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WO2018106184A1 - Application d'un inhibiteur multikinase - Google Patents

Application d'un inhibiteur multikinase Download PDF

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Publication number
WO2018106184A1
WO2018106184A1 PCT/SG2017/050598 SG2017050598W WO2018106184A1 WO 2018106184 A1 WO2018106184 A1 WO 2018106184A1 SG 2017050598 W SG2017050598 W SG 2017050598W WO 2018106184 A1 WO2018106184 A1 WO 2018106184A1
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WIPO (PCT)
Prior art keywords
alkyl
group
number selected
nitro
alkoxy
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PCT/SG2017/050598
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English (en)
Inventor
Boon Tin Chua
Barathi VELUCHAMY AMUTHA
Xiaomeng Wang
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Agency For Science, Technology And Research
Singapore Health Services Pte Ltd
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Publication of WO2018106184A1 publication Critical patent/WO2018106184A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine

Definitions

  • the present invention generally relates to the use of heterocylic compounds in the treatment of eye diseases.
  • Age-related macular degeneration is a leading cause of visual morbidity in patients aged 55 years and above in Asian countries. The disease is accountable for 8.7% of all blindness due to eye diseases. According to the World Health Organisation (WHO), approximately 20 million Asians are likely to suffer from visual loss, a number expected to increase especially in aging populations, where an increasing number of people will be at risk of visual impairment due to AMD, diabetic retinopathy (DR), and glaucoma.
  • WHO World Health Organization
  • AMD AMD is commonly classified as dry AMD or wet AMD.
  • wet AMD which affects ⁇ 10%— 15% of AMD patients, the disease progresses rapidly to blindness if left untreated with severe lesions in Bruch's membrane/retinal pigment epithelium (RPE) layer and concomitant choroidal neovascularization (CNV).
  • RPE Bruch's membrane/retinal pigment epithelium
  • CNV concomitant choroidal neovascularization
  • VEGF Vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • a method of treating visual impairment in a subject in need thereof comprises administering the subject a therapeutically effective amount of a compound of general formula (I) and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts
  • R 1 represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH 2 , -CO-O-alkyl or -CO-alkyl;
  • R 2 , R 3 and R 4 independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, -COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 represents alkyl-CO-O-alkyl, alkyl- CO-cycloalkyl or alkyl-CO-heterocyclyl
  • R can also represent hydrogen
  • Q represents a heterocyclyl group
  • W represents optionally substituted aromatic or non-aromatic heterocyclyl group or an substituted aryl group
  • X represents no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;
  • Y represents an optional substituent of the -(CH 2 ) r - chain and
  • R 5 represents an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH 2 , alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroal
  • k is a number selected from 0 or 1 ;
  • R 5 is the number of R 5 substituents independently selected and is itself a number selected from 0, 1, 2, 3, 4 or 5;
  • n is a number selected from 1, 2, 3, 4, 5 or 6;
  • n is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • p is a number selected from 0 or 1 ;
  • r is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • s is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • t is a number selected from 0 or 1 ;
  • u is a number selected from 0 or 1.
  • R 1 represents hydrogen, cyano, Ci-C 4 -alkylamino, Ci-C 4 -alkoxy, -COOH, -CO-NH 2 ,
  • R , R and R independently of each other represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Ci- C 6 -alkylcarbonyl, halogen, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 - alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano, or - NHR 6 wherein R 6 represents Ci-C 4 -alkyl-CO-0-Ci-C 8 -alkyl, d-C 4 -alkyl-CO-C 3 -C 8 - cycloalkyl or Ci-C 4 -alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O) and R can also represent hydrogen;
  • Q represents a heterocyclyl group
  • W represents an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aromatic or non- aromatic heterocyclyl group or a mono-, di-, tri-, or tetrasubstituted aryl group;
  • X represents no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;
  • Y represents of an optional substituent of the -(CH 2 ) r - chain and R 5 represents an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, Ci-C 4 -alkyl-thio-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH 2 , Ci- C 6 -alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo-C 2 -C 6 -alkynyl, hydroxyl, Ci-C 6 -alkoxy, Ci-
  • Ri represents hydrogen, cyano, -CH 2 -NH 2 , -CH 2 OH, -COOH, -CO-NH 2 , -CO-O-CH 3 or -CO-CH 3 ;
  • R 2 , R 3 and R4 independently of each other represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Q- Ce-alkylcarbonol, halo, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano or -NHR 6 wherein R 6 represents -CH 2 -CO-0-Ci-C 6 -alkyl, -CH 2 -CO-C 3 -C 8 -cycloalkyl or -CH 2 - CO-heterocyclyl(having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O);
  • Q represents a piperidin, tetrahydropyridin or piperazinyl group
  • W represents a heterocyclic ring having 5 to 6 ring members and 1 to 3 hetero atoms selected from N, O, or S or represents phenyl;
  • X represents no further substituent or represents a moiety that is benzofused to the heterocyclic ring or represents a C 3 to C 6 -bridge formed by two substituents of W in which 1 to 3 carbon atoms can be replaced by O, N, S or -C(O)-;
  • Y represents of an optional substituent of the -(CH 2 ) r - chain and R 5 represents an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, Ci-C 4 -alkyl-thio-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, fluorine, chlorine, bromine, iodine, -COOH, -CONH 2 , Ci-C 6 - alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo-C 2
  • k is a number selected from 0 or 1 ;
  • 1 is a number selected from 0, 1, or 2;
  • n is a number selected from 1, 2, 3, or 4;
  • n is a number selected from 0, 1, 2, 3, or 4;
  • p is a number selected from 0 or 1 ;
  • r is a number selected from 0, 1, 2 or 3;
  • s is a number selected from 2, 3, 4 or 5;
  • t is a number selected from 0 or 1 ;
  • u is a number selected from 0 or 1.
  • Ri represents hydrogen or a cyano group
  • R 2 , R 3 and R 4 independently of each other represent Ci-C 6 -alkyl, halo, -COOH, halo- Ci-C 6 -alkyl, Ci-C 6 -alkoxy, nitro, or cyano;
  • Q represents a piperidin or piperazinyl group
  • W represents a dioxo heterocyclic ring having 5 members and 1 to 2 hetero atoms selected from N, O, or S or represents a phenyl group;
  • X represents no further substituent or represents a moiety that is benzofused to the heterocycle or represents a C 3 or C 4 bridge formed by two substituents of W in which 1 to 3 C-atoms can be replaced by O, N, S or -CO-;
  • R5 represents a substitutent of the W or X-W moiety and is selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, halo, -COOH, -CONH 2 , Ci-C 6 - alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo-C 2 -C 6 -alkynyl, hydroxyl, Ci-C 6 -alkoxy, thio- Ci-C 6 -alkoxy, C 2 -C 6 -alkenyloxy, halo-Ci-C 6 -alkoxy, halo-C 2 -C 6 -alkenyloxy, nitro, amino, nitro-Ci-C 6 -alkyl, nitro-d-Ce-alkenyl, nitro-d-Ce-alkyn
  • k is a number selected from 0 or 1 ;
  • 1 is a number selected from 0, 1, or 2;
  • n is a number selected from 1, 2, or 3;
  • n is a number selected from 0, 1, 2, or 3;
  • p is a number selected from 0 or 1 ;
  • r is a number selected from 0 or 1 ;
  • s is a number selected from 2, 3, 4, or 5;
  • t is a number selected from 0 or 1 ;
  • u is a number selected from 0 or 1.
