Compounds for the treatment of eye disorders

Abstract

The compounds of formula I as defined herein, or a pharmaceutically acceptable salt, solvate or derivative thereof, are potent inhibitors of angiogenesis and are therefore useful in the treatment and prevention of angiogenesis-related disorders, such as cancer.

Description

[Technical field]

[0001] The present invention relates to the field of medicine, in particular to compounds that are inhibitors of angiogenesis.The compounds of the present invention are useful in the treatment of angiogenesis and angiogenesis-related disorders, such as ocular disorders (e.g., macular degeneration and diabetic retinopathy). [Background technology]

[0002] The listing or discussion of a prior-publication document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0003] Macular degeneration "MD" is a disease that affects the layer of cells in the eye known as the retinal pigment epithelium, which is located underneath the retina. The retinal pigment epithelium (RPE) acts as a wall or barrier, allowing oxygen, sugar, and other essential elements to pass through to the retina and moving waste products to the blood vessels underneath the retina (these vessels are called the choroid). The RPE also acts as a barrier between the choroid and the retina. When RPE cells die, the retinal cells above them also die, resulting in patches of "shedded" retina. This is commonly referred to as geographic atrophy or "dry" MD, a slower form of MD that causes gradual vision loss. "Wet" macular degeneration occurs when the RPE cells are unable to stop the growth of choroidal blood vessels underneath the retina. This growth is called choroidal neovascularization or CNV. The rapidly growing blood vessels have leaky and fragile walls that leak fluid and blood underneath the retina. This leads to scarring and severe loss of central vision, which can become permanent if left untreated. In the context of the present invention, the term "macular degeneration" refers in particular to "wet" MD, also known as neovascular or exudative AMD, but will be understood to also include "dry" MD.

[0004] 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) with abnormal blood vessel growth. Diabetic macular edema (DME) is also included within its scope. DME is a symptom of diabetic retinopathy that occurs in all severity levels of both NPDR and PDR and is the most common cause of blindness in patients. DME results from diabetes-induced breakdown of the blood-retinal barrier (BRB), resulting in vascular leakage of fluid and blood proteins into the neural retina. The leakage of fluid into the neural retina leads to abnormal retinal thickening and often cystoid macular edema.

[0005] In wet AMD and diabetic retinopathy, VEGFα is believed to play a key role in the formation of abnormally growing and leaking blood vessels under the macula. Constant exposure of endothelial cells to pro-angiogenic factors such as VEGFα leads to the formation of immature, semi-differentiated, fragile blood vessels that tend to leak and bleed. The three main receptor tyrosine kinases (RTKs) involved in abnormal blood vessel growth in MD are PDGFRα, PDGFRβ, and VEGFR2. These receptor tyrosine kinases are high affinity cell surface receptors for polypeptide growth factors such as VEGFα. It is therefore believed that compounds that can distinguish between "disease" and normal cells may exhibit a wider therapeutic window than compounds or agents that do not. Summary of the Invention

[0006] Without being bound by theory, the present invention is based on the surprising discovery that the compounds of formula I as defined herein exhibit high selectivity for the receptor tyrosine kinases (RTKs) PDGFRα, PDGFRβ, and VEGFR2. Therefore, it is believed that the compounds of formula I are particularly suitable for therapeutic use in patients with macular degeneration; i.e., patients with high density of receptor tyrosine kinases, since they may be able to inhibit the proliferation of only "disease" cells. It is believed that the compounds of the present invention may be effective in preventing the development of abnormal angiogenesis, and therefore may be advantageous in the treatment of MD and / or diabetic retinopathy.

[0007] Accordingly, the present invention provides the following numbered clauses:

[0008] 1. A compound of formula I, [ka] During the ceremony, X1 and X2 each independently represent N or CR a represents R a are independently H, NH2, halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl and C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; A is selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the rest of the molecule; Each R1 through R5 is independently halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; X3 represents N, CH, or CR3 [wherein R3 is as defined above], X4 represents N, CH, or CR4 [wherein R4 is as defined above], and X5 represents N, CH, or CR5 [wherein R5 is as defined above], with the proviso that only one or two of X3 to X5 are N; Each of X6 to X9 is independently N, CH or CR6, 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, wherein the four groups are unsubstituted or substituted with one or more halo substituents; In any moiety A, one of R1-R6 may be piperazine, methylpiperazine, or ethylpiperazine, each of which may be connected to the remainder of moiety A via a carbon or nitrogen atom of the piperazine ring; Y1, NR N , O or S; Y2 is NR N , N.R. Y represents O or S; R N , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 alkynyl, the latter three groups being unsubstituted or substituted with one or more halo substituents; R Y represents piperazine, methylpiperazine, or ethylpiperazine, each of which is bonded to the nitrogen atom of Y2 via a carbon atom in the piperazine ring; L is a group represented by the formula: -M-(CR L R M ) a -C(O)-NR7-; -M-(CR L R M ) a -NR 7’ -C(O)-; or -MC(O)-(CR N R O )-C(O)-M- where M represents a covalent bond, O, or NH; R L and R M each independently represents H, methyl, ethyl, fluoro or chloro, or R L and R M together with the carbon atom to which they are attached form a C3 or C4 cycloalkyl ring, a carbonyl group, or a thiocarbonyl group; a represents 0 or 1; R7 and R 7’ represents H or an optionally substituted alkyl group; R N and R O each independently represents H, methyl, ethyl, fluoro, or chloro; Z represents a heterocycle selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group; R8~R 10 each independently represents H, hydroxy, C1-C5 alkyl, C1-C5 alkoxy (the latter two groups being unsubstituted or substituted with one or more halo groups), OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl, which is unsubstituted or substituted with one or more halo groups, or NR 13 R 14 , and O-(C 1~4 (alkylenyl)-OC 1~4 alkyl, And R8~R 10 One of them is the formula: [ka] [Wherein, X is O, NR X may be a group represented by R X is H or C1~4 represents an alkyl group, R 11 and R 12 each independently at each occurrence represents optionally substituted alkyl; R 13 and R 14 represents each independently at each occurrence H or optionally substituted alkyl; R 15 is H or C 1~2 a compound, or A pharma- ceutically acceptable salt, solvate, or derivative thereof, However, X1 and X2 are both CH, and L is [ka] and A is [ka] then Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl; A compound of formula I, or a pharma- ceutically acceptable salt, solvate, or derivative thereof.

[0009] 2. R a are independently H, NH2, F, Cl, or C 1~3 Represents alkyl, where C 1~3 The alkyl group is unsubstituted or substituted with 1, 2, or 3 fluoro or chloro substituents, and optionally R a is H or F, or a pharma- ceutically acceptable salt, solvate, or derivative thereof.

[0010] 3. The compound according to clause 1 or 2, wherein X1 is selected from N and CH, and X2 is selected from CH and CF.

[0011] 4. Each of R1 through R5 is independently halo, C 1~3 Alkyl, C 1~3Alkoxy, C 2~3 Alkenyl and C 2~3 alkynyl, wherein the four groups are unsubstituted or substituted by one or more halo substituents, and optionally each R1-R5 independently represents fluoro, chloro, methyl or ethyl, wherein the methyl and ethyl groups are unsubstituted or substituted by one, two or three fluoro or chloro groups; or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0012] 5. Y1 and Y2 are independently O, NC 1~3 represents alkyl or NH; and / or R6 is independently C 1~3 Alkyl, C 1~3 Alkoxy, C 2~3 Alkenyl and C 2~3 alkynyl, which of the four groups is unsubstituted or substituted with one or more halo substituents; Optionally, Y1 and Y2 independently represent O, NMe, or NH; and / or A compound according to clause 1 or 2, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein R6 independently represents fluoro, chloro, methyl, or ethyl, wherein the methyl and ethyl groups are unsubstituted or optionally substituted with one, two, or three fluoro or chloro groups.

[0013] 6. The compound according to clause 4, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein each of R1-R5 and R6 independently represents methyl, trifluoromethyl, fluoro, or chloro.

[0014] 7. (a) Each R8~R 10 are independently H, hydroxy, Me, C 1~2 Alkoxy, which is unsubstituted or substituted with one or more halo groups, OC(O)R 11 , C(O)OR 12 , C2-C3 alkynyl (which is substituted with one or more halo groups), O-(C 1~2(alkylenyl)-OC 1~2 Alkyl or NR 13 R 14 represents R 11 and R 12 each independently represents methyl or ethyl; R 13 and R 14 each independently represents H, methyl or ethyl; or (b) R8~R 10 One of the expressions [ka] [In the formula, X is O, NH, or NC 1~2 represents an alkyl group; R 15 represents methyl, R8~R 10 or a pharma- ceutically acceptable salt, solvate or derivative thereof, according to any one of clauses 1 to 6, wherein the remaining two of said compounds are as defined in part (a).

