WO2021170811A1

WO2021170811A1 - Method of treating eye disease using trpv4 antagonists

Info

Publication number: WO2021170811A1
Application number: PCT/EP2021/054856
Authority: WO
Inventors: David J. BEHM; Allen Oliff
Original assignee: Glaxosmithkline Intellectual Property (No.2) Limited
Priority date: 2020-02-27
Filing date: 2021-02-26
Publication date: 2021-09-02

Abstract

Invented is a method of treating a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome, in a mammal in need thereof which comprises the administration of a therapeutically effective amount of a selected TRPV4 antagonist to such mammal.

Description

METHOD OF TREATING EYE DISEASE USING TRPV4 ANTAGONISTS

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under contract number HHS0100201700009C awarded by Biomedical Advanced Research and Development Authority (BARDA). The Government has certain rights in the invention.

FIELD OF THE INVENTION

This invention relates to a method of treating eye disease in a mammal, suitably a human, by administration of a selective TRPV4 antagonist and of pharmaceutical compositions comprising the same. Suitably, the method relates to methods of treating eye diseases by the administration of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa- 3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Transient receptor potential subfamily vanilloid member 4 (TRPV4) is a cation channel from the transient receptor potential (TRP) superfamily of sensory proteins. TRPV4 is activated by a broad range of stimuli including hypotonicity, temperature, pH, radiation, arachidonic acid metabolites such as 5,6-epoxyeicosatrienoic acid, dimethylallyl pyrophosphate and phorbol derivatives such as 4a-phorbol 12,13-didecanoate (4a-PDD) (White et al., 2016, Physiol. Rev. 9: 911-973). In addition, amongst other mechanisms proposed, PKA and PKC can also regulate TRPV4 (Fan et al., 2009 J. Biol. Chem. 284: 27884-27891).

TRPV4 is expressed in multiple cell types within the eye, including those which constitute the blood-retinal barrier (Phuong et al., 2017, J. Physiol. 595: 6869-6885). TRPV4 could play a pathophysiological role in eye diseases/injuries including but not limited to neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension (Ryskamp et al., 2016, Sci. Rep. 6: 30593-; Arredondo et al., 2017, Sci. Rep. 7:13094; Phuong et al., 2017, J. Physiol. 595: 6869-6885; Matsumoto et al., 2018, J. Neurosci. 38: 8745-8758).

The compounds of Formula (I) are disclosed in International Application No. PCT/US2012/042622, having an International filing date of June 15, 2012; International Publication Number WO 2013/012500 and an International Publication date of January 24, 2013. The compound l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l- oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is disclosed therein as Example 147. International Publication Number WO 2013/012500 does not indicate that the compounds disclosed therein are useful in the treatment of eye disease.

Diabetic Macular Edema (DME) is a common diabetic eye disease caused by an accumulation of fluid in the macula from damaged blood vessels in the retina. Current marketed DME treatment involves monthly anti-vascular endothelial growth factor (anti-VEGF) intraocular injections. Ranibizumab (Lucentis) and aflibercept (Eylea), both anti-VEGF intraocular injections, are approved for monthly dosing in DME. Side effects of these intraocular treatments include conjunctival hemorrhage, increased intraocular pressure (IOP), ocular pain, and vitreous floaters (Lucentis and Eylea USPIs, 2018 and 2019). Further, many patients may have DME in both eyes and intraocular administration is only effective in the injected eye. Non-adherence to monthly injections is high, driven by patient concerns, and this results in worse outcomes for the patients. Intraocular implants also exist as treatments for DME however, there are side effects including cataract, increased IOP, vitreous floaters, and conjunctival hemorrhage (Ozurdex and Illuvien USPIs, 2018 and 2019). There is a need in the art for a more patient friendly DME treatment which may present fewer side effects and drive better patience adherence.

SUMMARY OF THE INVENTION

In a first aspect, the present invention provides a method of treating eye diseases selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in a mammal, in need thereof which comprises administering to such mammal, a therapeutically effective amount of a compound of Formula (I):

wherein:

Ri is hydrogen, Ci-₃alkyl, CH2OH, CH2-O-CH3, CH₂OCH2Ph, CH2CN, CN, halo or C(0)0CH₃;

R2 is independently hydrogen, CN, CF3, halo, SC>2Ci-3alkyl, Ci salkyl or CECH; R3 is hydrogen, Ci-2alkyl, CF3 or OH;

R4 is hydrogen, halo or Ci salkyl;

X is CF or N;

A is (CH₂)n-Het; or A is (CH2)n-(CRaRb)-(CH₂)m-Het;

Ra is hydrogen or Ci salkyl, wherein the Ci salkyl may be further substituted with one or more halos;

Rb is Ci salkyl; or Ra and Rb together with the carbon atom they are attached form a C3-6cycloalkyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci-3alkyl, CH(0H)-Ci-5alkyl, C(CH3)2 - Rs, C(0)N(CH3)p, N(Ci- 3alkyl)_p, NH2, C(0)NH2, oxetane, oxetane-CH3, tetra hydrofury I, tetrahydropyranyl, morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or

OH;

Rs is CN, 0-Ci-4alkyl, (CH₂)m-OH, (CH₂)_P-0-C(0)-0-Ci-5alkyl, or 0-(CH2)_P-0-R₆;

R6 is Ci-4alkyl or P(0)2(CH3)2; n is independently 0, 1 or 2; m is independently 0, 1 or 2; p is independently 1 or 2; and y is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

In a second aspect, the present invention provides a method of treating a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in a human in need thereof, which comprises: administering to such human a therapeutically effective amount of a pharmaceutical combination of: a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and b) at least one further active ingredient.

In a third aspect, the present invention provides a compound of Formula (I), as defined herein, or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome.

In a further aspect the present invention provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome

In a still further aspect, the present invention provides a pharmaceutical composition for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in humans comprising the compound:

or a pharmaceutically acceptably salt thereof.