  • Ri represents hydrogen or a cyano group
  • R 2 , R3 and R 4 independently of each other represent halo, or Ci-C 6 -alkoxy
  • Q represents a piperidin-, or piperazinyl group
  • W represents a 2,5-dioxo-2,5-dihydro-pyrrol-l-yl group or represents a phenyl group;
  • R5 represents a substitutent of the W or X-W moiety and is selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, halo, -COOH, -CONH 2 , Q-Q,- alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo-C 2 -C 6 -alkynyl, hydroxyl, Ci-C 6 -alkoxy, thio- Ci-C 6 -alkoxy, C 2 -C 6 -alkenyloxy, halo-Ci-C 6 -alkoxy, halo-C 2 -C 6 -alkenyloxy, nitro, amino, nitro-Ci-C 6 -alkyl, nitro-C 2 -C 6 -alkenyl, nitro-C 2 -C 6
  • k is 0 or 1 ;
  • 1 is a number selected from 0, 1 or 2;
  • n is a number selected from 1 or 2;
  • n is a number selected from 0, 1, 2, or 3;
  • r is a number selected from 0 or 1 ;
  • s is a number selected from 2, 3 or 4;
  • Ri represents hydrogen or cyano
  • R 2 represents methoxy
  • R 3 represents chlorine
  • R4 represents chlorine
  • Q represents a piperazinyl group
  • W represents a 2,5-dioxo-2,5-dihydro-dihydro pyrrol-l-yl group or a 2,5-dioxo- pyrrolidin-l-yl group or together with X represents a l,3-dioxo-l,3-dihydro-isoindol- 2-yl group, a 5,7-dioxo-2,3,5,7-tetrahydro-[l,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]- piperazinyl group;
  • R5 represents hydrogen or represents a substitutent of the W or X-W moiety and is selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halogen, Ci-C 6 - alkylcarbonyloxy, or nitro;
  • k is 0 or 1 ;
  • 1 is a number selected from 0, 1 or 2;
  • n is a number selected from 1 or 2;
  • n is a number selected from 1, 2 or 3;
  • the visual impairment is a retina and/or choroid angiogenic disease.
  • the retina and/or choroid angiogenic disease is selected from the group consisting of age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, polypoidal choroidal vasculopathy (PCV), and retinopathy of prematurity (ROP).
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • PCV polypoidal choroidal vasculopathy
  • ROP retinopathy of prematurity
  • the subject has previously received anti-VEGF(vascular endothelial growth factor) antibody treatment.
  • the subject is responsive and/or not responsive to the anti- VEGF antibody treatment.
  • the administering is via intravitreal route, topical, and sub-conjunctival route.
  • the method further comprises administering one or more compound as described herein.
  • the method further comprises administering one or more inhibitor that is not described above for reducing vessel growth and permeability.
  • the inhibitor is an anti-angiogenic inhibitor.
  • the inhibitor is an agent that blocks VEGF activity.
  • the inhibitor is an anti-VEGF antibody.
  • the inhibitor is Bevacizumab.
  • the inhibitor is selected from the group consisting of Sorafenib, Sunitinib, and Vatalanib.
  • the compound is not
  • the present invention provides the use of a compound of general formula (I) and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts
  • R 1 represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH 2 , -CO-O-alkyl or -CO-alkyl;
  • R 2 , R 3 and R 4 independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, -COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 represents alkyl-CO-O-alkyl, alkyl- CO-cycloalkyl or alkyl-CO-heterocyclyl
  • R can also represent hydrogen
  • Q represents a heterocyclyl group
  • W represents optionally substituted aromatic or non-aromatic heterocyclyl group or an substituted aryl group
  • X represents no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;
  • Y represents an optional substituent of the -(CH 2 ) r - chain and R 5 represents an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH 2 , alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialky
  • k is a number selected from 0 or 1 ;
  • R 5 is the number of R 5 substituents independently selected and is itself a number selected from 0, 1, 2, 3, 4 or 5;
  • n is a number selected from 1, 2, 3, 4, 5 or 6;
  • n is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • p is a number selected from 0 or 1 ;
  • r is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • s is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • t is a number selected from 0 or 1 ;
  • u is a number selected from 0 or 1.
  • Figure 1 shows representative pictures and quantifications of vessel outgrowth from choroid explants upon drug treatment.
  • Top panel of Figure 1 shows bright light microscope images of choroid angiogenesis on treatment with either DMSO or exemplary compounds as described herein (i.e. VI 1-003, VI 1-008, and VI 1-010).
  • Bottom panel of Figure 1 shows a bar graph of the vessel area/choroid tissue area of cells treated with DMSO or exemplary compounds as described herein (i.e. VI 1-003, VI 1-008, and VI 1-010).
  • Figure 1 shows exemplary compounds as described herein (i.e. VI 1-003, VI 1-008, and VI 1-010) significantly inhibit angiogenesis at test concentration of 1 ⁇ .
  • Figure 2 shows representative pictures and quantifications of vessel outgrowth from metatarsal explants upon 1 ⁇ of drug treatment.
  • Left panel of Figure 2 shows bright light microscope images of metatarsal angiogenesis on treatment with either DMSO or exemplary compounds as described herein (i.e. VI 1-003, VI 1-008, and VI 1-010).
  • Right panel of Figure 2 shows a bar graph of the total vascular area in pixels of cells treated with DMSO or exemplary compounds as described herein (i.e. VI 1-003, VI 1-008, and VI 1-010).
  • Figure 2 shows the compounds do not appear to inhibit metatarsal angiogenesis.
  • FIG. 3 shows linear graphs of results from MTS (3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay on ARPE19 cells (i.e. human retinal pigmented epithelial cell lines) upon drug treatment. From the MTS assay, it appears that VI 1-003 is toxic to ARPE19 cells. However, both VI 1-008 and VI 1-010 are not toxic to ARPE19 cells.
  • Figure 4 shows photographical images of fundus photography and fundus fluorescein angiography (FFA) and posterior-segment Optical Coherence Tomography (PS-
  • OCT laser-induced mice choroidal neovascularization
  • IVT intravitreal
  • Figure 4 shows VI 1-010 and anti-VEGF significantly attenuate retinal angiogenesis after 2 weeks and 4 weeks post injection.
  • FIG. 5 shows quantification of leakage area in CNV mice after single dose VI 1-
  • VI 1-010 provides anti-angiogenic effect that is as good as anti-VEGF via single IVT route.
  • the group may be a terminal group or a bridging group. This is intended to signify that the use of the term is intended to encompass a situation where the group is a linker between two other portions of the molecule as well as where it is a terminal moiety.
  • alkyl alkyl
  • alkylene alkylene
  • Alkenyl as a group or part of a group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight, linear or branched preferably having 2-20 carbon atoms, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, more preferably 2-10 carbon atoms, most preferably 2-6 carbon atoms, in the normal chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and nonenyl.
  • the group may be a terminal group or a bridging group.
  • the group may be a terminal group or a bridging group.
  • alkenyloxy refers to an alkenyl-O- group in which alkenyl is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, vinyloxy, 1-propenyloxy and 2-butenyloxy.
  • alkenylamine refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an amino group as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, 2-butenylamine, 2-propenylamine and 3-pentenylamine.
  • Alkyl as a group or part of a group refers to a straight, linear or branched aliphatic hydrocarbon group, preferably a C 1 -C 20 alkyl, e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, more preferably a C 1 -C 16 alkyl, even more preferably a C 1 -C 12 alkyl, most preferably C 1 -C6 unless otherwise noted.
