring and severe loss of central vision, which, if left untreated, becomes permanent. In the context of the present invention, it will be appreciated that the term macular degeneration refers particularly to wet AMD, also known as neovascular or exudative AMD, but also includes dry AMD. Diabetic retinopathy is a microvascular complication of diabetes that can occur in the eye. There are multiple categories and classifications of diabetic retinopathy, such as the early stage of non-proliferative diabetic retinopathy (NPDR) and the advanced stage of proliferative diabetic retinopathy (PDR), associated with abnormal blood vessel growth. Diabetic macular edema (DME) is also included within its scope. DME is a manifestation of diabetic retinopathy that occurs at all levels of severity in both NPDR and PDR and represents the most common cause of vision loss in patients. DME arises from diabetes-induced disruption of the blood-retinal barrier (BRB), with subsequent vascular leakage of circulating fluids and proteins into the neural retina. This fluid leakage into the neural retina leads to abnormal retinal thickening and frequently cystoid macular edema. In wet AMD and diabetic retinopathy, VEGFA is believed to play a significant role in the formation of abnormally growing blood vessels that leak beneath the macula. Constant exposure of endothelial cells to pro-angiogenic factors, such as VEGFA, results in the formation of immature, semi-differentiated, and fragile blood vessels that are prone to leaking and bleeding. The three main receptor tyrosine kinases (RTKs) responsible for abnormal blood vessel growth in the context of diabetes mellitus are PDGFRa, pDGFRp, and VEGFR2. These receptor tyrosine kinases are high-affinity cell-surface receptors for polypeptide growth factors such as VEGFA. Consequently, compounds that can distinguish between diseased and normal cells are thought to have a broader therapeutic window than compounds or agents that cannot. BRIEF DESCRIPTION OF THE INVENTION Without intending to be limited to theory, the present invention is based on the surprising finding that a compound of Formula I, as defined herein, exhibits high selectivity for the receptor tyrosine kinase (RTK) receptors PDGFRa, PDGFRp, and VEGFR2. As such, the compounds of Formula I are believed to be particularly suitable for therapeutic application to patients with macular degeneration, as they can inhibit the proliferation of only diseased cells; that is, cells with a high density of receptor tyrosine kinases. It is believed that the compounds of the present invention may be effective in blocking the outbreak of abnormal blood vessel formation and, consequently, be advantageous for treating diabetes mellitus and / or diabetic retinopathy. Therefore, the present invention provides the following numbered clauses. 1. A compound of Formula I: X^Xl / XL:' A | where: Xi and X2 each independently represent N or CRa Rarepresents independently H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl and C2-5 alkynyl (whose last four groups are either unsubstituted or substituted with one or more halo substituents); cnaczn / zznz / q / YiAi A is selected from the group consisting of: cnaczn / zznz / q / YiA where: The dotted line represents the point of attachment to the rest of the molecule; Each Ri to R5 is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups of which are either unsubstituted or substituted with one or more halo substituents; X3 represents N, CH or CR3, where R3 is as defined above, X4 represents N, CH or CR4, where R4 is as defined above, X5 represents N, CH or CR5, where Rs is as defined above, provided that only one or two of X3 to X5 is N; each Xe to X9 independently represents N, CH or CRe, where each Re is independently selected from C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, having four groups unsubstituted or substituted by one or more halo substituents; where in any portion A, one of Ri to Re can be piperazine, methylpiperazine, or ethylpiperazine, each of which can be connected to the rest of the portion A by means of a carbon or nitrogen atom in the piperazine ring; Yi represents NRn, O or S; Y2 represents NRn, NRy O or S; Rn represents H, C1-5 alkyl, C2-s alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents; Ry represents piperazine, methylpiperazine, or ethylpiperazine, each of which is connected to the nitrogen atom at Y2 by a carbon atom in the piperazine ring; L is a linking group of the formula: -M- (CRlRm) aC (O)-NR7-; -M-(CRlRm) a-NR7'-C (0)-; or -MC(O)-(CRnRo)-C(O)-Mwhere M represents a covalent bond, 0 or NH; Rl and Rm each independently represent H, methyl, ethyl, fluoro or chlorine, or Rl and Rm together with the carbon atom to which they are attached, form a C3 or C4 cycloalkyl ring, carbonyl group or thiocarbonyl group; a represents 0 or 1; R7 and R7' represent H or an optionally substituted alkyl group; Rn and Ro each independently represent H, methyl, ethyl, fluoro or chlorine; cnaczn / zznz / q / YiAi Z represents a heterocycle selected from the group consisting of: where: The dotted line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group; Each of the groups from Rg to Rio is independently selected from H, hydroxy, Ci to Cs alkyl, Ci to Cs alkoxy (whose last two groups are either unsubstituted or substituted with one or more halo groups), OC(0)Rn, C(O)ORi2, C2 to C5 alkynyl (which is either unsubstituted or substituted with one or more halo groups) or NR13 R14, and O-(C1-4 alkylenyl)-O-C1-4 alkyl, and one of the groups from Ra to Rio can be a group of the formula: where X represents O, NRx, Rx represents H or C1-4 alkyl, Rn and R12 each independently represent, in each occurrence, optionally substituted alkyl; R13 and R14 each independently represent, in each occurrence, H or optionally substituted alkyl; R15 represents H or C1-2 alkyl; or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that when XI and X2 are both CH, L is > ry· -xr । |3 X►. XX Xo *V , and A is , then Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl. 2. A compound according to clause 1, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein Rain independently represents H, NH2, F, Cl or C1-3 alkyl, the C1-3 alkyl group being unsubstituted or substituted with one, two or three fluoro or chloro substituents, optionally wherein Ra is H or F. cnaczn / zznz / q / YiAi 3. A compound according to clause 1 or 2, wherein Xi is selected from N and CH, and X2 is selected from CH and CF. 4. A compound according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: Each Ri to R5 independently represents halo, C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl and C2-3 alkynyl (whose four groups are either unsubstituted or substituted with one or more halo substituents), optionally wherein each Ri to R5 independently represents fluoro, chloro, methyl or ethyl, wherein the methyl and ethyl groups may be unsubstituted or substituted with one, two or three fluoro or chloro groups. 5. A compound according to clause 1 or 2, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: Yi and 2 independently represent O, NC1-3 alkyl or NH; and / or Rs independently represents C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl, and C2-3 alkynyl (all four of which groups are either unsubstituted or substituted with one or more halo substituents), optionally wherein Yi and Y2 independently represent 0, NMe, or NH, and / or Re independently represents fluoro, chloro, methyl or ethyl, whose methyl and ethyl groups may be unsubstituted or substituted with one, two or three fluoro or chloro groups. 6. A compound according to clause 4, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein each of Ri to R5 and Re independently represents methyl, trifluoromethyl, fluoro or chlorine. 7. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein: cnaczn / zznz / q / YiAi (a) each Rs to Rio independently represents H, hydroxy, Me, C1-2 alkoxy (which is unsubstituted or substituted with one or more halo groups), OC(0)Rn, C(O)ORi2, C2a C3 alkynyl (which is substituted with one or more halo groups), O- ( a 1 qui 1 eni 1 C1-2 ) - Oa 1 qui lo C1-2, or cnaczn / zznz / q / YiA NR13R14, R11 and R12 each independently represent methyl or ethyl, R13 and R14 each independently represent H, methyl or ethyl; or where X represents O, NH, or C1-2 N-alkyl, Rio stands for methyl, and the remaining two from Rs to Rio are as defined in part (a). 8. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein Z represents a heterocycle selected from: 9. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein: (a) when any one of Rg to Rio is an alkyl group Ci to Cs, it is an unsubstituted methyl group; and / or (b) when any one of Rs to Rio is a C2 to C5 alkynyl group, it is a C2 to C5 alkynyl group that is substituted with one or more halo groups. 10. A compound in accordance with any one of the preceding clauses, wherein: R9 and Rio, when present, are H, and Rg is selected from H and , where X is O or NH. 11. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein A is selected from group 12. A compound in accordance with clause 11, where and where and when they are present: Ri is selected from C1 and CH, R2 is CF3, X3 and X5 are CH, X4es N, Xe is N, Xs and X9 are CH, Y2 are selected from N-CH3 and O. 13. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein: M represents O or NH; and / or Rl and Rm each independently represent H, methyl or chlorine, or Rl and Rm together represent thiocarbonyl or cyclopropyl; and / or oa represents 1. 14. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein L represents: cnaczn / zznz / q / YiAi where the dotted lines represent the point of attachment to the rest of the molecule. 15. A compound in accordance with clause 1 which is selected from: derived from this. 16. A compound according to any one of the cnaczn / zznz / q / Yi clauses 1 to 13, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein L is selected from: optionally where L is selected from cnaczn / zznz / q / vi and 17. A compound according to any one of clauses 1 to 13, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein L is: R7 18. A compound in accordance with clause 1 which is selected from: cnaczn / zznz / q / Y or a pharmaceutically acceptable salt, solvate or derivative thereof. 19. Use of a compound of Formula I as defined in any one of clauses 1 to 18, or a pharmaceutically acceptable salt, solvate or derivative thereof, in the manufacture of a medicament to treat one or more of macular degeneration, diabetic retinopathy and angiogenesis. 20. A method for treating one or more macular degeneration, diabetic retinopathy, and angiogenesis, the method comprising administering a therapeutically effective amount of a compound of formula as defined in any of clauses 1 to 18 or a pharmaceutically acceptable salt, solvate, or derivative thereof. 