WO2018106184A1

WO2018106184A1 - Application of multi-kinase inhibitor

Info

Publication number: WO2018106184A1
Application number: PCT/SG2017/050598
Authority: WO
Inventors: Boon Tin Chua; Barathi VELUCHAMY AMUTHA; Xiaomeng Wang
Original assignee: Agency For Science, Technology And Research; Singapore Health Services Pte Ltd
Priority date: 2016-12-05
Filing date: 2017-12-05
Publication date: 2018-06-14

Abstract

Disclosed is the use of heterocylic compounds of Formula (I) in the treatment of eye diseases, such as a retinal and/or choroid angiogenic disease selected from the group consisting of age-related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, polypoidal choroidal vasculopathy (PCV), and retinopathy of prematurity (ROP).

Description

APPLICATION OF MULTI-KINASE INHIBITOR

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of Singapore patent application No. 10201610203Q, filed on 5 December 2016, the contents of it being hereby incorporated by reference in its entirety for all purposes.

FIELD OF THE INVENTION

[0002] The present invention generally relates to the use of heterocylic compounds in the treatment of eye diseases.

BACKGROUND OF THE INVENTION

[0003] Age-related macular degeneration (AMD) 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.

[0004] AMD is commonly classified as dry AMD or wet AMD. In 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). As the disease progresses to late stages, central vision is deprived, either a result of tremendous RPE atrophy or proliferation of new vessels. Vascular endothelial growth factor (VEGF) generated from RPE cells is known to be a major factor driving new vessel proliferation.

[0005] The current standard of care for wet AMD is vascular endothelial growth factor (VEGF) antibodies administered through intravitreal route (administered through the sclera right into the vitreous cavity) to block VEGF activity, which underlies the CNV. Although this therapy improves visual acuity in a substantial proportion of patients, half of the eyes experience persistent CNV leakage, fibrotic scarring and/or geographic atrophy. Most patients do not achieve substantial visual improvement and a third of treated eyes progress to legal blindness. Further, frequent intravitreal injections represent a significant financial burden and entail risks that include bleeding, infection, traumatic injury, and retinal detachment.

[0006] Though these anti-angiogenic therapies are successful in reducing vessel growth and permeability, they do not address the underlying pathogenesis. Therefore, there is a need to provide an alternative anti-angiogenic therapy.

SUMMARY OF THE INVENTION

[0007] In one aspect, there is provided a method of treating visual impairment in a subject in need thereof, wherein the method 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

Y

(I)

wherein

R¹ represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH₂, -CO-O-alkyl or -CO-alkyl;

R 2 , R 3 and R 4 independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ represents alkyl-CO-O-alkyl, alkyl- CO-cycloalkyl or alkyl-CO-heterocyclyl

and 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 -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH₂, 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, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), - C(0)N(alkyl)₂ or -CH₂N(alkyl)₂;

k is a number selected from 0 or 1 ;

1 is the number of R⁵ 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;

m 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 ; and

u is a number selected from 0 or 1.

In one embodiment, wherein in formula (I),

R¹ represents hydrogen, cyano, Ci-C₄-alkylamino, Ci-C₄-alkoxy, -COOH, -CO-NH₂,

-CO-0-Ci-C₄-alkyl or -CO-Ci-C₄-alkyl ;

2 3 4

R , R and R independently of each other represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Ci- C₆-alkylcarbonyl, halogen, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆- alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano, or - NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-Ci-C₈-alkyl, d-C₄-alkyl-CO-C₃-C₈- cycloalkyl or Ci-C₄-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 -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, Ci-C₄-alkyl-thio-Ci-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH₂, Ci- C₆-alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, Ci-C₄-alkoxy-Ci-C₄-alkyl, thio-Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂- C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, Ci- C₄-alkylamino-Ci-C₄-alkyl, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Q- C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-Ci-C₄-alkyl, five to six ring membered optionally benzofused heterocyclyloxy, five to six ring membered optionally benzofused heterocyclylamino, five to six ring membered optionally benzofused haloheterocycloalkyl, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Q- C₆-alkylthio, Ci-C₆-acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl, Ci-C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused Ci-C₆-alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆-alkyl), -C(0)N(Ci-C₆-alkyl)₂ or -CH₂N(Ci-C₆-alkyl)₂.

[0009] In another embodiment, wherein in formula (I), t and p are both 0. In yet another embodiment, wherein in formula (I), m and s are both 0 or 1 and n and r are each selected from 3, 4, 5, and 6. In yet another embodiment, wherein in formula (I), Y is absent. In yet another embodiment, wherein in formula (I), u is 0. In yet another embodiment, wherein in formula (I),

Ri represents hydrogen, cyano, -CH₂-NH₂, -CH₂OH, -COOH, -CO-NH₂, -CO-O-CH₃ or -CO-CH₃;

R₂, R₃ and R4 independently of each other represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Q- Ce-alkylcarbonol, halo, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano or -NHR⁶ wherein R⁶ represents -CH₂-CO-0-Ci-C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂- 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 C₃ to C₆ -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 -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, Ci-C₄-alkyl-thio-Ci-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-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, -CONH₂, Ci-C₆- alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, Ci- C₄-alkyl-oxy-Ci-C₄-alkyl, thio-Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂- C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆- alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆- alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-Ci- C₄-alkyl- and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloxy and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloamino and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused haloheterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci-C₆-alkylthio, Ci-C₆-acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused Ci-C₆-alkylheteroaryl and 1 to 3 hetero atoms selected from N, O, or S, cyano, cyanate, isocyanate, - C(0)NH(Ci-C₆-alkyl), and -C(0)N(Ci-C₆-alkyl)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;

m 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 ; and

u is a number selected from 0 or 1.

In yet another embodiment, wherein in formula (I),

Ri represents hydrogen or a cyano group;

R₂, R₃ and R₄ independently of each other represent Ci-C₆-alkyl, halo, -COOH, halo- Ci-C₆-alkyl, Ci-C₆-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 C₃ or C₄ 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-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, halo, -COOH, -CONH₂, Ci-C₆- alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, thio- Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-d-Ce-alkenyl, nitro-d-Ce-alkynyl, , Ci-C₆- alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆- acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆- acyloxy, Ci-C₆-alkylsulfonyloxy, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Q-

C₆-alkylthio, Ci-C₆-acylthio, nitro , cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆- alkyl), and -C(0)N(Ci-C₆-alkyl)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, or 3;

m 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 ; and

u is a number selected from 0 or 1.

[0012] In yet another embodiment, wherein in formula (I), t, r und u are 0, k is 0 or 1 and s is 3, 4 or 5.