  • Examples of suitable straight and branched C 1 -C6 alkyl substituents include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • the group may be a terminal group or a bridging group.
  • Alkynyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight, linear or branched preferably having from 2-20 carbon atoms, e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms, more preferably 2-18 carbon atoms, more preferably 5-16 carbon atoms in the normal chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • the group may be a terminal group or a bridging group.
  • Alkynylamino refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with an amino group as defined herein.
  • the group may be a terminal group or a bridging group.
  • Alkoxy refers to an alkyl-O- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.
  • Alkoxyalkyl refers to an alkyl-O-alkyl group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, 2-methoxyethyl, 3-methoxypropyl, and 1- methy 1- 2-methoxyethyl .
  • Amino refers to groups of the form -NR a R b wherein R a and R are individually selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.
  • Diacylamino refers to an amino group in which two of the hydrogen atoms have been replaced with two acyl groups as defined herein, which may be same or different.
  • Alkylamino refers to -NH-alkyl group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, -NHCH 3 , -NHCH 2 CH 3 and -NH(CH 2 ) 2 CH 3 .
  • “Dialkylamino” means -N(alkyl)(alkyl) group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ) and -N(CH 2 CH 3 ) 2 .
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, acetyl, propionyl, butyryl and isobutyryl.
  • Alkylcarbonyloxy refers to an alkylcarbonyl-O- group in which the alkylcarbonyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Alkylsulfenyl refers to an alkyl-S(O) group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Alkylsulfonyloxy refers to an alkyl-S(0) 2 -0- group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring, e.g. 5, 6, 7, 8, 9, 10, 11, 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C5_ 7 cycloalkyl or C5_ 7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • the group may be a terminal group or a bridging group.
  • an aryl group is a C6-Ci 8 aryl group.
  • Alkylaryl refers to an aryl group as defined herein in which one or more of the hydrogen atoms has been replaced with an alkyl group as defined herein.
  • Exemplary structures include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.
  • oxo refers to a substituent, it is understood that the oxygen atom is double- bonded to the molecule of interest.
  • R 5 is an oxo group, the oxygen atom is attached to the W or X-W moiety via a double bond.
  • Halogen refers to chlorine, fluorine, bromine or iodine.
  • Haloalkyl refers to an alkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • a haloalkyl group typically has the formula C n H (2n+ i_ m) X m wherein each X is independently selected from the group consisting of F, CI, Br and I .
  • n is typically from 1 to 10 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10), more preferably from 1 to 6, most preferably 1 to 3.
  • m is typically 1 to 6, more preferably 1 to 3.
  • Haloalkyl examples include fluoromethyl, difluoromethyl and trifluoromethyl.
  • Haloalkoxy refers to a haloalkyl-O- group in which the haloalkyl is as defined herein. The group may be a terminal group or a bridging group. Exemplary structures include, but are not limited to, difluoromethoxy, trifluoromethoxy and chlorodifluoromethoxy .
  • Haloalkynyl refers to an alkynyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Haloalkenyl refers to an alkenyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Haloalkenyloxy refers to a haloalkenyl-O- group in which haloalkenyl is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, 2-chloro-2-propenyl, 3-chloro-2-propenyl and 3,3-difluoro-2-propenyl.
  • Fused when used herein refers to two or more cyclic rings are joined or bonded covalently via at least one pair of adjacent atoms included in adjacent rings.
  • benzofused when used herein refers to at least one cyclic ring is joined or bonded covalently with a benzene ring.
  • Exemplary benzofused structures include, but are not limited to, benzimidazole, benzoxazole and benzothiazole.
  • Thioalkyl or “thioalkoxy” or “alkylthio” refers to a -S-alkyl group in which the alkyl group is as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, -S-CH 3 , -S-CH 2 CH 3 and -S- (CH 2 ) 2 CH 3 .
  • Alkylthioalkyl means a -alkyl- S-alkyl group in which the -S-alkyl and alkyl groups are as defined herein.
  • the group may be a terminal group or a bridging group.
  • Exemplary structures include, but are not limited to, methylthiomethyl, ethylthiomethyl, n- propyl thiomethyl and isopropylthio methyl.
  • Cycloalkyl refers to a saturated monocyclic or fused or bridged or spiro polycyclic, carbocycle preferably containing from 3 to 12 carbons per ring (e.g. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms per ring), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic systems such as cyclopropyl and cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane.
  • the group may be a terminal group or a bridging group.
  • Cycloalkenyl means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-12 carbon atoms per ring (e.g. 5, 6, 7, 8, 9, 10, 11, 12 carbon atoms per ring).
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • the cycloalkenyl group may be substituted by one or more substituent groups The group may be a terminal group or a bridging group.
  • Heterocyclyl refers to saturated, partially unsaturated or fully unsaturated monocyclic, bicyclic or polycyclic ring system containing at least one heteroatom selected from the group consisting of nitrogen, sulfur and oxygen as a ring atom.
  • Each ring is preferably from 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10), more preferably 4 to 7 membered.
  • heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.
  • Heterocycloalkyl refers to a saturated monocyclic, fused or bridged or spiro polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring.
  • Each ring is preferably from 3 to 10 membered (e.g. 3, 4, 5, 6, 7, 8, 9, 10), more preferably 4 to 7 membered.
  • heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane, 1,4-diazapane, 1,4-oxazepane, and 1,4 oxathiapane.
  • a heterocycloalkyl group may comprise 3 to 9 ring atoms.
  • a heterocycloalkyl group may comprise 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The group may be a terminal group or a bridging group.
  • Heterocyclyloxy refers to -O-heterocyclyl group in which the heterocyclyl group is as defined herein.
  • Heterocyclylamino refers to an amino group as defined herein in which one or more of the hydrogen atoms has been replaced with a heterocyclyl group as defined herein.
  • Heteroaryl either alone or part of a group refers to groups containing an aromatic ring having one or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include nitrogen, oxygen and sulphur.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3- bjthiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, tetrazole, indole, isoindole, lH-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane,
  • a heteroaryl group is typically a Ci-Cig heteroaryl group (e.g. Q, C 2 , C 3 , C 4 , C5, C , C 7 , C 8 , C 9 , Cio, C 11 , Ci 2 , Ci 3 , Ci 4 , C 15 , C 16 , Ci 7 , or Cig).
  • a heteroaryl group may comprise 3 to 8 ring atoms.
  • a heteroaryl group may comprise 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The group may be a terminal group or a bridging group.
  • Alkylheteroaryl refers to a heteroaryl group as defined herein in which one or more of the hydrogen atoms has been replaced with an alkyl group as defined herein.
  • Haloheterocycloallkyl refers to a hetercycloalkyl group as defined herein in which one or more of the hydrogen atoms has been replaced with a halogen atom independently selected from the group consisting of F, CI, Br and I.
  • Neitro when used herein to describe a chemical structure refers to one containing -N0 2 .
  • nitro moiety include nitroalkyl, nitroalkenyl and nitroalkynyl.
  • Nitroalkyl means N0 2 -alkyl- in which the alkyl group is as defined herein.
  • Nonroalkenyl means N0 2 -alkenyl- in which the alkenyl group is as defined herein.
  • Neitroalkynyl means N0 2 -alkynyl- in which the alkynyl group is as defined herein.
  • Cyano or "cyanide” when used herein to describe a chemical structure refers to one containing -C ⁇ N group.