[0015] 8. The compound according to any one of clauses 1 to 7, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein Z represents a heterocycle selected from: [ka]

[0016] 9. (a) R8~R 10 is a C1-C5 alkyl group, it is an unsubstituted methyl group; and / or (b) R8~R 10 or a pharma- ceutically acceptable salt, solvate, or derivative thereof, according to any one of clauses 1 to 8, wherein when any of is a C2-C5 alkynyl group, it is a C2-C5 alkynyl group substituted by one or more halo groups.

[0017] 10. R9 and R 10 is H, if present; R8 is H and [ka] wherein X is O or NH; 10. The compound according to any one of clauses 1 to 9.

[0018] 11. The compound according to clause 1, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein A is selected from the group consisting of: [ka]

[0019] 12. A is selected from the group consisting of: [ka] If present, R1 is selected from Cl and CH; R2 is CF3, X3 and X5 are CH; X4 is N; X6 is N; X8 and X9 are CH; The compound according to clause 11, wherein Y2 is selected from N-CH3 and O.

[0020] 13. M represents O or NH; and / or R L and R M each independently represents H, methyl or chloro, or R L and R M together represent thiocarbonyl or cyclopropyl; and / or a represents 1, 13. A compound according to any one of clauses 1 to 12, or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0021] 14. L, [ka] 14. The compound according to any one of clauses 1 to 13, wherein the compound represents: wherein the dotted line represents the point of attachment to the remainder of the molecule, or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0022] 15. The compound according to clause 1, selected from: [ka] [ka] or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0023] 16. L is selected from the following: [ka] Optionally, L is selected from: [ka] 14. A compound according to any one of clauses 1 to 13, or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0024] 17. L, [ka] 14. The compound according to any one of clauses 1 to 13, or a pharma- ceutically acceptable salt, solvate or derivative thereof,

[0025] 18. The compound according to clause 1, selected from: [ka] [ka] or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0026] 19. Use of a compound of formula I, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, as defined in any one of clauses 1 to 18, in the manufacture of a medicament for treating one or more of macular degeneration, diabetic retinopathy, and angiogenesis.

[0027] 20. A method for treating one or more of macular degeneration, diabetic retinopathy, and angiogenesis, comprising administering a therapeutically effective amount of a compound of formula I, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, as defined in any one of clauses 1 to 18.

[0028] 21. A compound of formula I, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, as defined in any one of clauses 1-18, for use in treating one or more of macular degeneration, diabetic retinopathy, and angiogenesis.

[0029] 22. A pharmaceutical composition comprising a compound of formula I as defined in any one of clauses 1 to 18, or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0030] 23. X1 and X2 are each independently N or CR. a represents R a are independently H, NH2, halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl and C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; A is selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the rest of the molecule; Each R1 through R5 is independently halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; X3 represents N, CH, or CR3 [wherein R3 is as defined above], X4 represents N, CH, or CR4 [wherein R4 is as defined above], and X5 represents N, CH, or CR5 [wherein R5 is as defined above], with the proviso that only one or two of X3 to X5 are N; Each of X6 to X9 is independently N, CH or CR6, 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, wherein the four groups are unsubstituted or substituted with one or more halo substituents; Y1 and Y2 each independently represent NR N , O or S; R N , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 alkynyl, the latter three groups being unsubstituted or substituted with one or more halo substituents; L is a group represented by the formula: -M-(CR L R M ) a -C(O)-NR7-; or -M-(CR L R M ) a -NR 7’ -C(O)-; where M represents a covalent bond, O, or NH; R L and R M each independently represents H, methyl, ethyl, fluoro or chloro, or R L and R M together form a C3 or C4 cycloalkyl ring, a carbonyl group or a thiocarbonyl group; a represents 0 or 1; R7 and R 7’ represents H or an optionally substituted alkyl group; Z represents a heterocycle selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group; R8~R 10 each independently represents H, Me, C1-C5 alkoxy unsubstituted or substituted with one or more halo groups, OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl substituted with one or more halo groups, or NR 13 R 14 Selected from R8 to R 10 One of the expressions [ka] wherein X represents O or NH, R 11 and R 12 represents, independently at each occurrence, an optionally substituted alkyl; R 13 and R 14 represents each independently at each occurrence H or optionally substituted alkyl; However, X1 and X2 are both CH, and L is [ka] and A is [ka] 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 pharma- ceutically acceptable salt, solvate or derivative thereof.

[0031] The present invention also provides the following numbered statements:

[0032] 1. A compound of formula I, [ka] During the ceremony, X1 and X2 each independently represent N or CR a represents R a are independently H, NH2, halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl and C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; A is selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the rest of the molecule; Each R1 through R5 is independently halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; X3 represents N, CH, or CR3 [wherein R3 is as defined above], X4 represents N, CH, or CR4 [wherein R4 is as defined above], and X5 represents N, CH, or CR5 [wherein R5 is as defined above], with the proviso that only one or two of X3 to X5 are N; Each of X6 to X9 is independently N, CH or CR6, 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, wherein the four groups are unsubstituted or substituted with one or more halo substituents; Y1 and Y2 each independently represent NRN , O or S; R N , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 alkynyl, the latter three groups being unsubstituted or substituted with one or more halo substituents; L is a group represented by the formula: -M-(CR L R M ) a -C(O)-NR7-; or -M-(CR L R M ) a -NR 7’ -C(O)-; where M represents a covalent bond, O, or NH; R L and R M each independently represents H, methyl, ethyl, fluoro or chloro, or R L and R M together form a C3 or C4 cycloalkyl ring, a carbonyl group or a thiocarbonyl group; a represents 0 or 1; R7 and R 7’ represents H or an optionally substituted alkyl group; Z represents a heterocycle selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group, optionally where Z is attached to the remainder of the molecule via a covalent bond; R8~R 10 each independently represents H, Me, C1-C5 alkoxy unsubstituted or substituted with one or more halo groups, OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl substituted with one or more halo groups, or NR 13 R 14 Selected from R8 to R10 One of the expressions [ka] wherein A represents O or NH, R 11 and R 12 each independently at each occurrence represents optionally substituted alkyl; R 13 and R 14 represents, independently at each occurrence, H or optionally substituted alkyl; a compound of formula I, or A pharma- ceutically acceptable salt, solvate, or derivative thereof, However, X1 and X2 are both CH, and L is [ka] and A is [ka] or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl.

[0033] 2. R a are independently H, NH2, F, Cl, or C 1~3 Represents an alkyl group, and this C 1~3 The alkyl group is unsubstituted or substituted with 1, 2, or 3 fluoro or chloro substituents, preferably R a is H or F, or a pharma- ceutically acceptable salt, solvate, or derivative thereof.

[0034] 3. Each of R1 through R5 is independently halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~3 Alkenyl and C 2~3alkynyl, wherein the four groups are unsubstituted or substituted with one or more halo substituents, and preferably each R1-R5 independently represents fluoro, chloro, methyl or ethyl, and the methyl and ethyl groups are unsubstituted or substituted with one, two or three fluoro or chloro groups; or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0035] 4. Y1 and Y2 are independently O, NC 1~3 represents alkyl or NH; and / or R6 is independently C 1~3 Alkyl, C 1~3 Alkoxy, C 2~3 Alkenyl and C 2~3 alkynyl, which of the four groups is unsubstituted or substituted with one or more halo substituents; Preferably, Y1 and Y2 independently represent O, NMe or NH; and / or A compound according to statement 1 or 2, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein R6 independently represents fluoro, chloro, methyl, or ethyl, and the methyl and ethyl groups are unsubstituted or substituted with one, two, or three fluoro or chloro groups.

[0036] 4. The compound according to statement 3, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein each R1-R5 and R6 independently represents methyl, trifluoromethyl, fluoro, or chloro.

[0037] 5. (a) Each R8~R 10 are independently H, Me, C unsubstituted or substituted with one or more halo groups; 1~2 Alkoxy, OC(O)R 11 , C(O)OR 12 , C2-C3 alkynyl substituted with one or more halo groups, or NR 13 R 14 represents R 11 and R 12each independently represents methyl or ethyl; R 13 and R 14 each independently represents H, methyl or ethyl; or (b) R8~R 10 One of the expressions [ka] [wherein A represents O or NH], and R to R 10 the remaining two of which are as defined in part (a), A compound according to any one of statements 1 to 4, or a pharma- ceutically acceptable salt, solvate, or derivative thereof.

[0038] 6. The compound according to any one of statements 1 to 5, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein Z represents a heterocycle selected from the following: [ka]

[0039] 7. The compound according to any one of statements 1 to 6, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein A is selected from the group consisting of: [ka]

[0040] 8. M represents O or NH; and / or R L and R M each independently represents H, methyl or chloro, or R L and R M together represent thiocarbonyl or cyclopropyl; and / or a represents 1, A compound according to any one of statements 1 to 7, or a pharma- ceutically acceptable salt, solvate, or derivative thereof.

[0041] 9. L, [ka] or a pharma- ceutically acceptable salt, solvate, or derivative thereof.

[0042] 10. The compound according to statement 9, selected from: [ka] [ka] or a pharma- ceutically acceptable salt, solvate or derivative thereof.