21. A compound of Formula I as defined in any one of clauses 1 to 18 or a pharmaceutically acceptable salt, solvate or derivative thereof, for use in the treatment of one or more of macular degeneration, diabetic retinopathy and angiogenesis. 22. A pharmaceutical composition comprising a compound of Formula I as defined in any one of clauses 1 to 18 or a pharmaceutically acceptable salt, solvate or derivative thereof. 23. A compound according to clause 1, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: Xi and X2 each independently represent N or CRacnaczn / zznz / q / YiAi Ra represents independently H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl and C2-5 alkynyl (whose last four groups are either unsubstituted or substituted with one or more halo substituents); A is selected from the group consisting of: cnaczn / zznz / q / YiA where: The dotted line represents the point of attachment to the rest of the molecule; Each Ri to Rs is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups of which are either unsubstituted or substituted with one or more halo substituents; X3 represents N, CH or CR3, where R3 is as defined above, X4 represents N, CH or CR4, where R4 is as defined above, X5 represents N, CH or CR5, where R5 is as defined above, provided that only one or two of X3 to X5 is N; each Xg to Xg independently represents N, CH or CRg, where each Rg is independently selected from C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, having four groups unsubstituted or substituted by one or more halo substituents; Yi and Y2 each independently represent NRn, O or S; Rn represents H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents; L is a linking group of the formula: -M- (CRlRm)aC(O) -NR7-; or -M- (CRlRm) a-NRv-C (O) - ; where M represents a covalent bond, O or NH; Rl and Rm each independently represent H, methyl, ethyl, fluoro or chlorine, or Rl and Rm together form a C3 or C4 cycloalkyl ring, carbonyl group or thiocarbonyl group; a represents 0 or 1; R7 and R7' represent H or an optionally substituted alkyl group; Z represents a heterocycle selected from the cnaczn / zznz / q / YiAi group consisting of: cnaczn / zznz / q / YiA where: The dotted line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group; each of Rg to Rio are independently selected from H, Me, alkoxy Ci to Cs that is unsubstituted or substituted with one or more halo groups, OC(0)Rn, C(O)ORi2, alkynyl C2 to C5 substituted with one or more halo groups or NR13R14, and one of Rs to cnaczn / zznz / q / YiAi >bxy' Xy·. V. ,.Ά. ..yo Rio can be a group of the formula / j. ; where X represents O or NH R11 and R12 each independently represent, in each occurrence, optionally substituted alkyl; R13 and R14 each independently represent, at each occurrence, H or optionally substituted alkyl; provided that when Xi and X2 are both CH, L is Q .OA > ' T' JL [I ^7 , and A is2, then Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl. The invention also provides the following numbered statements. 1. A compound of Formula I: where: Xi and Χ2 each independently represent N or CRa Rain independently represents H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl and C2-5 alkynyl (whose last four groups are either unsubstituted or substituted with one or more halo substituents); A is selected from the group consisting of: cnaczn / zznz / q / YiA where: The dotted line represents the point of attachment to the rest of the molecule; Each Ri to Rs is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups of which are either unsubstituted or substituted with one or more halo substituents; X3 represents N, CH or CR3, where R3 is as defined above, X4 represents N, CH or CR4, where R4 is as defined above, X5 represents N, CH or CR5, where Rs is as defined above, provided that only one or two of X3 to X5 is N; Each Xe to X9 independently represents N, CH or CRg, where each Rg is independently selected from C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, having four groups that are either unsubstituted or substituted by one or more halo substituents; Yi and Y2 each independently represent NRn, O or S; Rn represents H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents; L is a linking group of the formula: -M-(CRlRm) aC (0)-NR7-; or -M- (CRlRm)a-NR7'-C (0) -; where M represents a covalent bond, O or NH; Rl and Rm each independently represent H, methyl, ethyl, fluoro or chlorine, or Rl and Rm together form a C3 or C4 cycloalkyl ring, carbonyl group or thiocarbonyl group; a represents 0 or 1; R7 and R?' represent H or an optionally substituted alkyl group; Z represents a heterocycle selected from the group cnaczn / zznz / q / YiAi cnaczn / zznz / q / YiAi consisting of: where: The dotted line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group, optionally where Z is attached to the rest of the molecule by a covalent bond; each of Rs to Rio are independently selected from H, Me, alkoxy Ci to Cs that is unsubstituted or substituted with one or more halo groups, OC(0)Rn, C(O)ORi2, alkynyl C2 to C5 substituted with one or more halo groups or NR13R14 and one of Rs to Rio may be a group of the cnaczn / zznz / q / YiAi where A represents O or NH R11 and R12 each independently represent, in each occurrence, an optionally substituted alkyl; R13 and R14 each independently represent, in each occurrence, H or an optionally substituted alkyl; or a pharmaceutically acceptable salt, solvate, or derivative thereof, provided that when XI and X2 are both CH, L is optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl. 2. A compound according to statement 1, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein Ra independently represents H, NH2, F, Cl or C1-3 alkyl, the C1-3 alkyl group being unsubstituted or substituted with one, two or three fluoro or chloro substituents, preferably wherein Ra is H or F. 3. A compound according to statement 1 or 2, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein: Each Ri to R5 independently represents halo, C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl and C2-3 alkynyl (all four of which are either unsubstituted or substituted with one or more halo substituents), preferably wherein each Ri to R5 independently represents fluoro, chloro, methyl or ethyl, wherein the methyl and ethyl groups may be unsubstituted or substituted with one, two or three fluoro or chloro groups. 4. A compound according to declaration 1 or 2, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein: Yi and Y2 independently represent O, NC1-3 alkyl or NH; and / or Rs independently represents C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl and C2-3 alkynyl (all four groups of which are either unsubstituted or substituted with one or more halo substituents), preferably where Yi and Y2 independently represent O, NMe or NH, and / or Re independently represents fluoro, chloro, methyl or ethyl, whose methyl and ethyl groups may be unsubstituted or substituted with one, two or three fluoro or chloro groups. cnaczn / zznz / q / YiAi 4. A compound in accordance with statement 3, or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein each of Ri to Rs and Re independently represents methyl, trifluoromethyl, fluoro or chlorine. 5. A compound according to any of the foregoing statements, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein: (a) each Rs to Rio independently represents H, Me, Ci-2 alkoxy that is unsubstituted or substituted with one or more halo groups, OC(0)Rn, C(O)ORi2, C2 to C3 alkynyl substituted with one or more halo groups, or NR13R14, R11 and R12 each independently represent methyl or ethyl, R13 and R14 each independently represent H, methyl or ethyl; or (b) one of Rs to Rio represents a group of the formula where A represents O or NH, and the remaining two of Rs to Rio are as defined in part (a). 6. A compound according to any one of the foregoing statements, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein Z represents acceptable, solvate or derivative thereof, wherein A is selected 8. A compound according to any one of the foregoing statements, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein: M represents O or NH; and / or Rl and Rm each independently represent H, methyl or chlorine, or Rl and Rm together represent thiocarbonyl or cyclopropyl; and / or oa represents 1. 9. A compound according to any one of the above statements, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein L represents: C> R? where the dotted lines represent the point of attachment to the rest of the molecule. 10. A compound in accordance with statement 9 that is selected from cnaczn / zznz / q / YiAi cnac7n / 77n7 / 3 / YiAi cnaczn / zznz / q / YiA or a pharmaceutically acceptable salt, solvate, or derivative thereof. 11. A compound according to any one of statements 1 to 8, or a pharmaceutically acceptable salt, solvate, or derivative thereof, wherein L is selected from: cnac7n / 77n7 / 3 / YiA cnaczn / zznz / q / YiA I am a pharmaceutically acceptable salt, solvate, or derivative thereof. 13. Use of a compound of Formula I as defined in any one of statements 1 to 12, or a pharmaceutically acceptable salt, solvate, or derivative thereof, in the manufacture of a drug to treat one or more of macular degeneration, diabetic retinopathy, cancer (e.g., prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia, or chronic myelomonocytic leukemia), and angiogenesis. 14. A method for treating one or more of macular degeneration, diabetic retinopathy, cancer (e.g., prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia, or chronic myelomonocytic leukemia), and angiogenesis, wherein the method comprises administering a therapeutically effective amount of a compound of the formula as defined in any one of statements 1 to 12 or a pharmaceutically acceptable salt, solvate, or derivative thereof. 15. A compound of Formula I as defined in any one of statements 1 to 12 or a pharmaceutically acceptable salt, solvate or derivative thereof, for use in the treatment of one or more of macular degeneration, diabetic retinopathy, cancer (e.g. prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia or chronic myelomonocytic leukemia) and angiogenesis. 