  • Phosphono when used herein to describe a chemical structure refers to one containing -P0 3 H 2 .
  • Phosphinyl when used herein to describe a chemical structure refers to one containing -PRR' wherein R and R' are each independently selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.
  • a “bond” is a linkage between atoms in a compound or molecule.
  • the bond may be a single bond, a double bond, or a triple bond.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof, are intended to be within the scope of the subject matter described and claimed.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • compounds of the invention may contain more than one asymmetric carbon atom.
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • optionally substituted means the group to which this term refers may be unsubstituted, or may be substituted with one or more groups independently selected from alkyl, alkenyl, alkynyl, thioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkenyl, heterocycloalkyl, cycloalkylheteroalkyl, cycloalkyloxy, cycloalkenyloxy, cycloamino, halo, carboxyl, oxo, haloalkyl, haloalkenyl, haloalkynyl, alkynyloxy, heteroalkyl, heteroalkyloxy, hydroxyl, hydroxyalkyl, alkoxy, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroal
  • arylalkyl When compounded chemical names, e.g. "arylalkyl” and “arylimine” are used herein, they are understood to have a specific connectivity to the core of the chemical structure.
  • the group listed farthest to the right e.g. alkyl in “arylalkyl”
  • alkyl in “arylalkyl” is the group that is directly connected to the core.
  • an "arylalkyl” group for example, is an alkyl group substituted with an aryl group (e.g. phenylmethyl (i.e., benzyl)) and the alkyl group is attached to the core.
  • An “alkylaryl” group is an aryl group substituted with an alkyl group (e.g., p-methylphenyl (i.e., p-tolyl)) and the aryl group is attached to the core.
  • pharmaceutically acceptable salts refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of formula (I) may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
  • inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present disclosure and specified formulae.
  • pharmaceutically acceptable excipient refers to a excipient that is generally safe, non-toxic that may be useful in the preparation of a pharmaceutical composition.
  • subject when used herein refers to a human or an animal.
  • the term "about”, in the context of concentrations of components of the formulations, typically means +/- 5% of the stated value, more typically +/- 4% of the stated value, more typically +/- 3% of the stated value, more typically, +/- 2% of the stated value, even more typically +/- 1% of the stated value, and even more typically +/- 0.5% of the stated value.
  • range format may be disclosed in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • RAD Retina angiogenic diseases
  • Patients suffering from RAD will have their vision affected. Depending on severity, blindness can set in if left untreated. Examples of RAD are age-related macular degeneration and diabetic retinopathy.
  • Current gold standard for treatment of retinal neo-vascularisation is anti-VEGF antibody known as Bevacizumab (CAS ID: 216974-75-3).
  • kinases including Abelson murine leukemia viral oncogene (Abl), Src (SRC proto-oncogene, nonreceptor tyrosine kinase) and Epidermal Growth Factor Receptor (EGFR).
  • Abl Abelson murine leukemia viral oncogene
  • Src SRC proto-oncogene
  • nonreceptor tyrosine kinase Src
  • EGFR Epidermal Growth Factor Receptor
  • the multi-tyrosine kinase inhibitor as described herein is found to have anti- angiogenic property.
  • Compounds as disclosed herein were tested for anti- angiogenic effect in ex vivo choroidal and metatarsal angiogenesis assays. Data showed that the compound as disclosed herein (for example VI 1-003, VI 1-008 and VI 1-010) selectively inhibit choroid angiogenesis at the dosage of ⁇ (see Figure 1 and 2). This indicates that small molecule drugs, such as exemplified VI 1-008 and VI 1-010, are specific for retinal angiogenesis indication. Subsequently, in vivo model was utilized to check efficacy of these molecules compared to current gold stand, anti-VEGF.
  • the inventors of the present disclosure found that when the compounds were given to Laser induced choridal neo-vascularization (CNV) in C57/BL6J (B6J) wild type mice through intravitreal (IVT) route at single injection of ⁇ volume at ⁇ g, area of leakage determined at week 2 and 4 post-treatment showed significant reduction up to ⁇ 70%, comparable to anti-VEGF treatment ( Figure 4 and 5).
  • CNV Laser induced choridal neo-vascularization
  • IVTT intravitreal
  • a method of treating visual impairment in a subject in need thereof comprises administering the subject a therapeutically effective amount of a compound of general formula (I) and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts
  • R 1 represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH 2 , -CO-O-alkyl or -CO-alkyl;
  • R 2 , R 3 and R 4 independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, - COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 represents alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO- heterocyclyl
  • R can also represent hydrogen
  • Q represents a heterocyclyl group
  • W represents optionally substituted aromatic or non-aromatic heterocyclyl group or an substituted aryl group
  • X represents no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;
  • Y represents an optional substituent of the -(CH 2 ) r - chain and R 5 represents an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH 2 , alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialky
  • k is a number selected from 0 or 1 ;
  • R 5 is the number of R 5 substituents independently selected and is itself a number selected from 0, 1, 2, 3, 4 or 5;
  • n is a number selected from 1, 2, 3, 4, 5 or 6;
  • n is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • p is a number selected from 0 or 1 ;
  • r is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • s is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • t is a number selected from 0 or 1 ;
  • u is a number selected from 0 or 1.
  • R 1 may be a hydrogen; cyano; alkylamino comprising 1 to 20 carbon atoms (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms), 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms; alkoxy comprising 1 to 20 carbon atoms (i.e.
  • R 1 may be hydrogen or a cyano group.
  • R 1 may represent hydrogen, cyano, Ci-C 4 - alkylamino, Ci-C 4 -alkoxy, -COOH, -CO-NH 2 , -CO-0-Ci-C 4 -alkyl or -CO-Ci-C 4 -alkyl.
  • Ri may represent hydrogen, cyano, -CH 2 -NH 2 , -CH 2 OH, -COOH, -CO-NH 2 , -CO-O-CH 3 or -CO-CH 3 .
  • Ri may represent hydrogen or a cyano group.
  • R may represent hydrogen, alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 may represent alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO- heterocyclyl and wherein the alkyl moiety in any of the abovementioned substituents may comprise 1 to 20 carbon atoms (i.e.
  • R may represent hydrogen, Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 - alkylcarbonyl, halogen, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano, or -NHR 6 wherein R 6 represents Ci-C 4 -alkyl-CO-0-Ci-C 8 -alkyl, Ci-C 4 -alkyl-CO-C 3 -C 8 -cycloalkyl or Ci-C 4 -alkyl- CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O).
  • R 2 may represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 -alkylcarbonol, halo, -COOH, - CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci- C 6 - alkylamino, Ci-C 6 -acyl, cyano or -NHR 6 wherein R 6 represents -CH 2 -CO-0-Ci-C 6 -alkyl, -CH 2 -CO-C3-C 8 -cycloalkyl or -CH 2 -CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O).
  • R 2 may represent Ci-C 6 -alkyl, halo, -COOH, halo- Ci-C 6 -alkyl, Ci-C 6 -alkoxy, nitro, or cyano.
  • R 2 may represent halo, or Ci-C 6 -alkoxy.
  • R 2 may represent methoxy.
  • R may represent alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 may represent alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO-heterocyclyl and wherein the alkyl moiety in any of the abovementioned substituents may comprise 1 to 20 carbon atoms (i.e.
  • R may represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 -alkylcarbonyl, halogen, -COOH, - CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci- C 6 - alkylamino, Ci-C 6 -acyl, cyano, or -NHR 6 wherein R 6 represents Ci-C 4 -alkyl-CO-0-Ci- Cg-alkyl, Ci-C 4 -alkyl-CO-C 3 -C 8 -cycloalkyl or Ci-C 4 -alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O).