[0043] 11. The compound according to any one of statements 1-8, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, wherein L is selected from the following: [ka]

[0044] 12. A compound according to statement 11, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, selected from: [ka] [ka] [ka]

[0045] 13. Use of a compound of formula I, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, as defined in any one of statements 1-12, in the manufacture of a medicament 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.

[0046] 14. A method of 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, comprising administering a therapeutically effective amount of a compound of the formula defined in any one of statements 1-12, or a pharma-ceutically acceptable salt, solvate, or derivative thereof.

[0047] 15. A compound of formula I, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, as defined in any one of statements 1-12, for use in 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.

[0048] 16. A pharmaceutical composition comprising a compound of formula I as defined in any one of statements 1 to 12, or a pharma- ceutically acceptable salt, solvate or derivative thereof. [Brief description of the drawings]

[0049] [Figure 1] 1 shows the results of Western blot analysis of the compounds of Example 1 and Example 2 on inhibition of PDGFRβ and p-SHP2 signaling in HEK293 cells expressing PDGFRβ. [Diagram 2] Figure 1 shows the effect of the compounds of Examples 1 to 4 on PDGFR-expressing Ba / F3 cells. Results for imatinib and quizartinib are provided as positive controls. [Diagram 3]1 shows the effect of the compounds of Examples 5 to 7 on Ba / F3 cells expressing Flt3 kinase. Results for imatinib (negative control) and quizartinib (positive control) are also provided. [Figure 4] Compounds of the invention demonstrate the ability to prevent choroidal damage in vivo.

[0050] Surprisingly, it has been found that the compounds of formula I described herein, including their pharma-ceutically acceptable salts, solvates and derivatives, are potent inhibitors of angiogenesis.The compounds of the present invention are useful for treating angiogenesis and angiogenesis-related diseases or disorders, such as ocular disorders, in particular macular degeneration (e.g., age-related macular degeneration) and diabetic retinopathy.

[0051] Thus, according to a first aspect of the invention, there is provided a compound of formula I, [ka] During the ceremony, X1 and X2 each independently represent N or CR a represents R a are independently H, NH2, halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl and C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; A is selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the rest of the molecule; Each R1 through R5 is independently halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; X3 represents N, CH, or CR3 [wherein R3 is as defined above], X4 represents N, CH, or CR4 [wherein R4 is as defined above], and X5 represents N, CH, or CR5 [wherein R5 is as defined above], with the proviso that only one or two of X3 to X5 are N; Each of X6 to X9 is independently N, CH or CR6, 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, wherein the four groups are unsubstituted or substituted with one or more halo substituents; In any moiety A, one of R1-R6 may be piperazine, methylpiperazine, or ethylpiperazine, each of which may be connected to the remainder of moiety A via a carbon or nitrogen atom of the piperazine ring; Y1, NR N , O or S; Y2 is NR N , N.R. Y represents O or S; R N , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 alkynyl, the latter three groups being unsubstituted or substituted with one or more halo substituents; R Y represents piperazine, methylpiperazine, or ethylpiperazine, each of which is bonded to the nitrogen atom of Y2 via a carbon atom in the piperazine ring; L is a group represented by the formula: -M-(CR L R M ) a -C(O)-NR7-; -M-(CR L R M ) a -NR 7’ -C(O)-; or -MC(O)-(CR N R O )-C(O)-M- wherein M represents a covalent bond, O, or NH; R L and R M each independently represents H, methyl, ethyl, fluoro or chloro, or R L and R M together form a C3 or C4 cycloalkyl ring, a carbonyl group or a thiocarbonyl group; a represents 0 or 1; R7 and R 7’ represents H or an optionally substituted alkyl group; R N and R O each independently represents H, methyl, ethyl, fluoro, or chloro; Z represents a heterocycle selected from the group consisting of: [ka] During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group; R8~R 10 each independently represents H, hydroxy, C1-C5 alkyl, C1-C5 alkoxy (the latter two groups being unsubstituted or substituted with one or more halo groups), OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl, which is unsubstituted or substituted with one or more halo groups, or NR 13 R 14 , and O-(C 1~4 (alkylenyl)-OC 1~4 alkyl, And R8~R 10 One of them is the formula: [ka] [Wherein, X is O, NR X represents R X is H or C 1~4 represents an alkyl group, R 11 and R 12 represents, independently at each occurrence, an optionally substituted alkyl; R 13 and R 14 represents each independently at each occurrence H or optionally substituted alkyl; R 15 is H or C 1~2 Represents alkyl, Compound, or A pharma- ceutically acceptable salt, solvate, or derivative thereof, However, X1 and X2 are both CH, and L is [ka] and A is [ka] then Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl; A compound, or a pharma- ceutically acceptable salt, solvate, or derivative thereof, is provided.

[0052] In the examples herein, the term "comprising" may be interpreted as requiring the recited features, but not limiting the presence of other features. Alternatively, the term "comprising" may also relate to a situation in which only the recited components / features are intended to be present (e.g., the term "comprising" may be replaced by the phrase "consists of" or "consists essentially of"). It is expressly contemplated that both the broader and narrower interpretations may be applied to all aspects and embodiments of the present invention. In other words, "comprising" and its synonyms may be replaced by the phrase "consisting of" or "essentially consisting of" or their synonyms, and vice versa.

[0053] "Alkyl" refers to a monovalent alkyl group, which may be linear or branched, preferably having 1 to 10 carbon atoms, or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like. As used herein, C1-C5 alkyl refers to an alkyl group having 1 to 5 carbon atoms.

[0054] "Alkylene" refers to a divalent alkyl group preferably having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of such alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like.

[0055] "Alkenyl" refers to a monovalent alkenyl group, which may be linear or branched, preferably having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and having at least one, preferably 1 to 2 carbon-carbon double bonds. Examples include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like. As used herein, C2-C5 alkylenyl refers to an alkylenyl group having 2 to 5 carbon atoms.

[0056] "Alkynyl" refers to an alkynyl group having preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and having at least one, preferably 1 to 2 carbon-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 herein, C2-C5 alkynyl refers to an alkynyl group having 2 to 5 carbon atoms.

[0057] "Alkoxy" refers to an alkyl-O- group, where the alkyl group is as described above. Examples include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. As used herein, C1-C5 alkoxy refers to an alkoxy group having 1 to 5 carbon atoms.

[0058] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0059] "Haloalkyl" refers to an alkyl group, wherein the alkyl group is substituted with one or more halo groups as defined above. The terms "haloalkenyl," "haloalkynyl," and "haloalkoxy" are similarly defined.

[0060] "Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), preferably having 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl, and the like.

[0061] "Heteroaryl" refers to a monovalent aromatic heterocyclic group that satisfies Hückel's rule for aromaticity (i.e., contains 4n+2 π electrons) and preferably has from 2 to 10 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur in the ring (and includes oxides of sulfur, selenium, and nitrogen). Such heteroaryl groups can have a single ring (e.g., pyridyl, pyrrolyl or N-oxide or furyl) or multiple condensed rings (e.g., indolizinyl, benzimidazolyl, coumarinyl, quinolinyl, isoquinolinyl, or benzothienyl).

[0062] Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, thiazole, thiadiazole, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine, and the like.

[0063] As used herein, "optionally substituted" means that a group is substituted with any of the following: 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, trihalomethyl, methylamino ... , trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclylamino, asymmetric disubstituted amines with different substituents selected from alkyl, aryl, heteroaryl, and heterocyclyl, and the like; and may also include attachment to a solid support material (e.g., substitution on a polymer resin). For example, an "optionally substituted amino" group may include amino acid and peptide residues.

[0064] When a moiety is disclosed herein as being substituted with "one or more" groups, the moiety may be substituted with one or more groups, for example, one, two, or three groups. In certain embodiments of the invention, the moiety may be substituted with one or two groups. In certain embodiments of the invention, the moiety may be substituted with a single group.

[0065] A reference herein (in any aspect or embodiment of the invention) to a compound of formula I includes a reference to such compound per se, a tautomer of such compound, as well as a pharma- ceutically acceptable salt or solvate, or a pharma- ceutically functional derivative of such compound.

[0066] Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reacting a compound of formula I in free acid or free base form 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, and then removing said solvent or said medium using standard techniques (for example, in vacuum, by lyophilization, or by filtration). Salts may also be prepared by exchanging the counterion of the compound of formula I in salt form with another counterion, for example, using a suitable ion exchange resin.

[0067] Examples of pharma- ceutically acceptable salts include acid addition salts derived from mineral and organic acids, and salts derived from metals such as sodium, magnesium, or preferably, potassium and calcium.

[0068] Examples of acid addition salts include acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g., D-gluconic acid), glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g., (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g., (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1 Examples of acid addition salts include those formed from -hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0069] Specific examples of salts are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid; those derived from organic acids such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acid; and those derived from metals such as sodium, magnesium, or, preferably, potassium and calcium.