The present invention may be advantageous in a number of ways. The compounds disclosed in the present invention may be used to treat certain disease states, as disclosed herein. In particular, the compounds disclosed herein may be used to treat DME. Further, compounds of the invention may be used to treat DME and other disease states orally. Oral treatment of DME may be advantageous over the current standard of care as both eyes could be treated simultaneously. Further, patient preference is highly likely to be for oral treatment rather than intraocular injection. This may therefore lead to better patient compliance.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows that TRPV4 blocker compound A attenuates TRPV4 agonist compound B-induced retinal leak in rats. DETAILED DESCRIPTION OF THE INVENTION

This invention relates to methods of treating eye disease, in a mammal, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof as described above. Suitably the mammal is a human. Suitably the compound is l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof. Suitably the compound is l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile. The compound 1- (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is represented by the following structure:

For the avoidance of doubt, the compound shown above may also be drawn as:

Both renditions of the structure are equivalent in meaning and may be used interchangeably. "Alkyl" refers to a monovalent saturated hydrocarbon chain having the specified number of carbon member atoms. For example, C1-4 alkyl refers to an alkyl group having from 1 to 4 carbon member atoms. Alkyl groups may be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes, but is not limited to, methyl, ethyl, propyl, (n-propyl and isopropyl), and butyl (n-butyl, isobutyl, s-butyl, and t-butyl). "Cycloalkyl" refers to a monovalent saturated or unsaturated hydrocarbon ring having the specified number of carbon member atoms. For example, C3-6cycloalkyl refers to a cycloalkyl group having from 3 to 6 carbon member atoms. Unsaturated cycloalkyl groups have one or more carbon-carbon double bonds within the ring. Cycloalkyl groups are not aromatic. Cycloalkyl includes, but is not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

When used herein, the terms 'halogen' and 'halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo, and iodo, respectively.

"Substituted" in reference to a group indicates that one or more hydrogen atoms, suitably from 1 to 5 hydrogen atoms, suitably from 1 to 3 hydrogen atoms, attached to a member atom within the group is replaced with a substituent selected from the group of defined substituents. It should be understood that the term "substituted" includes the implicit provision that such substitution be in accordance with the permitted valence of the substituted atom and the substituent and that the substitution results in a stable compound (i.e. one that does not spontaneously undergo transformation such as by rearrangement, cyclization, or elimination and that is sufficiently robust to survive isolation from a reaction mixture). When it is stated that a group may contain one or more substituents, one or more (as appropriate) member atoms within the group may be substituted. In addition, a single member atom within the group may be substituted with more than one substituent as long as such substitution is in accordance with the permitted valence of the atom. Suitable substituents are defined herein for each substituted or optionally substituted group.

With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers or diastereomeric mixtures. All such isomeric forms are included within the present invention, including mixtures thereof.

As used herein, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The skilled artisan will appreciate that pharmaceutically acceptable salts of the compounds according to Formula (I) may be prepared. These pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compound, or by separately treating the purified compound in its free acid or free base form with a suitable base or acid, respectively.

In certain embodiments, compounds according to Formula (I) may contain an acidic functional group and are, therefore, capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base. Examples of such bases include a) hydroxides, carbonates, and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminium, and zinc; and b) primary, secondary, and tertiary amines including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines such as methylamine, ethylamine, 2- hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.

In certain embodiments, compounds according to Formula (I) may contain a basic functional group and are therefore capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and organic acids. Representative pharmaceutically acceptable acids include hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, sulfonic acid, phosphoric acid, acetic acid, hydroxyacetic acid, phenylacetic acid, propionic acid, butyric acid, valeric acid, maleic acid, acrylic acid, fumaric acid, succinic acid, malic acid, malonic acid, tartaric acid, citric acid, salicylic acid, benzoic acid, tannic acid, formic acid, stearic acid, lactic acid, ascorbic acid, methylsulfonic acid, p-toluenesulfonic acid, oleic acid, lauric acid, and the like.

As used herein, the term "a compound of Formula (I)" or "the compound of Formula (I)" refers to one or more compounds according to Formula (I). The compound of Formula (I) may exist in solid or liquid form. In the solid state, it may exist in crystalline or non-crystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed from crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as, but not limited to, ethanol, isopropanol, dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

The skilled artisan will further appreciate that certain compounds of Formula (I) that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

The compounds according to Formula (I) and pharmaceutically acceptable salts thereof may contain isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶CI, ¹²³I and ¹²⁵I.

Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as ³H, ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. ⁿC and ¹⁸F isotopes are particularly useful in PET (positron emission tomography), and ¹²⁵I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) and pharmaceutically acceptable salts thereof can generally be prepared by carrying out the procedures disclosed in International Publication Number WO 2013/012500, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

Representative Aspects of the Compounds of Formula (I).

In one aspect:

Ri is hydrogen, Ci-₃alkyl, CHzOH, CH2-O-CH3, CHzOCHzPh, CHzCN, CN, halo or C(0)OCH₃;

R2 is independently hydrogen, CN, CF₃, halo, SC>2Ci-₃alkyl, Ci-₃alkyl or CECH;

R ₃ is hydrogen, Ci-2alkyl, CF₃ or OH;

R4 is hydrogen, halo or Ci-₃alkyl;

X is CR4 or N;

A is (CH₂)n-Het; or A is (CH2)n-(CRaRb)-(CH₂)m-Het;

Ra is hydrogen or Ci-₃alkyl, wherein the Ci-₃alkyl may be further substituted with one or more halos;

Rb is Ci-₃alkyl; or Ra and Rb together with the carbon atom they are attached form a C₃-6cycloalkyl group; or one of the carbon atoms in the C₃-6cycloalkyl group formed by Ra and Rb may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C₃-6cycloalkyl group formed by Ra and Rb may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group; Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-₃alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH3)-0-Ci-3alkyl, CH(OH)-Ci-salkyl, C(CH3)2 - Rs, C(0)N(CH3)p, N(Ci- 3alkyl)p, NH2, C(0)NH2, oxetane, oxetane-CH3, tetra hydrofury I, tetrahydropyranyl, morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH;

Rs is CN, 0-Ci-4alkyl, (CH₂)m-OH, (CH₂)p-0-C(0)-0-Ci-5alkyl, or 0-(CH2)_P-0-R₆;

R6 is Ci-4alkyl or P(0)2(CH3)2; n is independently 0, 1 or 2; m is independently 0, 1 or 2; p is independently 1 or 2; and y is 1, 2 or 3.