  • R may represent Ci-C 6 - alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 -alkylcarbonol, halo, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano or -NHR 6 wherein R 6 represents -CH 2 -CO-0-Ci-C 6 -alkyl, -CH 2 -CO-C 3 -C 8 -cycloalkyl or -CH 2 -CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O).
  • R 3 may represent Ci-C 6 -alkyl, halo, -COOH, halo-Ci-C 6 -alkyl, Ci-C 6 - alkoxy, nitro, or cyano.
  • R 3 may represent halo, or Ci-C 6 -alkoxy.
  • R 3 may represent methoxy.
  • R 4 may represent alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 may represent alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO-heterocyclyl and wherein the alkyl moiety in any of the abovementioned substituents may comprise 1 to 20 carbon atoms (i.e.
  • R 4 may represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 -alkylcarbonyl, halogen, -COOH, - CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci- C 6 - alkylamino, Ci-C 6 -acyl, cyano, or -NHR 6 wherein R 6 represents Ci-C 4 -alkyl-CO-0-Ci- C 8 -alkyl, Ci-C 4 -alkyl-CO-C 3 -C 8 -cycloalkyl or Ci-C 4 -alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O).
  • R 4 may represent Ci-C 6 - alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 -alkylcarbonol, halo, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 - alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano or -NHR 6 wherein R 6 represents -CH 2 -CO-0-Ci-C 6 -alkyl, -CH 2 -CO-C 3 -C 8 -cycloalkyl or -CH 2 -CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O).
  • R 4 may represent Ci-C 6 -alkyl, halo, -COOH, halo-Ci-C 6 -alkyl, Ci-C 6 - alkoxy, nitro, or cyano.
  • R 4 may represent halo, or Ci-C 6 -alkoxy.
  • R 4 may represent methoxy.
  • R 2 , R 3 and R 4 may be the same or different.
  • R 3 and R 4 may be the same but different from R 2.
  • R 3 and R 4 may each be a halogen independently selected from chlorine, fluorine, bromine or iodine.
  • R 3 and R 4 may be identical halogens selected from chlorine, fluorine, bromine or iodine.
  • R 3 and R 4 may both be chlorine.
  • R 2 may be an alkoxy group comprising 1 to 20 carbon atoms (i.e.
  • R 2 may be an alkoxy group comprising 1 to 4 carbon atoms.
  • R 2 may be a methoxy, ethoxy or isopropoxy group.
  • R 2 may be a methoxy group.
  • R 2 may be a methoxy group when R 3 and R 4 are each chloro.
  • R 1 may be a cyano group
  • R2 may be a methoxy group
  • R 3 and R 4 may both be chlorine
  • R 1 may be hydrogen
  • R2 may be a methoxy group
  • R 3 and R 4 may both be chlorine.
  • R 2 , R 3 and R 4 may independently of each other represent halo, or Ci-C6-alkoxy.
  • Q may represent a heterocyclyl group.
  • Q may be selected from 3- to 10- (i.e. 3, 4, 5, 6, 7, 8, 9, or 10) membered, or 4- to 7- membered ring structures.
  • Q may contain at least one heteroatom selected from nitrogen, sulfur or oxygen.
  • Q may be a 5 membered ring structure containing at least one heteroatom selected from nitrogen, sulfur or oxygen, or a 6 membered ring structure containing at least one heteroatom selected from nitrogen, sulfur or oxygen.
  • Q may be 5 membered or 6 membered ring structure containing at least one sulfur atom, or Q may be 5 membered or 6 membered ring structure containing at least one oxygen atom, or a 5 membered or 6 membered ring structure containing at least one nitrogen atom.
  • Q may be a 6 membered ring structure containing at least one nitrogen atom, or a 6 membered ring structure containing two nitrogen atoms.
  • Q may be a piperidinyl, tetrahydropyridinyl, or piperazinyl group.
  • W may represent optionally substituted aromatic or non-aromatic heterocyclyl group or an optionally substituted aryl group.
  • W may be a substituted aromatic or non- aromatic heterocyclyl group or a substituted aryl group.
  • W may be an unsubstituted aromatic or non-aromatic heterocyclyl group or an unsubstituted aryl group.
  • W may be an unsubstituted aryl group.
  • W may be an optionally substituted benzene ring.
  • W may be substituted with at least one R 5 substituent as disclosed herein.
  • W may represent an optionally substituted aromatic or non-aromatic heterocyclyl group.
  • W may be selected from 3- to 10- (i.e. 3, 4, 5, 6, 7, 8, 9, or 10) membered, or 4- to 7- membered ring structures.
  • W may contain at least one heteroatom selected from nitrogen, sulfur or oxygen.
  • W may be a 5- or 6- membered ring structure containing at least one heteroatom selected from nitrogen, sulfur or oxygen.
  • W may be 5- or 6- membered ring structure containing at least one sulfur atom.
  • W may be 5- or 6- membered ring structure containing at least one oxygen atom.
  • W may be 5- or 6- membered ring structure containing at least one nitrogen atom.
  • W may be an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aromatic or non- aromatic heterocyclyl group or an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aryl group.
  • W represents a dioxo heterocyclic ring having 5 members and 1 to 2 hetero atoms selected from N, O, or S or represents a phenyl group.
  • W may represent a succinimide, phenyl, 5-dioxo-2,5-dihydro-pyrrol-l-yl, 2,5-dioxo-2,5-dihydro-dihydro pyrrol- 1-yl, 2,5- dioxo-pyrrolidin-l-yl group, or together with X represents a l,3-dioxo-l,3-dihydro-isoindol-
  • X may represent no further substituent or may represent a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W.
  • X may be an optionally substituted benzene ring or a 1,4-dithiane group.
  • X may be an optionally substituted benzene ring.
  • X may be substituted with at least one R 5 as defined herein.
  • X may be a moiety that is benzofused, partially saturated benzofused or heterocyclic fused to W to form a X-W moiety.
  • X and W may be individually selected from
  • the X- W moiety may contain at least one heteroatom selected from nitrogen, sulfur or oxygen.
  • the X portion of the X-W moiety may be a 6 membered ring structure and the W portion of the X-W moiety may be a 5 membered ring structure.
  • the X portion and/or W portion of the X-W moiety may be substituted with at least one R 5 substituent as defined herein.
  • the X-W moiety may be an optionally substituted phthalimide, or a phthalimide group substituted with at least one R 5 substituent as defined herein.
  • X may represent no further substituent, or represent a moiety that is benzofused to the heterocyclic ring or represents a C 3 to C 6 -bridge formed by two substituents of W in which 1 to 3 carbon atoms can be replaced by O, N, S or -C(O)-.
  • the X-W moiety may be a 1,4-dithiane group (X) heterocyclic fused to succinimide group (W). Without wishing to be bound by theory, the inventors of the present disclosure found that this X-W moiety may surprisingly provide improved biological effect.
  • u may be 0 or 1. When u is 1, X may represent no further substituent. When u is 1 , W may be an optionally substituted benzene ring, a benzene ring that may be substituted at least with R5 or a 1,4-dithiane.
  • u may be 1
  • X may represent no further substituent
  • W may be an optionally substituted benzene ring.
  • having an acyl group in place of the phthamlimide (acyl-c-Bosutinib) may surprisingly increase activity, however this modification may increase the biological effect on normal epithelial cells also.