16. A pharmaceutical composition comprising a compound of Formula I as defined in any one of statements 1 to 12 or a pharmaceutically acceptable salt, solvate or derivative thereof. BRIEF DESCRIPTION OF THE FIGURES Figure 1 represents the Western blot analysis results of the compounds from Examples 1 and 2 in relation to the inhibition of PDGFRp and p-SHP2 signaling in PDGFRp-expressing HEK293 cells. Figure 2 illustrates the effect of the compounds in Examples 1 to 4 on Ba / F3 cells expressing PDGFR. The results for imatinib and quizartinib are provided as positive controls. Figure 3 illustrates the effect of the compounds in Examples 5 to 7 on Ba / F3 cells expressing Flt3 kinase. Results are also provided for imatinib (negative control) and quizartinib (positive control). Figure 4 shows the ability of a compound according to the invention to prevent choroidal damage in vivo. DETAILED DESCRIPTION OF THE INVENTION Surprisingly, the compounds of Formula I described herein, including pharmaceutically acceptable salts, solvates, and derivatives thereof, have been found to be potent inhibitors of angiogenesis. The compounds of the invention are useful in the treatment of angiogenesis and angiogenesis-related diseases or disorders, such as eye disorders, particularly macular degeneration (e.g., age-related macular degeneration) and diabetic retinopathy. Therefore, according to a first aspect of the cnaczn / zznz / q / YiAi Invention, a compound of Formula I is provided: L““*A :| where: Xi and X2 each independently represent N or CRa Ra represents independently H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl and C2-5 alkynyl (whose last four groups are either unsubstituted or substituted with one or more halo substituents); cnaczn / zznz / q / YiAi cnaczn / zznz / q / YiA where: The dotted line represents the point of attachment to the rest of the molecule; Each Ri to Rs is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups of which are either unsubstituted or substituted with one or more halo substituents; X3 represents N, CH or CR3, where R3 is as defined above, X4 represents N, CH or CR4, where R4 is as defined above, Xs represents N, CH or CRs, where Rs is as defined above, provided that only one or two of X3 to X5 is N; each Xe to Xg independently represents N, CH or CRe, where each Re is independently selected from C2-5 alkyl, C2-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, having four groups unsubstituted or substituted by one or more halo substituents; wherein in any portion A, one of Ri to Re can be piperazine, methylpiperazine or ethylpiperazine, each of which can be connected to the rest of portion A by a carbon or nitrogen atom in the piperazine ring; Yi represents NRn, O or S; Y2 represents NRn, NRy O or S; Rn represents H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents; Ry represents piperazine, methylpiperazine, or ethylpiperazine, each of which is connected to the nitrogen atom at Y2 by a carbon atom in the piperazine ring; L is a linking group of the formula: -M- (CRlRm) a~C(O) -NR7-; -M-(CRlRm) a-NR7'-C (O)-; or cnaczn / zznz / q / YiAi -MC(O)-(CRnRo)-C(O)-Mwhere M represents a covalent bond, O or NH; Rl and Rm each independently represent H, methyl, ethyl, fluoro or chlorine, or Rl and Rm together form a C3 or C4 cycloalkyl ring, carbonyl group or thiocarbonyl group; a represents 0 or 1; R7 and R7' represent H or an optionally substituted alkyl group; Rn and Ro each independently represent H, methyl, ethyl, fluoro or chlorine; Z represents a heterocycle selected from the group consisting of: cnaczn / zznz / q / YiAi cnaczn / zznz / q / YiA where: The dotted line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group; each of Rb to Rio are independently selected from H, hydroxy, C1 to C5 alkyl, C1 to C5 alkoxy (whose last two groups are either unsubstituted or substituted with one or more halo groups), OC(0)Rn, C(O)ORi2, C2 to C5 alkynyl (which is either unsubstituted or substituted with one or more halo groups) or NR13R14, and C1-4 O-(alkylenyl)C1-4 O-alkyl, where X represents O, NRX, Rx represents H or C1-4 alkyl, Rn and R12 each independently represent, in each occurrence, optionally substituted alkyl; R13 and R14 each independently represent, in each occurrence, H or optionally substituted alkyl; Ris represents H or C1-2 alkyl; or a pharmaceutically acceptable salt, solvate or derivative thereof, provided that when XI and X2 are both CH, L is EITHER optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl. In the embodiments of the present description, the word "comprising" may be interpreted as requiring the mentioned features, but not limiting the presence of other features. Alternatively, the word "comprising" may also relate to situations where only the listed components / features are intended to be present (e.g., the word "comprising" may be replaced by the phrases "consists of" or "consists essentially of"). It is explicitly contemplated that both the broader and narrower interpretations may be applied to all aspects and embodiments of the present invention. In other words, the word "comprising" and synonyms thereof may be replaced by the phrase "consists of" or "consists essentially of" or synonyms thereof, and vice versa. Alkyl refers to monovalent alkyl groups that may be linear or branched and preferably have 1 to 10 carbon atoms or, more preferably, 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl, and the like. As used in the present description, C1-C5 alkyl refers to an alkyl group having 1 to 5 carbon atoms. Alkylene refers to divalent alkyl groups that preferably have 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), and the isomers of propylene (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like. Alkenyl refers to a monovalent alkenyl group that may be linear or branched and preferably has 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms, and has at least 1, and preferably 1-2, carbon-to-carbon double bonds. Examples include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like. As used in the present description, C2-C5 alkylenyl refers to an alkylenyl group having 2 to 5 carbon atoms. Alkynyl refers to alkynyl groups that preferably have 2 to 10 carbon atoms and, more preferably, 2 to 6 carbon atoms and that have at least 1, and preferably 1-2, carbon-to-carbon triple bonds. Examples of alkynyl groups include ethynyl (C=CH), propargyl (-CH2C=CH), pent-2-ynyl (-CH2C=CCH2-CH3), and the like. As used in the present description, C2-C5 alkynyl refers to an alkynyl group that has 2 to 5 carbon atoms. Alkoxy refers to the alkyl-O- group where the alkyl group is as described above. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. As used in the present description, C1-C5 alkoxy refers to an alkoxy group having 1 to 5 carbon atoms. Halo or halogen refers to fluorine, chlorine, bromine, and iodine. Haloalkyl refers to an alkyl group where the alkyl group is substituted with one or more halo groups as described above. The terms haloalkenyl, haloalkynyl, and haloalkoxy are also defined. Aryl refers to an unsaturated aromatic carbocyclic group that has a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), preferably having 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl, and the like. Heteroaryl refers to a monovalent aromatic heterocyclic group that meets Hückel's criteria for aromaticity (i.e., contains 4n + 2n electrons) and preferably has 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium, and nitrogen). Such heteroaryl groups may have a single ring (e.g., pyridyl, pyrrolyl, or N-oxides of these, or furyl) or multiple fused rings (e.g., indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl, or benzothienyl). Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoindoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, tlazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine and the like. In this description, optionally substituted is understood to mean that a group may or may not be substituted or further fused (to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trialomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethoxy, cnaczn / zznz / q / YiAi trifluoroethenyl, mono- and dialkylamino, substituted mono- and dialkyliamino, mono- and diarylamino, mono- and diheteroarylamino, mono- and diheterocyclylamino,and non-symmetric disubstituted amines having different substituents selected from alkyl, aryl, heteroaryl, and heterocyclyl groups, and the like, and may also include a bond to a solid support material (e.g., substituted in a polymeric resin). For example, an optionally substituted amino group may include residues of amino acids and peptides. When a portion is described herein as being substituted for one or more groups, the portion may be substituted for one or more groups, such as one, two, or three groups. In certain embodiments of the invention, the portion may be substituted for one or two groups. In certain embodiments of the invention, the portion may be substituted for a single group. References in the present description (in any aspect or embodiment of the invention) to the compounds of Formula I include references to such compounds per se, to tautomers of such compounds, as well as to pharmaceutically acceptable salts or solvates, or pharmaceutically functional derivatives of such compounds. Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting a free acid or free base form of a compound of Formula I with one or more equivalents of a suitable acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., under vacuum, by lyophilization, or by filtration). Salts can also be prepared by exchanging a counterion of a compound of Formula I in the form of a salt with another counterion, for example, using a suitable ion-exchange resin. Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably potassium and calcium. Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic (e.g., benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic and p-toluenesulfonic), ascorbic (e.g., L-ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic (+)-(IS)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecyl sulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic acids (e.g. e.g., D-gluconic), glucuronic (e.g., D-glucuronic), glutamic (e.g., L-glutamic), α-oxoglutaric, glycolic, hippuric, bromhydric, hydrochloric, iodidric, isethionic, lactic (e.g., (+)-L-lactic and (±)-DL-lactic), maleic, malic (e.g.(-)-Malic), malonic, (±)-Dl-mandelic, metaphosphoric, methanesulfonic, l-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-aminosalicylic, sebacic. Stearic, succinic, sulfuric, tannic, tartaric (e.g., (+)-L-tartaric), thiocyanic, undecylenic and valeric acids. Particular examples of salts are salts derived from mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids; from organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arylsulfonic; and from metals such as sodium, magnesium or, preferably, potassium and calcium. As mentioned above, Formula I also covers any solvate of the compounds and their salts. Preferred solvates are those formed by incorporating molecules of a pharmaceutically acceptable, non-toxic solvent (hereafter referred to as the solvating solvent) into the solid-state structure (e.g., crystalline structure) of the compounds of the invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethyl sulfoxide. Solvates can be prepared by recrystallizing the compounds of the invention with a solvent or solvent mixture containing the solvating solvent. Whether a solvate has formed in any given case can be determined by subjecting crystals of the compound to analysis using known and standard techniques such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography. Solvates can be stoichiometric or non-stoichiometric. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates, and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-96706710-3. Pharmaceutically functional derivatives of the compounds of Formula I, as defined herein, include ester derivatives and / or derivatives that have, or provide, the same biological function and / or activity as any relevant compound of the invention. Therefore, for the purposes of this invention, the term cnaczn / zznz / q / YiAi also includes prodrugs of compounds of Formula I. The term prodrug of a relevant compound of Formula I includes any compound that, after oral or parenteral administration, is metabolized in vivo to form that compound in an experimentally detectable amount, and within a predetermined time (e.g., within a dosing interval of between 6 and 24 hours (i.e., once to four times a day)). Prodrugs of Formula I compounds can be prepared by modifying the functional groups present in the compound in such a way that the modifications are cleaved in vivo when the prodrug is administered to a mammalian subject. The modifications are typically achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include Formula I compounds in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in a Formula I compound is attached to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, e.g., in Bundedeard, H. Design of Prodrugs, p. cnaczn / zznz / q / YiAi 1-92, Elsevier, New York-Oxford (1985). The compounds of Formula I, as well as pharmaceutically acceptable salts, solvates, and pharmaceutically functional derivatives of such compounds, are, for the sake of brevity, hereafter referred to as compounds of Formula I. The compounds of Formula I may contain double bonds and, therefore, may exist as E (entgegen) and Z (zusammen) geometric isomers around each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention. The compounds of Formula I can exist as regioisomers and can also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. Compounds of Formula I may contain one or more asymmetric carbon atoms and, therefore, may exhibit optical isomerism and / or diastereomerism. Diastereomers can be separated using conventional techniques, e.g., chromatography or fractional crystallization. The various stereoisomers can be isolated by separating a racemic or other mixture of the compounds using conventional techniques, e.g., fractional crystallization or HPLC.Alternatively, the desired optical isomers can be prepared by reacting suitable optically active starting materials under conditions that will not cause racemization or epimerization (i.e., a chiral clustering method), by reacting the suitable starting material with a chiral auxiliary that can subsequently be removed in a suitable step, by derivatization (i.e., resolution, including dynamic resolution), for example, with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reacting with a suitable chiral reagent or chiral catalyst under conditions known to the person skilled in the art. All stereoisomers and mixtures thereof are included within the scope of the invention. Other embodiments of the invention that may be mentioned include those in which the compound of Formula I is isotopically labeled. However, other particular embodiments of the invention that may be mentioned include those in which the compound of Formula I is not isotopically labeled. The term "isotopically labeled," when used herein, includes references to compounds of Formula I in which there is a non-natural isotope (or a non-natural isotope distribution) at one or more positions in the compound. References herein to one or more positions in the compound shall be understood by those skilled in the art to refer to one or more of the atoms of the compound of Formula I. Therefore, the term "isotopically labeled" includes references to compounds of Formula I that are isotopically enriched at one or more positions in the compound. The isotopic labeling or enrichment of the compound of Formula I may be with a radioactive or non-radioactive isotope of any of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine, and / or iodine. Particular isotopes that may be mentioned in this respect include 2H, 3H, 13C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 35S, 18F, 37Cl, 77Br, 82Br, and 1251j. When the compound of Formula I is labelled or enriched with a radioactive or non-radioactive isotope, the compounds of Formula I that may be mentioned include those in which at least one atom of the compound shows an isotopic distribution in which a radioactive or non-radioactive isotope of the atom in question is present at levels at least 10% (e.g., from 10% to 5000%, particularly from 50% to 1000%, and more particularly from 100% to 500%) above the natural level of that radioactive or non-radioactive isotope. The compound of Formula I in the aforementioned aspect of the invention can be used in a medical treatment method. Therefore, in accordance with additional aspects of the invention, the following is provided: (a) a compound of Formula I for use in medicaments; (b) a compound of Formula I for use in the treatment or prevention of angiogenesis or an angiogenesis-related disease or disorder, particularly macular degeneration and diabetic retinopathy; (c) the use of a compound of Formula I for the preparation of a medicament for treating angiogenesis or an angiogenesis-related disease or disorder, particularly macular degeneration and diabetic retinopathy; and (d) a method of treating angiogenesis or an angiogenesis-related disease or disorder, particularly macular degeneration and diabetic retinopathy, the method comprising administering an effective amount of a compound of Formula I. The compounds of Formula I include a linking group of the formula: -M- (CRlRm)a_C(O) -NR7-; -M-(CRlRm) a-NR7'-C (O)-; or -MC(O)-(CRnRo)-C(O)-M- where M represents a covalent bond, 0 or NH; Rl and Rm each independently represent H, methyl, ethyl, fluoro or chlorine, or Rl and Rm together form a C3 or C4 cycloalkyl ring, carbonyl group or thiocarbonyl group; a represents 0 or 1; R? and Rv' represent H or an optionally substituted alkyl group; Rn and Ro each independently represent H, methyl, ethyl, fluoro or chlorine; To avoid any doubt, the linker can be oriented in either of the two possible configurations; that is, either end of the linker can be attached to portion A or to the six-membered ring containing Xi and X2. In some embodiments of the invention, the left portion of the linker, as shown herein, is attached to the six-membered ring containing Xi and X2. In other embodiments of the invention, the left portion of the linker is attached to portion A. In some embodiments of the invention, the linking group L may be of the formula: cnaczn / zznz / q / YiAi The Formula I compounds containing the linkers are believed to be particularly suitable for treating eye diseases or disorders related to angiogenesis, for example, macular degeneration (e.g., AMD) and diabetic retinopathy. Other useful linking groups in compounds of the cnaczn / zznz / q / YiAi Formula I includes linkers that have the following formula: In some embodiments of the invention, L is a linker cnaczn / zznz / q / yi group having one of the following formulas: EITHER, In some embodiments of the invention, the linker is selected from linkers having one of the following formulas: cnaczn / zznz / q / YiA R7 Xi and X2 each independently represent N or CRa, where Ra independently represents H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, and C2-5 alkynyl (the last four groups of which are either unsubstituted or substituted with one or more halo substituents). In some embodiments of the invention, Ra independently represents H, NH2, F, Cl, or C1-3 alkyl, the C1-3 alkyl group of which is either unsubstituted or substituted with one, two, or three fluoro or chloro substituents. In particular embodiments of the invention, Ra represents H or F. In some embodiments of the invention, Xi is selected from N and CH, and X2 is selected from CH and CF. The dotted line represents the point of attachment to the cnaczn / zznz / q / YiA rest of the molecule; Each Ri to Rs is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups of which are either unsubstituted or substituted with one or more halo substituents; X3 represents N, CH or CR3, where R3 is as defined above, X4 represents N, CH or CR4, where R4 is as defined above, X5 represents N, CH or CRs, where R5 is as defined above, provided that only one or two of X3 to X5 is N; each Xe to Xg independently represents N, CH or CRe, where each Re is independently selected from Ci-5 alkyl, Ci-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, having four groups unsubstituted or substituted by one or more halo substituents; wherein in any portion A, one of Ri to Re can be piperazine, methylpiperazine or ethylpiperazine, each of which can be connected to the rest of portion A by a carbon or nitrogen atom in the piperazine ring. In some embodiments of the invention, each Ri to R5 independently represents halo, C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl, and C2-3 alkynyl (all four groups being either unsubstituted or substituted with one or more halo substituents). In some embodiments of the invention, each Ri to Rs independently represents fluoro, chloro, methyl, or ethyl, the methyl and ethyl groups being either unsubstituted or substituted with one, two, or three fluoro or chloro groups. In some embodiments of the invention, each Re independently represents C2-3 alkyl, C2-3 alkoxy, C2-3 alkenyl, and C2-3 alkynyl (all four groups being either unsubstituted or substituted with one or more halo substituents). In some embodiments of the invention, each Re independently represents fluoro, chloro, methyl, or ethyl, the methyl and ethyl groups being either unsubstituted or substituted with one, two, or three fluoro or chloro groups. In some embodiments of the invention, each of Ri to Rs and Re independently represents methyl, trifluoromethyl, fluoro or chlorine. In some embodiments of the invention, Ri represents piperazine, methylpiperazine, or ethylpiperazine, each of which may be connected to the remainder of portion A by a carbon or nitrogen atom in the piperazine ring, and R2 to Re do not represent piperazine, methylpiperazine, or ethylpiperazine; Yi represents NRn, O or S; Y2 represents NRn, NRy O or S; Rn represents H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents; Ry represents piperazine, methylpiperazine, or ethylpiperazine, each of which is connected to the nitrogen atom at Y2 by a carbon atom on the piperazine ring. In some embodiments, Yi and Y2 each independently represent NRn, O, or S, where Rn represents H, C1-5 alkyl, C2-5 alkenyl, or C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents. In some embodiments of the invention, Yi and Y2 independently represent O, NC1-3 alkyl, or NH. In