In another aspect:

Ri is hydrogen, Ci-salkyl, CH2OH, CH2-O-CH3, CH₂OCH2Ph, CH2CN, CN, halo or C(0)0CH₃;

R2 is independently hydrogen, CN, CF3, halo, S02Ci-3alkyl, Ci salkyl or CECH;

R3 is hydrogen, Ci-2alkyl, CF3 or OH;

R4 is hydrogen, halo or Ci salkyl;

X is CR4 or N;

A is (CH₂)n-Het; or A is (CH2)n-(CRaRb)-(CH₂)m-Het;

Ra is hydrogen or Ci salkyl, wherein the Ci salkyl may be further substituted with one or more halos; Rb is Ci salkyl; or Ra and Rb together with the carbon atom they are attached form a C3-6cycloalkyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-₃alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci-3alkyl, C(CH₃)2-OH, C(CH₃)2-0-CH₃, C(CH₃)2-CN, C(CH₃)2- CH2OH, C(CH₃)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH₃)_P, N(Ci-₃alkyl)_P, NH₂, C(0)NH₂, oxetane, oxetane-CH3, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH; n is independently 0, 1 or 2; m is independently 0, 1 or 2; p is independently 1 or 2; and y is 1, 2 or 3.

In another aspect:

Ri is hydrogen, C1-3 alkyl or CH2OH;

R2 1S CN;

R3 is hydrogen;

X is N;

A is (CH₂)n-Het; or A is (CH2)n-(CRaRb)-(CH₂)m-Het;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-₃alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci-3alkyl, C(CH₃)2-OH, C(CH₃)2-0-CH₃, C(CH₃)2-CN, C(CH₃)2- CH2OH, C(CH₃)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH₃)_P, N(Ci-₃alkyl)_P, NHz, C(0)NH₂, oxetane, oxetane-CH3, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, C1-3 alkyl or CF3; and the C1-5 alkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH; n is independently 0 or 1; m is independently 0 or 1; p is independently 1 or 2; and y is 1 or 2.

In yet another aspect:

Ri is hydrogen, Ci salkyl or CH2OH;

R2 1S CN; R3 is hydrogen;

X is N;

A is (CH₂)n-Het; or A is (CH2)n-(CRaRb)-(CH₂)m-Het;

Rb is Ci salkyl; or Ra and Rb together with the carbon atom they are attached form a C3-6 cycloalkyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH₂F, CHF₂, CF3, C3-6cycloalkyl, (CH₂)_n-0-Ci-3alkyl, (CH₂)_n-phenyl, (CH₂)_n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci-3alkyl, C(CH₃)₂-OH, C(CH₃)₂-0-CH₃, C(CH₃)₂-CN, C(CH₃)₂- CHzOH, C(CH₃)₂-CH₂-0-C(0)-0-Ci-₅alkyl, C(0)N(CH₃)_P, N(Ci-₃alkyl)_P, NH₂, C(0)NH₂, oxetane, oxetane-CH3, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl, or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH; n is independently 0 or 1; m is independently 0 or 1; p is independently 1 or 2;and y is 1 or 2;

In yet another aspect:

Ri is hydrogen, Ci salkyl or CH₂OH;

R2 is CN; R3 is hydrogen;

X is N;

A is (CH₂)n-Het;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-₃alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci-3alkyl, C(CH₃)2-OH, C(CH₃)2-0-CH₃, C(CH₃)2-CN, C(CH₃)2- CHzOH, C(CH₃)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH₃)_P, N(Ci-₃alkyl)_P, NHz, C(0)NH₂, oxetane, oxetane-CH3, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl, or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH; n is independently 0 or 1; p is independently 1 or 2; and y is 1 or 2.

In yet another aspect: Ri is hydrogen, Ci salkyl or CH2OH;

R2 1S CN;

R3 is hydrogen;

X is N;

A is (CH₂)n-Het; Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, , (CH2)n-0-Ci-₃alkyl, (CFhVphenyl, (CFhVpyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci-3alkyl, C(CH₃)2-OH, C(CH₃)2-0-CH₃, C(CH₃)2-CN, C(CH₃)2- CH2OH, C(CH₃)2-CH2-0-C(0)-0-Ci-5alkyl, C(0)N(CH₃)_P, N(Ci-₃alkyl)_P, NH₂, C(0)NH₂, oxetane, oxetane-CH3, tetrahydrofuryl or tetrahydropyranyl; wherein the phenyl and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl, or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH; n is 0; p is independently 1 or 2; and y is 1 or 2.

It is to be understood that aspects of the present invention includes all combinations of particular groups described hereinabove.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof are prepared generally according to the procedures in International Publication Number WO 2013/012500. Methods of preparing the compounds described herein are disclosed in W02013/012500 and are hereby incorporated by reference.

Biological Activity

TRPV4 is expressed in multiple cell types within the eye, including those which constitute the blood-retinal barrier (Phuong et al., 2017, J. Physiol. 595: 6869-6885). TRPV4 could play a pathophysiological role in in several eye diseases/injuries including but not limited to neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension (Ryskamp et al., 2016, Sci. Rep. 6: 30593-; Arredondo et al., 2017, Sci. Rep. 7: 13094; Phuong et al., 2017, J. Physiol. 595: 6869-6885; Matsumoto et al., 2018, J. Neurosci. 38: 8745-8758).