[0070] As stated above, formula I also encompasses any solvates of the compounds and their salts. Preferred solvates are those formed by incorporating molecules of non-toxic pharma- ceutically acceptable solvents (hereinafter referred to as solvating solvents) into the solid-state structure (e.g., crystalline structure) of the compounds of the present invention. Examples of such solvents include water, alcohols (such as ethanol, isopropanol, and butanol), and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compounds of the present invention with a solvent or a mixture of solvents containing a solvating solvent. Whether a solvate is formed in any given case can be determined by analyzing the crystals of the compound using well-known standard techniques, such as thermogravimetric analysis (TGE), differential scanning calorimetry (DSC), and X-ray crystallography.

[0071] The solvates can be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, examples of which include hemihydrates, monohydrates, and dihydrates.

[0072] For a more detailed discussion of solvates and methods used to prepare and characterize them, see Brynet al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0073] "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 of the relevant compounds of the invention. Thus, for the purposes of the present invention, the above term also includes prodrugs of the compounds of formula I.

[0074] The term "prodrug" of a related compound of formula I includes any compound that, following oral or parenteral administration, is metabolized in vivo to form the compound in experimentally detectable amounts and within a given time period (e.g., within a 6-24 hour dosing interval (i.e., 1-4 times daily)).

[0075] Prodrugs of compounds of formula I can be prepared by modifying functional groups present on the compounds such that the modifications are cleaved in vivo when such prodrugs are administered to a mammalian subject. The modifications are typically carried out by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula I in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in the compound of formula I can be cleaved in vivo to regenerate a free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively.

[0076] 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, for example, in Bundegaard, H. "Design of Prodrugs" pI-92, Elsevier, New York-Oxford (1985).

[0077] The compounds of formula I, as well as the pharma- ceutically acceptable salts, solvates, and pharma- ceutically functional derivatives of such compounds, are hereinafter jointly referred to as "compounds of formula I" for brevity.

[0078] Compounds of formula I may contain double bonds and therefore may exist as E (entgegen) and Z (zusammen) geometric isomers about each double bond, and all such isomers and mixtures are included within the scope of the present invention.

[0079] Compounds of formula I may exist as positional isomers and may also exhibit tautomerism, all tautomeric forms and mixtures thereof are included within the scope of the present invention.

[0080] The compounds of formula I may contain one or more asymmetric carbon atoms and therefore may exhibit optical isomerism and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, for example chromatography or fractional crystallization. The various stereoisomers may be isolated by separating racemic or other mixtures of the compounds, for example using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired isomer may be prepared by reacting the appropriate optically active starting material under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), by reacting the appropriate optically active starting material with a "chiral auxiliary" that can be removed at a suitable later stage, by derivatization (i.e., resolution, such as dynamic resolution), for example with a homochiral acid, followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with a suitable chiral reagent or chiral catalyst, all under conditions known to those skilled in the art. All stereoisomers and mixtures thereof are included within the scope of the present invention.

[0081] Further embodiments of the invention that may be mentioned include those in which the compound of formula I is isotopically labeled, whereas particular embodiments of the invention that may be mentioned include those in which the compound of formula I is not isotopically labeled.

[0082] As used herein, the term "isotopically labeled" includes reference to a compound of formula I in which a non-natural isotope (or a non-natural distribution of isotopes) is present at one or more positions in the compound. It will be understood by one of skill in the art that a reference herein to "one or more positions in a compound" refers to one or more of the atoms of a compound of formula I. Thus, the term "isotopically labeled" includes reference to a compound of formula I that is isotopically enriched at one or more positions in the compound.

[0083] The isotopic labeling or enrichment of the compounds of formula I may be with any radioactive or non-radioactive isotope of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and / or iodine. Particular isotopes that may be mentioned in this respect include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 35 S, 18 F, 37 C.I., 77 Br, 82 Br and 125 l) are listed.

[0084] When a compound of formula I is labeled or enriched with a radioactive or non-radioactive isotope, compounds of formula I that may be mentioned include those in which at least one atom in the compound exhibits an isotopic distribution in which the radioactive or non-radioactive isotope of that atom is present at a level that is at least 10% (e.g., 10% to 5000%, particularly 50% to 1000%, more particularly 100% to 500%) higher than the natural level of that radioactive or non-radioactive isotope.

[0085] In the above aspect of the invention, the compounds of formula I may be used in medical treatment. Thus, according to a further aspect of the invention: (a) a compound of formula I for use in medicine; (b) a compound of formula I for use in the treatment or prevention of angiogenesis or angiogenesis-related diseases or disorders, in particular macular degeneration and diabetic retinopathy; (c) the use of a compound of formula I for the preparation of a medicament for the treatment of angiogenesis or angiogenesis-related diseases or disorders, in particular macular degeneration and diabetic retinopathy; and (d) A method for treating angiogenesis or angiogenesis-related diseases or disorders, particularly macular degeneration and diabetic retinopathy, comprising administering an effective amount of a compound of formula I. is provided.

[0086] Compounds of formula I have the formula: -M-(CR L R M ) a -C(O)-NR7-; -M-(CR L R M ) a -NR 7’ -C(O)-; or -MC(O)-(CR N R O )-C(O)-M- wherein M represents a covalent bond, O, or NH; R L and R M each independently represents H, methyl, ethyl, fluoro or chloro, or R L and R M together form a C3 or C4 cycloalkyl ring, a carbonyl group or a thiocarbonyl group; a represents 0 or 1; R7 and R 7’ represents H or an optionally substituted alkyl group; R N and R O each independently represents H, methyl, ethyl, fluoro or chloro.

[0087] For the avoidance of doubt, the linker may be oriented in each of two possible configurations, i.e., either end of the linker may be attached to moiety A or to a six-membered ring containing X1 and X2. In some embodiments of the invention, the left-hand portion of the linker depicted herein is attached to a six-membered ring containing X1 and X2. In other embodiments of the invention, the left-hand portion of the linker is attached to moiety A.

[0088] In some embodiments of the invention, the linker group L may be of the formula: [ka]

[0089] Compounds of Formula I having such linkers are believed to be particularly suitable for the treatment of angiogenesis-related ocular diseases or disorders, such as macular degeneration (eg, AMD) and diabetic retinopathy.

[0090] Other linker groups useful in compounds of formula I include linkers having the formula: [ka]

[0091] In some embodiments of the invention, L is a linker group having one of the following formulae: [ka]

[0092] In some embodiments of the invention, the linker is selected from linkers having one of the following formulas: [ka] X1 and X2 each independently represent N or CR a R a are independently H, NH2, halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl and C 2~5 alkynyl (the latter four groups being unsubstituted or substituted with one or more halo substituents). In some embodiments of the invention, R a are independently H, NH2, F, Cl, or C 1~3 represents alkyl, C 1~3 The alkyl group is unsubstituted or substituted with one, two, or three fluoro or chloro substituents. In certain embodiments of the invention, R a is H or F.

[0093] In some embodiments of the invention, X1 is selected from N and CH, and X2 is selected from CH and CF.

[0094] A is selected from the group consisting of: [ka] For each part A: The dotted line represents the point of attachment to the rest of the molecule; Each R1 through R5 is independently halo, C 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, the latter four groups being unsubstituted or substituted with one or more halo substituents; X3 represents N, CH, or CR3 [wherein R3 is as defined above], X4 represents N, CH, or CR4 [wherein R4 is as defined above], and X5 represents N, CH, or CR5 [wherein R5 is as defined above], with the proviso that only one or two of X3 to X5 are N; Each of X6 to X9 is independently N, CH or CR6, 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, C 2~5 alkynyl, wherein the four groups are unsubstituted or substituted with one or more halo substituents; In any moiety A, one of R1-R6 may be piperazine, methylpiperazine, or ethylpiperazine, each of which may be connected to the remainder of moiety A via a carbon or nitrogen atom of the piperazine ring.

[0095] In some embodiments of the present invention, each R1-R5 is independently selected from halo, C 1~3 Alkyl, C 1~3 Alkoxy, C 2~3 Alkenyl and C 2~3alkynyl, the four groups of which are unsubstituted or substituted with one or more halo substituents. In some embodiments of the invention, each R1-R5 independently represents fluoro, chloro, methyl, or ethyl, the methyl and ethyl groups being optionally unsubstituted or substituted with one, two, or three fluoro or chloro groups.

[0096] In some embodiments of the present invention, each R6 is independently selected from the group consisting of C 1~3 Alkyl, C 1~3 Alkoxy, C 2~3 Alkenyl and C 2~3 R6 independently represents alkynyl, which is unsubstituted or substituted with one or more halo substituents. In some embodiments of the invention, each R6 independently represents fluoro, chloro, methyl, or ethyl, where the methyl and ethyl groups are optionally unsubstituted or substituted with one, two, or three fluoro or chloro groups.

[0097] In some embodiments of the invention, each of R1-R5 and R6 independently represents methyl, trifluoromethyl, fluoro, or chloro.