[0013] In yet another embodiment, wherein in formula (I),

Ri represents hydrogen or a cyano group;

R₂, R3 and R₄ independently of each other represent halo, or Ci-C₆-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; X represents no further substituent or represents a moiety that is benzofused to the pyrrolyl group or represents a bridge selected from -O-CH₂-CH₂-O-, -S-CH₂-CH₂-S-, -CH₂-CH=CH-CH₂-, -CH=NH-CH₂-CH₂-, -NH=CH-CH₂-CH₂- -CH=CH-S- or -CO- NH-CO-;

R5 represents a substitutent of the W or X-W moiety and is selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, halo, -COOH, -CONH₂, Q-Q,- alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, thio- Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆- alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆- acyl, C2-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆- acyloxy, Ci-C₆-alkylsulfonyloxy, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Q- C₆-alkylthio, Ci-C₆-acylthio, cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆-alkyl), and -C(0)N(C₁-C₆-alkyl)₂;

k is 0 or 1 ;

1 is a number selected from 0, 1 or 2;

n is a number selected from 1 or 2;

m is a number selected from 0, 1, 2, or 3;

p is 0;

r is a number selected from 0 or 1 ;

s is a number selected from 2, 3 or 4;

t is 0; and

u is 0.

In yet another embodiment, wherein in formula (I),

Ri represents hydrogen or cyano;

R₂ represents methoxy;

R₃ 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-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, Ci-C₆- 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;

m is a number selected from 1, 2 or 3;

p is 0;

r is a number selected from 0 or 1 ; s is a number selected from 2, 3 or 4;

t is 0; and

u is 0

and Y is absent.

[0015] In yet another embodiment, wherein the compound has one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:

and

[0016] In yet another embodiment, wherein the compound has one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:

and

In yet another embodiment, wherein the visual impairment is a retina and/or choroid angiogenic disease. In yet another embodiment, wherein 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). In yet another embodiment, wherein the subject has previously received anti-VEGF(vascular endothelial growth factor) antibody treatment. In yet another embodiment, wherein the subject is responsive and/or not responsive to the anti- VEGF antibody treatment. In yet another embodiment, wherein the administering is via intravitreal route, topical, and sub-conjunctival route. In yet another embodiment, wherein the method further comprises administering one or more compound as described herein. In yet another embodiment, the method further comprises administering one or more inhibitor that is not described above for reducing vessel growth and permeability. In yet another embodiment, wherein the inhibitor is an anti-angiogenic inhibitor. In yet another embodiment, wherein the inhibitor is an agent that blocks VEGF activity. In yet another embodiment, wherein the inhibitor is an anti-VEGF antibody. In yet another embodiment, wherein the inhibitor is Bevacizumab. In yet another embodiment, wherein the inhibitor is selected from the group consisting of Sorafenib, Sunitinib, and Vatalanib. In yet another embodiment, wherein the compound is not

[0017] In yet another aspect, the present invention provides the use of a compound of general formula (I) and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts

Y

(I)

in the manufacture of a medicament for treating visual impairment in a subject in need thereof,

wherein

and 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;

Y represents an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH₂, 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, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), - C(0)N(alkyl)₂ or -CH₂N(alkyl)₂;

k is a number selected from 0 or 1 ;

n is a number selected from 1, 2, 3, 4, 5 or 6;

m 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 ; and

u is a number selected from 0 or 1.

BRIEF DESCRIPTION OF THE DRAWINGS [0018] The invention will be better understood with reference to the detailed description when considered in conjunction with the non-limiting examples and the accompanying drawings, in which:

[0019] 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 μιη.

[0020] Figure 2 shows representative pictures and quantifications of vessel outgrowth from metatarsal explants upon 1 μΜ 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.

[0021] Figure 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.

[0022] Figure 4 shows photographical images of fundus photography and fundus fluorescein angiography (FFA) and posterior-segment Optical Coherence Tomography (PS-

OCT) of single dose VI 1-008, VI 1-010, anti-VEGF, and vehicle (control) in laser-induced mice choroidal neovascularization (CNV) model via intravitreal (IVT) route after 28 day.

Figure 4 shows VI 1-010 and anti-VEGF significantly attenuate retinal angiogenesis after 2 weeks and 4 weeks post injection.

[0023] Figure 5 shows quantification of leakage area in CNV mice after single dose VI 1-

008, VI 1-010, or anti-VEGF treatment. CNV mice were administered with single dose of VI 1-008, VI 1-010, or anti-VEGF treatment via IVT route. Figure 5 shows VI 1-010 provides anti-angiogenic effect that is as good as anti-VEGF via single IVT route.

DEFINITION

[0024] In this specification a number of terms are used which are well known to a skilled addressee. Nevertheless for the purposes of clarity a number of terms will be defined. The following words and terms used herein shall have the meaning indicated:

[0025] In the definitions of a number of substituents below it is stated that "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. Using the term alkyl as an example, some publications would use the term "alkylene" for a bridging group and hence in these other publications there is a distinction between the terms "alkyl" (terminal group) and "alkylene" (bridging group). In the present application no such distinction is made and most groups may be either a bridging group or a terminal group.

[0026] "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. Exemplary 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.

[0027] "Alkenoyl" refers to a -C(=0)-alkenyl group in which alkenyl is as defined herein. The group may be a terminal group or a bridging group.

[0028] "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.

[0029] "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.

[0030] "Alkyl" as a group or part of a group refers to a straight, linear or branched aliphatic hydrocarbon group, preferably a C₁-C₂₀ 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 C₁-C₁₆ alkyl, even more preferably a C₁-C₁₂ alkyl, most preferably C₁-C6 unless otherwise noted. Examples of suitable straight and branched C₁-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.

[0031] "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.

[0032] "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.

[0033] "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.

[0034] "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 .

[0035] "Acyl" refers to groups of the form RC(=0) wherein R is selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl groups, optionally substituted heteroaryl groups, optionally substituted cycloalkyl groups, optionally substituted heterocyclyl groups, or optionally substituted heteroalkenyl groups, wherein C may refer to a carbon atom belonging to the R group when R is an optionally substituted aryl group, optionally substituted heteroaryl group, optionally substituted cycloalkyl group, optionally substituted heterocyclyl group, or optionally substituted heteroalkenyl group.

[0036] "Amino" refers to groups of the form -NR_aR_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.

[0037] "Acylamino" refers to groups of the form RC(=0)-amino— in which amino is as defined herein. "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.

[0038] "Acyloxy" refers to the groups of the form RC(=0)-0- wherein R is selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.

[0039] "Acylthio" refers to the groups of the form R-C(=0)-S- wherein R is selected from the group including but not limited to hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and optionally substituted aryl groups.

[0040] "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, -NHCH₃, -NHCH₂CH₃ and -NH(CH₂)₂CH₃. "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(CH₃)₂, -N(CH₃)(CH₂CH₃) and -N(CH₂CH₃)₂.

[0041] "Alkylcarbonyl" refers to an alkyl-C(=0)- 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, acetyl, propionyl, butyryl and isobutyryl.

[0042] "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. [0043] "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.

[0044] "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.

[0045] "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. Examples of 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. Typically an aryl group is a C6-Ci₈ aryl group.

[0046] "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.

[0047] "Carbonyl" refers to a -C(=0)- group.