The compounds of Formula (I), suitably l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, are tested for their ability to treat ocular diseases/injuries in vivo in pre-clinical models in which retinal edema is induced, for example the diabetic rat model cited in Arredondo et al. above. The efficacy of compounds of Formula (I), suitably l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, are tested for their ability to treat eye diseases/injuries including but not limited to neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension, in people using ophthalmic examination, intraocular pressure, ocular imaging (including but not limited to optical coherence tomography), visual acuity, Diabetic Retinopathy Severity Scale and other ocular disease severity scoring scales (Heier et al, 2016 Ophthalmology 123: 2376-2385; Asrani et al, Am J Ophthalmol. 207: 248-257).

The compound, l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is also known as GSK2798745.

Ligand-gated assay:

TRP channel activation/opening results in an influx of divalent and monovalent cations including calcium. The resulting changes in intracellular calcium were monitored using a calcium selective fluorescent dye Fluo4 (MDS Analytical Technologies). Dye loaded cells were initially exposed to test compound to verify a lack of agonist activity. Cells were subsequently activated by addition of an agonist and inhibition of the agonist-induced activation was recorded. Human embryonic kidney 293 cells stably expressing the macrophage scavenger receptor class II (HEK- 293-MSR-II) and transduced with 1% BacMam (J.P. Condreay, S.M. Witherspoon, W.C. Clay and T.A. Kost, Proc Natl Acad Sci 96 (1999), pp. 127-132) virus expressing the human TRPV4 gene were plated at 15000 cells/well in a volume of 50 pL in a 384 well poly-D lysine coated plate. Cells were incubated for 24 hours at 37 degrees and 5% CO2. Media was then aspirated using a Tecan Plate-washer and replaced with 20 pL of dye loading buffer: HBSS, 500 pM Brilliant Black (MDS Analytical Technologies), 2 uM Fluo-4. Dye loaded plates were then incubated in the dark at room temperature for 1-1.5 hours. 10 pL of test compound diluted in HBSS (HBSS with 1.5 mM Calcium Chloride, 1.5 mM Magnesium Chloride and 10 mM HEPES. pH 7.4), + 0.01% Chaps was added to the plate, incubated for 10 min at room temperature in the dark and then 10 pL of agonist was added at a final concentration equal to the agonist ECso. Calcium release was measured using the FLIPRtetra (MDS Analytical Technologies) or FLIPR384 (MDS Analytical Technologies).

All compounds of Formula (I) tested in International Publication Number WO 2013/012500 demonstrated TRPV4 biological activity with IC50 ranges from 0.1 nM - 0.5 pM. The compound l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile demonstrated TRPV4 biological activity with IC50 between 0.1-10 nM.

Methods of Use

The compounds of Formula (I) are TRPV4 antagonists, and maybe useful in the treatment or prevention of eye disease in a mammal. Suitably l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, may be useful in the treatment of eye disease. Accordingly, an aspect of the invention is directed to methods of treating or preventing eye diseases selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome comprise administering a safe and effective amount of a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

Accordingly, an aspect the invention is directed to methods of treating or preventing eye disease (including, but not limited to neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension comprise administering a safe and effective amount of a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof to a patient in need thereof.

The methods of treatment of the invention comprise administering a safe and effective amount of a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof, suitably l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

As used herein, "treating", and derivatives thereof, in reference to a condition means:

(1) to ameliorate the condition or one or more of the biological manifestations of the condition,

(2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The term "treating" and derivatives thereof refers to therapeutic therapy. Therapeutic therapy is appropriate to alleviate symptoms or to treat at early signs of disease or its progression.

The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "safe and effective amount" in reference to a compound of the invention or other pharmaceutically-active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/ risk ratio) within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular compound chosen (e.g. considering amongst other aspects the potency, efficacy, and half-life of the compound); the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be determined by the skilled artisan.

As used herein, "patient" or "subject" refers to a human or other mammal. Suitably the patient or subject is a human.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including both systemic administration, intravitreal administration, and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Intravitreal administration includes injection into the vitreous of the eye. Topical administration includes application to the skin as well as intraocular, optic, intravaginal, and intranasal administration. Suitably the administration is oral. Alternatively, the administration is parenteral. In particular embodiments of the invention, compounds are administered orally. The compounds of the invention may be of particular benefit when administered orally. Oral treatment of DME may be advantageous over the current standard of care as both eyes could be treated simultaneously. Further, patient preference is highly likely to be for oral treatment rather than intraocular injection. This may therefore lead to better patient compliance.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one or more (for instance two, three, or four) times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half- life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors. It will be further understood that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per patient per dose. Preferred dosages are 1 - 500 mg once daily or BID per patient.

Additionally, the compounds of Formula (I) may be administered as prodrugs. As used herein, a "prodrug" of a compound of Formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of Formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo,- (b) modify the duration of action of the compound in vivo,- (c) modify the transportation or distribution of the compound in vivo,- (d) modify the solubility of the compound in vivo,- and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications include the preparation of phosphates, amides, ethers, esters, thioesters, carbonates, and carbamate. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.

An aspect of this invention provides a method of treating eye disease, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a pharmaceutical combination of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof; and at least one further active ingredient. Suitably, the l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. In an embodiment, the amount of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile monohydrate administered to the human is from 0.5 to 30 mg per day e.g. from 1 to 10 mg per day e.g. 1 to 4 mg per day.

Suitably the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: l.Omg; l.lmg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg,

3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg,

4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg,

5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg,

6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg,

7.8mg, 7.9mg, 8.0mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg,

9.0mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and lO.Omg. Suitably, the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile monohydrate is 3.2mg.