[0098] In some embodiments of the invention, R1 represents piperazine, methylpiperazine, or ethylpiperazine, each of which may be connected to the remainder of moiety A via a carbon atom or a nitrogen atom of the piperazine ring; R2-R6 do not represent piperazine, methylpiperazine, or ethylpiperazine.

[0099] Y1, NR N , O or S; Y2 is NR N , N.R. Y represents O or S; R N , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 alkynyl, the latter three groups being unsubstituted or substituted with one or more halo substituents; R Yrepresents piperazine, methylpiperazine, or ethylpiperazine, each of which is bonded to the nitrogen atom of Y2 via a carbon atom in the piperazine ring.

[0100] In some embodiments, Y and Y are each independently NR N , O or S; R N , H, C 1~5 Alkyl, C 2~5 Alkenyl, C 2~5 In some embodiments of the present invention, Y1 and Y2 independently represent O, NC 1~3 In some embodiments of the invention, Y1 and Y2 independently represent O, NMe, or NH.

[0101] In some embodiments of the present invention, Y1 and Y2 are not S.

[0102] R Y In some embodiments of the invention where represents piperazine, methylpiperazine, or ethylpiperazine, the piperazine, methylpiperazine, or ethylpiperazine moiety is attached to the nitrogen atom of Y2 via a carbon atom in the piperazine ring.

[0103] In some embodiments of the invention, A is selected from the group consisting of: [ka]

[0104] In some embodiments of the invention, A is selected from the group consisting of: [ka]

[0105] In some embodiments of the invention, A is selected from: [ka] During the ceremony, R1 is selected from methyl and chlorine; R2 is CF3; X3 and X5 are CH; X4 is N; X6 is N; Y2 is O or N-CH3; X8 is C-CF3; and X9 is CH.

[0106] Z represents a heterocycle selected from the group consisting of: [ka] Wherein in each moiety Z: The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group; R8~R 10 each independently represents H, hydroxy, C1-C5 alkyl, C1-C5 alkoxy (the latter two groups being unsubstituted or substituted with one or more halo groups), OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl, which is unsubstituted or substituted with one or more halo groups, or NR 13 R 14 , and O-(C 1~4 (alkylenyl)-OC 1~4 alkyl, And R8~R 10 One of them is the formula, [ka] [Wherein, X is O, NR X represents R X is H or C 1~4 represents an alkyl group, R 11 and R 12represents, independently at each occurrence, an optionally substituted alkyl; R 13 and R 14 represents each independently at each occurrence H or optionally substituted alkyl; R 15 is H or C 1~2 Represents alkyl.

[0107] In any embodiment of the present invention, R 10 Each alkyl group may be a methyl group.

[0108] In any embodiment of the invention described herein, R to R 10 Each of the C2 to C5 alkynyl groups may be a C2 to C5 alkynyl group substituted with one or more halo groups.

[0109] In some embodiments of the invention, Z represents a heterocycle selected from the group consisting of: [ka]

[0110] In some embodiments of the invention, Z represents a heterocycle selected from: [ka]

[0111] In some embodiments of the invention, Z represents a heterocycle selected from: [ka] In some embodiments of the present invention, each R to R 10 are independently H, hydroxy, Me, C 1~2 Alkoxy, which is unsubstituted or substituted with one or more halo groups, OC(O)R 11 , C(O)OR 12, C2-C3 alkynyl (which is substituted with one or more halo groups), O-(C 1~2 (alkylenyl)-OC 1~2 Alkyl or NR 13 R 14 wherein: R 11 and R 12 each independently represents methyl or ethyl; R 13 and R 14 each independently represents H, methyl or ethyl.

[0112] In another embodiment of the present invention, R 10 One of the expressions [ka] [In the formula, X is O, NH, or NC 1~2 represents an alkyl group, R 15 represents methyl] group, R8~R 10 The remaining two are as defined above.

[0113] In some embodiments of the present invention, R 10 each independently represents H, hydroxy, Me, C1-C5 alkoxy (which is unsubstituted or substituted with one or more halo groups), OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl, which is substituted with one or more halo groups, or NR 13 R 14 , O-(C 1~4 (alkylenyl)-OC 1~4 alkyl, Or R8~R 10 One of the groups may be a group of the formula: [ka] R8~R 10 The remaining two of these, as well as R 11 ~R 14is as defined above.

[0114] In some embodiments of the present invention, each R to R 10 are independently H, Me, C1-C5 alkoxy unsubstituted or substituted with one or more halo groups, OC(O)R 11 , C(O)OR 12 , C2-C5 alkynyl, which is substituted with one or more halo groups, or NR 13 R 14 Selected from R8 to R 10 One of the expressions [ka] [In the formula, X may be a group of the formula: R 11 and R 12 represents, independently at each occurrence, an optionally substituted alkyl; R 13 and R 14 represents each independently at each occurrence H or optionally substituted alkyl.

[0115] In some embodiments of the present invention, R and R 10 is H (if it exists). Therefore, R8 to R 10 One of the expressions [ka] For example, R8~R 10 One of the expressions [ka] When the group is This group may be present as R8, R9 and R 10 may be H (if present).

[0116] In some embodiments of the invention, Z is linked to the remainder of the molecule via a covalent bond.

[0117] In some embodiments of the invention, M represents O or NH. In other embodiments of the invention, M represents a covalent bond.

[0118] In some embodiments of the invention, when Z is linked to the remainder of the molecule through a covalent bond, M is -O- or -NH-. In some embodiments of the invention, when Z is linked to the remainder of the molecule through an -O- or -NH- group, M is a covalent bond.

[0119] In some embodiments of the present invention, R L and R M each independently represents H, methyl or chloro, or R L and R M taken together represent thiocarbonyl or cyclopropyl.

[0120] In some embodiments of the invention, a represents 1.

[0121] In some embodiments of the present invention, R and R 7’ represents H.

[0122] In formula I, X1 and X2 are both CH and L is [ka] and A is [ka] When Z is, then Z is not an optionally substituted heteroaryl selected from optionally substituted tetrazolyl or optionally substituted imidazopyridinyl.

[0123] The invention also provides the following compounds, and pharma- ceutically acceptable salts, solvates, and derivatives thereof: [ka] [ka]

[0124] The invention also provides the following compounds, and pharma- ceutically acceptable salts, solvates, and derivatives thereof: [ka] [ka]

[0125] As used herein, "macular degeneration" or "MD" is intended to include age-related macular degeneration (AMD), but does not exclude macular degeneration in non-elderly patients. Thus, AMD and MD as referred to herein may be used interchangeably. MD is a disease that affects a special layer of cells in the eye called the retinal pigment epithelium. This layer of cells is located underneath the retina. The retinal pigment epithelium (RPE) is like a wall or barrier, responsible for allowing oxygen, sugar, and other essential elements to pass through to the retina and moving waste products to the blood vessels underneath the retina (these blood vessels are called the choroid). The RPE also acts as a barrier between the choroid and the retina. When RPE cells die, the retinal cells above them also die, resulting in patches of "shedded" retina. This is commonly referred to as geographic atrophy or "dry" MD, a slow form of MD that gradually causes vision loss. "Wet" macular degeneration occurs when RPE cells are unable to stop the growth of choroidal blood vessels underneath the retina. This growth is called choroidal neovascularization or CNV. The rapid growth of blood vessels causes the blood vessel walls to become leaky and fragile, leaking fluid and blood under the retina. This leads to scarring and severe loss of central vision, which can become permanent if left untreated.In the context of the present invention, the term "macular degeneration" is understood to refer specifically to "wet" MD, also known as neovascular or exudative AMD.

[0126] As used herein, the term "diabetic retinopathy" refers to microvascular complications of diabetes. This complication can occur in the eye. Thus, "diabetic retinopathy" is intended to include all categories and classifications, such as the early stage of non-proliferative diabetic retinopathy (NPDR) and the advanced stage of proliferative diabetic retinopathy (PDR) with abnormal blood vessel growth. Diabetic macular edema (DME) is also included within its scope. DME is a symptom of diabetic retinopathy that occurs in all severity levels of both NPDR and PDR and is the most common cause of blindness in patients. DME results from diabetes-induced breakdown of the blood-retinal barrier (BRB), resulting in vascular leakage of fluid and blood proteins into the neural retina. The leakage of fluid into the neural retina leads to abnormal retinal thickening and often cystoid macular edema.

[0127] In wet AMD and diabetic retinopathy, VEGFα is believed to play a key role in the formation of abnormally growing and leaking blood vessels under the retinal macula. Constant exposure of endothelial cells to pro-angiogenic factors such as VEGFα results in the formation of immature, partially differentiated, fragile blood vessels that have a tendency to leak and bleed. Without being bound by theory, the present invention is based on the discovery that compounds of formula I as defined herein exhibit high selectivity for the receptor tyrosine kinases (RTKs) PDGFRα, PDGFRβ, and VEGFR2, the three main RTKs involved in abnormal blood vessel growth in MD. These receptor tyrosine kinases are high affinity cell surface receptors for polypeptide growth factors such as VEGFα. It is therefore believed that the compounds of the present invention may exhibit a broader therapeutic window than compounds or agents that do not distinguish between "disease" and normal cells. This selectivity means that the compounds of formula I, and their pharma- ceutically acceptable salts, solvates, or prodrugs, may be particularly suitable for therapeutic use in patients with macular degeneration; i.e., patients with a high density of receptor tyrosine kinases, since they may be able to inhibit the proliferation of only "diseased" cells. It is believed that the compounds of the present invention may be effective in blocking the onset of abnormal angiogenesis and therefore may be advantageous in the treatment of MD and / or diabetic retinopathy.