  • W may be a succinimide, phenyl, 5-dioxo-2,5-dihydro-pyrrol-l-yl, 2,5-dioxo-2,5-dihydro-dihydro pyrrol- 1-yl, 2,5-dioxo-pyrrolidin-l-yl group, or together with X represents a l,3-dioxo-l,3-dihydro-isoindol-2-yl group, or a 5,7-dioxo-2,3,5,7-tetrahydro- [l,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]-piperazinyl group.
  • X When u is 0, X may be a benzene ring benzofused to W.
  • the X-W moiety When u is 0, the X-W moiety may be an optionally substituted phthalimide group.
  • the X-W moiety When u is 0, the X-W moiety may be a phthalimide group substituted with at least one R 5 substituent as defined herein.
  • R 5 may be selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, - CONH 2 , alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino, acyl, alkenoyl, alkynoyl, acyl, al
  • R 5 may be selected from oxo, halogen and alkyl groups comprising 1 to 20 carbon (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms) atoms, 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 14 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms or 1 to 4 carbon atoms.
  • R 5 may be selected from fluoride, chlorine, methyl, ethyl, iso-propyl and tert-butyl groups.
  • k may be 0 or 1. When k is 1, Q may be a piperazine group. When k is 1, Q may be a piperazine group, u may be 0 and X-W may be a phthalimide group.
  • Q may be a piperazine group, r, t and u may be 0, s may be 4 and X- W may be a phthalimide group.
  • Q may be a piperazine group, s, t and u may be 0, r may be 4 and X-W may be a phthalimide group.
  • s may be a number selected from 0, 1, 2, 3, 4, 5 and 6. s may be a number selected from 2, 3, 4 and 5. s may be 2 or 4.
  • r may be a number selected from 0, 1, 2, 3, 4, 5 and 6. r may be a number selected from 2, 3, 4 and 5. r may be 2 or 4.
  • r may be 2 or 4.
  • 1 represents the number of R 5 substituents on the W or X-W moiety.
  • 1 may be a number selected from 0, 1, 2, 3, 4 and 5.
  • 1 may be 0, 1 or 2.
  • 1 is greater than 1, the more than one R 5 substituent may be independently selected to be the same or different.
  • the first R 5 substituent may be an oxo group and the second R 5 substituent may be an oxo group or a substituent other than oxo group.
  • n may be a number selected from 1, 2, 3, 4, 5 and 6.
  • m may be a number selected from 0, 1, 2, 3, 4, 5 and 6.
  • t may be 0 or 1.
  • p may be 0 or l.Both t and p may be 0. Both t and p may be 1.
  • k and u may be 0, t and p may be 1, m, n, r and s may be 2, Q may be a piperazine group and X-W may be a phthalimide group.
  • K, t and u may be 0, p may be 1, m, n, r and s may be 2, Q may be a piperazine group and X-W may be a phthalimide group, k, p and u may be 0, p may be 1, m, n, r and s may be 2, Q may be a piperazine group and X-W may be a phthalimide group.
  • k, m, p, r and t may be 0, s may be 4 and R 1 may be hydrogen. In another embodiment, k, m, p, s and t may be 0, r may be 4 and R 1 may be hydrogen.
  • Q may be a piperazine group
  • X-W may be a phthalimide group
  • k may be 1 or 0, s
  • t and u may be 0, r may be selected from 1, 2 and 3 and Y may represent no further substituent or Y may be a methyl group.
  • Q may be a piperazine group
  • X-W may be a phthalimide group
  • k may be 1 or 0, t and u may be
  • r may be 0 or 1
  • Y may represent no further substituent or Y may be a methyl group
  • s may be selected from 0, 1, 2 and 3.
  • Y may be an optional substituent of the -(CH 2 ) r - chain selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH 2 , alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialkylamino, alkenylamine, alkynylamino,
  • the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts is formula (I), wherein
  • R 1 may represent hydrogen, cyano, Ci-C 4 -alkylamino, Ci-C 4 -alkoxy, -COOH, - CO-NH 2 , -CO-0-Ci-C 4 -alkyl or -CO-Ci-C 4 -alkyl ;
  • R , R and R independently of each other represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Ci-C 6 -alkylcarbonyl, halogen, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, d-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano, or -NHR 6 wherein R 6 represents Ci-C 4 -alkyl-CO-0-Ci-C 8 -alkyl, Ci-C 4 -alkyl-CO-C 3 -C 8 -cycloalkyl or C C 4 - alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O) and R may also represent hydrogen;
  • Q may represent a heterocyclyl group
  • W may represent an unsubstituted, or mono-, di-, tri-, or tetrasubstituted aromatic or non-aromatic heterocyclyl group or a mono-, di-, tri-, or tetrasubstituted aryl group;
  • X may represent no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;
  • Y may represent of an optional substituent of the -(CH 2 ) r - chain and R 5 may represent an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, Ci-C 4 - alkyl-thio-Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH 2 , Ci-C 6 -alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo-C 2 -C 6 -alkynyl, hydroxyl, Ci-C 6 -alkyl,
  • n and r may each be selected from 3, 4, 5, and 6.
  • Y may be absent.
  • Ri may represent hydrogen, cyano, -CH 2 -NH 2 , -CH 2 OH, -COOH, -CO-NH 2 , -CO-O-CH 3 or -CO-CH 3 ;
  • R 2 , R 3 and R4 independently of each other may represent Ci-C 6 -alkyl, thio-Ci-C 6 -alkyl, Q- C 6 -alkylcarbonol, halo, -COOH, -CONH 2 , halo-Ci-C 6 -alkyl, hydroxyl, Ci-C 6 -alkoxy, nitro, amino, Ci-C 6 -alkylamino, di-Ci-C 6 -alkylamino, Ci-C 6 -acyl, cyano or -NHR 6 wherein R 6 represents -CH 2 -CO-0-Ci-C 6 -alkyl, -CH 2 -CO-C 3 -C 8 -cycloalkyl or -CH 2 -CO- heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O); Q represents a piperidin, tetrahydropyridin or piperazin
  • W may represent a heterocyclic ring having 5 to 6 ring members and 1 to 3 hetero atoms selected from N, O, or S or represents phenyl;
  • X may represent no further substituent or may represent a moiety that is benzofused to the heterocyclic ring or represents a C 3 to C 6 -bridge formed by two substituents of W in which 1 to 3 carbon atoms can be replaced by O, N, S or -C(O)-;
  • Y may represent of an optional substituent of the -(CH 2 ) r - chain and R 5 may represent an optional substituent of the W or X-W moiety and Y and R 5 may be independently of another selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, Ci-C 4 -alkyl-thio- Ci-C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, fluorine, chlorine, bromine, iodine, -COOH, -CONH 2 , Ci-C 6 -alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo- C
  • k may be a number selected from 0 or 1 ;
  • n may be a number selected from 1, 2, 3, or 4;
  • n may be a number selected from 0, 1, 2, 3, or 4;
  • p may be a number selected from 0 or 1 ;
  • r may be a number selected from 0, 1, 2 or 3;
  • s may be a number selected from 2, 3, 4 or 5;
  • t may be a number selected from 0 or 1 ;
  • u may be a number selected from 0 or 1.