An aspect of this invention provides a method of treating eye disease, in a human in need thereof, which comprises administering to such human a therapeutically effective amount of a pharmaceutical combination of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, and at least one further active ingredient, wherein l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

An aspect of this invention provides method of treating eye disease (selected from but not restricted to choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome), in a human in need thereof, which method comprises administering to such human a therapeutically effective amount of a pharmaceutical combination of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, and at least one further active ingredient, wherein l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

An aspect of this invention provides method of treating eye disease (selected from but not restricted in to neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension), in a human in need thereof, which method comprises administering to such human a therapeutically effective amount of a pharmaceutical combination of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, and at least one further active ingredient, wherein l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1-(((5S,7S)- 3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7- yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

An aspect of this invention provides a combination of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof; and at least one further active ingredient for use in therapy. Suitably, the l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. In an embodiment l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile monohydrate is administered to a human in an amount from 0.5 to 30 mg per day e.g. from 1 to 10 mg per day e.g. 1 to 4 mg per day. Suitably the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-

2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile monohydrate is selected from: l.Omg; l.lmg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg,

2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg,

4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg,

5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg,

6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg,

7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg,

8.9mg, 9.0mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg, 9.8mg, 9.9mg, and lO.Omg. Suitably, the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile monohydrate is 3.2mg.

An aspect of this invention provides a combination of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, and at least one further active ingredient, wherein l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized 1-(((5S,7S)-

3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7- yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

An aspect of this invention provides a method of treating a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating a disease state selected from: neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating neovascular (wet) age-related macular degeneration (AMD) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating Diabetic macular edema (DME) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating macular edema following retinal vein occlusion (RVO) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating diabetic retinopathy (DR) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating macular edema, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating retinal detachment, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating glaucoma in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating ocular hypertension in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating neovascular (wet) age-related macular degeneration (AMD) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating Diabetic macular edema (DME) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating macular edema following retinal vein occlusion (RVO) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating diabetic retinopathy (DR) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof. An aspect of this invention provides a method of treating macular edema, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating retinal detachment, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating glaucoma in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating ocular hypertension in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating macular edema following retinal vein occlusion (RVO) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof. An aspect of this invention provides a method of treating diabetic retinopathy (DR) in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof.

An aspect of this invention provides a method of treating macular edema, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile.

An aspect of this invention provides a method of treating retinal detachment, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile.

An aspect of this invention provides a method of treating glaucoma in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile.

An aspect of this invention provides a method of treating ocular hypertension in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile.

An aspect of this invention provides a method of treating eye disease, in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof. Suitably, the l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. In an embodiment l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile or pharmaceutically acceptable salt thereof is administered to the mammal in an amount of from 0.5 to 30 mg per day e.g. from 1 to 10 mg per day e.g. 1 to 4 mg per day. Suitably the amount of 1-(((5S,7S)- 3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7- yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile monohydrate is selected from: l.Omg; l.lmg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg, 2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg,

3.6mg, 3.7mg, 3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg,

4.8mg, 4.9mg, 5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg,

6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg,

7.2mg, 7.3mg, 7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1mg, 8.2mg, 8.3mg,

8.4mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg,

9.6mg, 9.7mg, 9.8mg, 9.9mg, and lO.Omg. Suitably, the amount of l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile monohydrate is 3.2mg.

An aspect of this invention provides a method of treating eye disease in a mammal, suitably a human, in need thereof which comprises administering to such mammal a therapeutically effective amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof, wherein l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of neovascular (wet) age-related macular degeneration (AMD).

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of Diabetic macular edema (DME).

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of macular edema following retinal vein occlusion (RVO).

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic retinopathy (DR).

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of macular edema.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of retinal detachment.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of glaucoma.

An aspect of this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of ocular hypertension.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of neovascular (wet) age-related macular degeneration (AMD).

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of Diabetic macular edema (DME). An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of macular edema following retinal vein occlusion (RVO).

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic retinopathy (DR).

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of macular edema.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of retinal detachment.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of glaucoma.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile or a pharmaceutically acceptable salt thereof, for use in the treatment of ocular hypertension.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of a disease state selected from neovascular (wet) age- related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of neovascular (wet) age-related macular degeneration (AMD). An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of Diabetic macular edema (DME).

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of macular edema following retinal vein occlusion (RVO).

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of diabetic retinopathy (DR).

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of macular edema.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of retinal detachment.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of glaucoma.

An aspect of this invention provides l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2- yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6- carbonitrile, for use in the treatment of ocular hypertension.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age- related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of neovascular (wet) age-related macular degeneration (AMD).

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Diabetic macular edema (DME).

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of macular edema following retinal vein occlusion (RVO).

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetic retinopathy (DR).

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of macular edema.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of retinal detachment.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of glaucoma.

An aspect of this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ocular hypertension.

An aspect pf this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of neovascular (wet) age-related macular degeneration (AMD).

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Diabetic macular edema (DME).

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of macular edema following retinal vein occlusion (RVO).

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetic retinopathy (DR).

An aspect of this invention provides for the use l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of macular edema. An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of retinal detachment.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of glaucoma.

An aspect of this invention provides for the use l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ocular hypertension.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of neovascular (wet) age-related macular degeneration (AMD).

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of Diabetic macular edema (DME).

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of macular edema following retinal vein occlusion (RVO).

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of diabetic retinopathy (DR). An aspect of this invention provides for the use l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of macular edema.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of retinal detachment.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of glaucoma.