[0128] The disease pathology of MD and / or diabetic retinopathy may be multifactorial. In the treatment of MD and / or diabetic retinopathy, different therapies may be combined (i.e., combination therapy). As used herein, the terms "therapeutic agent", "other therapeutic agent", "another therapeutic agent", "second therapeutic agent", and the like are intended to include other therapeutic compounds or treatments that may be used in combination with the compounds according to the present invention.

[0129] Thus, according to the present invention, the compound of formula I can be administered alone (i.e., as a monotherapy, such as a monotherapy for angiogenesis-related disease or disorder). However, in alternative embodiments of the present invention, the compound of formula I can be administered in combination with another therapeutic agent (e.g., another therapeutic agent for the treatment of angiogenesis-related disease or disorder). In yet another embodiment of the present invention, the compound of formula I can be administered as an adjuvant therapy after surgical treatment or as a neoadjuvant therapy before the main treatment (e.g., surgery) of angiogenesis-related disorder or disease, either as a stand-alone compound or in combination with another therapeutic agent (e.g., another therapeutic agent for the treatment of angiogenesis-related disease or disorder).

[0130] Second or other therapeutic agents useful for treating ocular disorders such as MD and / or diabetic retinopathy include, but are not limited to, angiogenesis inhibitors, vascular endothelial growth factor (VEGF) inhibitors, other receptor tyrosine kinase inhibitors, photodynamic therapy, laser photocoagulation, and other MD or AMD and / or diabetic retinopathy specific therapies. For example, the compound of formula I or a pharma- ceutically acceptable salt, solvate or prodrug may be administered in combination with one or more VEGF inhibitors, such as Avastin, Lucentis, and / or Macugen.

[0131] For the avoidance of doubt, in the context of the present invention, the term "treatment" includes reference to the curative or palliative treatment of patients in need of such treatment, as well as to the prophylactic treatment and / or diagnosis of patients susceptible to the relevant disease state.

[0132] The term "patient" (singular and plural) includes reference to a mammalian (e.g., human) patient. As used herein, the terms "subject" or "patient" are well-recognized in the art and are used interchangeably herein to refer to mammals, including dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is a subject in need of treatment or a subject having a disease or disorder. However, in other embodiments, the subject may be a normal subject. The term does not denote a particular age or sex. Thus, it is intended to cover adult and neonatal subjects, whether male or female.

[0133] The term "effective amount" refers to that amount of a compound that confers a therapeutic effect on the treated patient (e.g., sufficient to treat or prevent a disease). The effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0134] For the avoidance of doubt, where the identities of two or more substituents in a compound of formula I may be the same, the actual identities of the respective substituents are not in any way interdependent.

[0135] The compounds of formula I may be administered by any suitable route, in particular oral, intravenous, intramuscular, cutaneous, subcutaneous, mucosal (e.g. sublingual or buccal), rectal, transdermal, nasal, pulmonary (e.g. tracheal or bronchial), topical, ocular (i.e. subconjunctival, intravitreal, retrobulbar, intracameral), or any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharma- ceutically acceptable dosage form. Particular modes of administration that may be mentioned include oral, topical, ocular (i.e. subconjunctival, intravitreal, retrobulbar, intracameral), intravenous, cutaneous, subcutaneous, nasal, intramuscular, or intraperitoneal administration.

[0136] When the compound of formula I is used to treat an ocular disease or disorder, the compound of formula I is typically administered locally to the eye, i.e., topically instilled. Thus, in one embodiment, the compound of formula I or a pharma- ceutically acceptable salt, solvate, or prodrug is directly injected into the eye, particularly the vitreous of the eye. The compounds, compositions, or combinations of the present invention can be administered to the vitreous of the eye using intravitreal or transscleral administration methods. For example, the compounds, compositions, or combinations can be administered to the vitreous of the eye by intravitreal injection. Intravitreal injection typically involves administering the compounds of the present invention or a pharma- ceutically acceptable salt, solvate, or prodrug thereof in a total amount of 0.1 ng to 10 mg per administration.

[0137] Injectables for such use can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for preparation as a solution or suspension prior to injection, or as emulsions. Carriers include, for example, water, saline (e.g., normal saline (NS), phosphate buffered saline (PBS), balanced salt solution (BSS)), sodium lactate Ringer's solution, dextrose, glycerol, ethanol, and the like, and can include small amounts of auxiliary substances, such as wetting or emulsifying agents, buffers, etc., if necessary. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. By way of example, the compound, composition, or combination can be dissolved in a pharma- ceutically effective carrier and injected into the vitreous of the eye by a lateral approach (e.g., about 3 to about 4 mm posterior to the limbus of the human eye to avoid lens damage) using a fine gauge hollow bore needle (e.g., 30 gauge, 1 / 2 or 3 / 8 inch needle).

[0138] In one embodiment, a compound of formula I or a pharma- ceutically acceptable salt, solvate, or prodrug thereof may be formulated in saline and injected into the vitreous of the eye.

[0139] Although intravitreal administration is likely to be the form of administration to the eye, the present invention also includes other modes of administration, such as topical or intravenous administration. For example, a solution or suspension of the compound, composition, or combination of the present invention may be formulated as eye drops or as a membranous ocular patch that is applied directly to the surface of the eye. Topical application typically involves administering the compound of the present invention in an amount of 0.1 ng to 100 mg.

[0140] In another embodiment, the compound of formula (I) or its pharma- ceutically acceptable salt, solvate or prodrug is provided on the surface of the eye.The compound can be provided on the surface of the eye as eye drops, particularly as eye drop compositions or combinations.The compound, composition or combination of the present invention can be administered to the surface of the eye using any known administration technique.For example, the compound or combination can be administered to the surface of the eye by dropping the formulation on the eye.

[0141] The compounds of formula I are generally administered as pharmaceutical preparations mixed with pharma- ceutically acceptable adjuvants, diluents, or carriers, which can be selected with due consideration of the intended route of administration and standard pharmaceutical practice. Such pharma-ceutically acceptable carriers are expected to be chemically inert to the active compounds and to have no adverse side effects or toxicity under the conditions of use. Suitable pharmaceutical preparations can be found, for example, in Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, parenterally acceptable aqueous solutions may be used, which are pyrogen-free and have the required pH, isotonicity, and stability. Suitable solutions are well known to those skilled in the art, and many methods are described in the literature. A brief review of methods of drug delivery can also be found, for example, in Langer, Science (1990) 249, 1527.

[0142] Alternatively, the preparation of suitable formulations may be routinely achieved by one skilled in the art by the use of conventional techniques and / or by following standard and / or accepted pharmaceutical practices.

[0143] The amount of the compound of formula I in any pharmaceutical formulation used in accordance with the present invention will vary depending on a variety of factors, such as the severity of the condition being treated, the particular patient being treated, as well as the compound(s) being used. In any case, the amount of the compound of formula I in the formulation can be routinely determined by one of ordinary skill in the art.

[0144] For example, a solid oral composition such as a tablet or capsule may contain 1-99% (w / w) active ingredient; 0-99% (w / w) diluent or filler; 0-20% (w / w) disintegrant; 0-5% (w / w) lubricant; 0-5% (w / w) flow aid; 0-50% (w / w) granulating agent or binder; 0-5% (w / w) antioxidant; and 0-5% (w / w) pigment. A sustained release tablet may further contain 0-90% (w / w) release controlling polymer.

[0145] Parenteral formulations (such as solutions or suspensions for injection, or solutions for infusion) may contain 1-50% (w / w) of the active ingredient, 50% (w / w) to 99% (w / w) of a liquid or semisolid carrier or vehicle (e.g., a solvent such as water), and 0-20% (w / w) of one or more other excipients, such as, for example, buffers, antioxidants, suspension stabilizers, isotonicity agents, and preservatives.

[0146] Depending on the disorder and patient to be treated, as well as the route of administration, the compounds of formula I may be administered to a patient in need thereof in various therapeutically effective doses.

[0147] However, in the context of the present invention, the dose administered to a mammal, particularly a human, should be sufficient to effect a therapeutic response in said mammal over a reasonable time frame. Those skilled in the art will appreciate that the selection of the exact dose and composition as well as the most appropriate delivery regimen will also depend on, inter alia, the pharmacological properties of the formulation, the nature and severity of the condition to be treated, the physical condition and intelligence of the recipient, and the potency of the specific compound, the age, condition, weight, sex and response of the patient to be treated, and the stage / severity of the disease.