[0048] "Alkoxycarbonyl" refers to groups of the form alkoxy-C(=0)- wherein the alkoxy group is as defined herein. Exemplary structures include, but are not limited to, methoxycarbonyl and ethoxycarbonyl.

[0049] "Oxo" as a substituent refers to a double-bonded oxygen group of the formula =O. When "oxo" refers to a substituent, it is understood that the oxygen atom is double- bonded to the molecule of interest. For instance, when R⁵ is an oxo group, the oxygen atom is attached to the W or X-W moiety via a double bond.

[0050] "Halogen" refers to chlorine, fluorine, bromine or iodine.

[0051] "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_nH_(2n+i__m)X_m wherein each X is independently selected from the group consisting of F, CI, Br and I . In groups of this type 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. Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl. [0052] "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 .

[0053] "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.

[0054] "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.

[0055] "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.

[0056] "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. The term "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.

[0057] "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-CH₃, -S-CH₂CH₃ and -S- (CH₂)₂CH₃.

[0058] "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.

[0059] "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.

[0060] "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.

[0061] "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. Examples of heterocyclic moieties include heterocycloalkyl, heterocycloalkenyl and heteroaryl.

[0062] "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. Examples of suitable 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.

[0063] "Heterocyclyloxy" refers to -O-heterocyclyl group in which the heterocyclyl group is as defined herein.

[0064] "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.

[0065] "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. Examples of heteroaryl 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, phenoxazine, 2-, 3- or 4- pyridyl, 2-, 3-, 4-, 5-, or 8- quinolyl, 1-, 3-, 4-, or 5- isoquinolinyl 1-, 2-, or 3- indolyl, and 2-, or 3 thienyl. A heteroaryl group is typically a Ci-Cig heteroaryl group (e.g. Q, C₂, C₃, C₄, C5, C , C₇, C₈, C₉, Cio, C₁₁, Ci₂, Ci₃, Ci₄, C₁₅, C₁₆, Ci₇, 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.

[0066] "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.

[0067] "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.

[0068] "Nitro" when used herein to describe a chemical structure refers to one containing -N0₂. Examples of nitro moiety include nitroalkyl, nitroalkenyl and nitroalkynyl. "Nitroalkyl" means N0₂-alkyl- in which the alkyl group is as defined herein. "Nitroalkenyl" means N0₂-alkenyl- in which the alkenyl group is as defined herein. "Nitroalkynyl" means N0₂-alkynyl- in which the alkynyl group is as defined herein.

[0069] "Cyano" or "cyanide" when used herein to describe a chemical structure refers to one containing -C≡N group. "Isocyanate" when used herein to describe a chemical structure refers to one containing -N=C=0 group.

[0070] "Phosphono" when used herein to describe a chemical structure refers to one containing -P0₃H₂.

[0071] "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.

[0072] 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.

[0073] It is understood that included in the family of compounds of Formula (I) are isomeric forms including diastereoisomers, enantiomers, tautomers, and geometrical isomers in "E" or "Z" configurational isomer or a mixture of E and Z isomers. It is also understood that some isomeric forms such as diastereomers, enantiomers, and geometrical isomers can be separated by physical and/or chemical methods and by those skilled in the art.

[0074] 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.

[0075] Additionally, Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.

[0076] Further, it is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, 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.

[0077] The term "optionally substituted" as used herein 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, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroheterocyclyl, alkylamino, dialkylamino, alkenylamine, aminoalkyl, alkynylamino, acyl, alkyloxy, alkyloxyalkyl, alkyloxyaryl, alkyloxycarbonyl, alkyloxycycloalkyl, alkyloxyheteroaryl, alkyloxyheterocycloalkyl, alkenoyl, alkynoyl, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, heterocyclyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkenyl, heterocycloalkylheteroalkyl, heterocycloalkyloxy, heterocycloalkenyloxy, heterocycloxy, heterocycloamino, haloheterocycloalkyl, alkylsulfinyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, aminosulfonyl, phosphorus- containing groups such as phosphono and phosphinyl, sulfinyl, sulfinylamino, sulfonyl, sulfonylamino, aryl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroalkyl, heteroarylamino, heteroaryloxy, arylalkenyl, arylalkyl, alkylaryl, alkylheteroaryl, aryloxy, arylsulfonyl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), and -C(0)N(alkyl)₂.

[0078] 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"), is the group that is directly connected to the core. Thus, 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.

[0079] Any carbon or heteroatom with unsatisfied valences in the text, schemes, examples, and structural formulae herein is assumed to have the hydrogen atom or atoms to satisfy the valences.

[0080] The term "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. In the case of agents that are solids, it is understood by those skilled in the art that the 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.

[0081] The term "pharmaceutically acceptable excipient" refers to a excipient that is generally safe, non-toxic that may be useful in the preparation of a pharmaceutical composition.

[0082] The word "subject" when used herein refers to a human or an animal.

[0083] The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.

[0084] Unless specified otherwise, the terms "comprising" and "comprise", and grammatical variants thereof, are intended to represent "open" or "inclusive" language such that they include recited elements but also permit inclusion of additional, unrecited elements.

[0085] As used herein, 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.

[0086] Throughout this disclosure, certain embodiments 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.

[0087] Certain embodiments may also be described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the embodiments with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0088] At the back of the eye is a layer of tissue that responses to light and creates visual images. This layer of tissue is known as the retina with macula tissue sitting in the middle which is responsible for sharp and central vision. Retina angiogenic diseases (RAD) are diseases resulting from abnormal vascularisation of the retina tissue. 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).

[0089] The inventors of the present disclosure discovered the disclosed small molecule inhibitor. Kinase profiling showed that this set of compounds inhibits multiple kinases including Abelson murine leukemia viral oncogene (Abl), Src (SRC proto-oncogene, nonreceptor tyrosine kinase) and Epidermal Growth Factor Receptor (EGFR).

[0090] 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 ΙμΜ (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 Ιμΐ 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). Thus, the inventors found that even at a single administration, the compounds as disclosed herein could treat visual impairment. Accordingly, the inventors of the present disclosure found that the compounds as described herein can be used to treat visual impairment. [0091] Thus, in one aspects, there is provided a method of treating visual impairment in a subject in need thereof, wherein the method 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

Y

(I) wherein

R 2 , R 3 and R 4 independently of each other represent alkyl, thioalkyl, alkylcarbonyl, halogen, - COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ represents alkyl-CO-O-alkyl, alkyl-CO-cycloalkyl or alkyl-CO- heterocyclyl

and R can also represent hydrogen;

Q represents a heterocyclyl group;

Y represents an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH₂, 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, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), -C(0)N(alkyl)₂ or -CH₂N(alkyl)₂;

k is a number selected from 0 or 1 ;

n is a number selected from 1, 2, 3, 4, 5 or 6;

m 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 ; and

u is a number selected from 0 or 1.