some embodiments of the invention, Yi and Y2 independently represent O, NMe, or NH. In some forms of the invention, Yi and Y2 are not S. In some embodiments of the invention in which RY represents piperazine, methylpiperazine or ethylpiperazine, the piperazine, methylpiperazine or ethylpiperazine portion is attached to the nitrogen atom at Y2 by means of a carbon atom in the piperazine ring. In some embodiments of the invention, A is selected In some embodiments of the invention, A is selected In some embodiments of the invention, A is selected from: and where Ri is selected from methyl and chlorine; R2 is CF3; X3y Xδ are CH; X4es N; Xe is N; Y2es O o n-ch3; X8es C-CF3; and X9es CH. cnaczn / zznz / q / YiA Z represents a heterocycle selected from the group consisting of: cnaczn / zznz / q / YiA where in each portion Z: The dotted line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group; Each of Rb to Rio is independently selected from H, hydroxy, C5 alkyl, C5 alkoxy (whose last two groups are either unsubstituted or substituted with one or more halo groups), OC(0)Rn, C(O)ORi2, C2 to C5 alkynyl (which is either unsubstituted or substituted with one or more halo groups) or NR13R14, and O-(C1-4 alkylenyl)O-C1-4 alkyl, and one of R8a Rio can be a group of the formula: where X represents O, NRx, Rx represents H or someone Ciu, Rn and R12 each independently represent, in each occurrence, optionally substituted alkyl; R13 and Rn each independently represent, at each occurrence, H or optionally substituted alkyl; Ris represents H or C1-2 alkyl. In any embodiment of the invention, the alkyl group for each of Rs to Rio can be a met i 1o group. In any embodiment of the invention described herein, the C2 to C5 alkynyl group for each of Rs to Rio may be a C2 to C5 alkynyl group that is substituted with one or more halo groups. cnaczn / zznz / q / YiAi In some embodiments of the invention, Z represents a In some embodiments of the invention, Z represents a heterocycle selected from: cnaczn / zznz / q / YiA In some embodiments of the invention, Z represents a In some embodiments of the invention, each Rs to Rio independently represents H, hydroxy, Me, Ci-2 alkoxy (which is unsubstituted or substituted with one or more halo groups), OC(0)Rn, C(O)ORi2, C2a C3 alkynyl (which is substituted with one or more halo groups), O-(C1-2 alkylenyl)-O-Ci-2alkyl, or NR13R14, where R11 and R12 each independently represent methyl or ethyl, R13 and R14 each independently represent H, methyl or ethyl. In other embodiments of the invention, one of Rs to Rio represents a group of the formula cnaczn / zznz / q / YiAi where X represents O, NH, or N-alkyl Ci-2, R15 represents methyl, and the remaining two from Rs to Rio are as defined above. In some embodiments of the invention, each of Rs to Rio are independently selected from H, hydroxy, Me, alkoxy Ci to C5 (which is unsubstituted or substituted with one or more halo groups), OC(0)Rn, C(O)ORi2, alkynyl C2a C5 (which is substituted with one or more halo groups) or NR13R14, and O-(alkylenyl C1-4) -O-alkyl Ci-4, or one from Rs to Rio can be a group of the formula: cnaczn / zznz / q / YiAi and the two remaining ones from Rs to Rio, as well as Rn to Ri4, are as defined above. In some embodiments of the invention, each Rs to Rio is independently selected from H, Me, C5 alkoxy that is unsubstituted or substituted with one or more halo groups, OC(0)Rn, C(O)ORi2, C2 to C5 alkynyl (which is substituted with one or more halo groups) or NR13R14 and one of the Rs to Rio may be a group of the formula *7 ; where: X represents O or NH Rn and R12 each independently represent, in each occurrence, optionally substituted alkyl; R13 and R14 each independently represent, at each occurrence, H or optionally substituted alkyl. In some embodiments of the invention, R9 and Rio (when present) are H. Therefore, when one of Rs to Rio represents a group of the formula RW cnaczn / zznz / q / YiA ·>' rí % \__ / \ / / ' o ' , for example, when one of Rg a RioχΛί Υ'''^ may be a group of the formula O ; This group can be present as Rg, and R9 and Rio (when present) can be H. In some embodiments of the invention, Z is joined to the rest of the molecule by a covalent bond. In some embodiments of the invention, M represents O or NH. In other embodiments of the invention, M represents a covalent bond. In some embodiments of the invention, when Z is joined to the rest of the molecule by a covalent bond, then M is -O- or -NH-. In some embodiments of the invention, when Z is joined to the rest of the molecule by an -O- or -NH- group, then M is a covalent bond. In some embodiments of the invention, Rl and Rm each independently represent H, methyl or chlorine, or Rl and Rm together represent thiocarbonyl or cyclopropyl. In some embodiments of the invention, one represents 1. In some embodiments of the invention, R? and R?' represent H. cnaczn / zznz / q / vi In Formula 1, when XI and X2 are both CH, L is optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl. The invention also provides the following compounds, as well as pharmaceutically acceptable salts, solvates, and derivatives thereof. solvates and their derivatives. cnaczn / zznz / q / YiA cnac7n / 77n7 / 3 / Y cnaczn / zznz / q / YiA In this description, the term macular degeneration or DM is intended to include age-related macular degeneration (AMD), but does not exclude macular degeneration in patients who are not elderly. Accordingly, DM and AMD as referred to herein may be used interchangeably. DM is a disease that affects a special layer of cells in the eye called the retinal pigment epithelium. This layer of cells lies beneath the retina. The retinal pigment epithelium (RPE) acts as a wall or barrier and is responsible for passing oxygen, sugar, and other essential substances to the retina and moving waste products to the blood vessels beneath (these vessels are called the choroid). The RPE also acts as a barrier between the choroid and the retina. When the RPE cells die, the retinal cells above them also die, leading to patches of missing retina.This is commonly referred to as geographic atrophy or dry AMD, which is a slow form of the disease that causes a gradual loss of vision. Wet macular degeneration occurs when the RPE cells fail to stop the growth of conoid blood vessels under the retina. This growth is called conoid neovascularization or CN. The rapidly growing vessels are fragile, with leaky walls, and they leak fluid and blood under the retina. This leads to scarring and severe loss of central vision, which, if left untreated, becomes permanent. In the context of the present invention, it will be appreciated that the term macular degeneration refers particularly to wet AMD, also known as neovascular or exudative AMD. As used in this description, the term diabetic retinopathy refers to a microvascular complication of diabetes. This complication can occur in the eye. Accordingly, diabetic retinopathy is intended to include all categories and classifications, for example, the early stage of non-proliferative diabetic retinopathy (NPDR) and the advanced stage of proliferative diabetic retinopathy (PDR) associated with abnormal blood vessel growth. Diabetic macular edema (DME) is also included within its scope. DME is a manifestation of diabetic retinopathy that occurs at all levels of severity in both NPDR and PDR and represents the most common cause of vision loss in patients. DME arises from diabetes-induced disruption of the blood-retinal barrier (BRB), with subsequent vascular leakage of circulating fluids and proteins into the neural retina.Extravasation of fluid into the neural retina leads to abnormal thickening of the retina and often cystoid edema of the macula. In wet AMD and diabetic retinopathy, VEGFa is believed to play a significant role in the formation of abnormally growing blood vessels that leak beneath the macula. Constant exposure of endothelial cells to pro-angiogenic factors, such as VEGFa, results in the formation of immature, semi-differentiated, and fragile blood vessels that have a tendency to leak and bleed. Not merely theoretical, the present invention is based on the discovery that a compound of Formula I, as defined herein, exhibits high selectivity for the receptor tyrosine kinase (RTK) receptors PDGFRa, PDGFR3, and VEGFR2, the three main RTKs responsible for abnormal blood vessel growth in the context of diabetes mellitus. These receptor tyrosine kinases are high-affinity cell-surface receptors for polypeptide growth factors such as VEGFa.Therefore, it is postulated that the compounds of the present invention may exhibit a broader therapeutic window than compounds or agents that do not distinguish between diseased and normal cells. This selectivity means that the compounds of Formula I, as well as the pharmaceutically acceptable salt, solvate, or prodrug thereof, may be particularly suitable for therapeutic application to patients with macular degeneration, as they can inhibit the proliferation of only diseased cells; that is, cells with a high density of tyrosine kinase receptors. It is believed that the present compounds may be effective in blocking the outbreak of abnormal blood vessel formation and, consequently, are advantageous for treating diabetes mellitus and / or diabetic retinopathy. The pathology of diabetes mellitus (DM) and / or diabetic retinopathy can be multifactorial. In the treatment of DM and / or diabetic retinopathy, different therapies can be combined (i.e., combination therapies). The terms "therapeutic agent," "other therapeutic agent," "second therapeutic agent," and the like, as used herein, are intended to include other compounds or therapeutic treatments that may be used in combination with the compound according to the present invention. Therefore, according to the invention, the compounds of Formula I can be administered alone (i.e., as monotherapy, such as monotherapy for an angiogenesis-related disease or disorder). However, in alternative embodiments of the invention, the compounds of Formula I can be administered in combination with another therapeutic agent (e.g., another therapeutic agent for the treatment of an angiogenesis-related disease or disorder). In another further embodiment of the invention, the compounds of Formula I can be administered as adjuvant therapy after surgical treatment or as neoadjuvant therapy prior to the principal treatment (e.g., surgery) of the angiogenesis-related disorder or disease, either as a single compound or in combination with another therapeutic agent (e.g.,, another therapeutic agent for the treatment of a disease or disorder related to angiogenesis). Secondary or other therapeutic agents useful in the treatment of ocular disorders such as diabetes mellitus (DM) and / or diabetic retinopathy include, but are not limited to, angiogenesis inhibitors, vascular endothelial growth factor (VEGF) inhibitors, other tyrosine kinase receptor