[0148] Administration can be continuous or intermittent (e.g., by bolus injection). The dosage can also be determined by the timing and frequency of administration. For oral or parenteral administration, the dosage can vary from about 0.01 mg to about 1000 mg of the compound of formula I per day.

[0149] In any event, a medical practitioner or other skilled artisan may routinely determine the actual dosage that will be most appropriate for an individual patient. The above dosages are exemplary of the average case, and there can, of course, be individual instances in which higher or lower dosage ranges are merited, and these are within the scope of this invention.

[0150] Other compounds of formula I may be prepared according to techniques well known to those skilled in the art, for example as described below in the Examples section.

[0151] The compounds of the invention may be isolated from their reaction mixtures using conventional techniques, such as recrystallization, column chromatography, preparative HPLC, and the like.

[0152] In the processes described below the functional groups of intermediate compounds may need to be protected by protecting groups.

[0153] Protection and deprotection of functional groups may be carried out before or after the reaction in the above-mentioned schemes.

[0154] Protecting groups can be removed by techniques known to those skilled in the art and as described below. For example, protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques.

[0155] The type of chemistry involved will dictate the need, and type, of protecting groups, as well as the procedures for accomplishing the synthesis.

[0156] The use of protecting groups is described in detail in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd Edition, TW Greene & P. ​​G.M.Wutz, Wiley-Interscience (1999).

[0157] As used herein, the term "functional group" means, in the case of unprotected functional groups, hydroxyl functions, thiol functions, amino functions, carboxylic acids, and in the case of protected functional groups, lower alkoxy groups, N-, O-, S-acetyl, carboxylic acid esters.

[0158] Also disclosed are compounds of formula I, where the linker group is of the following formula: [ka]

[0159] Compounds of formula I containing these linker groups may be useful in the treatment of ocular diseases and disorders according to the invention. Such compounds 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.

[0160] Compounds having a linker of the following formula may also be useful in treating cancers such as prostate cancer, colon cancer, rectal cancer, colorectal cancer, acute myeloid leukemia, or chronic myelomonocytic leukemia. [ka]

[0161] Second 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, such as chemotherapeutic agents. Examples of second or other therapeutic agents that can be used with the compounds of formula I in the treatment of cancer include actinomycin, all-trans retinoic acid, azacitidine, azathioprine, bleomycin, bortezomib, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarucitabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarucitabine, daunorubicin, docetaxel, docetaxel, doxifluridine, doxorubicin, epirubicin, daunorubicin, docetaxel ... Rubicin, Imatinib, Irinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone, Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Thioguanine, Topotecan, Valrubicin, Vemurafenib, Vinblastine, Vincristine, Vindesine, Avastin (Bevacizumab), Bevacizumab, Camptosar (Irinotecan Hydrochloride), Cetuximab, Cyramza (Ramucirumab), Erbitux (Cetuximab), 5-FU (Flu) Orouracil injection), Fusilev (leucovorin calcium), ipilimumab, irinotecan hydrochloride, Keytruda (pembrolizumab), leucovorin calcium, Lonsurf (trifludine-tipiracil hydrochloride), Mvasi (bevacizumab), nivolumab, Opdivo (nivolumab), panitumumab, pembrolizumab, ramucirumab, regorafenib, Stivarga (regorafenib), trifluridine-tipiracil hydrochloride, Vectibix (panitumumab), Y Ervoy (ipilimumab), Zaltrap (aflibercept), abiraterone acetate, apalutamide, bicalutamide, cabazitaxel, Casodex (bicalutamide), degarelix, Eligard (leuprolide acetate), enzalutamide, Erleada (apalutamide), Firagon (degarelix), flutamide, goserelin acetate, Jevtana (cabazitaxel), leuprolide acetate, Lupron (leuprolide acetate), LupronDepot, (leuprolide acetate), mitoxantrone hydrochloride, Nilandron (nilutamide), Provenge (sipuleucel-T), radium-223 chloride, Xofigo (radium-223 chloride), Xtandi (enzalutamide), Zoladex (goserelin acetate), and Zytiga (abiraterone acetate).

[0162] The following examples are illustrative of the invention and should not be construed as limiting. EXAMPLES

[0163] The example compounds were prepared according to the synthetic routes shown.

[0164] Example 1 [ka] LCMS(ESI) m / z=417.05[M+H] + ;HPLC:RT 5.52,purity:95.17%; 1 H NMR(400MHz,DMSO-d6) δ=11.00(s,1H),8.46(d,J=6.9Hz,1H),8.38(d,J=2.0Hz,1H),8.07(dd,J=2.2,8.6Hz,1H),7.75(s,1H),7. 65(d,J=9.4Hz,1H),7.26-7.33(m,1H),7.12(d,J=8.4Hz,1H),6.92-6.98(m,2H),5.01(s,2H),3.88(s,3H)

[0165] Example 2 [ka]

[0166] Example 3 [ka] LCMS(ESI) m / z=429.00[M+H] +; HPLC: RT 7.70, purity: 99.29%; 1 H NMR (400 MHz, DMSO-d6) 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)

[0167] Example 4

Chem.

[0168] Example 5

Chem.

[0169] Example 6

change

[0170] Example 7

change

[0171] Example 8

change

[0172] Example 9

change

[0173] Embodiments 10 to 19 Additional compounds were produced by similar methods and are listed in Table 1 below.

[0174] [Table 1-1]

[0175] [Table 1-2]

[0176] Example 12 [ka] LCMS(ESI) m / z=475.00[M+1] + ; 1 H NMR(400MHz, CDCl3) δppm:9.19(s,1H),8.80(s,1H),8.70(s,1H),8.45(d,1H,J=2.8Hz),8.35(s,1H),8.13(d,1H,J=4.4Hz) ,7.94(d,1H,J=4.4Hz),7.87-7.89(m,2H),7.09(d,1H,J=8.4Hz),1.80-1.83(m,2H),1.35-1.38(m,2H)

[0177] Example 13 [ka] LCMS (ESI) m / z=463.2[M+1] + ; 1 H NMR(400MHz,DMSO-d6) δppm:11.46(s,1H),9.12(s,1H),8.72(s,1H),8.53(d,1H,J=3.6Hz),8.50(s,1H),8.43(d,1H,J=2.0Hz),8.14( m,1H),8.03(s,1H),7.90(d,1H,J=4.4Hz),7.13(d,1HJ=4.4Hz),5.53(q,1H,J=6.80Hz),1.60(d,1H,J=6.80Hz)

[0178] Example 14

change

[0179] Example 15

change

[0180] Example 16

change

[0181] Example 17

change

[0182] Example 18

change

[0183] Activity Data The compounds of the examples were tested in various assays as described below.

[0184] Determination of activity in HEK293 cell line model Human embryonic kidney cells (HEK293) were constructed to express human PDGFRWT under the control of the CMV promoter. The cells were grown in the presence of 20ng / mL PDGF (ligand for PDGFRβ) to activate PDGFRβ. Compounds of Examples 1 and 2 were added at different concentrations to study their effects on signal transduction mediated by PDGFRβ. PDGFRβ autophosphorylation and Shp2 phosphorylation were monitored by Western blotting and used as markers of PDGFRβ signal transduction. β-actin was used as an internal control.

[0185] The results are shown in Figure 1. It is clear that both Examples 1 and 2 can inhibit PDGFRβ signaling.

[0186] Cell viability by MTS assay The effect of compounds on cell viability was determined using the MTS assay. The MTS cell proliferation assay kit is a colorimetric method for sensitive quantification of viable cells in proliferation and cytotoxicity assays. The method is based on viable cells reducing the MTS tetrazolium compound to produce a colored formazan product that is soluble in cell culture medium. BA / F3 cells expressing receptor tyrosine kinases (either PDGFR [MTS assay 1] or Flt3 [MTS assay 2]) were cultured in 96-well microtiter plates (final volume 200 μL / well) under standard culture conditions in the absence or presence of test compounds and incubated for 20-48 h. MTS reagent (20 μL / well) was added to each well and incubated at 37 °C for 0.5-4 h under standard culture conditions. The absorbance at 490 nm was recorded using a plate reader.

[0187] The results are shown in Figures 2 and 3 and Table 2 (IC 50 (Indicates the concentration of compound required to reduce cell viability by 50%). It is clear that the compounds of Examples 1-7 have potent antitumor activity, with at least Examples 1, 3 and 4 having improved activity compared to the imatinib and quizartinib controls.

[0188] In vitro activity and selectivity assays To determine the inhibitory activity of compounds, in vitro kinase assays were performed on recombinant GST-fusion or His-tagged proteins for each enzyme purified from Sf9 insect cells or E. coli. All protein kinase assays 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 each kinase, [γ-33P]-ATP (approximately 9×1005 cpm / well)), protein kinase, and peptide substrate. IC of test compounds was 50 The data is shown in Table 2 below (a dash indicates that the compound was not tested).