  • Ri may represent hydrogen or a cyano group
  • R 2 , R 3 and R4 independently of each other may represent Ci-C 6 -alkyl, halo, -COOH, halo-Ci-
  • Q may represent a piperidin or piperazinyl group
  • W may represent a dioxo heterocyclic ring having 5 members and 1 to 2 hetero atoms selected from N, O, or S or represents a phenyl group;
  • X may represent no further substituent or may represent a moiety that is benzofused to the heterocycle or may represent a C 3 or C 4 bridge formed by two substituents of W in which 1 to 3 C-atoms can be replaced by O, N, S or -CO-;
  • R5 may represent a substitutent of the W or X-W moiety and is selected from Ci-C 6 -alkyl, C 2 - Ce-alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, halo, -COOH, -CONH 2 , Ci-C 6 -alkoxycarbonyl, halo-Ci-C 6 -alkyl, halo-C 2 -C 6 -alkynyl, hydroxyl, Ci-C 6 -alkoxy, thio-Ci-C 6 -alkoxy, C 2 -C 6 - alkenyloxy, halo-Ci-C 6 -alkoxy, halo-C 2 -C 6 -alkenyloxy, nitro, amino, nitro-Ci-C 6 -alkyl, nitro-
  • k may be a number selected from 0 or 1 ;
  • 1 may be a number selected from 0, 1, or 2;
  • n may be a number selected from 1, 2, or 3;
  • n may be a number selected from 0, 1, 2, or 3;
  • p may be a number selected from 0 or 1
  • r may be a number selected from 0 or 1 ;
  • s may be a number selected from 2, 3, 4, or 5;
  • t may be a number selected from 0 or 1 ;
  • u may be a number selected from 0 or 1.
  • Ri may represent hydrogen or a cyano group
  • R 2 , R 3 and R 4 independently of each other represent halo, or Ci-C 6 -alkoxy
  • Q may represent a piperidin-, or piperazinyl group
  • W may represent a 2,5-dioxo-2,5-dihydro-pyrrol-l-yl group or may represent a phenyl group;
  • R5 may represent a substitutent of the W or X-W moiety and is selected from Ci-C 6 -alkyl, C 2 - Ce-alkenyl, C 2 -C 6 -alkynyl, thio-Ci-C 6 -alkyl, halo, -COOH, -
  • k may be 0 or 1 ;
  • 1 may be a number selected from 0, 1 or 2;
  • n may be a number selected from 1 or 2;
  • n may be a number selected from 0, 1, 2, or 3;
  • p may be 0
  • r may be a number selected from 0 or 1 ;
  • u may be 0.
  • Ri may represent hydrogen or cyano
  • R 2 may represent methoxy
  • R 3 may represent chlorine
  • R4 may represent chlorine
  • Q may represent a piperazinyl group
  • W may represent a 2,5-dioxo-2,5-dihydro-dihydro pyrrol-l-yl group or a 2,5-dioxo- pyrrolidin-l-yl group or together with X represents a l,3-dioxo-l,3-dihydro-isoindol-2-yl group, a 5,7-dioxo-2,3,5,7-tetrahydro-[l,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]-piperazinyl group;
  • R5 may represent hydrogen or represents a substitutent of the W or X-W moiety and is selected from Ci-C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, halogen, Ci-C 6 -alkylcarbonyloxy, or nitro;
  • k may be 0 or 1 ;
  • 1 may be a number selected from 0, 1 or 2;
  • n may be a number selected from 1 or 2;
  • n may be a number selected from 1, 2 or 3;
  • p may be 0
  • r may be a number selected from 0 or 1 ;
  • s may be a number selected from 2, 3 or 4;
  • t may be 0;
  • u may be 0
  • the disclosed compound may have one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:
  • VI 1-003 is toxic to human retinal pigmented epithelial cell lines (i.e. ARPE-19) at the dosage of 0.5 ⁇ , 1 uM, 1.5 ⁇ and 2 ⁇ as shown by MTS assay.
  • ARPE-19 retinal pigmented epithelial cell lines
  • the compound may not be
  • the term "visual impairment” refers to a condition where less than optimal signaling between the eyes and visual cortex occurs in a subject.
  • Visual impairment in the context of the present disclosure, may be caused by defects in angiogenesis that could be due to an underlying chronic disease or due to other acute disease that are not related to the eyes and/or visual cortex.
  • the visual impairment may be a retina and/or choroid angiogenic disease.
  • the retina and/or choroid angiogenic disease may include, but is not limited to, age-related macular degeneration (AMD) (including, but not limited to, Asian subtype AMD), diabetic retinopathy (DR), glaucoma, polypoidal choroidal vasculopathy (PCV), retinopathy of prematurity (ROP), and the like.
  • AMD age-related macular degeneration
  • DR diabetic retinopathy
  • PCV polypoidal choroidal vasculopathy
  • ROP retinopathy of prematurity
  • the compound of the present disclosure may be administered to the subject in a dosage of about 0.1 ⁇ / ⁇ 1 to about lOOmg/ml, about 0.5 ⁇ / ⁇ 1 to about 50mg/ml, or about 0.6 ⁇ / ⁇ 1 to about lOmg/ml, or about 0.7 ⁇ , or about 0.8 ⁇ / ⁇ 1, or about 0.9 ⁇ , or about 1 ⁇ / ⁇ 1, or about 1.1 ⁇ / ⁇ 1, or about 1.2 ⁇ / ⁇ , or about 1.3 ⁇ / ⁇ 1, or about 1.4 ⁇ / ⁇ 1, or about 1.5 ⁇ / ⁇ 1, or about 1.6 ⁇ / ⁇ 1, or about 1.7 ⁇ / ⁇ , or about 1.8 ⁇ / ⁇ 1, or about 1.9 ⁇ / ⁇ 1, or about 2 ⁇ / ⁇ , or about 2 ⁇ ⁇ , or about 2.2 ⁇ / ⁇ , or about 2.3 ⁇ / ⁇ , or about 2.4 ⁇ / ⁇ , or about 2.5 ⁇ / ⁇ , or about 0.5mg/ml, or about 0.6mg/ml, or about
  • about 0.05mg/0.05ml or about 2 mg/ml (i.e. about 0.10 mg/0.05ml), or about 3 mg/ml (i.e. about 0.15mg/0.05ml), or about 4 mg/ml (i.e. about 0.2 mg/0.05ml), or about 5 mg/ml (i.e. about 0.25mg/0.05ml), or about 6 mg/ml (i.e. about 0.30mg/0.05ml), or about 7 mg/ml (i.e. about 0.35mg/0.05ml), or about 8 mg/ml (i.e. about 0.4mg/0.05ml), or about 9 mg/ml (i.e.
  • about 0.45mg/0.05ml or about 10 mg/ml (i.e. about 0.50 mg/0.05ml), or about 15 mg/ml (i.e. about 0.75mg/0.05ml), or about 20 mg/ml (i.e. about lmg/0.05ml), or about 25 mg/ml (i.e. about 1.25mg/0.05ml), or about 30 mg/ml (i.e. about 1.50mg/0.05ml), or about 35 mg/ml (i.e. about 1.75mg/0.05ml), or about 40 mg/ml (i.e. about 2.00mg/0.05ml), or about 45 mg/ml (i.e. about 2.25mg/0.05ml), or about 50 mg/ml (i.e. about 2.50mg/0.05ml).
  • the compound may be administered weekly, or every two weeks, or every 2-3 weeks, or every 2-4 weeks, or every 3-6 weeks, or every 4-6 weeks, or every 5-7 weeks, or monthly, or yearly, or twice yearly.
  • the compound of the present disclosure may be provided in a targeted approach where an effective amount of the compound is to be provided directly to the diseased eye of the subject.