inhibitors, photodynamic therapy, laser photocoagulation, and other treatments specific to DM or age-related macular degeneration (AMD) and / or diabetic retinopathy. For example, a Formula I compound or a pharmaceutically acceptable salt, solvate, or prodrug may be administered in combination with one or more VEGF inhibitors such as Avastine, Lucentis, and / or Macugen. For the avoidance of doubt, in the context of the present invention, the term treatment includes references to therapeutic or palliative treatment of patients who need treatment, as well as to prophylactic and / or diagnostic treatment of patients who are susceptible to the relevant disease states. The terms patient and patients include references to mammalian patients (e.g., humans). As used herein, the terms subject or patient are recognized in the art and are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human being. In some modalities, the subject is a person in need of treatment or a person with an illness or disorder. However, in other modalities, the subject may be a normal person. The term does not denote a particular age or sex. Therefore, adult subjects and newborns, whether male or female, are intended to be covered. The term effective dose refers to an amount of a compound that confers a therapeutic effect on the treated patient (e.g., sufficient to treat or prevent the disease). The effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject indicates or feels an effect). To avoid doubt, in cases where the proportion of two or more substituents in a compound of Formula I may be equal, the actual identities of the respective substituents are in no way interdependent. cnaczn / zznz / q / YiAi The compounds in Formula I may be administered by any suitable route, but particularly by oral, intravenous, intramuscular, cutaneous, subcutaneous, transmucosal (e.g., sublingual or buccal), rectal, transdermal, nasal, pulmonary (e.g., tracheal or bronchial), topical, local ocular (i.e., subconjunctival, intravitreal, retrobulbar, intracameral), or any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form. Particular modes of administration that may be mentioned include oral, topical, local ocular (i.e., subconjunctival, intravitreal, retrobulbar, intracameral), intravenous, cutaneous, subcutaneous, nasal, intramuscular, or intraperitoneal administration. When a compound of Formula I is used to treat an eye disease or disorder, the compound of Formula I is typically administered topically to the eye by local ocular administration. Therefore, in one modality, the compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug is injected directly into the eye, and in particular the vitreous humor. The compound, composition, or combination of the invention can be administered to the vitreous humor using any intravitreal or transscleral delivery technique. For example, the compound, composition, or combination cnaczn / zznz / q / YiAi can be administered to the vitreous humor by intravitreal injection. Intravitreal injection typically involves administering a compound of the invention or a pharmaceutically acceptable salt, solvate, or prodrug in a total amount between 0.1 ng and 10 mg per dose. Injectables for this use can be prepared in conventional forms, either as a liquid solution or suspension, or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion. Carriers may include, for example, water, saline solution (e.g., normal saline (NS), phosphate-regulated saline (PRS), balanced saline (BSS), Ringer's sodium lactate solution), dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of excipients, such as wetting or emulsifying agents, regulators, and the like, may be added. Adequate flowability can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion, and by using surfactants.As an example, the compound, composition, or combination can be dissolved in a pharmaceutically effective carrier and injected into the vitreous of the eye using a fine-gauge hollow-punch needle (e.g., 30 gauge, 3 / 8 or 1 / 2 inch needle) using a temporal focus (e.g., approximately 3 to approximately 4 mm posterior to the limbus for the human eye to avoid damaging the lens). In one embodiment, a compound of Formula I or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be formulated in a saline solution and injected into the vitreous humor of the eye. Although intravitreal administration is a likely method of administration to the eye, the present invention also includes other modes of administration, including topical or intravenous administration. For example, solutions or suspensions of the compound, composition, or combinations of the invention may be formulated as eye drops or as a membranous eye patch applied directly to the surface of the eye. Topical application typically involves administering the compound of the invention in an amount between 0.1 ng and 100 mg. In another embodiment, the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is delivered to the surface of the eye. The compound may be delivered to the surface of the eye as an eye drop, particularly as a composition or combination of eye drops. The compound, composition, or combinations of the invention may be administered to the surface of the eye using any known delivery technique. For example, the compound or combinations may be administered to the surface of the eye by dripping the formulation into the eye. The compounds in Formula I are generally administered as a pharmaceutical formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier, which may be selected with regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may not have harmful side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations may be found, for example, in Remington's The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, a parenterally acceptable aqueous solution, which is pyrogen-free and has the required pH, isotonicity, and stability, may be used. Suitable solutions will be well known to the person skilled in the art, with numerous methods described in the literature.A brief review of drug delivery methods can also be found in, e.g., Langer, Science (1990) 249, 1527. Otherwise, the preparation of suitable formulations can be routinely achieved by the expert using routine techniques and / or in accordance with standard and / or accepted pharmaceutical practices. The amount of compound of Formula I in any pharmaceutical formulation used according to the present invention will depend on various factors, such as the severity of the condition being treated, the particular patient being treated, and the compound or compounds being used. In any case, a person skilled in the art can routinely determine the amount of compound of Formula I in the formulation. For example, a solid oral composition such as a tablet or capsule may contain 1 to 99% (w / w) of active ingredient; 0 to 99% (w / w) of diluent or filler; 0 to 20% (w / w) of a disintegrant; 0 to 5% (w / w) of a lubricant; 0 to 5% (w / w) of a flow aid; 0 to 50% (w / w) of a granulating or binding agent; 0 to 5% (w / w) of an antioxidant; and 0 to 5% (w / w) of a pigment. A controlled-release tablet may also contain 0 to 90% (w / w) of a release-control polymer. A parenteral formulation (such as a solution or suspension for injection or a solution for infusion) may contain from 1 to 50% (w / w) of active ingredient; and from 50% (w / w) to 99% (w / w) of a liquid or semi-solid vehicle or carrier (e.g., a solvent such as water); and 0-20% (w / w) of one or more other excipients such as regulating agents, antioxidants, suspension stabilizers, tonicity-adjusting agents, and preservatives. Depending on the disorder, and the patient, to be treated, as well as the route of administration, Formula I compounds can be administered at varying therapeutically effective doses to a patient who needs it. However, the dose administered to a mammal, particularly a human, in the context of the present invention must be sufficient to effect a therapeutic response in the mammal for a reasonable period of time. A person skilled in the art will recognize that the selection of the exact dose and the most suitable composition and administration regimen will also be influenced by, inter alia, the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex, and response of the patient to treatment, and the stage / severity of the disease. Administration may be continuous or intermittent (e.g., by bolus injection). The dose may also be determined by the timing and frequency of administration. For oral or parenteral administration, the dose may range from approximately 0.01 mg to approximately 1000 mg per day of a Formula I compound. In any case, the physician or other expert in the art will be able to routinely determine the actual dose that will be most appropriate for an individual patient. The doses mentioned above are illustrative of the average case; there may, of course, be individual cases where higher or lower dose intervals are required, and such are within the scope of this invention. Other compounds of Formula I can be prepared according to techniques that are well known to those skilled in the art, for example, as described hereafter in the examples section. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques (e.g., recrystallization, column chromatography, preparative HPLC, etc.). In the processes described from here on, the functional groups of intermediate compounds may need to be protected by protecting groups. The protection and deprotection of functional groups can take place before or after a reaction in the reaction schemes mentioned above. Protecting groups can be removed using techniques well known to those skilled in the art, as described below. For example, the protected compounds / intermediates described below can be chemically converted into unprotected compounds using standard deprotection techniques. The type of chemistry involved will determine the need for and type of protecting groups as well as the sequence to achieve cnaczn / zznz / q / YiAi synthesis. The use of protective groups is fully described in Protective Groups in Organíc Chemistry, edited by JWF McOmie, Plenum Press (1973), and Protective Groups in Organíc Synthesís, 3rd edition, TW Greene & PGM Wutz, WileyInterscience (1999). As used herein, the term functional groups means, in the case of unprotected functional groups, hydroxy-, thiolo-, amino function, carboxylic acid and, in the case of protected functional groups, lower alkoxy, N-, O-, sacethyl, carboxylic acid ester. This description also describes compounds of Formula I where the linking group is of the formula: cnaczn / zznz / q / YiAi The compounds of Formula I comprising these linking groups may be useful in the treatment of eye diseases and disorders according to the invention. Such compounds may also be suitable for treating cancers such as prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia, or chronic