[0189] L has an IC of less than 500 nM 50 represents M is IC from 500nM to 5000nM 50 represents H has an IC of over 5000 nM 50 Represents. For the MTS assay, the results show the concentration of compound required to reduce cell viability by 50%.

[0190] [Table 2]

[0191] Effect on capillary formation (in vivo) FIG. 4 shows the efficacy of compounds of the invention in a laser CNV mouse model for wet AMD.

[0192] In vivo testing of the test compounds of the present invention in a CNV (choroidal neovascularization)-laser mouse model was performed. Young mouse eyes were laser treated to produce choroidal damage that leads to vascular leakage (shown as bright areas in FIG. 4). In each mouse, one eye was injected with a given amount of test compound, while the other eye was left untreated and served as a "treatment (-)" control. The mouse eyes were imaged intermittently for two weeks. The efficacy of the test compounds is indicated by their ability to prevent vascular leakage (reduction or disappearance of bright areas). The efficacy of the compounds was very close to that of the commercial product Eylea (Aflibercept).

[0193] Reference Example 1: Results of additional assays

[0194] [Table 3]

[0195] In Table 3: L has an IC of less than 500 nM 50 represents M is IC from 500nM to 5000nM 50 represents H has an IC of over 5000 nM 50 Represents. For the MTS assay, the results show the concentration of compound required to reduce cell viability by 50%.

Claims

1. A compound of formula 1, 【Chemistry 1】 During the ceremony, X １ and X ２ are each independently N or CR ａ represents R ａ are independently H, NH ２ , Haro, C １～５ Alkyl, C １～５ Alkoxy, C ２～５ Alkenyl and C ２～５ alkynyl, the latter four groups being unsubstituted or substituted with one or more halo groups; A is selected from the group consisting of: 【Chemistry 2】 During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule; Each R １ ~R ５ are independently halo, C １～５ Alkyl, C １～５ Alkoxy, C ２～５ Alkenyl, C ２～５ alkynyl, the latter four groups being unsubstituted or substituted with one or more halo groups; X ３ is N, CH, or CR ３ [In the formula, R ３ is as defined above; X ４ is N, CH, or CR ４ [In the formula, R ４ is as defined above], X ５ is N, CH, or CR ５ [In the formula, R ５ is as defined above, ３ ~X ５ is N; Each X ６ ~X ９ are independently N, CH or CR ６ [In the formula, each R ６ is independently １～５ Alkyl, C １～５ Alkoxy, C ２～５ Alkenyl, C ２～５ alkynyl, wherein the four radicals are unsubstituted or substituted with one or more halo groups; In any part A, R １ ~R ６ may be piperazine, methylpiperazine, or ethylpiperazine, each of which may be connected to the remainder of moiety A via a carbon atom or a nitrogen atom of the piperazine ring; Y １ is N.R. Ｎ , O or S; Y ２ is N.R. Ｎ , N.R. Ｙ , O or S; R Ｎ is H, C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ Represents alkynyl, followed by each of the three groups is unsubstituted or substituted with one or more halo groups; R Ｙ represents piperazine, methylpiperazine, or ethylpiperazine, each of which is connected to Y via a carbon atom in the piperazine ring. ２ is attached to a nitrogen atom of L is a linking group selected from the group consisting of: 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 where the dotted line represents the point of attachment to the remainder of the molecule; R ７ represents H or an optionally substituted alkyl group; Z represents a heterocycle selected from the group consisting of: 【Chemistry 6】 During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group; R ８ ~R １０ Each of is independently H, hydroxy, C １ ~C ５ Alkyl, C １ ~C ５ alkoxy (the latter two groups are unsubstituted or substituted with one or more halo groups), OC(O)R １１ , C(O)OR １２ , C ２ ~C ５ Alkynyl, which may be unsubstituted or or one or more halo groups), or NR １３ R １４ , and O-(C １～４ (alkylenyl)-O-C １～４ alkyl, And R ８ ~R １０ One of the formula: 【Chemistry 7】 [Wherein, X is O, NR Ｘ represents R Ｘ is H or C １～４ represents alkyl; R １１ and R １２ represents independently at each occurrence an optionally substituted alkyl; R １３ and R １４ represents each independently at each occurrence H or optionally substituted alkyl; R １５ is H or C １～２ Represents alkyl, Compound, or A pharma- ceutically acceptable salt or solvate thereof, However, X １ and X ２ are both CH and L is 【Chemistry 8】 and A is 【Chemistry 9】 Z is not optionally substituted imidazopyridinyl; and L 【Chemistry 10】 where Z is attached to the remainder of the molecule via the -NH- group, or a pharma- ceutically acceptable salt, or solvate thereof.

2. R ａ However, independently, H, NH ２ , F, Cl, or C １～３ represents alkyl, C １～３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein the alkyl group is unsubstituted or substituted with one, two or three fluoro or chloro groups.

3. Each R １ ~R ５ But independently, Halo, C １～３ Alkyl, C １～３ Alkoxy, C ２～３ Alkenyl and C ２～３ 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof, which represents alkynyl, the latter four groups being unsubstituted or substituted by one or more halo groups.

4. Y １ and Y ２ However, independently, O, NC １～３ alkyl or NH; and / or R ６ But independently, C １～３ Alkyl, C １～３ Alkoxy, C ２～３ Alkenyl and C ２～３ 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof, which represents alkynyl, wherein the four radicals are unsubstituted or substituted with one or more halo groups.

5. R ９ and R １０ is H, if present; R ８ But H and 【Chemistry 11】 5. The compound according to any one of claims 1 to 4, wherein X is O or NH, or a pharma- ceutically acceptable salt or solvate thereof.

6. 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt, or solvate thereof, wherein A is selected from the group consisting of: 【Chemistry 12】

7. A is selected from the group consisting of: 【Chemistry 13】 And, if present, R １ is selected from Cl and CH3; R ２ CF ３ and X ３ and X ５ is CH, X ４ is N, X ６ is N, X ８ and X ９ is CH, Y ２ is N-CH ３ and O, or a pharma- ceutically acceptable salt, or solvate thereof.

8. The compound of claim 1 selected from: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 or a pharma- ceutically acceptable salt, or solvate thereof.

9. X １ and X ２ each independently represents N or CR ａ represents R ａ However, independently, H, NH ２ , Haro, C １～５ Alkyl, C １～５ Alkoxy, C ２～５ Alkenyl and C ２～５ alkynyl, the latter four groups being unsubstituted or substituted by one or more halo groups; A is selected from the group consisting of: 【Chemistry 20】 During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule; Each R １ ~R ５ are independently halo, C １～５ Alkyl, C １～５ Alkoxy, C ２～５ Alkenyl, C ２～５ alkynyl, the latter four groups being unsubstituted or substituted with one or more halo groups; X ３ is N, CH or CR ３ [In the formula, R ３ is as defined above, N is N, CH or CR ４ [In the formula, R ４ is as defined above], X ５ is N, CH or CR ５ [In the formula, R ５ is as defined above, ３ ~X ５ is N; Each X ６ ~X ９ are independently N, CH or CR ６ [In the formula, each R ６ is independently １～５ Alkyl, C １～５ Alkoxy, C ２～５ Alkenyl, C ２～５ alkynyl, wherein the four radicals are unsubstituted or substituted with one or more halo groups; Y １ and Y ２ are each independently NR Ｎ , O or S; R Ｎ is H, C １～５ Alkyl, C ２～５ Alkenyl, C ２～５ alkynyl, the latter three groups being unsubstituted or substituted with one or more halo groups; L is a linking group selected from the group consisting of: 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 where the dotted line represents the point of attachment to the remainder of the molecule; R ７ represents H or an optionally substituted alkyl group; Z represents a heterocycle selected from the group consisting of: 【Chemistry 24】 During the ceremony, The dotted line represents the point of attachment to the remainder of the molecule, where Z is attached to the remainder of the molecule via a covalent bond or via an -O- or -NH- group; R ８ ~R １０ each independently represents H, Me, C unsubstituted or substituted with one or more halo groups; １ ~C ５ Alkoxy, OC(O)R １１ , C(O)OR １２ , C substituted with one or more halo groups ２ ~C ５ Alkynyl, or NR １３ R １４ is selected from R ８ ~R １０ One of the expressions 【Chemistry 25】 wherein X represents O or NH, R １１ and R １２ represents independently at each occurrence an optionally substituted alkyl; R １３ and R １４ represents independently at each occurrence H or optionally substituted alkyl; However, X １ and X ２ are both CH and L is 【Chemistry 26】 and A is 【Chemical 27】 Z is not optionally substituted imidazopyridinyl; and L 【Chemistry 28】 2. The compound of claim 1, or a pharma- ceutically acceptable salt, or solvate thereof, wherein, when: Z is attached to the remainder of the molecule via the -NH- group.

10. A compound of formula 1 according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof. or a solvate thereof.

11. The pharmaceutical composition of claim 10 for treating one or more of macular degeneration, diabetic retinopathy, and neovascularization.

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