An aspect of this invention provides for the use l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile in the manufacture of a medicament for the treatment of ocular hypertension.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension. In an embodiment l-(((5S,7S)-3-(5-(2- hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile or pharmaceutical salt thereof is administered in an amount of from 0.5 to 30 mg per day e.g. from 1 to 10 mg per day e.g. 1 to 4 mg per day. Suitably, the l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Suitably the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile monohydrate is selected from: l.Omg; l.lmg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg,

2.6mg, 2.7mg, 2.8mg, 2.9mg, 3.0mg, 3.1mg, 3.2mg, 3.3mg, 3.4mg, 3.5mg, 3.6mg, 3.7mg,

3.8mg, 3.9mg, 4.0mg, 4.1mg, 4.2mg, 4.3mg, 4.4mg, 4.5mg, 4.6mg, 4.7mg, 4.8mg, 4.9mg,

5.0mg, 5.1mg, 5.2mg, 5.3mg, 5.4mg, 5.5mg, 5.6mg, 5.7mg, 5.8mg, 5.9mg, 6.0mg, 6.1mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 6.6mg, 6.7mg, 6.8mg, 6.9mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg,

7.4mg, 7.5mg, 7.6mg, 7.7mg, 7.8mg, 7.9mg, 8.0mg, 8.1mg, 8.2mg, 8.3mg, 8.4mg, 8.5mg,

8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg, 9.1mg, 9.2mg, 9.3mg, 9.4mg, 9.5mg, 9.6mg, 9.7mg,

9.8mg, 9.9mg, and lO.Omg. Suitably, the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile monohydrate is 3.2mg.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof in the manufacture of a medicament for the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome wherein l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized.

An aspect of this invention provides for the use of l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof in the manufacture of a medicament for the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension, wherein l-(((5S,7S)-3-(5-(2-hydroxypropan- 2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. An aspect of this invention provides for a pharmaceutical composition for use in the treatment of eye disease in humans comprising a compound of Formula (I), or a pharmaceutically acceptably salt thereof.

An aspect of this invention provides a pharmaceutical composition for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in humans comprising l-(((5S,7S)-3-(5- (2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof.

An aspect of this invention provides a pharmaceutical composition for use in the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension, in humans comprising l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof. Suitably, the l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. In an embodiment l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile monohydrate is administered to a human in an amount of from 0.5 to 30 mg per day e.g. from 1 to 10 mg per day e.g. 1 to 4 mg per day. Suitably the amount of l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile monohydrate is selected from: l.Omg; l.lmg, 1.2mg, 1.3mg, 1.4mg, 1.5mg, 1.6mg, 1.7mg, 1.8mg, 1.9mg, 2.0mg, 2.1mg, 2.2mg, 2.3mg, 2.4mg, 2.5mg,

An aspect of this invention provides a pharmaceutical composition for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in humans comprising l-(((5S,7S)-3-(5- (2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)- lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof wherein 1- (((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3- azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized.

An aspect of this invention provides a pharmaceutical composition for use in the treatment of a disease state selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension in humans comprising l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof wherein l-(((5S,7S)-3-(5-(2-hydroxypropan-2- yl)pyrazin-2-yl)-7-methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile, or a pharmaceutically acceptably salt thereof is micronized. Suitably, the micronized l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo- l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH-benzo[d]imidazole-6-carbonitrile is in the form of a hydrate, suitably the monohydrate. Compositions

The compounds of Formula (I) or a pharmaceutically acceptable salt thereof will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient.

The pharmaceutical compositions may be prepared and packaged in bulk form wherein a safe and effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a safe and effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. When prepared in unit dosage form, the pharmaceutical compositions typically contain from 0.1 mg to 1000 mg.

The pharmaceutical compositions typically contain one compound of Formula (I) or a pharmaceutically acceptable salt thereof. However, in certain embodiments, the pharmaceutical compositions contain more than one compound of Formula (I) or a pharmaceutically acceptable salt thereof. For example, the pharmaceutical compositions contain two compounds of Formula (I) or a pharmaceutically acceptable salt thereof. In addition, the pharmaceutical compositions may optionally further comprise one or more additional pharmaceutically active compounds.

As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of Formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically- acceptable.

The compound of Formula (I) or a pharmaceutically acceptable salt thereof and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of Formula (I) or pharmaceutically acceptable salts thereof once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavouring agents, flavour masking agents, colouring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically-acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatin ized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. corn starch, potato starch, and pre-gelatin ized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesuim stearate, calcium stearate, and talc.

The compounds may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of intravitreal anti- vascular endothelial growth factor (anti-VEGF), intravitreal corticosteroid injections, intravitreal corticosteroid implants, 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors (statins), biguanides, insulin, insulin sensitizers, prostaglandins, alpha-adrenergic agonists, carbonic anhydrase inhibitors, rho kinase inhibitors, miotic or cholinergic agents, codeine, proton pump inhibitors, quinolones, thyroid hormone, anti-arthritic medication, anticonvulsants, anti-seizure medication, antibiotics, anti-platelets, selective serotonin reuptake inhibitors (SSRIs), benzodiazepines, sulfonylureas, dipeptidyl peptidase-4 (DPP-4) inhibitors, endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, vasopeptidase inhibitors, vasopressin receptor modulators, diuretics, digoxin, beta blocker, aldosterone antagonists, inotropes, NSAIDS, nitric oxide donors, calcium channel modulators, muscarinic antagonists, steroidal anti-inflammatory drugs, bronchodilators, anti histamines, leukotriene antagonists, HMG-CoA reductase inhibitors, dual non-selective b- adrenoceptor and a^-adrenoceptor antagonists, type-5 phosphodiesterase inhibitors, and renin inhibitors.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

Examples

Example 1

Experimental design:

Following a 2-week acclimation period, female Brown Norway rats (aged 10-11 weeks; 130- 160g ; Charles River Laboratories, Raleigh, NC) were randomly assigned to one of three study groups. The first group received oral gavage (PO) of vehicle (1 % methyl cellulose) at hour 0, followed by single bilateral intravitreal injections ( I VT) of vehicle (0.001% DMSO, 40% Captisol, 20 mM Tris in PBS, pH 7.4) at hour 2. Using the same timings, the second and third groups received either PO vehicle or TRPV4 blocker compound A (20 mg/kg in 1 % methyl cellulose), respectively, followed by TRPV4 agonist compound B (300mM in 0.001% DMSO, 40% Captisol, 20 mM Tris in PBS, pH 7.4; bilateral IVT). Preparation of compound A is described in international patent application number WO 2013/012500 at for e.g. example 22 of said example is incorporated herein by reference. Preparation of compound B is described in international patent application number WO 2007/070865. With an estimated vitreous volume of 60pL per eye, the starting vitreous concentration of Compound B was approximately 25mM. At hour 5 (3 hours after compound B IVT administration) , fluorophotometry was performed to measure retinal vascular leakage (see fluorophotometry methods below).