myelomonocytic leukemia. Compounds that have linkers of the following formula may also be useful in the treatment of cancers such as prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia, or chronic myelomonocytic leukemia. cnaczn / zznz / q / YiAi Secondary or other therapeutic agents useful in the treatment of cancers such as prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia or chronic myelomonocytic leukemia include therapeutic agents useful in the treatment of hyperproliferative diseases or disorders, for example, chemotherapy drugs. Examples of second or other therapeutic agents that may be used in conjunction with a Formula I compound in the treatment of cancer include actinomycin, total trans-retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxyfluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, thioguanine, topotecan, valrubicin,vemufarafenib, vinblastine, vincristine, vindesine, Avastin (bevacizumab), bevacizumab, Camptosar (irinotecán hydrochloride), cetuximab, Cyramza (ramucirumab), Erbitux (cetuximab), 5-FU (fluorouracil injection), Fusilevocin, I lepilimucomab irinotecan hydrochloride, Keytruda (pembrolizumab), leucovorin calcium, Lonsurf (trifluridine and tipiracil hydrochloride), Mvasi (bavacizumab), nivolumab, Update cnaczn / zznz / q / YiAi 100 (nivolumab), panitumumab, pembrolizumab, ramucirumab, regorafenib, Stivarga (regorafenib), trifluoridine and tipiracil hydrochloride, Vectibix (panitumumab) Yervoy (ipilimumab), Zaltrap (ziv-aflibercept), abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, Casodex (bicalutamide), degarelix, Eligard (leuprolide acetate), enzalutamide, Erleada (apalutamide), Firmagon (degarelix), flutamide, goserelin acetate, Jevtana (cabazitaxel), leuprolide acetate. Lupron (leuprolide acetate), Lupron Depot, (leuprolide acetate), mitoxantrone hydrochloride, Nilandron (nilutamide), Provenge (sipuleucel-T), 223-radium dichloride, Xofigo (223-radium dichloride), of abiraterone). The following examples illustrate the invention and should not be interpreted as limitations. EXAMPLES The compounds in the examples were prepared using the synthetic routes shown. Ejemplo 1 cnaczn / zznz / q / Yi LCMS (ESI) m / z = 417.05 [M+H]+; HPLC: RT 5.52, pureza: 95.17 %; RMN-1H (400 MHz, DMSO-de) δ = 11.00 101 (s, 1H), 8.46 (d, J= 6.9 Hz, 1H), 8.38 (d, J= 2.0 Hz, cnaczn / zznz / q / vi 1H), 8.07 (dd, J= 2.2, 8.6 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 9.4 Hz, 1H), 7.26 - 7.33 (m, 1H), 7.12 (d, J = 8.4 Hz, 1H) , 6.92 - 6.98 (m, 2H), 5.01 (s, 2H), 3.88 (s, 3H) . Ej emplo 2 Br E j emplo 3 Etapa 1 LCMS (ESI) m / z = 429.00 [M+H]+; HPLC: RT 7.70, pureza: 99.29 %; RMN-1H (400 MHz, DMSO-dg) δ = 11.12 (br s, 1H) , 9.14 (d, J = 1.5 Hz, 1H) , 8.56 (dd, J = 1.2, 4.6 Hz, 1H) , 8.45 8.49 (m, 2H) , 8.33 (s, 1H) , 8.15 (dd, J = 2.4, 8.3 Hz, 1H) , 8.05 (s, 1H) , 7.91 (d, J= 4.4 Hz, 1H) , 7.16 (d, J= 8.8 Hz, 1H), 5.11 (s, 2H), 2.38 (s, 3H). 102 Ej emplo 4 cnaczn / zznz / q / Yi LCMS (ESI) m / z = 428.20 [M+H]+; HPLC: RT 7.88, pureza: 98.07 %; RMNΉ (400 MHz, EMSO-dd δ = 10.41 (s, 1H) , 9.14 (s, 1H), 8.56 (d, J= 4.9 Hz, 1H), 8.50 (d, J= 2.0 Hz, 1H) , 8.16 (dd, J= 2.5, 8.4 Hz, 1H), 8.03 - 8.07 (m, 2H), 7.92 (d, J= 4.4 Hz, 1H), 7.73 (d, J= 8.4 Hz, 1H) , 7.39 (d, J = 8.4 Hz, 1H), 7.18 (d, J= 8.9 Hz, 1H) , 5.03 (s, 2H) , 2.38 (s, 3H) . Ejemplo 5 LCMS (ESI) m / z = 427.30 [M+H]+; HPLC: RT 6.22, pureza: 99.78 %; RMNΉ (400 MHz, EMSO-dd δ = 10.40 (s, 1H) , 8.48 (d, J = 6.9 Hz, 1H) ,8.41 (d, J= 2.0 Hz, 1H) , 8.09 (dd, J = 2.5, 8.4 Hz, 1H) , 8.05 (d, J= 2.0 Hz, 1H), 7.79 (s, 1H) , 7.73 (d, J= 8.4 Hz, 1H) , 7.67 (d, J = 8.9 Hz, 1H) , 7.38 (d, J= 8.4 Hz, 1H), 7.36-7.41 (m, 1H) , 7.15 (d, J= 8.9 Hz,1H) , 6.98 (t, J= 6.9 Hz, 1H), 5.02 (s, 2H) , 2.38 (s, 3H). Ejemplo 6 103 Ej emplo 7 cnaczn / zznz / q / vi NBS, ACN TA, 4 h Stage 1 ?3 X-Pho?. Cc <npd-5 °C, Lí Stage 5 Example 8 Trimethylboroxine, Stage 1 1 3 B2Pin2, PdCl2dppf. DCM, kOAc, dioxane, 80 °C, 18 Stage 2 Pd(PPh3)4, Na2CO3, Dioxane / H20, 80 °Cr16 h Stage 3 B AlMe,, dioxane, 70 °C, 16 h Stage 4 It is . 8 LCMS (ESI) m / z = 428.20 [M+H]1; HPLC: RT 5.85, purity: 99.51 %; NMR-^ (400 MHz, CLOROFORM-d) δ = 8.80 (br s, 1H) , 8.57 (s, 1H), 8.38 (d, J= 2.0 Hz, 1H), 8.25 (s, 1H), 8.20 (d, J = 6.8 Hz, 1H), 7.86 (dd, J = 2.2, 8.6 Hz, 1H) , 7.65 - 7.77 (m, 2H) , 7.12 (d, J = 8.3 Hz, 1H) , 6.86 (H4) Hz, J= 6, 5.07 (s, 2H), 2.44 (s, 3H). 104 For example 9 cnaczn / zznz / q / Yi LCMS (ESI) m / z = 418.20 [M+H]+; HPLC: RT 7.00, purity: 98.45 %; RMN-1H (400 MHz, DMSO-ds) δ = 11.01 (s, 1H) , 9.14 (s, 1H), 8.55 (d, J= 4.9 Hz, 1H), 8.47 (d, J = 2.5 Hz, 1H (dd 2), 8.14. 1H) , 8.05 (s, 1H) , 7.92 (d, J= 4.9 Hz, 1H), 7.15 (d, J= 8.4 Hz, 1H), 6.96 (s, 1H), 5.02 (s, 2H), 3.88) (s., 3H Examples 10 to 19 Additional compounds were produced by analogous methods and are listed in Table 1 below. 105 cnaczn / zznz / q / YiA 106 16 A··^ N 4 zw IV„ yy “ 17 r\ Ί í > xx A ,X s 18 -'-η 1 >' K XN- ? / A. v / X. / / v \\ / x___ / (í F ®,S V ^z-'-7 * CJ f-ί / ^ 19 Z x •^' / f Example 12 jScheme: and 9 I , .3⁄4ÚaV 4 Δ / } ?> ·γ·'· -w S f <íν·χ j ;. j’ v., < §. 4- acoplamiento de suzuki n vr· íí $ ?k ύδ· | 1 a etapa z \ 2 i 7 u$ n--z §Me3Al, tol, reflujo X V” Á;<.Z h .,.? , ,?s· - v Etapa 3 r Ej. 12 LCMS (ESI) m / z = 475.00 [M+l]+; RMN-iR (400 MHz, CDCI3) δ 107 ppm: 9.19 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.45 (d, 1H, J = 2.8 Hz), 8.35 (s, 1H) , 8.13 (d, 1H, J = 4.4 Hz) , 7.94 (d, 1H, J= 4.4 Hz), 7.87-7.89 (m, 2H), 7.09 (d, 1H, J= 8.4 Hz), 1.80-1.83 (m, 2H), 1.35-1.38 (m, 2H) cnaczn / zznz / q / YiAi Ejemplo 13 LCMS (ESI) m / z = 463.2 [M+l]+; RMN-1H (400 MHz, DMSO-d6) δ ppm: 11.46 (s, 1H), 9.12 (s, 1H), 8.72 (s, 1H), 8.53 (d, 1H, J = 3.6 Hz), 8.50 (s, 1H) , 8.43 (d, 1H, J = 2.0 Hz), 8.14 (m, 1H), 8.03 (s, 1H), 7.90 (d, 1H, J= 4.4 Hz), 7.13 (d, 1H, J= 4.4 Hz), 5.53 (q, 1H, J= 6.80 Hz), 1.60 (d, 1H, J= 6.80 Hz). Ejemplo 14 LCMS (ESI) m / z = 412.05 [M+l]+; RMN-1H (400 MHz, DMSO-d6) δ ppm: 10.17 (s, 1H), 9.06 (s, 1H), 8.81 (s, 1H), 8.16 (s, 1H), 108 8.08 (d, 1H, J = 4.4 Hz), 7.80-7.95 (m, 4H), 7.81 (s, 1H), 7.38 cnaczn / zznz / q / YiA (d, 1H, J= 8.0 Hz), 6.75 (d, 1H, J= 8.8 Hz), 2.39 (s, 3H) Ejemplo 15 LCMS (ESI) m / z = 426.05 [M+l]+; RMN-1H (400 MHz, DMSO-d6) δ ppm: 10.31 (s, 1H), 9.06 (s, 1H) , 8.48 (d, 1H, J = 4.4 Hz), 8.05 (s, 1H), 7.85-7.88 (m, 2H), 7.75 (d, 1H, J= 7.6 Hz), 7.46 (d, 1H, J= 8.4 Hz), 7.36 (d, 1H, J= 8.4 Hz), 6.78 (d, 1H, J = 8.4 Hz), 6.49 (t, 1H, J= 6.0 Hz), 3.97 (d, 1H, J = 6.0 Hz), 2.37 (s, 3H) Ejemplo 16 109 LCMS: 96.13 %, m / z=448.2 [M+2H]+; ΗΜΝ-^ (DMSOd6, 400 MHz): δ 11.14-11.23 (m, 1H), 9.08 (d, J= 1 .3 4 Hz, 1H), 8.72 (s, 1H), 8.54-8.59 (m, 1H), 8.50 (dd, J=1.41, 4.71 Hz, 1H), 7.85-7.91 (m, 2H), 7.47 (d, J= 8 . 6 8 Hz, 2H), 6.80 (d, J= 8 . 6 8 Hz, 2H), 6.51 (t, J= 6 . 4 2 Hz, 1H), 4.12 (d, J= 6 . 4 8 Hz, 2 H ) ; cnaczn / zznz / q / Yi Ejemplo 17 LCMS: 98.08%, m / z=416.2 [M+H]+; 1H-NMR (DMSOde, 400 MHz): δ 10.84 (s, 1H), 9.06 (d, J=1.34 Hz, 1H), 8.48 (dd, J=1.41, 4.71 Hz, 1H), 7.84-7.88 (m, 2H), 7.44 (d, J=8.56 Hz, 2H), 6.98 (s, 1H), 6.76 (d, J=8.56 Hz, 2H), 6.41-6.47 (m, 1H), 3.97 (d, J=6.36 Hz, 2H), 3.87 (s, 3H) . 110 cnaczn / zznz / q / YiAi Example 18 LCMS: 99.27%, m / z=434.2 [M+H]+; H-NMR (DMSOde, 400 MHz): δ 10.90 (s, 1H), 9.09-9.11 (m, 1H), 8.19-8.22 (m, 1H), 7.85-7.90 (m, 2H), 7.33-7.39 (m, 1H), 6.99 (s, 1H), 6.766.81 (m, 1H), 6.57-6.63 (m, 2H), 4.00 (d, 5=6.48 Hz, 2H), 3.88 (s, 3H); Activity data The compounds in the Examples were tested in various assays as described below. Determination of activity in the HEK293 cell line model Human embryonic kidney cells (HEK293) were constructed to express human PDGFRWT under constitutive CMV promoter control. The cells were cultured in the presence of 20 ng / ml of PDGF (the ligand for PDGFRp) to activate PDGFRp. Different concentrations of The compounds from Examples 1 and 2 were used to study their effect on PDGFRp-mediated signaling. PDGFRp autophosphorylation and Shp2 phosphorylation were monitored by Western blot and used as markers for PDGFRp signaling. β-Actin was used as an internal control. The results are shown in Figure 1. It is clear that both Examples 1 and 2 are able to inhibit PDGFRP signaling. Cell viability by MTS assay The effect of the compounds on cell viability was determined using an MTS assay. The MTS cell proliferation assay kit is a colorimetric method for the sensitive quantification of viable cells in proliferation and cytotoxicity assays. The method is based on the reduction of the tetrazolium compound MTS by viable cells to generate a colored formazan product that is soluble in cell culture media. BA / F3 cells expressing the tyrosine kinase receptor (PDGFR [MTS Assay 1] or Flt3 [MTS Assay 2]) were cultured under standard culture conditions in a 96-well microtiter plate (final volume 200 µA / well) in the absence or presence of the compound to be analyzed and incubated for 20–48 h. The MTS reagent (20 μA / well) was added to each well and incubated for 0.5-4 hours at 37 °C under standard culture conditions. cnaczn / zznz / q / YiAi 112 The absorbance at 490 nm was recorded using a plate reader. The results are shown in Figures 2 and 3 and Table 2 (where IC50 indicates the concentration of the compound required to reduce cell viability by 50%). It is evident that the compounds in Examples 1 to 7 have potent antitumor activity, with at least Examples 1, 3, and 4 showing enhanced activity when compared to the controls imatinib and quizartinib. In vitro activity and selectivity assay To determine the inhibitory activity of the compounds, in vitro kinase assays were performed on the respective enzymes purified from Sf9 insect cells or E. coli as recombinant GST fusion proteins or His-tagged proteins. The assay for all protein kinases contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na-orthovanadate, 1.2 mM DTT, ATP (variable amounts, corresponding to the apparent ATP-Km of the respective kinase), [γ-33P]-ATP (approx. 9 x 1005 cpm per well), protein kinase, and the peptide substrate. IC50 data for the analyzed compounds are provided in Table 2 below (a dash indicates that a compound was not analyzed). L represents an IC50 of less than 500 nM M represents an IC50 between 500 nM and 5000 nM H represents an IC50 of more than 5000 nM For the MTS test, the result indicates the 113 concentration of the compound required to reduce the cnaczn / zznz / q / YiAi cell viability to 50%. Table 2: CI50 test results E j emp10 IC50 (nM) PDGFR-β PDGFR-a VEGFR-2 MTS Test 1 1 LLLL 2 / 5 - - - L 3 / 8 LLLL 4 - - - L 6 - - - M 7 - - - L 9 - - - L 10 - - - L 12 HHH - 13 MMM - 14 HHH - 15 LLL - 16 LLL - 17 LLL - 18 LLL - 19 LLL - Effect on capillary formation in vivo Figure 4 illustrates the effectiveness of a compound of the present invention in the CNVmouse laser model for wet AMD. An in vivo test of a test compound according to the invention was performed in a laser mouse model. 114 NVC (choroidal neovascularization). The eyes of young mice were laser-treated to create choroidal damage resulting in blood vessel leakage (shown as light areas in Figure 4). In each mouse, one eye was injected with a predetermined amount of the test compound, while the other eye remained untreated to serve as a treatment control. Images of the mouse eyes were acquired intermittently for two weeks. The efficacy of the test compound was indicated by its ability to prevent blood vessel leakage (reduction or disappearance of light areas). The compound's efficacy was very similar to that of the commercially available product Eylea (aflibercept). Table 3: Results of the additional CI50 test Reference Example 1: Additional Trial Results E j emp10 IC50 (nM) Flt3 CDK8 CDK19 Test 2 MTS 1 LLLL 2 / 5 L - - L 3 / 8 LLL - 4 - - - - 6 - - - L 7 - - - L 9 - LL - 10 - - - - 12 HHH - 115 13 MMM - 14 HMM - 15 LLLL 16 LLL - 17 LLL - 18 LLL - 19 LLL - cnaczn / zznz / q / YiA In Table 3: L represents an IC50 of less than 500 nM M represents an IC50 between 500 nM and 5000 nM H represents an IC50 of more than 5000 nM For the MTS assay, the result indicates the concentration of the compound required to reduce cell viability to 50%. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