  • the administering of the compound of the present disclosure may be routes that are suitable for treating eye diseases, such as, but not limited to, via intravitreal route, topical (such as eye drop), sub-conjunctival route, and the like.
  • the compound of the present disclosure may be further used in conjunction with one another.
  • more than one of the compound as described herein may be administered to the subject.
  • the method of treatment as disclosed herein comprises administering one or more compounds as described herein.
  • the method further comprises administering one or more inhibitor for reducing vessel growth and permeability.
  • the inhibitor as described herein may be an anti- angiogenic inhibitor.
  • the inhibitor may be an agent that blocks VEGF (vascular endothelial growth factor) activity.
  • the inhibitor may be an anti- VEGF antibody.
  • the inhibitor may be Bevacizumab (CAS Registry Number: 216974-75-3).
  • the inhibitor may include, but is not limited to, Sorafenib (IUPAC name: 4-[4-[[4-chloro-3-
  • the present invention provides the use of a therapeutically effective amount of a compound of general formula (I) and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts
  • R 1 represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH 2 , -CO-O-alkyl or -CO-alkyl;
  • R 2 , R 3 and R 4 independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, - COOH, -CONH 2 , haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR 6 wherein R 6 represents alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO- heterocyclyl
  • R can also represent hydrogen
  • Q represents a heterocyclyl group
  • W represents optionally substituted aromatic or non-aromatic heterocyclyl group or an substituted aryl group
  • X represents no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;
  • Y represents an optional substituent of the -(CH 2 ) r - chain and R 5 represents an optional substituent of the W or X-W moiety and Y and R 5 are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH 2 , alkoxycarbonyl, haloalkyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, thioalkoxy, alkenyloxy, haloalkoxy, haloalkenyloxy, nitro, amino, nitroalkyl, nitroalkenyl, nitroalkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, alkylaminoalkyl, dialky
  • k is a number selected from 0 or 1 ;
  • R 5 is the number of R 5 substituents independently selected and is itself a number selected from 0, 1, 2, 3, 4 or 5;
  • n is a number selected from 1, 2, 3, 4, 5 or 6;
  • n is a number selected from 0, 1, 2, 3, 4, 5 or 6;
  • p is a number selected from 0 or 1 ;
  • t is a number selected from 0 or 1 ;
  • u is a number selected from 0 or 1.
  • the term "about" in the context of concentration of a substance, size of a substance, length of time, or other stated values means +/- 5% of the stated value, or +/- 4% of the stated value, or +/- 3% of the stated value, or +/- 2% of the stated value, or +/- 1% of the stated value, or +/- 0.5% of the stated value.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosed ranges. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • CNV Laser induced choridal neo-vascularization
  • VI 1-008 and VI 1-010 was injected via intravitreal (IVT) route, single injection of ⁇ volume at ⁇ g.
  • Laser induced CNV 4 laser photocoagulation sites were placed concentrically around the optic disc of both eyes to induce CNVs.
  • a diode laser (810 nm) was used with a relative potency scale of 100 mW for mice, an exposure time of 0.05 second, and a spot size of 50 ⁇ . Laser spots were focused with crystal covers to avoid laser beam dispersion. Bubble formation was confirmed the rupture of Bruch's membrane.
  • FFA fundus photography and fundus fluorescein angiography
  • Eyes were enucleated from P3 C56/BL6 mice and kept in ice-cold medium before dissection. After removing the cornea and the lens from the anterior of the eye, the central or peripheral choroid- scleral complex was separated from the retina and cut into approximately 1 mm xl mm. Choroid fragments were then embedded in growth factor-reduced MatrigelTM (BD Biosciences, Cat. 354230) seeded in 48 well plates. Plates were incubated in a 37°C cell culture incubator without medium for 10 minutes in order for the MatrigelTM to solidify. 250 ⁇ ⁇ of drug containing medium was then added to each well and incubated at 37°C with 5% C02 for 3-5 days.
  • MatrigelTM growth factor-reduced MatrigelTM
  • Phase contrast photos of individual explants were taken daily using a ZEISS Axio Oberver.Zl microscope. Vessel outgrowth was labelled by NG2 or CD31. The areas of sprouting were quantified with ImageJ. 6-8 choroid explants were used for each treatment and each experiment was repeated 3 times.
  • Metatarsal bones were isolated from E16.5-18.5 mouse embryos (C57/BL6) and seeded on gelatin coated 24 well cell culture plate. 500 ⁇ of medium was then added to each well and incubated at 37°C with 5% C02 for 2 days before treatment. After 7-10 days of culture, metatarsals were fixed in 4% paraformaldehyde and vessel outgrowths were labelled by CD31 antibody. Fluorescent images were taken by epifluorescent microscope and analyzed by TRI2 software. 8-10 metatarsals were used for each treatment and each experiment was repeated 3 times.
  • ARPE19 cells i.e. human retinal pigmented epithelial cell lines
  • MTS (3-(4,5-dimethylthiazol-2-yl)-5-
  • V3-030 fc-Bosutinib (also known as phthalimide -protected Bosutinib)
  • exemplary compounds of the present disclosure i.e. VI 1-003, VI 1-008 and VI 1-010) selectively inhibit choroid angiogenesis at the dosage of ⁇ ( Figure 1), but not the metatarsal angiogenesis assay ( Figure 2).
  • cell viability MTS assay showed that VI 1-003 is toxic to ARPE19 cells at all tested dosages ( Figure 3). This indicates that the small molecule inhibitors as described herein, for example VI 1-008 and VI 1-010, are specific for retinal angiogenesis indication and they were subsequently tested in mouse model of Laser induced CNV.
  • VI 1-008 and VI 1-010 fared similarly to clinically acceptable anti-VEGF to attenuate the retinal angiogenesis.
  • VI 1-010 shows efficacy similar to anti-VEGF.
  • the compounds as disclosed herein may be useful to anti-VEGF non-responders. With favorable pharmacokinetic, it can be an alternative to the current frequent IVT delivery of anti-VEGF.

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Abstract

La présente invention concerne l'utilisation de composés hétérocycliques de formule (I) dans le traitement de maladies oculaires telles qu'une maladie rétinienne et/ou une maladie angiogénique choroïde choisie dans le groupe constitué par la dégénérescence maculaire liée à l'âge (DMLA), la rétinopathie diabétique (RD), le glaucome, la vasculopathie choroïdienne polypoïdale (VCP) et la rétinopathie de prématurité (RP).
PCT/SG2017/050598 2016-12-05 2017-12-05 Application d'un inhibiteur multikinase WO2018106184A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187247A1 (en) * 2004-02-20 2005-08-25 Wyeth 3-Quinolinecarbonitrile protein kinase inhibitors
WO2017135901A1 (fr) * 2016-02-05 2017-08-10 Agency For Science, Technology And Research Composés hétérocycliques, leurs méthodes de synthèse et leurs utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187247A1 (en) * 2004-02-20 2005-08-25 Wyeth 3-Quinolinecarbonitrile protein kinase inhibitors
WO2017135901A1 (fr) * 2016-02-05 2017-08-10 Agency For Science, Technology And Research Composés hétérocycliques, leurs méthodes de synthèse et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BULLARD, L. E. ET AL.: "Role for Extracellular Signal-Responsive Kinase-1 and -2 in Retinal Angiogenesi s", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 44, no. 4, 30 April 2003 (2003-04-30), pages 1722 - 1731, [retrieved on 20180205] *

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