[0092] R¹ 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. 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; -COOH; -CO-NH₂; -CO-O-alkyl 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 or -CO-alkyl comprising 1 to 20 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms) 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. R¹ may be hydrogen or a cyano group. R¹ may represent hydrogen, cyano, Ci-C₄- alkylamino, Ci-C₄-alkoxy, -COOH, -CO-NH₂, -CO-0-Ci-C₄-alkyl or -CO-Ci-C₄-alkyl. Ri may represent hydrogen, cyano, -CH₂-NH₂, -CH₂OH, -COOH, -CO-NH₂, -CO-O-CH₃ or -CO-CH₃. Ri may represent hydrogen or a cyano group.

[0093] R may represent hydrogen, alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ 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. 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. R may represent hydrogen, Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Ci-C₆- alkylcarbonyl, halogen, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-Ci-C₈-alkyl, Ci-C₄-alkyl-CO-C₃-C₈-cycloalkyl or Ci-C₄-alkyl- CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O). R₂ may represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Ci-C₆-alkylcarbonol, halo, -COOH, - CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci- C₆- alkylamino, Ci-C₆-acyl, cyano or -NHR⁶ wherein R⁶ represents -CH₂-CO-0-Ci-C₆-alkyl, -CH₂-CO-C3-C₈-cycloalkyl or -CH₂-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O). R₂ may represent Ci-C₆-alkyl, halo, -COOH, halo- Ci-C₆-alkyl, Ci-C₆-alkoxy, nitro, or cyano. R₂ may represent halo, or Ci-C₆-alkoxy. R₂ may represent methoxy.

[0094] R may represent alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ 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. 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. R may represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Ci-C₆-alkylcarbonyl, halogen, -COOH, - CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci- C₆- alkylamino, Ci-C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-Ci- Cg-alkyl, Ci-C₄-alkyl-CO-C₃-C₈-cycloalkyl or Ci-C₄-alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O). R may represent Ci-C₆- alkyl, thio-Ci-C₆-alkyl, Ci-C₆-alkylcarbonol, halo, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano or -NHR⁶ wherein R⁶ represents -CH₂-CO-0-Ci-C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O). R³ may represent Ci-C₆-alkyl, halo, -COOH, halo-Ci-C₆-alkyl, Ci-C₆- alkoxy, nitro, or cyano. R 3 may represent halo, or Ci-C₆-alkoxy. R 3 may represent methoxy.

[0095] R⁴ may represent alkyl, thioalkyl, alkylcarbonyl, oxo, halogen, -COOH, -CONH₂, haloalkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, dialkylamino, acyl, cyano, or -NHR⁶ wherein R⁶ 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. 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. R⁴ may represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Ci-C₆-alkylcarbonyl, halogen, -COOH, - CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci- C₆- alkylamino, Ci-C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-Ci- C₈-alkyl, Ci-C₄-alkyl-CO-C₃-C₈-cycloalkyl or Ci-C₄-alkyl-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 3 heteroatoms selected from S, N or O). R⁴ may represent Ci-C₆- alkyl, thio-Ci-C₆-alkyl, Ci-C₆-alkylcarbonol, halo, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆- alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano or -NHR⁶ wherein R⁶ represents -CH₂-CO-0-Ci-C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-CO-heterocyclyl (having 5 to 6 ring atoms including 1 to 2 heteroatoms selected from S, N or O). R⁴ may represent Ci-C₆-alkyl, halo, -COOH, halo-Ci-C₆-alkyl, Ci-C₆- alkoxy, nitro, or cyano. R⁴ may represent halo, or Ci-C₆-alkoxy. R⁴ may represent methoxy.

[0096] R², R³ and R⁴ may be the same or different. R³ and R⁴ 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. R³ and R⁴ may be identical halogens selected from chlorine, fluorine, bromine or iodine. R 3 and R 4 may both be chlorine. When R 2 is different, R 2 may be an alkoxy group 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. 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 R³ and R⁴ are each chloro.

[0097] In one embodiment, R 1 may be a cyano group, R2 may be a methoxy group, and R 3 and R 4 may both be chlorine. In another embodiment, R 1 may be hydrogen, R2 may be a methoxy group, and R³ and R⁴ may both be chlorine.

[0098] R₂, R₃ and R₄ may independently of each other represent halo, or Ci-C6-alkoxy.

[0099] 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.

[00100] 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 R⁵ substituent as disclosed herein.

[00101] 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. [00102] 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-

2- yl group, a 5,7-dioxo-2,3,5,7-tetrahydro-[l,4]dithiino[2,3-c]pyrrol-6-yl)-butyryl]- piperazinyl group.

[00103] X may represent no further substituent or may represent a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W.

[00104] 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 R⁵ as defined herein.

[00105] 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

3- to 10- (i.e. 3, 4, 5, 6, 7, 8, 9, or 10) membered, or 4- to 7- membered ring structures. 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 R⁵ substituent as defined herein. The X-W moiety may be an optionally substituted phthalimide, or a phthalimide group substituted with at least one R⁵ substituent as defined herein.

[00106] X may represent no further substituent, or represent a moiety that is benzofused to the heterocyclic ring or represents a C₃ to C₆ -bridge formed by two substituents of W in which 1 to 3 carbon atoms can be replaced by O, N, S or -C(O)-. X may represent no further substituent or may represent a moiety that is benzofused to the pyrrolyl group or represents a bridge selected from -0-CH₂-CH₂-0-, -S-CH₂-CH₂-S-, -CH₂-CH=CH-CH₂-, -CH=NH-CH₂- CH₂-, -NH=CH-CH₂-CH₂- -CH=CH-S- or -CO-NH-CO-.

[00107] In some examples, 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. [00108] 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.

[00109] In an embodiment, u may be 1, X may represent no further substituent, W may be an optionally substituted benzene ring. Advantageously, 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.

[00110] When u is 0, 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. When u is 0, X may be a benzene ring benzofused to W. When u is 0, the X-W moiety may be an optionally substituted phthalimide group. When u is 0, the X-W moiety may be a phthalimide group substituted with at least one R⁵ substituent as defined herein.

[00111] R⁵ may be selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, - CONH₂, 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, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, - C(0)NH(alkyl), -C(0)N(alkyl)₂ or -CH₂N(alkyl)₂.

[00112] R⁵ 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. R⁵ may be selected from fluoride, chlorine, methyl, ethyl, iso-propyl and tert-butyl groups. [00113] 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.

[00114] When k is 1, 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. When k is 1, 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.

[00115] 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.

[00116] 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.

[00117] When s is 2 or 4, r may be 2 or 4.

[00118] 1 represents the number of R⁵ 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. When 1 is greater than 1, the more than one R⁵ substituent may be independently selected to be the same or different. For instance, when 1 is 2, the first R⁵ substituent may be an oxo group and the second R⁵ substituent may be an oxo group or a substituent other than oxo group.

[00119] n may be a number selected from 1, 2, 3, 4, 5 and 6.

[00120] m may be a number selected from 0, 1, 2, 3, 4, 5 and 6.

[00121] 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.

[00122] 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.