cnaczn / zznz / q / YiAi Having described the invention as above, the contents of the following claims are claimed as property:

1. A compound of Formula 1: characterized in that: Xi and X2 each independently represent N or CRa Ra independently represents H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-s alkenyl and C2-5 alkynyl (the last four groups of which are unsubstituted or substituted by one or more halo substituents); A is selected from the group consisting of: 117 cnaczn / zznz / q / YiA where: the dashed line represents the point of attachment to the rest of the molecule; Each Rl to Rs is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups of which are either unsubstituted or substituted by one or more halo substituents;X3 represents N, CH, or CR3, where R3 is as defined above; X4 represents N, CH, or CR4, where R4 is as defined above; X5 represents N, CH, or CRs, where R5 is as defined above, provided that only one or two of X3 to X5 are N; each Xg to X9 independently represents N, CH, or CRg; 118 where each Re is independently selected from C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, or C2-5 alkynyl, all four groups being either unsubstituted or substituted by one or more halo substituents; wherein in any portion A, one of Ri to Re can be piperazine, methylpiperazine, or ethylpiperazine, each of which can be connected to the remainder of portion A by a carbon or nitrogen atom on the piperazine ring. Yi represents NRn, O, or S; Y2 represents NRn, NRy, O, or S; Rn represents H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents;Ry represents piperazine, methylpiperazine, or ethylpiperazine, each of which is connected to the nitrogen atom at Y2 by a carbon atom in the piperazine ring; L is a linking group of the formula: -M-(CRlRm) aC(O) -NR7; -M-(CRlRm) a-NR7'C(O)-; or -MC(O) -(CRnRo) -C(O) -M where M represents a covalent bond, O or NH; Rl and Rm each independently represent H, methyl, ethyl, fluoro, or chlorine, or Rl and Rm together with the carbon atom to which they are attached, form a C3 or C4 cycloalkyl ring, carbonyl group, or thiocarbonyl group; a represents O or I; R7 and R?' represent H or an optionally substituted alkyl group; Rn and Ro each independently represent H, methyl, ethyl, fluoro or chlorine;Z represents a heterocycle selected from the group consisting of: where: the dotted line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group; 120 each from Ra to Rio are independently selected from H, hydroxy, C1 to C5 alkyl, C1 to C5 alkoxy (the last two groups of which are either unsubstituted or substituted by one or more halo groups), OC(0)Rn, C(O)ORi2, C2 to C5 alkynyl (which is either unsubstituted or substituted by one or more halo groups) or NR13R14, and O-(C1-4 alkylenyl)-C1-4 alkyl, and one from Ra to Rio may be a group of the formula: cnaczn / zznz / q / YiAi where X represents O, NRx, Rx represents H or C1-4 alkyl, R11 and R12 each independently represent, at each occurrence, optionally substituted alkyl; R13 and R14 each independently represent, at each occurrence, H or optionally substituted alkyl; R15 represents H or C1-2 alkyl;or a pharmaceutically derived salt thereof, provided that when Xi and X2 Λ > , and A is '' acceptable, solvate 0 are both CH, L is then Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl.; 2. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate or derivative thereof, characterized in that Ra independently represents H, NH2, F, Cl or C1-3 alkyl, wherein the C1-3 alkyl group is either unsubstituted or substituted by one, two or three fluoro or chloro substituents, optionally wherein Ra is H or F.

3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, solvate, or derivative thereof, characterized in that: each Ri to R5 independently represents halo, C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl, and C2-3 alkynyl (all four groups being either unsubstituted or substituted by one or more halo substituents), optionally wherein each Ri to Rs independently represents fluoro, chloro, methyl, or ethyl, the methyl and ethyl groups being either unsubstituted or substituted by one, two, or three fluoro or chloro groups.

4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or derivative thereof, characterized in that: Yi and Y2 independently represent O, NC1-3 alkyl, or NH; and / or Re independently represents C1-3 alkyl, C1-3 alkoxy, C2-3 alkenyl, and C2-3 alkynyl (all four groups being either unsubstituted or substituted by one or more halo substituents), optionally wherein Yi and Y2 independently represent O, NMe, or NH, and / or Re independently represents fluoro, chloro, methyl, or ethyl, the methyl and ethyl groups being either unsubstituted or substituted by one, two, or three fluoro or chloro groups.

5. A compound according to any of the preceding claims, characterized in that: Rg and Rio, when present, are H, and ί Ί Rs is selected from H and θ where X is O or NH.

6. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt, solvate or derivative thereof, characterized in that A cnaczn / zznz / q / vi 123 cnaczn / zznz / q / YiA 7. A compound according to claim 6, characterized in that A is selected from the group consisting of and where, when present: Ri is selected from Cl, CH3 and H, R2 is CF3, X3 and X5 are CH, X4 is N, Xe is N, Xg and Xg are CH, Y2 is selected from N-CH3 and O.

8. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt, solvate, or derivative thereof, characterized in that: M represents O or NH; and / or Rl and Rm each independently represent H, methyl, or chlorine, or Rl and Rm together represent thiocarbonyl or cyclopropyl; and / or oa represents 1.

9. A compound according to any of the preceding claims, or a pharmaceutically acceptable salt, solvate or derivative thereof, characterized in that L cnaczn / zznz / q / YiA represents: where the dotted lines represent the point of attachment to the rest of the molecule.

10. A compound according to claim 1, characterized in that it is selected from: 125 cnaczn / zznz / q / YiAi 126 cnaczn / zznz / q / YiAi 127 cnaczn / zznz / q / Y 128 cnaczn / zznz / q / Y or a pharmaceutically acceptable salt, solvate or derivative thereof.

11. A compound according to any of claims 1 to 13, or a pharmaceutically acceptable salt, solvate, or derivative thereof, characterized in that L is selected from: 129 cnaczn / zznz / q / YiA R7 optionally wherein L is selected from 12. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate or derivative thereof, characterized in that L is: 130 cnaczn / zznz / q / YiAi 13. A compound according to claim 1, or a pharmaceutically acceptable salt, solvate, or derivative thereof, characterized in that: Xi and X2 each independently represent N or CRa; Ra independently represents H, NH2, halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, and C2-5 alkynyl (the last four groups being either unsubstituted or substituted by one or more halo substituents); A is selected from the group consisting of: 131 cnaczn / zznz / q / YiAi 132 where: the dashed line represents the point of attachment to the rest of the molecule; each R1 to R2 is independently selected from halo, C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the last four groups being either unsubstituted or substituted by one or more halo substituents;X3 represents N, CH or CR3, where R3 is as defined above; N represents N, CH or CR4, where R4 is as defined above; X5 represents N, CH or CR5, where R5 is as defined above, provided that only one or two of X3 to X5 are N; each Xβ to X9 independently represents N, CH or CRg, where each Re is independently selected from C1-5 alkyl, C1-5 alkoxy, C2-5 alkenyl, C2-5 alkynyl, the four groups of which are either unsubstituted or substituted with one or more halo substituents; Yi and Y2 each independently represent NRn, O or S; Rn represents H, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, the last three groups of which are either unsubstituted or substituted with one or more halo substituents; L is a linking group of the formula: -M-(CRlRm) aC (O)-NR7; or cnaczn / zznz / q / YiAi -M- (CRlRm) a-NR7'-C (O) -; 133 where M represents a covalent bond, O or NH;Rl and Rm each independently represent H, methyl, ethyl, fluoro or chlorine, or Rl and Rm together form a C3 or C4 cycloalkyl ring, carbonyl group or thiocarbonyl group; a represents 0 or 1; R7 and R7' represent H or an optionally substituted alkyl group; Z represents a heterocycle selected from the group consisting of: where: the dashed line represents the point of attachment to the rest of the molecule, and Z is attached to the rest of the molecule by a covalent bond, or by an -O- or -NH- group; 134 each from Ra to Rio are independently selected from H, Me, C5 to C5 alkoxy that is unsubstituted or substituted by one or more halo groups, 0C(0)Ru, C(O)ORi2, C2 to C5 alkynyl substituted by one or more halo groups or NR13R14 and one from Ra to Rio may be a group of the formula cnaczn / zznz / q / YiAi where X represents O or NH R11 and R12 each independently, at each occurrence, optionally substituted alkyl;R13 and R14 each independently represent, at each occurrence, H or optionally substituted alkyl; provided that when XI and X2 are both CH, L is optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl.

14. A compound of Formula I according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, solvate, or derivative thereof, for use in the treatment of one or more of macular degeneration, diabetic retinopathy, and angiogenesis. 135 15. A pharmaceutical composition characterized in that it comprises a compound of Formula I according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, solvate, or derivative thereof. cnaczn / zznz / q / YiAi