Prior to administration, the test articles (i.e. , PO and IVT dosing solutions) were formulated by independent scientists and the identity of the PO and IVT test articles were masked. The identities were unmasked following the completion of the in-life experiments and internal quality control review of the data.

Anesthesia For intravitreal injections, rats were anesthetized by inhalation of isoflurane (3.5% for induction and 2.5% for maintenance). The animals regained consciousness within 5 minutes of isoflurane removal and remained awake and mobile until the fluorophotometry procedure. Immediately prior to fluorophotometry, rats were anesthetized by Ketamine (60 mg/kg) and Xylazine (9 mg/kg) administered using a U-100 syringe via IP injection at 1 pl/g and 5 pl/g, respectively (body weight). Sedation was verified by the lack of a response to a toe pinch prior to measurement, and breath and heart rate were monitored throughout the procedure.

Oral gavage

Oral gavage was performed in conscious animals using utilizing a 22G x 1.5" and 1.25 mm curved feeding needle (Cadence Science, Cranston, RI) attached to a 3-mL Luer lock syringe, which was placed in the rat's mouth and advanced via the esophagus to the stomach where the drug was dispensed. A volume of 5 mL/kg of the vehicle or compound A formulation was dosed once daily in accordance with the Good Practice Guide (Journal of Applied Toxicology 21: 15- 23). Following removal of the syringe, the animal was held for another 30-60 seconds for observation of possible reflux, or signs of distress.

Intravitreal administration

Animals were anesthetized by isoflurane inhalation, and pupils were dilated with topical administration of a single drop each of 1.0% Cyclopentolate and 10% Phenylephrine. Following sedation and dilation, a total volume of 5 pi per eye of vehicle or test article was injected into the vitreous at the pars plana using a Hamilton syringe and a 33-gauge needle.

Fluorophotometry

Animals were placed on a heating pad throughout the fluorophotometry procedure. Eyes were dilated with topical application of 1% Cyclopentalate. Fluorescein was injected into a lateral tail vein at lOmg/kg from a preparation of stock fluorescein (lOOmg/mL; Akorn, AK-Fluor®, cat.# 17478-253-10) diluted to a final concentration of 10 mg/ml in 0.9% sterile saline (Teknova cat. # S5852). 25 minutes post-injection, the rat was anesthetized with ketamine and xylazine, and placed on an adjustable platform and the eye is presented to the FI uorotron™ Master (OcuMetrics, Mountain View, CA) using a rat eye adapter lens (OcuMetrics). Each eye was scanned with software (OcuMetrics) gating set at 200 ms to quantify the fluorescein concentration in the vitreous humor from the posterior to the anterior of the eye.

Data and Statistical Analyses Statistical analyses were performed with GraphPad Prism software (version 9.0.0), using one way analysis of variance for significance across groups on the log-transformed average of the two (one for each eye) fluorescein values for each animal. Pairwise comparisons between the three arms were reported, using Tukey's post-test to adjust for multiple comparisons. Changes with an adjusted p-value < 0.05 were deemed statistically significant.

Results

Retinal vascular leakage was measured by fluorophotometry to determine the efficacy of oral administration of TRPV4 blocker compound A to reduce TRPV4 agonist compound B-induced leakage in Brown Norway rats. The data are presented as the log-transformed independent values for each animal after averaging the fluorescein values for the left and right eyes (Figure 1).

Intravitreal administration of TRPV4 agonist compound B induced significant retinal vascular leakage compared to vehicle when measured 3 hours post-induction (Figure 1; Tables 1 and 2; ***, p=0.0003). Oral administration of compound A resulted in an almost complete block of compound B-induced vascular leakage (Figure 1; Tables 1 and 2; ***, p=0.0004) with the mean fluorescein in the vitreous returning to levels comparable to vehicle-induction alone (Figure 1; Tables 1 and 2; n.s.).

Table 1: Descriptive Statistics of Raw Fluorescein Measurements * One eye was excluded from analysis due to the presence of blood in the vitreous that interfered with scanning.

** Two eyes were excluded from analysis due to the presence of blood in the vitreous that interfered with scanning.

Table 2: Summary of One-way ANOVA Analyses with Tukey's adjustment for Pairwise

Comparisons

This experiment provides evidence that an oral/systemically-delivered TRPV4 blocker could reach the site of action to mitigate DME.

Example 2 An experiment similar to Experiment 1 is prepared using the following TRPV4 blocker:

The method is the same as in Experiment 1 however a larger dose range of the TRPV4 blocker is explored (15, 1.5, 0.15, 0.015 mg/kg) and a lower dose of TRPV4 agonist Compound B (60uM) is to cause leak. The response to the lower dose of agonist is more in line with the leak caused by VEGF (a clinically relevant inducer of retinal vascular leak), and the level of leak seen in ocular disease models.

Compounds with chemical structures similar to Compound A that exhibit suitable systemic PK and in vitro TRPV4 potency profiles would be predicted to exhibit similar efficacy in the Experiments 1 and 2.

Example 2 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by preparing a solution in water with the ingredients in the concentrations shown in Table 3, below.