[00123] k, m, p, r and t may be 0, s may be 4 and R¹ may be hydrogen. In another embodiment, k, m, p, s and t may be 0, r may be 4 and R¹ may be hydrogen.

[00124] 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 0, r may be 0 or 1, Y may represent no further substituent or Y may be a methyl group, and s may be selected from 0, 1, 2 and 3.

[00125] Y may be an optional substituent of the -(CH₂)_r- chain selected from alkyl, alkenyl, alkynyl, thioalkyl, alkylthioalkyl, cycloalkyl, cycloalkenyl, optionally benzofused heterocycloalkyl, oxo, halogen, -COOH, -CONH₂, 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, acylamino, diacylamino, acyloxy, alkylsulfonyloxy, optionally benzofused heterocyclylalkyl, optionally benzofused heterocyclyloxy, optionally benzofused heterocyclylamino, optionally benzofused haloheterocycloalkyl, alkylsulfenyl, alkylcarbonyloxy, alkylthio, acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl, optionally benzofused heteroaryl, alkylaryl, benzofused alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(alkyl), -C(0)N(alkyl)₂ or -CH₂N(alkyl)₂. In an embodiment, Y may be absent.

[00126] In some examples, the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts is formula (I), wherein

[00127] R¹ may represent hydrogen, cyano, Ci-C₄-alkylamino, Ci-C₄-alkoxy, -COOH, - CO-NH₂, -CO-0-Ci-C₄-alkyl or -CO-Ci-C₄-alkyl ;

2 3 4

[00128] R , R and R independently of each other represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Ci-C₆-alkylcarbonyl, halogen, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, d-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano, or -NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-Ci-C₈-alkyl, Ci-C₄-alkyl-CO-C₃-C₈-cycloalkyl or C C₄- 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;

[00129] 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;

[00130] X may represent no further substituent or represents a moiety that is benzofused, partially saturated benzofused, or heterocyclic fused to W;

[00131] Y may represent of an optional substituent of the -(CH₂)_r- chain and R⁵ may represent an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, Ci-C₄- alkyl-thio-Ci-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH₂, Ci-C₆-alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, Ci-C₄-alkoxy-Ci-C₄-alkyl, thio-Ci-C₆-alkoxy, d-Ce-alkenyloxy, halo-Ci-C₆-alkoxy, halo-d-Ce-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, Ci-C₄-alkylamino-Ci-C₄-alkyl, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆- alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-Ci-C₄-alkyl, five to six ring membered optionally benzofused heterocyclyloxy, five to six ring membered optionally benzofused heterocyclylamino, five to six ring membered optionally benzofused haloheterocycloalkyl, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci-C₆-alkylthio, Ci-C₆- acylthio, phosphorus -containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl, Ci-C₄- alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused Ci-C₆-alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆-alkyl), - C(0)N(Ci-C₆-alkyl)₂ or -CH₂N(Ci-C₆-alkyl)₂.

[00132] In some examples, the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), t and p may both be 0.

[00133] In some examples, wherein the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), m and s may both be 0 or 1 and n and r may each be selected from 3, 4, 5, and 6.

[00134] In some examples, wherein the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), Y may be absent.

[00135] In some examples, wherein the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), u may be 0.

[00136] In some examples, wherein the compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I),

Ri may represent hydrogen, cyano, -CH₂-NH₂, -CH₂OH, -COOH, -CO-NH₂, -CO-O-CH₃ or -CO-CH₃;

R₂, R₃ and R4 independently of each other may represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Q- C₆-alkylcarbonol, halo, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆-alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano or -NHR⁶ wherein R⁶ represents -CH₂-CO-0-Ci-C₆-alkyl, -CH₂-CO-C₃-C₈-cycloalkyl or -CH₂-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 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 C₃ to C₆ -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 -(CH₂)_r- chain and R⁵ may represent an optional substituent of the W or X-W moiety and Y and R⁵ may be independently of another selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, Ci-C₄-alkyl-thio- Ci-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-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, -CONH₂, Ci-C₆-alkoxycarbonyl, halo-Ci-C₆-alkyl, halo- C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, Ci-C₄-alkyl-oxy-Ci-C₄-alkyl, thio-Ci-C₆-alkoxy, C₂- C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylamino, di-Ci- C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂- C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-Ci-C₄-alkyl- and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloxy and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloamino and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused haloheterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci-C₆- alkylthio, Ci-C₆-acylthio, phosphorus -containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused Ci-C₆-alkylheteroaryl and 1 to 3 hetero atoms selected from N, O, or S, cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆- alkyl), and -C(0)N(Ci-C₆-alkyl)₂;

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, 3, or 4;

m 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 ; and

u may be a number selected from 0 or 1.

[00137] In some examples, the compounds of the present disclosure and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), Ri may represent hydrogen or a cyano group;

R₂, R₃ and R4 independently of each other may represent Ci-C₆-alkyl, halo, -COOH, halo-Ci-

C₆-alkyl, Ci-C₆-alkoxy, nitro, or cyano;

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 C₃ or C₄ 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-C₆-alkyl, C₂- Ce-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, halo, -COOH, -CONH₂, Ci-C₆-alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, thio-Ci-C₆-alkoxy, C₂-C₆- alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-

C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆- acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆-alkylsulfonyloxy, Ci-C₆-alkylsulfenyl,

Ci-C₆-alkylcarbonyloxy, Ci-C₆-alkylthio, Ci-C₆-acylthio, nitro , cyano, cyanate, isocyanate, -

C(0)NH(Ci-C₆-alkyl), and -C(0)N(Ci-C₆-alkyl)₂;

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;

m 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 ; and

u may be a number selected from 0 or 1.

[00138] In some examples, wherein the disclosed compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), t, r und u may be 0, k may be 0 or 1 and s may be 3, 4 or 5

[00139] In some examples, wherein the disclosed compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I), Ri may represent hydrogen or a cyano group;

R₂, R₃ and R₄ independently of each other represent halo, or Ci-C₆-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; X may represent no further substituent or represents a moiety that is benzofused to the pyrrolyl group or represents a bridge selected from -0-CH₂-CH₂-0-, -S-CH₂-CH₂-S-, -CH₂- CH=CH-CH₂-, -CH=NH-CH₂-CH₂-, -NH=CH-CH₂-CH₂- -CH=CH-S- or -CO-NH-CO-; R5 may represent a substitutent of the W or X-W moiety and is selected from Ci-C₆-alkyl, C₂- Ce-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, halo, -COOH, -CONH₂, Ci-C₆-alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, thio-Ci-C₆-alkoxy, C₂-C₆- alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro- C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆- acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆-alkylsulfonyloxy, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci-C₆-alkylthio, Ci-C₆-acylthio, cyano, cyanate, isocyanate, - C(0)NH(Ci-C₆-alkyl), and -C(0)N(Ci-C₆-alkyl)₂;

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;

m 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 ;

s may be a number selected from 2, 3 or 4; t may be 0; and

u may be 0.

[00140] In some examples, wherein the disclosed compound and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts wherein in formula (I) Ri may represent hydrogen or cyano;

R₂ may represent methoxy;

R₃ 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-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, Ci-C₆-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;

m 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; and

u may be 0

and Y may be absent.

[00141] In some examples, wherein the disclosed compound may have one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:

[00142] In some examples, wherein the disclosed compound has one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:

[00143] As shown in Figure 3, in vitro, VI 1-003 is toxic to human retinal pigmented epithelial cell lines (i.e. ARPE-19) at the dosage of 0.5 μΜ, 1 uM, 1.5 μΜ and 2 μΜ as shown by MTS assay. Thus, in some examples, the compound may not be

[00144] As used herein, 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. In some examples, the visual impairment may be a retina and/or choroid angiogenic disease. As used herein, 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.

[00145] Current gold standard for treatment of retinal neo-vascularisation is the use of an anti-VEGF antibody known as bevacizumab. It is believed that the compound of the present disclosure may also be used in subject that may have previously received anti-VEGF antibody treatment. Thus, in one example, the subject to be treated in the present disclosure may have previously received anti-VEGF antibody treatment. In some examples, the subject may be responsive and/or not responsive to the anti-VEGF antibody treatment. [00146] It is believed that the exact determination of a suitable dosage to provide effective therapy would be within the skill of a person of the art. In some examples, the compound of the present disclosure may be administered to the subject in a dosage of about 0.1 μ /μ1 to about lOOmg/ml, about 0.5μ /μ1 to about 50mg/ml, or about 0.6μ /μ1 to about lOmg/ml, or about 0.7μ^μ\, or about 0.8μ /μ1, or about 0.9μ^μ\, or about 1 μ /μ1, or about 1.1 μ /μ1, or about 1.2μ§/μΙ, or about 1.3μ /μ1, or about 1.4μ /μ1, or about 1.5μ /μ1, or about 1.6μ /μ1, or about 1.7μ§/μΙ, or about 1.8μ /μ1, or about 1.9μ /μ1, or about 2μ§/μΙ, or about 2Λ μ^μ\, or about 2.2μ§/μΙ, or about 2.3μ§/μΙ, or about 2.4 μ§/μΙ, or about 2.5μ§/μΙ, or about 0.5mg/ml, or about 0.6mg/ml, or about 0.7mg/ml, or about 0.8 mg/ml, or about 0.9 mg/ml, or about 1 mg/ml (i.e. 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).

[00147] Depending on the severity of the disease symptoms or the suitability of the subject, the person skilled in the art would be able to determine a suitable administration frequency of the compound of the present disclosure. Thus, in one example, 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.

[00148] To specifically target diseased eye, it is envisaged that 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. Thus, in one example, 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.

[00149] To provide added treatment to the eye disease, the compound of the present disclosure may be further used in conjunction with one another. For example, more than one of the compound as described herein may be administered to the subject. In some examples, the method of treatment as disclosed herein comprises administering one or more compounds as described herein.

[00150] Alternatively, more than one compound of the present disclosure may be used in conjunction with one or more inhibitor that is not part of the compound as described herein. For example, in some example, the method further comprises administering one or more inhibitor for reducing vessel growth and permeability. As used herein, the inhibitor as described herein may be an anti- angiogenic inhibitor. In some examples, the inhibitor may be an agent that blocks VEGF (vascular endothelial growth factor) activity. In some examples, the inhibitor may be an anti- VEGF antibody. In some examples, the inhibitor may be Bevacizumab (CAS Registry Number: 216974-75-3).

[00151] Alternatively, in some examples, the inhibitor may include, but is not limited to, Sorafenib (IUPAC name: 4-[4-[[4-chloro-3-

(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methyl-pyridine-2-carboxamide (CAS Registry Number: 284461-73-0)), Sunitinib (IUPAC name: N-(2-diethylaminoethyl)-5-[(Z)- (5-fluoro-2-oxo-lH-indol-3-ylidene)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide; CAS Registry Number: 341031-54-7), Vatalanib (IUPAC name: N-(4-chlorophenyl)-4-(pyridin-4- ylmethyl)phthalazin- 1-amine; CAS Registry Number: 212141-54-3), and the like.

[00152] In another aspect, 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

Y

(I)

wherein R¹ represents hydrogen, cyano, alkylamino, alkoxy, -COOH, -CO-NH₂, -CO-O-alkyl or -CO-alkyl;

and R can also represent hydrogen;

Q represents a heterocyclyl group;

k is a number selected from 0 or 1 ;

n is a number selected from 1, 2, 3, 4, 5 or 6;

m 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 ; and

u is a number selected from 0 or 1.

[00153] As used in this application, the singular form "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" includes a plurality of compounds, including mixtures and combinations thereof.

[00154] As used herein, 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.

[00155] Throughout this disclosure, certain embodiments 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.

[00156] The invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention. [00157] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[00158] Other embodiments are within the following claims and non- limiting examples. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

EXPERIMENTAL SECTION

[00159] Material and Methods

[00160] Animal model

[00161] Laser induced choridal neo-vascularization (CNV) in C57/BL6J (B6J) wild type mice.

[00162] Sample size

[00163] Twenty C57BL/6J mice (or also known as B6J mice or C56/BL6 mice) was used in this experimental section.

[00164] Treatment mode

[00165] VI 1-008 and VI 1-010 was injected via intravitreal (IVT) route, single injection of Ιμΐ volume at ^g.

[00166] 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 μιη. Laser spots were focused with crystal covers to avoid laser beam dispersion. Bubble formation was confirmed the rupture of Bruch's membrane.

[00167] Fundus photography and fundus fluorescein angiography (FFA) was imaged using a MICRON IV fundus camera (Phoenix Laboratories USA). For FFA, animals were intraperitoneally injected with 10% sodium fluorescein at a dose of 0.01 ml per 5-6 gm body weight. Retinal structure was monitored real time by posterior-segment OCT (Optical Coherence Tomography). The whole procedure took about 10-15 minutes per animal. At day 28, animals were euthanized by overdose of pentobarbital for blood and tissue collection. [00168 ] Choroidal angiogenesis assay

[00169] 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 Matrigel™ (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 Matrigel™ to solidify. 250 μΐ_^ of drug containing medium was then added to each well and incubated at 37°C with 5% C02 for 3-5 days. 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.

[00170] Metatarsal angiogenesis assay

[00171] Metatarsal bones were isolated from E16.5-18.5 mouse embryos (C57/BL6) and seeded on gelatin coated 24 well cell culture plate. 500 μΐ 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.

[00172] MTS assay

[00173] ARPE19 cells (i.e. human retinal pigmented epithelial cell lines) were treated with different drugs at various concentrations upon seeding. MTS (3-(4,5-dimethylthiazol-2-yl)-5-

(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay was used to evaluate the cell viability over 24 hours after the treatment. Absorbance at 490 nm was recorded at 2 hours after the addition of MTS/PMS reagent

[00174] Exemplary Compounds

[00175] V3-030

V3-030: fc-Bosutinib (also known as phthalimide -protected Bosutinib)

[00177] 2-[4-(4-{ 3-[4-(2,4-Dichloro-5-methoxy-phenylarnino)-6-methoxy-quinolin-7- yloxy] -propyl } -piperazin- 1 -yl)-butyl] -isoindole- 1 ,3 -dione

[00178] (0.062 g, 18%) light yellow solid

[00179] Mw calc: 691.23 m/z 692.3 [M+H]⁺ 690.4 [M-H]^" Rt = 2.70 min (Method A).

[00180] 1H NMR (300 MHz, DMSO-i¾ δ ppm 8.69 (br. s, IH), 8.23 (d, = 4.2 Hz, IH), 7.79-7.91 (ovl. m, 4H), 7.73 (s, IH), 7.69 (s, IH), 7.23 (s, IH), 7.20 (s, IH), 6.18 (d, 7 = 4.2 Hz, IH), 4.13 (t, J = 6.4 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.58 (t, J = 6.9 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 2.32-7.42 (ovl. m, 8H), 2.28 (t, J = 6.6 Hz, 2H), 1.94 (m, 2H), 1.60 (m, 2H), 1.41 (m, 2H)

[00181] Vll-010

[00182] 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-{4-[5-(5-methyl- l,3- dioxo- l,3-dihydro-isoindol-2-yl)-pentanoyl] -piperazin- l-yl}-propoxy)-quinoline-3- carbonitrile

[00183] (0.117 g, 62%) pale yellow solid

[00184] Mw calc: 758.24 m/z 759.5 [M+H]⁺ 757.5 [M-H]^" Rt = 3.27 min (Method A).

[00185] 1H NMR (300 MHz, DMSO-i¾) δ ppm 9.66 (br. s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.74 (d, = 7.5 Hz, 1H), 7.70 (s, 1H), 7.69 (d, = 1.5 Hz, 1H), 7.63 (dd, = 7.5 and 1.5 Hz, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 4.20 (t, = 6.2 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.56 (t, = 6.7 Hz, 2H), 3.37-3.67 (ovl. m, 4H), 2.47 (s, 3H), 2.45 (t, = 7.0 Hz, 2H), 2.27-2.38 (ovl. m, 6H), 1.96 (m, 2H), 1.60 (m, 2H), 1.48 (m, 2H)

[00186] Vll-008

[00187] 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-(3-{4-[4-(5,7-dioxo-2,3,5,7- tetrahydro-[l,4]dithiino[2,3-c]pyrrol-6-yl)-butyl] -piperazin- l-yl}-propoxy)-6-methoxy- quinoline-3-carbonitrile [00188] (0.074 g, 39%) vivid yellow solid

[00189] Mw calc: 756.17 m/z 757.3 [M+H]⁺ 755.3 [M-H]^~ Rt = 2.99 min (Method A).

[00190] 1H NMR (300 MHz, DMSO-i¾ δ ppm 9.61 (br. s, 1H), 8.40 (s, 1H), 7.82 (s, 1H), 7.72 (s, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 4.18 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.41 (t, = 7.0 Hz, 2H), 3.38 (s, 4H), 2.44 (t, = 7.0 Hz, 2H), 2.28-2.43 (ovl. m, 8H), 2.23 (t, J = 6.9 Hz, 2H), 1.95 (m, 2H), 1.50 (m, 2H), 1.35 (m, 2H)

[00191 ] Experimental Result

[00192] The present disclosure showed that the compounds as disclosed herein selectively inhibit choroid angiogenesis. For example, 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 ΙμΜ (Figure 1), but not the metatarsal angiogenesis assay (Figure 2). However, 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.

[00193] In vivo study result showed that VI 1-010 and anti-VEGF significantly attenuate the retinal angiogenesis after 2 weeks and 4 weeks post injection (Figure 4). Quantitative measurements of mean leakage area demonstrated that the anti-angiogenic effect of 1 μg/ul VI 1-010 is comparable to anti-VEGF in mice via single IVT route (Figure 5).

[00194] The present study showed that in single dose testing, both VI 1-008 and VI 1-010 fared similarly to clinically acceptable anti-VEGF to attenuate the retinal angiogenesis. In particular, 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.

[00195] Reference:

[00196] Lopez, P.F., Sippy, B.D., Lambert, H.M., Thach, A.B., Hinton, D.R., 1996. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci 37, 855-868. [00197] Ho, T., Law, N.M., Goh, L.G., Yoong, T., 1997. Eye diseases in the elderly in Singapore. Singapore Med J 38, 149-155.

[00198] See, J.L., Wong, T.Y., Yeo, K.T., 1998. Trends in the pattern of blindness and major ocular diseases in Singapore and Asia. Ann Acad Med Singapore 27, 540-546

[00199] Wong TY, Klein R, Sun C, et al. Age-related macular degeneration and risk for stroke. Ann Intern Med 2006; 145: 98-106.

Claims

1. Method of treating visual impairment in a subject in need thereof, wherein the method 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

Y

(I)

wherein

and R can also represent hydrogen;

Q represents a heterocyclyl group;

k is a number selected from 0 or 1 ;

n is a number selected from 1, 2, 3, 4, 5 or 6;

m 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 ; and

u is a number selected from 0 or 1.

The method of claim 1, wherein in formula (I),

R¹ represents hydrogen, cyano, Ci-C₄-alkylamino, Ci-C₄-alkoxy, -COOH, -CO-NH₂, -CO-0-Ci-C₄-alkyl or -CO-Ci-C₄-alkyl ;

R 2 , R 3 and R 4 independently of each other represent Ci-C₆-alkyl, thio-Ci-C₆-alkyl, Q- C₆-alkylcarbonyl, halogen, -COOH, -CONH₂, halo-Ci-C₆-alkyl, hydroxyl, Ci-C₆- alkoxy, nitro, amino, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, Ci-C₆-acyl, cyano, or - NHR⁶ wherein R⁶ represents Ci-C₄-alkyl-CO-0-Ci-C₈-alkyl, d-C₄-alkyl-CO-C₃-C₈- cycloalkyl or Ci-C₄-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 -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, Ci-C₄-alkyl-thio-Ci-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-cycloalkenyl, five to six membered optionally benzofused heterocycloalkyl, halogen, -COOH, -CONH₂, Ci- C₆-alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, Ci-C₄-alkoxy-Ci-C₄-alkyl, thio-Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂- C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl, Q- C₄-alkylamino-Ci-C₄-alkyl, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆- alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Q- C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆-alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-Ci-C₄-alkyl, five to six ring membered optionally benzofused heterocyclyloxy, five to six ring membered optionally benzofused heterocyclylamino, five to six ring membered optionally benzofused haloheterocycloalkyl, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Q- C₆-alkylthio, Ci-C₆-acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl, Ci-C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused Ci-C₆-alkylheteroaryl, cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆-alkyl), -C(0)N(Ci-C₆-alkyl)₂ or -CH₂N(Ci-C₆-alkyl)₂.

The method of claim 1 or 2, wherein in formula (I), t and p are both 0.

The method of any one the claims 1 to 3, wherein in formula (I), m and s are both 0 or and n and r are each selected from 3, 4, 5, and 6.

The method of any one of the claims 1 to 4, wherein in formula (I), Y is absent.

The method of any one of the claims 1 to 5, wherein in formula (I), u is 0. The method of claim 1, wherein in formula (I),

Q represents a piperidin, tetrahydropyridin or piperazinyl group;

Y represents of an optional substituent of the -(CH₂)_r- chain and R⁵ represents an optional substituent of the W or X-W moiety and Y and R⁵ are independently of another selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, Ci-C₄-alkyl-thio-Ci-C₄-alkyl, C₃-C₈-cycloalkyl, C₃-C₈-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, -CONH₂, Ci-C₆- alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, Q- C₄-alkyl-oxy-Ci-C₄-alkyl, thio-Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂- C₆-alkynyl, five to six ring membered optionally benzofused nitro-heterocyclyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆-acyl, C₂-C₆-alkenoyl, C₂-C₆- alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆-acyloxy, Ci-C₆- alkylsulfonyloxy, five to six ring membered optionally benzofused heterocyclyl-Ci- C₄-alkyl- and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloxy and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused heterocyclyloamino and 1 to 3 hetero atoms selected from N, O, or S, five to six ring membered optionally benzofused haloheterocycloalkyl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci-C₆-alkylthio, Ci-C₆-acylthio, phosphorus-containing groups such as phosphono and phosphinyl, aryl having 6 to 10 carbon atoms, five to six ring membered optionally benzofused heteroaryl and 1 to 3 hetero atoms selected from N, O, or S, Ci-C₄-alkylaryl having 6 or 10 carbon atoms in the aryl, five to six ring membered optionally benzofused Ci-C₆-alkylheteroaryl and 1 to 3 hetero atoms selected from N, O, or S, cyano, cyanate, isocyanate, - C(0)NH(Ci-C₆-alkyl), and -C(0)N(Ci-C₆-alkyl)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;

m 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 ; and

u is a number selected from 0 or 1.

The method of claim 1, wherein in formula (I),

Ri represents hydrogen or a cyano group;

Q represents a piperidin or piperazinyl group;

R5 represents a substitutent of the W or X-W moiety and is selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, halo, -COOH, -CONH₂, Ci-C₆- alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, thio-

Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆- alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆- acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆- acyloxy, Ci-C₆-alkylsulfonyloxy, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci-

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;

m 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 ; and

u is a number selected from 0 or 1.

The method of claims 7 or 8, wherein in formula (I),

t, r und u are 0, k is 0 or 1 and s is 3, 4 or 5.

The method of claim 1, wherein in formula (I),

Ri represents hydrogen or a cyano group;

Q represents a piperidin-, or piperazinyl group;

R5 represents a substitutent of the W or X-W moiety and is selected from Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, thio-Ci-C₆-alkyl, halo, -COOH, -CONH₂, Ci-C₆- alkoxycarbonyl, halo-Ci-C₆-alkyl, halo-C₂-C₆-alkynyl, hydroxyl, Ci-C₆-alkoxy, thio- Ci-C₆-alkoxy, C₂-C₆-alkenyloxy, halo-Ci-C₆-alkoxy, halo-C₂-C₆-alkenyloxy, nitro, amino, nitro-Ci-C₆-alkyl, nitro-C₂-C₆-alkenyl, nitro-C₂-C₆-alkynyl, , Ci-C₆- alkylamino, di-Ci-C₆-alkylamino, C₂-C₆-alkenylamine, C₂-C₆-alkynylamino, Ci-C₆- acyl, C₂-C₆-alkenoyl, C₂-C₆-alkynoyl, Ci-C₆-acylamino, di-Ci-C₆-acylamino, Ci-C₆- acyloxy, Ci-C₆-alkylsulfonyloxy, Ci-C₆-alkylsulfenyl, Ci-C₆-alkylcarbonyloxy, Ci- C₆-alkylthio, Ci-C₆-acylthio, cyano, cyanate, isocyanate, -C(0)NH(Ci-C₆-alkyl), and -C(0)N(Ci-C₆-alkyl)₂;

k is 0 or 1 ;

1 is a number selected from 0, 1 or 2;

n is a number selected from 1 or 2;

m is a number selected from 0, 1, 2, or 3;

p is 0;

r is a number selected from 0 or 1 ;

s is a number selected from 2, 3 or 4;

t is 0; and

u is 0.

11. The method of claim 1, wherein in formula (I),

Ri represents hydrogen or cyano;

R₂ represents methoxy;

R₃ represents chlorine;

R4 represents chlorine;

Q represents a piperazinyl group;

W represents a 2,5-dioxo-2,5-dihydro-dihydro pyrrol- 1-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;

k is 0 or 1 ; 1 is a number selected from 0, 1 or 2;

n is a number selected from 1 or 2;

m is a number selected from 1, 2 or 3;

p is 0;

r is a number selected from 0 or 1;

s is a number selected from 2, 3 or 4;

t is 0; and

u is 0

and Y is absent.

12. The method of claim 1, wherein the compound has one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:

13. The method of claim 1, wherein the compound has one of the following formulas and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts:

14. The method of any one of the preceding claims, wherein the visual impairment is a retina and/or choroid angiogenic disease.

15. The method of claim 14, wherein 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).

16. The method of any one of the preceding claims, wherein the subject has previously received anti-VEGF(vascular endothelial growth factor) antibody treatment.

17. The method of claim 16, wherein the subject is responsive and/or not responsive to the anti-VEGF antibody treatment.

18. The method of any one of the preceding claims, wherein the administering is via intravitreal route, topical, and sub-conjunctival route.

19. The method of any one of the preceding claims, wherein the method further comprises administering one or more compound as stated in the claims 1 to 13. 20. The method of any one of the preceding claims, wherein the method further comprises administering one or more inhibitor that is not stated in the claims 1 to 13 for reducing vessel growth and permeability.

21. The method of claim 20, wherein the inhibitor is an anti- angiogenic inhibitor.

22. The method of claim 19 or 20, wherein the inhibitor is an agent that blocks VEGF activity.

23. The method of any one of the claims 19 to 22, wherein the inhibitor is an anti-VEGF antibody.

24. The method of any one of the claims 19 to 23, wherein the inhibitor is Bevacizumab.

25. The method of any one of the claims 19 to 22, wherein the inhibitor is selected from the group consisting of Sorafenib, Sunitinib, and Vatalanib.

26. The method of any one of the preceding claims, wherein the compound is not

27. Use of a compound of general formula (I) and/or its analogues, solvates, hydrates and pharmaceutically acceptable salts

Y

(I)

wherein

and R can also represent hydrogen;

k is a number selected from 0 or 1 ;

n is a number selected from 1, 2, 3, 4, 5 or 6;

m 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 ; and

u is a number selected from 0 or 1.