Table 3

INGREDIENTS CONCENTRATION l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- 0.5 mg/mL methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile

Acetic acid 35 mM

Kleptose HBP 150 mg/mL

NaCI q.S to 300 mOsmol/kg

Example 3 - Tablet Composition

The active pharmaceutical ingredient and excipients, as shown in Table 4 below, are screened, blended using a suitable size blender and then milled. Milled material is mixed with excipients /lubricant and blended. The blend is compressed using a suitable tablet press. Tablets are coated using Aquarius film coat material in a suitably size coating pan.

Table 4

TABLET CORE INGREDIENTS AMOUNTS l-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7- 3.2 mg methyl-2-oxo-l-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-lH- benzo[d]imidazole-6-carbonitrile

Lactose 46.45 mg

Microcrystalline cellulose 92.1 mg Croscarmellose 7.5 mg Magnesium stearate 0.75mg

FILM COAT INGREDIENTS AMOUNTS Aquarius film coating 4.5 mg Purified water QS mg

While the preferred aspects of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.

Claims

Claims:

1. A method of treating a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in a mammal in need thereof which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I):

wherein:

Ri is hydrogen, Ci-₃alkyl, CH2OH, CH2-O-CH3, O-hOO-hPh, CH2CN, CN, halo or C(0)0CH₃; R2 is independently hydrogen, CN, CF₃, halo, S02Ci-₃alkyl, Ci-₃alkyl or CECH;

RB is hydrogen, Ci-2alkyl, CF₃ or OH;

R4 is hydrogen, halo or Ci-₃alkyl;

X is CR4 or N;

A is (CH₂)_n - Het; or A is (CH2)n-(CRaRb)-(CH₂)m-Het; Ra is hydrogen or Ci-3alkyl, wherein the Ci-3alkyl may be further substituted with one or more halos; Rb is Ci-3alkyl; or Ra and Rb together with the carbon atom they are attached form a C3-6cycloalkyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with oxygen to form an oxetane, tetrahydrofuryl or tetrahydropyranyl group; or one of the carbon atoms in the C3-6cycloalkyl group formed by Ra and Rb may be replaced with nitrogen to form a pyrrolidinyl or piperidinyl group;

Het is

wherein Het may be substituted by one, two or three substituents chosen from: halo, Ci-salkyl, CN, CH2F, CHF2, CF3, C3-6cycloalkyl, (CH2)n-0-Ci-3alkyl, (CH2)n-phenyl, (CH2)n-pyridyl, pyrimidinyl, pyrazinyl, CH(CH₃)-0-Ci-3alkyl, CH(OH)-Ci-₅alkyl, C(CH₃)2 - Rs, C(0)N(CH₃)_P, N(Ci-₃alkyl)_P, NH₂, C(0)NH2, oxetane, oxetane-CH3, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, or pyrazolyl; wherein the phenyl, pyrazolyl, and pyridyl substituent on the Het may be further substituted by one or two substituents chosen from: halo, CN, OCH3, Ci salkyl or CF3; and the Ci-salkyl and C3-6cycloalkyl substituent on the Het may be further substituted by CN or OH;

Rs is CN, 0-Ci-₄alkyl, (CH₂)m-OH, (CH₂)_P-0-C(0) -O-Ci-salkyl, or 0-(CH₂)_P-0-R₆; R6 is Ci-4alkyl or P(0)2(CH3)2; n is independently 0, 1 or 2; m is independently 0, 1 or 2; p is independently 1 or 2; and y is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein the mammal is a human.

3. The method of claim 1 or claim 2 wherein the compound is:

or a pharmaceutically acceptably salt thereof.

4. The method of any of claims 1 to 3 wherein the compound is:

5. The method of any of claims 1 to 4 wherein the compound is administered orally.

6. The method of any of claims 1 to 5 wherein the disease state is diabetic macular edema (DME).

7. A method of treating a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in a human in need thereof, which comprises: administering to such human a therapeutically effective amount of a pharmaceutical combination of: a compound as disclosed in claim 3 or a pharmaceutically acceptable salt thereof; and at least one further active ingredient.

8. A compound of Formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome.

9. The compound for use according to Claim 8, wherein the compound is

or a pharmaceutically acceptably salt thereof and wherein the disease state is selected from neovascular (wet) age-related macular degeneration (AMD), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema, retinal detachment, glaucoma and ocular hypertension.

10. The compound for use according to Claim 9, wherein the disease state is Diabetic macular edema (DME).

11. The compound for use according to any of Claims 8 to 10, wherein the compound is

12. Use of a compound of Formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome

13. Use of the compound

or a pharmaceutically acceptably salt thereof in the manufacture of a medicament for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome.

14. Use of the compound

or a pharmaceutically acceptably salt thereof in the manufacture of a medicament for use in the treatment Diabetic macular edema (DME).

15. Use of the compound:

in the manufacture of a medicament for use in the treatment Diabetic macular edema (DME).

16. A pharmaceutical composition for use in the treatment of a disease state selected from choroidal neovascularization (such as neovascular (wet) age-related macular degeneration (AMD)), Diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), diabetic retinopathy (DR), macular edema (such as post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, retinal detachment, glaucoma (including but not limited to open angle glaucoma, closed angle glaucoma, neovascular glaucoma, vascularized glaucoma filtering blebs), ocular hypertension, rubeosis irides, pterygium, conjunctival papilloma, myopia, uveitis, ocular ischemic syndrome, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, Eale's disease, and genetic disorders such as VonHippel-Lindau syndrome in humans comprising the compound:

or a pharmaceutically acceptably salt thereof.

17. A pharmaceutical composition for use in the treatment of Diabetic macular edema (DME) in humans comprising the compound:

or a pharmaceutically acceptably salt thereof.

18. A pharmaceutical composition for use in the treatment of Diabetic macular edema

(DME) in humans comprising the compound: