NZ751237B2 - Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases - Google Patents

Abstract

The present invention relates to a method for treating ocular inflammatory diseases in a subject in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of Formyl peptide receptor 2 such as compounds of Formula III and related structures. of Formula III and related structures.

Description

USE OF AGONISTS OF FORMYL PEPTIDE RECEPTOR 2 FOR TREATING OCULAR INFLAMMATORY DISEASES By: Veena Viswanath, Richard L. Beard and John E. Donello RELATED APPLICATIONS This application is a divisional of New Zealand Application 710173, which claims the benefit of United States Provisional Patent Application Serial No. 61/773,773 filed March 06, 2013, the disclosure of which is hereby incorporated in its entirety by reference BACKGROUND OF THE INVENTION 1. Field of the invention The present disclosure relates to a method for treating ocular inflammatory diseases in a subject in need of such treatment, which comprises administering a ceutical composition comprising a eutically effective amount of at least one agonist of Formyl peptide receptor 2 (FPR2). 2. y of the related art The formyl peptide receptor (FPR) family is involved in host defense against pathogens, but also in g internal molecules that may provide s of cellular dysfunction. This family es 3 members in humans and one member of this family FPR2 (also known as FPRL-1, ALXA4) is a G proteincoupled receptor that is expressed predominantly on inflammatory cells such as monocytes and neutrophils, as well as on T cells and has been shown to play a critical role in leukocyte trafficking during inflammation and human pathology (Chiang N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, u T, Yokomizo T, Brink, C. The lipoxin receptor ALX: Potent ligandspecific and stereoselective actions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 is an exceptionally promiscuous receptor that responds to a large array of exogenous and endogenous ligands, including serum amyloid A (SAA), chemokine variant sCKβ8-1, the rotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocotricoid-modulated protein n A1 g N, Serhan CN, Dahlen, S, Drazen JM, Hay DWP, Rovati E, Shimizu T, Yokomizo T, Brink, C. The lipoxin receptor ALX: Potent ligand-specific and stereoselective actions in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 transduces anti-inflammatory effects of LXA4 in many systems, and has been shown to play a key role in the resolution of inflammation (Dufton N, Perretti M. Therapeutic anti-inflammatory potential of formyl peptide receptor agonists. Pharmacology & Therapeutics 2010; 127: 175-188). FPR2 knockout mice show exaggerated inflammation in disease conditions as expected by the biological role of the receptor (Dufton N, Hannon R, Brancaleone V, Dalli J, Patel HB, Gray M, D’Aquisto F, Buckingham JC, Perretti M, Flower RJ. Anti-inflammatory role of the murine formyl-peptide receptor 2: Ligand-specific effects on leukocyte responses and mental inflammation. Journal of Immunology 2010; 184: 2611-2619).

Activation of FPR2 by lipoxin A4 or its analogs and by n I protein has been shown to result in nflammatory activity by promoting active resolution of inflammation which involves inhibition of polymorphonuclear neutrophils (PMNs) and phils migration and also stimulate monocyte migration enabling clearance of apoptotic cells from the site of inflammation in a nonphlogistic manner (Maderna P, Cottell DC, en T, Dufton N, Dalli J, Perretti M, Godson C. FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated ytosis.

FASEB 2010; 24: 4240-4249; Reville K, Cream JK, Vivers S, Dransfield I, Godson C. Lipoxin A4 redistributes Mysoin IIA and Cdc42 in macrophages: ations for phagocytosis of apoptotic leukocytes. Journal of Immunology 2006; 176: 1878-1888). In addition, FPR2 has been shown to inhibit NK cytotoxicity and promote activation of T cells which r contributes to down regulation of tissue damaging inflammatory signals. FPR2/ LXA4 interaction has been shown to be beneficial in experimental models of ischemia reperfusion, angiogenesis, ocular inflammation such as endotoxin-induced uveitis, and corneal wound healing (Serhan C. Resolution phase of inflammation: Novel endogenous anti-inflammatory and proresolving lipid mediators and ys. Annual reviews of Immunology 2007; 25: 101-137; Medeiros R, ues GB, Figueiredo CP, Rodrigues EB, n A Jr, Menezes-de-Lima O Jr, Passos GF, Calixto JB. Molecular mechanisms of topical anti-inflammatory effects of n A(4) in endotoxin-induced s.

Molecular Pharmacology 2008; 74: 154-161; Gronert K, Maheshwari N, Khan N, Hassan IR, Dunn M, Schwartzmann ML. A role for the mouse 12/15- genase pathways in promoting epithelial wound healing and host defense. Journal of Biological Chemistry 2005; 280: 15267-15278; Leedom A, Sullivan AB, Dong B, Lau D, Gronert K. Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic .

American Journal of Pathology 2010; 176: 74-84; Gronert K. Lipoxins in the eye and their role in wound healing. Prostaglandins, Leukotrienes and Essential fatty Acids. 2005; 73: 221-229). Pharmaceutical utility of lipoxin A4 and its analogs are hampered by inherent physicochemical properties of the natural poly-olefinic natural t. Therefore, small molecule anti-inflammatory agonists of FPR2 would have a wide variety of therapeutic benefit in inflammatory disorders especially in the eye. Targeting FPR2 selectively would also have benefits of reduced side s as compared to more broad acting anti-inflammatories such as steroids or NSAIDs which have icant side effects of elevated IOP and delays in wound healing in the eye. FPR2 is also expressed in ocular tissues in the cornea and also the posterior of eye, in addition to the inflammatory cells that migrate into the ocular tissues. FPR2 thus represents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in ocular es with ive inflammatory responses. It is an object of the present invention to go someway towards providing these new therapeutic agents and/or to provide the public with a useful choice.

Y OF THE INVENTION In a first aspect the present invention provides a use of at least one formyl peptide receptor 2 (FPR2) agonist of Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular disease in a patient in need thereof: Formula III R1 is halogen, en, optionally tuted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R2 is halogen, optionally substituted C 1-8 alkyl, CF3, OR9, C(O)R10, NO2, 4, CN, SR15 or ; R3 is hydrogen, optionally substituted C1-8 alkyl, optionally substituted C3- 8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R5 forms a 10- or 11- membered polycyclic ring which is optionally substituted; R4 is hydrogen, optionally substituted C 1-8 alkyl, , , , , , , , , , , , , , , , , , , , , , , , ,optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R5 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted; R5 is en, optionally substituted C 1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R4 forms a spiro monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is ally substituted or together with R3 forms a 5 or 6 member ring which is optionally substituted; R6 is n, hydrogen, ally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R7 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, 0, NO2, NR13R14, CN, SR15 or SO2R16; R8 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or ; R9 is hydrogen, C(O)(C1-8 alkyl) or optionally substituted C 1-8 alkyl; R10 is hydrogen, optionally substituted C 1-8 alkyl, O(C 1-8 alkyl), NR11R12 or OH; R11 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R12 is hydrogen, optionally substituted C 6-10 aryl or ally substituted C 1-8 alkyl; R13 is en, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R14 is hydrogen, optionally tuted C 6-10 aryl, optionally tuted C 1-8 alkyl, C(O)(C 1-8 alkyl) or SO2(C 1-8 alkyl); R15 is hydrogen, optionally substituted C 1-8 alkyl or O(C 1-8 alkyl); R16 is OH, O(C 1-8 alkyl), (C 1-8 alkyl) or NR11R12; R17 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R18 is hydrogen, C(O)(C1-8 alkyl), optionally substituted C 6-10 aryl, or optionally substituted C 1-8 alkyl; R19 is en, C(O)(C1-8 alkyl), optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R20 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R21 is en, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; n is 1, 2, 3, 4, or 5; and m is 1, 2, 3, 4, or 5; wherein the substituent on the optionally substituted C1-8 alkyl is one or more tuents selected from halogen atoms, hydroxyl groups, C3- 8 cycloalkyl groups, amino groups, C3-10 heterocyclic groups, C6-10 aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid , phosphoric acid groups, nitro groups, amide , and sulfonamide groups; the substituent on the optionally substituted C3-8 cycloalkyl is one or more tuents ed from halogen atoms, sulfonyl C1-8 alkyl groups, sulfoxide C1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC1-8 alkyl groups, -SC1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 l groups, -C2-6 alkynyl groups, ketone groups, alkylamino , amino groups, C6-10 aryl groups, C3-8 cycloalkyl groups and hydroxyl groups; the substituent on the optionally substituted heterocycle is one or more substituents selected from halogen atoms, sulfonyl groups, sulfoxide groups, nitro , cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, C6-10 aryl groups, C3-8 cycloalkyl groups and/or hydroxyl groups; the substituent on the optionally substituted C6-10 aryl is one or more substituents selected from halogen atoms, yl C1-6 alkyl groups, sulfoxide C1-6 alkyl groups, sulfonamide groups, carboxylic acid groups, C1-6 alkyl carboxylate ester groups, amide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, aldehydes, alkylamino groups, amino groups, C6-10 aryl groups, C3-8 cycloalkyl groups and hydroxyl groups; and the substituent on the optionally substituted C3-8 cycloalkenyl is one or more substituents selected from halogen atoms, sulfonyl groups, ide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, - SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, C6- aryl groups, C3-8 cycloalkyl groups and hydroxyl groups; n the ocular inflammatory disease is selected from the group consisting of uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid t epitheliopathy, ’s disease, post-surgical corneal wound healing, wet agerelated r degeneration (ARMD) and dry ARMD, and wherein a therapeutically efficient amount of the FPR2 agonist is between about 0.001 and about 5% (w/v) in a liquid formulation.

In a second aspect the present invention provides a use of at least one formyl peptide receptor 2 (FPR2) agonist in the cture of a medicament for treating an ocular matory disease in a subject in need of such treatment; wherein the ocular inflammatory disease is selected from the group consisting of uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, ic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid t liopathy, Behcet’s disease, post-surgical corneal wound healing, wet age-related macular degeneration (ARMD) and dry ARMD; n the FPR2 agonist is a compound selected from the group consisting of: ethyl 3-{[(4-bromophenyl)carbamoyl]amino}-2,4-dioxo-1,3- diazaspiro[4.5]decanecarboxylate; 1-[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidinyl]phenylurea; 1-(2-fluorophenyl)[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidin a, and wherein a therapeutically efficient amount of the FPR2 t is between about 0.001 and about 5% (w/v) in a liquid formulation.

BRIEF DESCRIPTION OF THE INVENTION The present disclosure pertains to the ability of FPR2 agonists to exhibit ocular anti-inflammatory activity with chemical stability and le for ocular delivery. These FPR2 compounds show good potency at the receptor, a subset of compounds is exemplified in the tables below, and importantly, the FPR2 compounds are active topically, and therefore could be administered in many forms, including but not limited to eye drops. These compounds may also be administered directly or through a local drug ry device applied to ocular tissue, and via IV, uscularly, intrathecally, subcutaneously, , intravitreally or intraperitoneally. These compounds will be useful for the treatment of ocular inflammatory diseases including, but not limited to, uveitis, dry eye, tis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet’s disease, post-surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, wet and dry age-related macular degeneration (ARMD), , conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, ive age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), retinopathy of urity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; birdshot retinochoroidopathy, infectious (syphilis, lyme, ulosis, toxoplasmosis), intermediate uveitis (pars planitis), ocal choroiditis, multiple evanescent white dot me (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal is and uveitis syndrome, Vogt-Koyanagi and Harada syndrome; ar diseases/ exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, ds macular edema, disseminated intravascular coagulopathy, branch retinal vein ion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat’s e, parafoveal telangiectasis, hemi-retinal vein occlusion, ophlebitis, central retinal artery ion, branch l artery occlusion, carotid artery disease (CAD), d branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial ive vitreoretinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, conditions caused by photodynamic y, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; erative disorders such as proliferative l retinopathy and epiretinal membranes, and proliferative ic retinopathy; infectious disorders such as ocular lasmosis, ocular toxocariasis, presumed ocular histoplasmosis me (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic disorders with accosiated l dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt’s disease and fundus flavimaculatus, Best’s disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby’s fundus dystrophy, benign concentric maculopathy, Bietti’s crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease associated with tumors, congenital hypertrophy of the retinal ted epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and l pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and cular lymphoid tumors; and miscellaneous other diseases affecting the posterior part of the eye such as te inner choroidopathy, acute posterior multifocal d pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigment epitheliitis, post-surgical corneal inflammation, blepharitis, MGD, glaucoma, branch vein occlusion, Best’s vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative diseases of either the photoreceptors or the retinal pigment epithelial (RPE).

In another aspect these compounds will be useful for the treatment of ocular inflammatory diseases associated with CNS disorders such as Alzheimer’s disease, arthritis, , inflammatory bowel disease, cachexia, angina pectoris, toid arthritis and related inflammatory disorders, ia, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological ers, , allergic disorders, inflammation, systemic lupus erythematosus, ,.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 FPR2 agonists show potent anti-inflammatory activity in endotoxin- induced uveitis model in rats.

Figure 2 FPR2 agonists show potent nflammatory activity in endotoxin- induced uveitis model in rats.

Figure 3 shows accelerated healing and re-epithelialization in a rabbit model of corneal wound as exemplified by Compound 3, 3S){[(4- bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid.

DETAILED DESCRIPTION OF THE INVENTION Described herein is a method for treating ocular inflammatory es in a t in need of such treatment, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2.

Also described is the use of at least one agonist of FPR2 for the manufacture of a medicament for the treatment of an ocular inflammatory disease or condition mediated by FPR2 in a mammal.

Also bed is a method for treating ocular inflammatory diseases, which comprises administering a ceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N.13/668,835, provided that the compounds have binding activity at the FPR2 receptor.

Still r described is the use of at least one compound as disclosed in U.S. patent application S.N.13/668,835 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor .

Also described is the use of at least one nd as disclosed in U.S. patent application S.N.13/668,835 for treating an ocular disease or condition ed by FPR2 in a mammal, provided that the compounds have binding ty at the FPR2 receptor .

The compounds disclosed in U.S. patent application S.N.13/668,835 are represented by Formula I: Formula I wherein: R1 is sec-butyl, C6-10 aryl, -CH2- (C6-10)aryl, eterocycle, C4-8 cycloalkyl or C3-8 cycloalkenyl or heterocycle; R2 is halogen or methyl; R3 is halogen; R4 is H, methyl or halogen; R5 is OR6 or NH2; R6 is H or C2-4 alkyl.

In r aspect, described is a method for treating ocular inflammatory diseases, which ses administering a ceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent ation S.N.13/523,579, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, described is the use of at least one compound as disclosed in U.S. patent application S.N. 13/523,579 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor. .

In r aspect, described is the use of at least one compound as disclosed in U.S. patent application S.N. 13/523,579 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding ty at the FPR2 receptor.

The compounds disclosed in U.S. patent application S.N. 13/523,579 are represented by Formula II: Formula II wherein: a is 1 and b is 0; a is 0 and b is 1; a is 1 and b is 1; R1 is optionally substituted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted heterocycle, optionally tuted C3-8 cycloalkyl, optionally substituted C6-10 aryl, ally substituted C3-8 cycloalkenyl, - NR11R12 or -OR13; R2 is ally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - 2, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, ally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally tuted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R5 is halogen, -CF3 or –S(O)nR14; n is 0, 1 or 2; R6 is hydrogen, optionally substituted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R7 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 lkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 lkenyl; R8 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10 is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or ally tuted C6-10 aryl; R10a is en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R11 is hydrogen or ally substituted C1-8 alkyl; R12 is hydrogen or optionally substituted C1-8 alkyl; R13 is hydrogen or optionally substituted C1-8 alkyl; R14 is hydrogen, CF3 or optionally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; Also described is a method for treating ocular inflammatory es, which comprises administering a ceutical ition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/673,800, provided that the compounds have binding activity at the FPR2 receptor..

In another aspect, described is the use of at least a compound as disclosed in U.S. patent application S.N. 13/673,800 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor..

In another aspect, described is the use of at least a compound as disclosed in U.S. patent application S.N. 13/673,800 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have g activity at the FPR2 receptor.

The nds disclosed in U.S. patent application S.N. 13/673,800 are represented by Formula III: Formula III R1 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R2 is halogen, optionally substituted C 9, C(O)R10, NO 1-8 alkyl, CF3, OR 2, NR13R14, CN, SR15 or SO2R16; R3 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally tuted heterocycle, or er with R5 forms a 10- or 11- membered polycyclic ring which is optionally substituted; R4 is hydrogen, ally substituted C 1-8 alkyl, , ( )n O , , , OR17 , , , , , , , , , , , , , , , , , , , , , , , optionally substituted C3-8 lkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or together with R5 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or rated 5 to 10 member ring which is ally substituted; R5 is hydrogen, optionally substituted C 1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, optionally substituted heterocycle, or er with R4 forms a spiro monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R3 forms a 5 or 6 member ring which is optionally substituted; R6 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or ; R7 is halogen, en, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R8 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R9 is hydrogen, C(O)(C1-8 alkyl) or optionally substituted C 1-8 alkyl; R10 is hydrogen, optionally substituted C 1-8 alkyl, O(C 1-8 , NR11R12 or OH; R11 is hydrogen, optionally substituted C 6-10 aryl or optionally tuted C 1-8 alkyl; R12 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R13 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R14 is hydrogen, optionally substituted C 6-10 aryl, optionally substituted C 1-8 alkyl, C(O)(C 1-8 alkyl) or SO2(C 1-8 alkyl); R15 is hydrogen, optionally substituted C 1-8 alkyl or O(C 1-8 alkyl); R16 is OH, O(C 1-8 alkyl), (C 1-8 alkyl) or NR11R12; R17 is en, optionally substituted C 6-10 aryl or optionally tuted C 1-8 alkyl; R18 is hydrogen, C(O)(C1-8 alkyl), optionally substituted C 6-10 aryl, or optionally substituted C 1-8 alkyl; R19 is en, C(O)(C1-8 alkyl), optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R20 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R21 is hydrogen, ally substituted C 6-10 aryl or ally substituted C 1-8 alkyl; n is 1, 2, 3, 4, or 5; m is 1, 2, 3, 4, or 5.

Also described is a method for treating ocular matory diseases, which comprises administering a pharmaceutical composition comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent ation S.N. ,527, provided that the compounds have g activity at the FPR2 receptor.

Also described is the use of at least one compound as sed in U.S. patent application S.N. 13/765,527 for the manufacture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

Also described is the use of at least one compound as disclosed in U.S. patent application S.N. 13/765,527 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The nds disclosed in U.S. patent application S.N. 13/765,527 are represented by Formula IV: Formula IV wherein: R1 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl substituted or unsubstituted heterocycle or substituted or tituted C6-10 aryl, or together with R2 can form an optionally substituted cyclobutyl; R2 is isopropyl or together with R3 can form a substituted or unsubstituted 3 to 6 member ring heterocycle or er with R1 can form an optionally substituted cyclobutyl, cyclopropyl; and R3 is hydrogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl, tuted or unsubstituted heterocycle, substituted or unsubstituted C6-10 aryl or together with R2 can form a substituted or tituted 3 to 6 member ring heterocycle.

Also described is a method for treating ocular inflammatory diseases, which comprises administering a therapeutically effective amount of a pharmaceutical composition, comprising at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/409,228, provided that the compounds have binding activity at the FPR2 receptor.

Also described is the use of at least one compound as sed in U.S. patent application S.N. 13/409,228 for the cture of a medicament for the treatment of an ocular disease or condition mediated by FPR2 in a mammal, ed that the compounds have binding activity at the FPR2 or.

Also described is the use of at least one compound as disclosed in U.S. patent application S.N. 13/409,228 for treating an ocular disease or condition ed by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

The compounds disclosed in U.S. patent application S.N. 13/409,228 are represented by Formula V: Formula V wherein: “ ” is a single bond or a double bond; “ ”is a single bond or a double bond; R1 is H, halogen, -S(O)R10, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl or yl; R2 is H, n, -S(O)R10, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, 4, C3-8 cycloalkyl, C3-8 cycloalkenyl or hydroxyl; R3 is H, halogen, -S(O)R10, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl, C3-8 cycloalkenyl, C6-10 aryl or hydroxyl; R4 is H or C(O)R12; R5 is H, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl or - C2-6 alkynyl; R6 is H, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl or - C2-6 alkynyl; Y is O or S; X is O, NR, or CH2; Ra is C6-10 aryl, , heteroaryl, C3-8 cycloalkyl, C3-8 lkenyl or H; Rb is halogen; c is 0, 1 or 2; is , , , , or , ; R7 is H, halogen, -S(O)R10, -S(O)2R11, nitro, hydroxyl, cyano, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkenyl or C3-8 cycloalkyl; R8 is H, halogen, -S(O)R10, -S(O)2R11, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 lkenyl or C3-8 lkyl; R9 is H, -S(O)2R11, -OC1-6 alkyl, -SC1-6 alkyl, -C1-6 alkyl, -C2-6 alkenyl, - C2- 12, C 6 alkynyl, C(O)R 3-8 cycloalkenyl or C3-8 cycloalkyl ; R10 is -C1-6 alkyl, C3-8 lkyl, or C3-8 cycloalkenyl ; R11 is H, hydroxyl, -C1-6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkenyl; R12 is H, hydroxyl, -C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, 4 or -OC1-6 alkyl; R13 is H, -C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkenyl SO2R11 or C(O)R15; R14 is H, -C1-6 alkyl, C3-8 cycloalkenyl, aryl, heterocycle or C3-8 cycloalkyl; R15 is H, -C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl; and R is H, -C1-6 alkyl, C3-8 cycloalkenyl or C3-8 cycloalkyl; with the provisos: when “ ” is a double bond then R5 is void ; and when“ ” is a double bond R6 is void.

Also described is a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one t of FPR2 as disclosed in U.S. patent application S.N. 13/370,472, ed that the compounds have binding activity at the FPR2 receptor.

Also described is the use of at least one compound as disclosed in U.S. patent application S.N. 13/370,472 for the manufacture of a medicament for the treatment of an ocular disease or condition ed by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

Also bed is the use of at least one compound as disclosed in U.S. patent application S.N. 13/370,472 for treating an ocular disease or condition ed by FPR2 in a mammal, provided that the compounds have g activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent application S.N. 13/370,472 are represented by Formula VI: Formula VI wherein: A is C6-10 aryl, heterocyle, C3-8 cycloalkyl or C3-8 cycloalkenyl; R17 is C1-6 alkyl or ; B is C6-10 aryl, heterocyle, C3-8 cycloalkyl or C3-8 cycloalkenyl; R1 is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, 2, NR13R14, C3-8 cycloalkyl or hydroxyl; R2 is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R3 is H, C1-6 alkyl or C3-8 cycloalkyl; R4 is H, C1-6 alkyl or C3-8 cycloalkyl; R5a is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R5b is H, halogen, 15, R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, 2, NR13R14, C3-8 cycloalkyl or hydroxyl; R5c is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or R5d is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R6 is H, -S(O)2R11, -C1-6 alkyl, n NR13R14, -(CH2)m cycle , C(O)R12, NR13R14, C3-8 cycloalkyl, C6-10 aryl, or heterocycle; R7 is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R8 is H, halogen, -S(O)R15, -S(O)2R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R9 is H, halogen, -S(O)R15, R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; R10 is H, halogen, -S(O)R15, R11, nitro, cyano, -OC1-6 alkyl, -SC1-6 alkyl, - C1-6 alkyl, -C2-6 alkenyl, - C2-6 alkynyl, C(O)R12, NR13R14, C3-8 cycloalkyl or hydroxyl; X is O or S; Y is O or S; R11 is H, hydroxyl, -C1-6 alkyl, C3-8 cycloalkyl or NR13R14; R12 is H, hydroxyl, -C1-6 alkyl, hydroxyl, C3-8 cycloalkyl, NR13R14 or -OC1-6 alkyl; R13 is H, -C1-6 alkyl, C3-8 lkyl, SO2R11 or C(O)R16; R14 is H, -C1-6 alkyl or C3-8 cycloalkyl; R15 is -C1-6 alkyl, or C3-8 lkyl; R16 is H, -C1-6 alkyl or C3-8 cycloalkyl; n is 1-4; and m is 1-4.

Also described is a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition, comprising a therapeutically effective amount of at least one agonist of FPR2 as disclosed in U.S. patent application S.N. 13/863,934, ed that the compounds have binding activity at the FPR2 receptor.

Also described is the use of at least one compound as disclosed in U.S. patent application S.N. 13/863,934 for the manufacture of a medicament for the ent of an ocular disease or condition mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

Also described is the use of at least one compound as sed in U.S. patent ation S.N. 13/863,934 for treating an ocular disease or condition mediated by FPR2 in a mammal, provided that the nds have binding activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent application S.N. 13/863,934 are represented by Formula VII: Formula VII n is 0 or 1; R1 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, -NR8R9, - NC(O)R20, -OR10, -OC(O)R21 -SR11 , -C(O)R12, CN or NO2; R2 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, - NR8R9, - NC(O)R20 , -OR10, -OC(O)R21 , -SR 11, -C(O)R12, CN or NO2; R3 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, - NR8R9, - NC(O)R20 , -OR10, -OC(O)R21 , -SR11 , -C(O)R12, CN, NO2, CF3, S(O)R15 or R4 is en, tuted or unsubstituted C1-8 alkyl, halogen, - NR8R9, - NC(O)R20 , -OR10, -OC(O)R21 , -SR11 , 12, CN or NO2; R5 is hydrogen, substituted or unsubstituted C1-8 alkyl, halogen, - NR8R9, - NC(O)R20 ,-OR10, -OC(O)R21 , SR11 , -C(O)R12, CN or NO2; R6 is hydrogen, substituted or unsubstituted C1-8 alkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C6-10 aryl, substituted or unsubstituted C3-8 cycloalkenyl or -CH2R19; R7 is substituted or tituted heterocycle, -SR11, -NR8R9 , - N(H)C(O)N(H)S(O)2R19, -BR13R14, -S(O)R15, -C(O)N(H)(CN), - C(O)N(H)S(O)2R19, -S(O)(N)(PO3H2)-, -S(O)2R16 or -P(O)R17R18; R8 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C6-10 aryl; R9 is en, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or tuted or unsubstituted C6-10 aryl; R10 is hydrogen or substituted or unsubstituted C1-8 alkyl ; R11 is hydrogen , substituted or unsubstituted C1-8 alkyl or -CF3; R12 is hydrogen, substituted or unsubstituted C1-8 alkyl, hydroxyl, -OR24 or - NR8R9; R13 is -OR22; R14 is -OR23; R15 is substituted or unsubstituted C1-8 alkyl; R16 is substituted or unsubstituted C1-8 alkyl, -NR8R9 , -NHS(O)2R19 or hydroxyl; R17 is OR10 or NR8R9; R18 is OR10 or NR8R9; R19 is substituted or unsubstituted cycle, substituted or tituted C3-8 cycloalkyl, substituted or unsubstituted C6-10 aryl or substituted or unsubstituted C3-8 cycloalkenyl; R20 is hydrogen, tuted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C6-10 aryl; R21 is en, substituted or unsubstituted C1-8 alkyl substituted or tituted C3-8 cycloalkyl, substituted or unsubstituted cycle, or substituted or unsubstituted C6-10 aryl; R22 is hydrogen, substituted or unsubstituted C1-8 alkyl, or together with R23 can form a cycle; R23 is hydrogen, substituted or unsubstituted C1-8 alkyl, or together with R22 can form a cycle; R24 is hydrogen, substituted or unsubstituted C1-8 alkyl substituted or unsubstituted C3-8 cycloalkyl, substituted or tituted heterocycle, or substituted or unsubstituted C6-10 aryl.

The term ”, as used herein, refers to ted, monovalent or nt hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 8 carbon atoms. One methylene (- CH2-) group, of the alkyl group can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, e, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group.

Alkyl groups can have one or more chiral centers. Alkyl groups can be independently substituted by halogen atoms, hydroxyl groups, cycloalkyl groups, amino , heterocyclic groups, aryl groups, carboxylic acid groups, phosphonic acid groups, sulphonic acid groups, oric acid groups, nitro , amide groups, sulfonamide groups.

The term “cycloalkyl”, as used herein, refers to a monovalent or nt group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon. lkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C1-8 alkyl , ide C1-8 alkyl groups, sulfonamide , nitro groups, cyano groups, - OC1-8 alkyl groups, -SC1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups, ketone groups, alkylamino , amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups..

The term “cycloalkenyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cycloalkyl having at least one double bond. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be independently substituted by n atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.

The term “halogen”, as used herein, refers to an atom of chlorine, bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one double bond. One methylene (-CH2-) group, of the alkenyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. C 2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by alkyl groups, as defined above or by halogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a ted alkyl, having at least one triple bond. One methylene (-CH2-) group, of the alkynyl can be replaced by oxygen, sulfur, ide, en, yl, carboxyl, sulfonyl, e, sulfonate, amide, sulfonamide, by a divalent C 3-8 cycloalkyl, by a divalent heterocycle, or by a divalent aryl group. Alkynyl groups can be substituted by alkyl groups, as defined above, or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 ed ring, which can be aromatic or non-aromatic, ted or unsaturated, ning at least one heteroatom selected form oxygen, en, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by a C=O; the S and N heteroatoms can be oxidized.

Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone groups, alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.

The term “aryl” as used , refers to an organic moiety derived from an aromatic arbon consisting of a ring containing 6 to 10 carbon atoms, by removal of one hydrogen atom. Aryl can be substituted by halogen atoms, sulfonyl C1-6 alkyl groups, sulfoxide C 1-6 alkyl groups, sulfonamide groups, carboxcyclic acid groups, C1-6 alkyl carboxylates (ester) groups, amide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, - C2-6 alkynyl groups , ketone , aldehydes, alkylamino groups, amino groups, aryl , C3-8 cycloalkyl groups or hydroxyl . Aryls can be monocyclic or polycyclic.

The term “hydroxyl” as used herein, represents a group of formula “–OH”.

The term “carbonyl” as used herein, represents a group of formula “- C(O)-“.

The term “ketone” as used herein, represents an organic compound having a carbonyl group linked to a carbon atom such as x wherein Rx can be alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “amine” as used herein, represents a group of formula “-NRxRy “,wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “carboxyl” as used herein, represents a group of formula “- C(O)O-“.

The term “sulfonyl” as used herein, represents a group of formula “-SO2-”.

The term “sulfate” as used herein, represents a group of a “-OS The term “sulfonate” as used herein, represents a group of the formula “- O-”.

The term xylic acid” as used herein, represents a group of formula “-C(O)OH“.

The term “nitro” as used , represents a group of formula “–NO2“.

The term “cyano” as used herein, represents a group of formula “-CN“.

The term “amide” as used herein, represents a group of formula “- C(O)NRxRy,” wherein Rx and Ry can be the same or independently H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle as defined above.

The term “sulfonamide” as used , represents a group of formula “- S(O)2NRxRy” wherein Rx and Ry can be the same or independently H, alkyl, aryl, lkyl, cycloalkenyl, heterocycle as defined above.

The term “sulfoxide” as used herein, represents a group of formula “- S(O)-”.

The term “phosphonic acid” as used herein, represents a group of formula “-P(O)(OH)2”.

The term “phosphoric acid” as used herein, represents a group of formula “-OP(O)(OH)2”.

The term “sulphonic acid” as used herein, represents a group of formula “-S(O)2OH“.

The formula “H “, as used herein, represents a en atom.

The formula “O “, as used herein, represents an oxygen atom.

The formula “N “, as used herein, represents a nitrogen atom.

The formula “S “, as used herein, represents a sulfur atom.

In another aspect, agonists of FPR2 are compounds selected from Table Table 1 FPR2 IUPAC name HO Structure EC50 (efficacy) 2-({[(4- chlorophenyl)amino]carbonyl}amino) 110 nM phenylpropanoic acid (1.0) (2S)({[(4- methoxyphenyl)amino]carbonyl}amino) 1754 nM nylpropanoic acid (0.90) H H (2S)phenyl[({[4- N N HO (trifluoromethyl)phenyl]amino}carbonyl) 120 nM O F amino]propanoic acid (0.97) -({[(3,4- dichlorophenyl)amino]carbonyl}amino)- 10 μM 3-phenylpropanoic acid (0.57) O (2S)({[(4- H H N N HO nitrophenyl)amino]carbonyl}amino) 574 nM phenylpropanoic acid O O- (0.82) 3-phenyl[({[4- (trifluoromethoxy)phenyl]amino}carbon 1572 nM yl)amino]propanoic acid (0.79) 2-({[(3,4- dimethoxyphenyl)amino]carbonyl}amin 2793 nM henylpropanoic acid (0.72) methyl 2-({[(4- iodophenyl)amino]carbonyl}amino) 14.3 nM phenylpropanoate (1.0) (2S)({[(4- bromophenyl)amino]carbonyl}amino)- 31 nM 3-phenylpropanoic acid (1.0) H H (2R)({[(4- N N HO bromophenyl)amino]carbonyl}amino)- 1819 nM O 3-phenylpropanoic acid Br (0.99) yl{[(pyridin ylamino)carbonyl]amino}propanoic acid >10000 nM (2S,3S)({[(4- bromophenyl)amino]carbonyl}amino)- 4.1 nM 3-methylpentanoic acid (0.89) (2S)-({[(4- bromophenyl)amino]carbonyl}amino)(p 25.8 nM henyl)acetic acid (0.94) 2-({[(4- bromophenyl)amino]carbonyl}amino)- 3-(1H-indolyl)propanoic acid 67.0 nM (0.89) (2S)({[(4- bromophenyl)amino]carbonyl}amino)- 72 nM 3-methylbutanoic acid (0.91) (2S)({[(4-bromo fluorophenyl)amino]carbonyl}amino) 152 nM methylbutanoic acid (0.91) US 2005/0137230 A1 and US 3 disclose inhibitors of coagulation Factor Xa and can be employed for the prophylaxis and/or therapy of oembolic diseases and or the treatment of tumors. 2-({[(4- chlorophenyl)amino]carbonyl}amino)phenylpropanoic acid, (2S)({[(4- methoxyphenyl)amino]carbonyl}amino)phenylpropanoic acid, (2S)phenyl- 2-[({[4-(trifluoromethyl)phenyl]amino} carbonyl)amino]propanoic acid, methyl 2- ({[(4-iodophenyl)amino]carbonyl}amino)phenylpropanoate, (2S)({[(4- bromophenyl) amino]carbonyl}amino)phenylpropanoic acid, (2R)({[(4- bromophenyl)amino] carbonyl}amino)phenylpropanoic acid, are intermediates in the synthesis of urea derivatives as activated blood coagulation factor X (FXa) inhibitors.

JP 63232846 discloses the resolution of N-(p-bromophenylcarbamyl) derivatives ((2S)({[(4-bromophenyl)amino]carbonyl}amino) propanoic acid, (2S,3S)({[(4-bromophenyl)amino]carbonyl}amino) pentanoic acid, 2-({[(4-bromophenyl)amino]carbonyl}amino)(1H-indol- ropanoic acid, (2S)({[(4-bromophenyl)amino]carbonyl}amino) methylbutanoic acid) on HPLC column with novel chromatographic chiral stationary phases.

Journal of Chromatography (1987), , 117-22 and Chromatographia (1987), 23(10), 727-30 describe the resolution of p-Bromophenylcarbamyl derivatives of enantiomeric protein amino acids 2-({[(4- bromophenyl)amino]carbonyl}amino)phenylpropanoic acid, (2S)({[(4- bromophenyl)amino]carbonyl}amino)phenylpropanoic acid), on novel chiral stationary phase by elution with an aqueous mobile phase.

Biochimica et Biophysica Acta, Nucleic Acids and Protein Synthesis , 272(4), 667-71 describes compound (2S)({[(4- nitrophenyl)amino]carbonyl}amino)phenylpropanoic acid) in poly(uridylic acid)-dependent binding of para nitrophenyl-carbamyl-phenylalanyl tRNA .

In another , agonists of FPR2 are compounds ed from Table Table 2 Structure FPR2 Ga16-CHO IUPAC name EC50 (efficacy) 1-(4-chlorophenyl)(2,4-dioxo- 49 nM 1,3-diazaspiro[4,5]decanyl) (0.98) urea 1-(4-chlorophenyl)(4-ethyl 157 nM methyl-2,5-dioxoimidazolidin (0.96) 1-[4-methyl-2,5-dioxo(2- 223 nM phenylethyl)imidazolidinyl] (1.0) phenylurea HN N N H 1-(8-methyl-2,4-dioxo-1,3- N 363 nM diazaspiro[4,5]decanyl)(p- O O (0.91) tolyl)urea 1-(2-fluorophenyl)[4-methyl- 258 nM 2,5-dioxo(2- (0.94) phenylethyl)imidazolidinyl]urea Compounds of Table 2 are available from Chemical Libraries such as Aurora Fine Chemicals.

In another aspect, agonists of FPR2 are compounds selected from Table Table 3 FPR2 Ga16-CHO Structure IUPAC name EC50 (efficacy) HN N H N-(4-bromophenyl)(4,4-dimethyl- N 719 nM 2,5-dioxoimidazolidinyl)acetamide O (0.94) HN N H N N-(4-bromophenyl)(4,4-diethyl- 96 nM O O 2,5-dioxoimidazolidinyl)acetamide (0.98) HN N H N-(4-bromophenyl)(2,4-dioxo-1,3- N 738 nM diazaspiro[4.5]decyl)acetamide (0.89) HN N H N-(4-bromophenyl)(2,4-dioxo-1,3- N 322 nM diazaspiro[4.4]nonyl)acetamide O O (0.96) HN N H N N-(4-bromophenyl)(2,5-dioxo-4,4- 645 nM O O dipropylimidazolidinyl)acetamide (0.98) HN N H N-(4-bromophenyl)(4-ethyl-2,5- N 523 nM dioxophenylimidazolidin O O (0.83) tamide HN N H N-(4-bromophenyl)(4-cyclopropyl- N 166 nM 4-methyl-2,5-dioxoimidazolidin O O (0.84) yl)acetamide HN N H N-(4-bromophenyl)(2,4-dioxo-1,3- N 679 nM diazaspiro[4.6]undecyl)acetamide O (0.96) HN N H N-(4-bromophenyl)(4-ethyl N 485 nM methyl-2,5-dioxoimidazolidin (1.0) O O tamide HN N H N N-(4-chlorophenyl)(4,4-diethyl- 314 nM O O 2,5-dioxoimidazolidinyl)acetamide (0.79) HN N H N 2-(4,4-diethyl-2,5-dioxoimidazolidin- 2771 nM O O 1-yl)-N-(4-fluorophenyl)acetamide (0.67) HN N H N-(4-bromophenyl)[4-methyl-2,5- N 860 nM dioxo(2-phenylethyl)imidazolidin- O O (0.88) 1-yl]acetamide N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-4,7-methano- (0.90) 2H-isoindoleacetamide N-(4-bromophenyl)-1,3,3a,4,7,7a- hexahydro-1,3-dioxo-2H-isoindole (0.98) acetamide The nds of Table 3 are available from Chemical Libraries such as Chemical Block Ltd.

In a further embodiment described , there are described methods for treating disorders associated with modulation of the FPR2 Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a eutically effective amount of at least one compound described .

Therapeutic utilities of the FPR2 are ocular inflammatory diseases including, but not limited to, wet and dry age-related macular degeneration , uveitis, dry eye, Keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration ing non-exudative age related r ration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy (proliferative), pathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and ic macular edema; infectious keratitis, herpetic keratitis, l angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, ’s e, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, ior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/ exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, cystoids macular edema, disseminated intravascular coagulopathy, branch l vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat’s disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, d artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative retinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, post-surgical corneal wound healing, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome , endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral tis, acute l necrosis, progressive outer retinal necrosis, fungal retinal es, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; c disorders such as retinitis pigmentosa, systemic disorders with accosiated retinal dystrophies, congenital nary night blindness, cone dystrophies, Stargardt’s e and fundus flavimaculatus, Best’s disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby’s fundus dystrophy, benign tric maculopathy, Bietti’s crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal e ated with tumors, congenital hypertrophy of the retinal pigmented lium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular , retinal ytoma, and intraocular id ; and miscellaneous other diseases affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior ocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis, systemic inflammatory diseases such as stroke, coronary artery disease, obstructive airway diseases, HIV-mediated retroviral infections, cardiovascular disorders including coronary artery disease, neuroinflammation, neurological disorders, pain and immunological disorders, asthma, allergic disorders, inflammation, systemic lupus erythematosus, psoriasis, CNS disorders such as Alzheimer’s disease, arthritis, sepsis, inflammatory bowel disease, cachexia, angina pectoris, post-surgical corneal inflammation, blepharitis, MGD, dermal wound healing, burns, rosacea, atopic dermatitis, acne, psoriasis, heic dermatitis, actinic keratoses, viral warts, photoaging rheumatoid tis and related inflammatory disorders, alopecia, glaucoma, branch vein occlusion, Best’s vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other rative disease of either the photoreceptors or the RPE (Perretti, Mauro et al.

Pharmacology & Therapeutics 127 (2010) 175-188.) These compounds are useful for the treatment of mammals, including , with a range of conditions and diseases that are alleviated by the modulation of FPR2 : including, but not limited to the treatment of wet and dry age-related macular degeneration , diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), diabetic macular edema, uveitis, dry eye, retinal vein occlusion, cystoids macular edema, glaucoma, branch vein occlusion, Best’s vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE.

In still another ment described , there are described methods for treating disorders ated with tion of the FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound bed , or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereisomers thereof.

The actual amount of the compound to be administered in any given case will be determined by a ian taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient’s general physical condition, the cause of the condition, and the route of administration.

The patient will be stered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, ermal, parenteral, aneous, intranasal, via an t stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy.

In another embodiment of the disclosure, there are described pharmaceutical compositions including at least one compound described herein in a pharmaceutically acceptable carrier thereof. The phrase "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions described herein can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds bed herein, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Compounds described herein may be combined, for example, with the usual non-toxic, pharmaceutically acceptable rs for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form le for use. The rs which can be used include glucose, lactose, gum acacia, gelatin, ol, starch paste, magnesium trisilicate, talc, corn , keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and es may be used. Compounds described herein are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition. ceutical compositions containing compounds described herein may be in a form suitable for oral use, for e, as tablets, troches, lozenges, aqueous or oily suspensions, sible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions ed for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets containing compounds described herein in admixture with non-toxic ceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, m phosphate or sodium ate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium te, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the intestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

In some cases, ations for oral use may be in the form of hard gelatin capsules wherein the compounds described herein are mixed with an inert solid diluent, for example, calcium carbonate, calcium ate or kaolin.

They may also be in the form of soft gelatin capsules wherein the compounds bed herein are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions containing compounds described herein may be in a form le for topical use, for example, as oily suspensions, as solutions or suspensions in aqueous liquids or nonaqueous liquids, or as oil-in-water or water-in-oil liquid ons.

Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound ing to the present disclosure, or a pharmaceutically acceptable salt thereof, as an active ingredient with conventional lmically acceptable pharmaceutical excipients and by preparation of unit dosage suitable for topical ocular use. The therapeutically efficient amount typically is between about 0.001 and about 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquid formulations.

For ophthalmic application, preferably solutions are prepared using a physiological saline solution as a major vehicle. The pH of such ophthalmic solutions should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a neutral pH being preferred but not essential. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.

Preferred preservatives that may be used in the pharmaceutical compositions described herein include, but are not limited to, konium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate.

A preferred surfactant is, for e, Tween 80. Likewise, various preferred vehicles may be used in the ophthalmic preparations described herein. These vehicles include, but are not d to, polyvinyl alcohol, ne, ypropyl methyl ose, poloxamers, carboxymethyl ose, hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or ient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as .

In a similar manner an ophthalmically acceptable antioxidant for use herein includes, but is not limited to, sodium metabisulfite, sodium lfate, acetylcysteine, butylated hydroxyanisole and ted hydroxytoluene.

Other excipient components which may be included in the ophthalmic preparations are chelating . The preferred chelating agent is edentate disodium, although other chelating agents may also be used in place of or in conjunction with it.

The ingredients are usually used in the following amounts: Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10 pH adjustor q .s. pH 8 antioxidant as needed surfactant as needed purified water to make 100% The actual dose of the active compounds described herein depends on the specific compound, and on the ion to be treated; the selection of the appropriate dose is well within the dge of the skilled artisan.

The ophthalmic formulations described herein are conveniently packaged in forms suitable for metered application, such as in containers equipped with a dropper, to facilitate ation to the eye. Containers suitable for dropwise application are usually made of suitable inert, xic plastic material, and generally contain n about 0.5 and about 15 ml solution. One package may contain one or more unit doses. Especially preservative-free solutions are often ated in non-resealable containers containing up to about ten, preferably up to about five units doses, where a typical unit dose is from one to about 8 drops, preferably one to about 3 drops. The volume of one drop usually is about 20-35 µl.

The pharmaceutical compositions may be in the form of a sterile able suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending .

The sterile able preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a on in 1,3-butanediol. e, fixed oils are tionally employed as a solvent or suspending . For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as ed.

The compounds described herein may also be stered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the compounds described herein with a suitable nonirritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

Since dual subjects may present a wide variation in severity of ms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein are useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of FPR2. Thus, in further ments described herein, there are described methods for treating a er associated with modulation of FPR2. Such methods can be performed, for example, by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound described herein. As used herein, the term "therapeutically effective amount" means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.

As used herein the term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification, and claims which include the term “comprising”, it is to be understood that other features that are additional to the features prefaced by this term in each ent or claim may also be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

Materials and Methods FPR2 agonists would be expected to have significant effects in many ent types of ocular inflammation, but have been exemplified by demonstrating anti-inflammatory ty in endotoxin-induced uveitis in rats (Figures 1 and 2). Anti-inflammatory activity in this model has been exemplified with the FPR2 agonists described in Table 4.

FLIPR: HEK-Gα16 cells stably sing the human FPR2 or was utilized. Cells were plated into 384-well poly-D-lysine coated plates at a y of 18,000 cells per well one day prior to use. The growth media was DMEM medium supplemented with 10% fetal bovine serum (FBS), 1% antibioticantimycotic , 50 µg/ml ycin, and 400 µg/ml geneticin. On the day of the experiment, the cells were washed twice with Hank’s Balanced Salt Solution supplemented with 20 mM HEPES (HBSS/hepes buffer). The cells were then dye loaded with 2 µM Fluo-4 diluted in the HBSS/Hepes buffer and incubated at 37oC for 40 minutes. Extracellular dye was removed by washing the cell plates four times prior to placing the plates in the FLIPR ometric Imaging Plate Reader, Molecular Devices). Ligands were diluted in HBSS/Hepes buffer and prepared in 384-well microplates. Data for Ca+2 responses were obtained in relative fluorescence units.

Table 4 Compound IUPAC name FPR2 number Structure EC50 (efficacy) 1 1-(4-bromophenyl)[4-ethyl- 2,5-dioxo(2- phenylethyl)imidazolidin 3.0 yl]urea (0.96) 2 {[(4- bromophenyl)carbamoyl]ami 2 no}pentanoyl]amino}acetic (0.91) acid 3 {[(2S,3S){[(4- O O bromophenyl)carbamoyl]ami H 1.98 no} N N OH (1.0) methylpentanoyl]amino}aceti H H O c acid 4 1-(4-bromophenyl)[4-ethyl- 2,5-dioxo(propan yl)imidazolidinyl]urea 6.7 (0.90) (2S,3S){[(4-bromo fluorophenyl)carbamoyl]amin o}methylpentanoic acid (0.96) 6 2-{[(2S){[(4- bromophenyl)carbamoyl]ami 1.66 no} (0.91) methylpentanoyl]amino} methylpropanoic acid 7 {[(4-bromo fluorophenyl)carbamoyl]amin o} 3.57 methylpentanoyl]amino}aceti (1.0) c acid 8 {[(2S){[(4- bromophenyl)carbamoyl]ami 0.78 no} (0.78) methylpentanoyl]amino}aceti c acid 9 (2S){[(4- bromophenyl)carbamoyl]ami 5.95 no}methylpentanoic acid (0.77) 2-{[(4- Br bromophenyl)carbamoyl]ami O O 11 nM H no}-N-(2-oxoazepanyl) N N NH (0.89) H H phenylpropanamide 11 3-[(4- iodophenyl)carbamoyl]spiro[b I icyclo[2.2.1]heptane-7,1'- 1.6 nM cyclopropane]ene (1.00) N carboxylic acid O H 12 OH 3-[(4- O bromophenyl)carbamoyl]spir Br 4 nM o[bicyclo[2.2.1]heptane-7,1'- (0.97) N cyclopropane]ene O H carboxylic acid 13 N cetylphenyl){3-(4- O cyanophenyl)[2-(1H- 11 nM O imidazolyl)ethyl]oxo- N 1,2,3,4-tetrahydroisoquinolin- (0.80) N N H H NH O N 7-yl}urea 14 R,3S)[(4- henyl)carbamoyl]spir 4 nM CO2H o[bicyclo[2.2.1]heptane-7,1'- (0.90) cyclopropane]carboxylic O N Br H acid 3-[(4- iodophenyl)carbamoyl]spiro[b 0.60 nM CO2H icyclo[2.2.1]heptane-7,1'- (0.87) cyclopropane]carboxylic O N I H acid 16 N 1-[2-(3-aminopropyl)(4- cyanophenyl)oxo-1,2,3,4- S 2.5 nM O tetrahydroisoquinolinyl] N NH2 (0.70) N N [4- H H O (methylsulfanyl)phenyl]urea 17 1-{3-(4-cyanophenyl)[2- N (1H-imidazolyl)ethyl] S oxo-1,2,3,4- 5.5 nM N tetrahydroisoquinolinyl} (0.92) N N H H NH [4- O N (methylsulfanyl)phenyl]urea 18 N 1-[2-(3-aminopropyl)(4- O O cyanophenyl)oxo-1,2,3,4- S 10 nM O tetrahydroisoquinolinyl] N NH2 (0.86) N N [4- H H O (methylsulfonyl)phenyl]urea 19 1-{3-(4-cyanophenyl)[2- (1H-imidazolyl)ethyl] O O S oxo-1,2,3,4- 20 nM N tetrahydroisoquinolinyl} (1.00) N N H H NH [4- O N (methylsulfonyl)phenyl]urea 3-[(4-iodophenyl)carbamoyl]- 7-(propan ylidene)bicyclo[2.2.1]hept 11 nM CO2H enecarboxylic acid (0.94) O N I 21 3-[(4- bromophenyl)carbamoyl]-7,7- nM CO2H dimethylbicyclo[2.2.1]heptan (0.85) rboxylic acid O N Br 22 3-[(4-iodophenyl)carbamoyl]- 7,7- 1.7 nM CO2H dimethylbicyclo[2.2.1]heptan (0.97) ecarboxylic acid O N I 23 O furanyl)[2-(1H- O imidazolyl)ethyl]oxo- N 19 nM N N 1,2,3,4-tetrahydroisoquinolin- H H NH (0.83) O N 7-yl}[4- (methylsulfanyl)phenyl]urea 24 F 5-fluoropyridinyl) S [2-(1H-imidazolyl)ethyl] O N 11.8 nM N oxo-1,2,3,4- N N (0.93) H H NH tetrahydroisoquinolinyl} O N [4-(methylsulfinyl)phenyl]urea 1-{3-(5-fluoropyridinyl) O O [2-(1H-imidazolyl)ethyl] O N oxo-1,2,3,4- 10.5 nM N N tetrahydroisoquinolinyl} (1.0) H H NH O N [4- (methylsulfonyl)phenyl]urea 26 N-(4- bromophenyl)spiro[bicyclo[2. 4.8 nM 2.1]heptane-7,1'- (0.91) cyclopropane]ene-2,3- dicarboxamide 27 Cl 1-{3-(5-chlorofuranyl)[2- O (1H-imidazolyl)ethyl] O oxo-1,2,3,4- 17 nM N N NH tetrahydroisoquinolinyl} (0.81) H H O N [4- lsulfanyl)phenyl]urea 28 Cl 1-{3-(6-chloropyridinyl) S N O [2-(1H-imidazolyl)ethyl] N 2,3,4- 6.3 nM N N H H NH O N tetrahydroisoquinolinyl} (0.89) (methylsulfanyl)phenyl]urea 29 3-{[4- (methylsulfanyl)phenyl]carba 7 nM moyl}spiro[bicyclo[2.2.1]hept (0.96) ane-7,1'-cyclopropane] carboxylic acid N-(4- bromophenyl)spiro[bicyclo[2. 2.5 nM 2.1]heptane-7,1'- (0.96) cyclopropane]-2,3- dicarboxamide 31 3-{[4- (methylsulfanyl)phenyl]carba moyl}spiro[bicyclo[2.2.1]hept 14 nM ane-7,1'-cyclopropane] (0.85) enecarboxylic acid 32 Cl 1-{3-(5-chloropyridinyl) S [2-(1H-imidazolyl)ethyl] O N N oxo-1,2,3,4- 13.5 nM N N H H NH tetrahydroisoquinolinyl} (0.91) O N (methylsulfanyl)phenyl]urea 33 Cl 1-{3-(5-chloropyridinyl) O O S [2-(1H-imidazolyl)ethyl] O N N oxo-1,2,3,4- 9.5 nM N N H H NH tetrahydroisoquinolinyl} (0.99) O N (methylsulfonyl)phenyl]urea 34 romophenyl)-7,7- dimethylbicyclo[2.2.1]heptan e-2,3-dicarboxamide 15 nM (0.83) N-(4-iodophenyl)-7,7- dimethylbicyclo[2.2.1]heptan e-2,3-dicarboxamide 2.6 nM (0.81) 36 (+)1-[(3R)(3-aminopropyl)- 3-(4-cyanophenyl)oxo- 3.3 nM 1,2,3,4-tetrahydroisoquinolin- (0.97) 3-[4- lsulfanyl)phenyl]urea 37 7,7-dimethyl-N-[4- (methylsulfanyl)phenyl]bicycl o[2.2.1]heptane-2,3- 17 nM dicarboxamide (0.85) 38 N-(4- enyl)spiro[bicyclo[2.2. 1.9 nM 1]heptane-7,1'- (0.95) cyclopropane]-2,3- dicarboxamide 39 N-(4- iodophenyl)spiro[bicyclo[2.2. 1.6 nM 1]heptane-7,1'- (0.90) cyclopropane]ene-2,3- dicarboxamide 40 (+) tert-butyl {3-[(3R)(4- cyanophenyl)({[4- (methylsulfinyl)phenyl]carba 103 nM moyl}amino)oxo-3,4- (0.91) dihydroisoquinolin-2(1H)- yl]propyl}carbamate 41 (+) 1-[(3R)(3- aminopropyl)(4- .6 nM cyanophenyl)oxo-1,2,3,4- (0.94) tetrahydroisoquinolinyl] [4-(methylsulfinyl)phenyl]urea 42 S 1-[2-(3-aminopropyl) methyloxo-1,2,3,4- N NH2 N N ydroisoquinolinyl] 15 nM H H O [4- (1.00) (methylsulfanyl)phenyl]urea 43 N 1-[2-(3-aminopropyl)(4- cyanophenyl)oxo-1,2,3,4- O 13.7 nM tetrahydroisoquinolinyl] N NH2 (0.94) N N (4-iodophenyl)urea H H 44 (+) (2S,3R)[(4- bromophenyl)carbamoyl]spir o[bicyclo[2.2.1]heptane-7,1'- <1 nM cyclopropane]carboxylic (0.98) acid 45 (-) N-(4- bromophenyl)spiro[bicyclo[2. 2.1]heptane-7,1'- <1 nM cyclopropane]-2,3- (0.91) dicarboxamide 46 N-(4-bromophenyl)-N'- methylspiro[bicyclo[2.2.1]hep N tane-7,1'-cyclopropane]-2,3- 8.5 nM (1.0) O dicarboxamide O N Br 47 N-(4-bromophenyl)-N'- H ethylspiro[bicyclo[2.2.1]hepta N '-cyclopropane]-2,3- 9.3 nM dicarboxamide (1.0) O N Br 48 N-(4-bromophenyl)-N'- (propan NH yl)spiro[bicyclo[2.2.1]heptane 6.7 nM -7,1'-cyclopropane]-2,3- (1.0) O N Br dicarboxamide 49 O 1-(4-bromophenyl)(4,4- HN N N H diethyl-2,5-dioxoimidazolidin- N 11.5 nM 1-yl)urea O O (0.98) 50 O HN 1-(4-bromo N N H F N fluorophenyl)(4,4-diethyl- 15.7 nM O O 2,5-dioxoimidazolidin (1.0) 51 (2S){[(4- iodophenyl)carbamoyl]amino} 14.5 nM phenylpropanoic acid (1.0) 52 O 1-(4-bromophenyl)(2,4- HN N N H dioxo-1,3-diazaspiro[4.5]dec- N 3-yl)urea 15.1 nM O O (1.0) (2S,3S){[(4- 12.9 nM bromophenyl)carbamoyl]ami (0.9) no}methylpentanoic acid 54 O 1-(4-bromophenyl)[4- HN N H methyl-2,5-dioxo(2- N phenylethyl)imidazolidin 5.1 nM O O yl]urea (0.87) 55 {[(4- henyl)carbamoyl]ami 7.7 nM no} (0.99) phenylpropanoyl]amino}aceti c acid 56 3-{[(2S){[(4- bromophenyl)carbamoyl]ami 18 nM no} (0.98) phenylpropanoyl]amino}prop anoic acid 57 (+) 1-(4-bromophenyl)[4- methyl-2,5-dioxo(2- phenylethyl)imidazolidin 3.2 nM yl]urea (0.93) (2S){[(4- 7.0 nM bromophenyl)carbamoyl]ami (0.86) no}-N-(2-hydroxyethyl) phenylpropanamide 59 {[(2S,3S){[(4-bromo fluorophenyl)carbamoyl]amin .5 nM o} (0.95) methylpentanoyl]amino}aceti c acid 60 (2S,3S)-N-(2-amino oxoethyl){[(4- 4.6 nM henyl)carbamoyl]ami (0.91) no}methylpentanamide 61 O 1-(4-bromofluorophenyl)- HN N H 3-[4-ethyl-2,5-dioxo N F N (propanyl)imidazolidin 9.2 nM O O yl]urea (0.97) )-N-(2-amino .3 nM oxoethyl){[(4-bromo (1.0) fluorophenyl)carbamoyl]amin ethylpentanamide 63 (2S,3S){[(4- bromophenyl)carbamoyl]ami .5 nM no}methyl-N-(2- (0.97) pyl)pentanamide 64 O 1-(4-bromophenyl)[2,5- H dioxo-4,4-di(propan HN N N H N yl)imidazolidinyl]urea 3.8 nM O O (1.0) 65 O 1-(4-bromophenyl)(4,4- H dicyclopropyl-2,5- HN N N H N dioxoimidazolidinyl)urea 14.3 nM O O (1.0) 66 (+)1-(4-bromophenyl)[4- ethyl-2,5-dioxo(propan yl)imidazolidinyl]urea 4.3 nM (0.96) 67 (-)1-(4-bromophenyl)[4- ethyl-2,5-dioxo(propan yl)imidazolidinyl]urea 3.3 nM (1.0) 68 (2S){[(4-bromo fluorophenyl)carbamoyl]amin 12.4 nM o}-N-(2-oxopropyl) (0.94) phenylpropanamide 69 O 1-(4-bromofluorophenyl)- HN 3-[4-ethyl-2,5-dioxo(2- N N H F N phenylethyl)imidazolidin 13.4 nM (0.91) O O yl]urea 70 (2S){[(4- bromophenyl)carbamoyl]ami 7.1 nM no}pentanoic acid (1.0) 71 (2S){[(4-bromo fluorophenyl)carbamoyl]amin 15.6 nM o}-N-(2-hydroxyethyl) (0.98) phenylpropanamide 72 O methyl {[(2S){[(4- H H O N N bromophenyl)carbamoyl]ami 16.4 nM H no}pentanoyl]amino}acetate (0.86) O O 73 propanyl {[(2S){[(4- bromophenyl)carbamoyl]ami 14.5 nM no}pentanoyl]amino}acetate (1.0) 74 {[(2S){[(4-bromo phenyl)carbamoyl]amin 4.1 nM o}pentanoyl]amino}acetic (0.91) acid 75 (2S){[(4- bromophenyl)carbamoyl]ami 13.5 nM (2-hydroxyethyl) (0.76) methylpentanamide 76 O 1-(4-bromophenyl){4-[2- HN (furanyl)ethyl]methyl- N N H N 2,5-dioxoimidazolidin 5.2 nM O yl}urea (0.99) (2S)-N-(2-aminooxoethyl)- 1.1 nM 2-{[(4- (1.0) bromophenyl)carbamoyl]ami no}methylpentanamide 78 (2S){[(4- bromophenyl)carbamoyl]ami 4.7 nM no}methyl-N-(2- (0.82) oxopropyl)pentanamide 79 (2S)-N-(2-aminooxoethyl)- 2-{[(4- 2.5 nM bromophenyl)carbamoyl]ami (0.97) no}pentanamide 80 O 1-(4-bromophenyl){4-[2-(2- HN N H fluorophenyl)ethyl]methyl- F N N oxoimidazolidin 14.3 nM O O yl}urea (99) 81 (2S)-N-(2-aminooxoethyl)- -bromo 5.2 nM fluorophenyl)carbamoyl]amin (0.96) o}pentanamide 82 O 1-(4-bromophenyl){4-[2-(4- HN N N H fluorophenyl)ethyl]methyl- N 2,5-dioxoimidazolidin 16.3 nM F O O yl}urea (1.0) 83 O 1-(4-bromophenyl){4-[2-(3- HN phenyl)ethyl]methyl- N N H N 2,5-dioxoimidazolidin 11.1 nM O O yl}urea (1.0) F Br 84 (2S)-N-(2-aminooxoethyl)- 2-{[(4-bromo 4.5 nM phenyl)carbamoyl]amin (0.95) o}methylpentanamide 85 (2S){[(4-bromo fluorophenyl)carbamoyl]amin 20 nM o}methyl-N-(2- (0.99) oxopropyl)pentanamide 86 O 1-(4-bromophenyl){4-[2-(4- HN N N H hydroxyphenyl)ethyl] N methyl-2,5-dioxoimidazolidin- 13.3 nM HO O O 1-yl}urea (1.0) 87 (2S){[(2S){[(4-bromo fluorophenyl)carbamoyl]amin 12.1 nM o} (0.95) methylpentanoyl]amino}prop anoic acid 88 O 1-(4-bromophenyl){4- HN methyl-2,5-dioxo[2- N N H N (thiophen 7.9 nM O O yl)ethyl]imidazolidinyl}urea (0.94) 89 O 1-(4-bromofluorophenyl)- HN N N H 3-{4-[2-(4- N hydroxyphenyl)ethyl] 8.7 nM HO O O methyl-2,5-dioxoimidazolidin- (0.85) 1-yl}urea 90 -{[(2S){[(4- bromophenyl)carbamoyl]ami 11.6 nM no} (1.0) methylpentanoyl]amino}prop anoic acid 91 (2S){[(2S){[(4- bromophenyl)carbamoyl]ami 1.7 nM no} (0.97) methylpentanoyl]amino} methylbutanoic acid 92 (2S)-N-[(2S)amino methyloxobutanyl] .8 nM {[(4- (1.0) bromophenyl)carbamoyl]ami no}methylpentanamide 93 (2S){[(4- bromophenyl)carbamoyl]ami 2.5 nM no}-N-(2-hydroxy (0.93) propyl) methylpentanamide 94 (2S){[(4- bromophenyl)carbamoyl]ami 7.4 nM no}-N-(1,3-dihydroxypropan- (0.96) 2-yl)methylpentanamide 95 (2S){[(4- bromophenyl)carbamoyl]ami 5.1 nM no}-N-(2,3-dihydroxypropyl)- (0.98) 4-methylpentanamide 96 (2S){[(4- bromophenyl)carbamoyl]ami 3.0 nM no}-N-[(2R) (1.0) hydroxypropanyl] methylpentanamide 97 O 1-(4-bromophenyl){4- HN N H methyl[2-(5-methylfuran N yl)ethyl]-2,5- 3.5 nM O O dioxoimidazolidinyl}urea (0.95) 98 O 1-(4-bromofluorophenyl)- F HN N N H 3-{4-[2-(3-fluoro N hydroxyphenyl)ethyl] 7.4 nM HO O O methyl-2,5-dioxoimidazolidin- (0.91) 1-yl}urea 99 O 1-(4-bromophenyl){4-[2-(3- HN N H fluoro F N N hydroxyphenyl)ethyl] 8.0 nM HO O O methyl-2,5-dioxoimidazolidin- (1.0) 1-yl}urea 100 tert-butyl (2S){[(2S){[(4- bromophenyl)carbamoyl]ami no} 13.0 nM methylpentanoyl]amino}penta (1.0) noate 101 (2S){[(2S){[(4- bromophenyl)carbamoyl]ami no} 1.0 nM methylpentanoyl]amino}penta (0.95) noic acid (2S)-N-[(2S)amino- 1-oxopentanyl]{[(4- 7.3 nM henyl)carbamoyl]ami (0.99) no}methylpentanamide 103 (2S)-{[(2S){[(4- bromophenyl)carbamoyl]ami no} 9.1 nM methylpentanoyl]amino}(phe (1.0) nyl)ethanoic acid (2S){[(4- 2.3 nM bromophenyl)carbamoyl]ami (0.81) no}methyl-N-(1H-tetrazol- -ylmethyl)pentanamide 105 ethyl hydrogen ({[(2S){[(4- bromophenyl)carbamoyl]ami 0.95 nM no} (0.88) pentanoyl]amino}meth sphonate 106 O 1-(4-bromofluorophenyl)- HN N N H 3-{4-[2-(2- N hydroxyphenyl)ethyl] 4.0 nM O O methyl-2,5-dioxoimidazolidin- (0.91) 1-yl}urea OH Br 107 O 1-(4-bromofluorophenyl)- HN N N H F 3-{4-[2-(3- N hydroxyphenyl)ethyl] 2.2 nM O O methyl-2,5-dioxoimidazolidin- (0.79) 1-yl}urea HO Br 108 O 1-(4-bromophenyl){4-[2-(3- HN N N H yphenyl)ethyl] N -2,5-dioxoimidazolidin- 2.1 nM O O 1-yl}urea (1.0) HO Br 109 O 1-(4-bromophenyl){4-[2-(2- HN N N H hydroxyphenyl)ethyl] N methyl-2,5-dioxoimidazolidin- 0.97 nM O O 1-yl}urea (0.93) OH Br 110 2-{[(4- bromophenyl)carbamoyl]ami 19.4 nM 4-dimethylpentanoic (0.98) acid 111 [(2-{[(4- bromophenyl)carbamoyl]ami 19.1 nM no}-2,4- (0.99) dimethylpentanoyl)amino]ace tic acid 112 diethyl ({[(2S){[(4- bromophenyl)carbamoyl]ami no} 0.48 nM methylpentanoyl]amino}meth (0.95) yl)phosphonate 113 (2-{[(4- bromophenyl)carbamoyl]ami 18.7 nM no} (1.0) ethylbutanoyl)amino]acetic acid 114 diethyl ({[(2S,3S){[(4- bromophenyl)carbamoyl]ami no} 2.9 nM methylpentanoyl]amino}meth (1.0) yl)phosphonate 115 ethyl hydrogen ({[(2S,3S) {[(4- 2.7 nM bromophenyl)carbamoyl]ami (0.88) no} methylpentanoyl]amino}meth yl)phosphonate 116 (2S){[(4- bromophenyl)carbamoyl]ami 12.0 nM no}-N-[(3-hydroxy-1,2-oxazol- (1.0) -yl)methyl] methylpentanamide 117 diethyl ({[(2S){[(4- bromophenyl)carbamoyl]ami 0.27 nM no}pentanoyl]amino}methyl)p (1.0) hosphonate 118 diethyl ){[(4- bromophenyl)carbamoyl]ami no} 16.1 nM phenylpropanoyl]amino}meth (0.93) yl)phosphonate 119 diethyl (2-{[(2S){[(4- bromophenyl)carbamoyl]ami 16.1 nM no} (0.97) methylpentanoyl]amino}ethyl) phosphonate (2S){[(4- bromophenyl)carbamoyl]ami 1.7 nM no}-N-[2-(dimethylamino) (0.99) oxoethyl] pentanamide 121 (2S){[(4- iodophenyl)carbamoyl]amino} 4.0 nM methylpentanoic acid (0.93) 122 ){[(4- bromophenyl)carbamoyl]ami 10 μM no}methylpentanoic acid (0.59) 123 ethyl hydrogen ({[(2S){[(4- bromophenyl)carbamoyl]ami 1 nM no}pentanoyl]amino}methyl)p (0.96) hosphonate 124 methyl({[4- (trifluoromethyl)phenyl]carba 1.8 nM moyl}amino)pentanoyl]amino (1.0) }acetic acid 125 dipropanyl ({[(2S){[(4- bromophenyl)carbamoyl]ami 1.2 nM no}pentanoyl]amino}methyl)p (1.0) hosphonate 126 ethyl hydrogen ({[(2S){[(4- henyl)carbamoyl]ami 16.0 nM no} (1.0) phenylpropanoyl]amino}meth yl)phosphonate 127 {[(2S){[(4- bromophenyl)carbamoyl]ami 2.0 nM no} (0.91) methylpentanoyl]amino}meth anesulfonic acid 128 (2S)methyl({[4- (methylsulfanyl)phenyl]carba 16.8 nM moyl}amino)pentanoic acid (0.92) 129 propanyl hydrogen {[(2- {[(4- bromophenyl)carbamoyl]ami 1.87 nM tanoyl)amino]methyl}p (0.89) hosphonate 130 {[(2S)methyl({[4- (methylsulfanyl)phenyl]carba 3.0 nM moyl}amino)pentanoyl]amino (1.0) }acetic acid 131 dipropanyl ){[(4- bromophenyl)carbamoyl]ami 4.0 nM no} (1.0) methylpentanoyl]amino}meth yl)phosphonate 132 O 1-(4-bromophenyl)[4- HN N H (hydroxymethyl)-2,5-dioxo N (propanyl)imidazolidin 16.2 nM HO O O yl]urea (0.86) 133 O 2-[1-{[(4- O H HN N H bromophenyl)carbamoyl]ami HO N N no}-2,5-dioxo(propan 2.7 nM O O yl)imidazolidinyl]-N-(2- (1.0) hydroxyethyl)acetamide 134 diethyl ({[(2S)methyl ({[4- .5 nM (trifluoromethyl)phenyl]carba (0.97) moyl}amino)pentanoyl]amino }methyl)phosphonate 135 ethyl hydrogen ) ({[4- (trifluoromethyl)phenyl]carba 1.9 nM moyl}amino)pentanoyl]amino (0.91) }methyl)phosphonate 136 (2S)methyl-N-(1H-tetrazol- -ylmethyl)({[4- 3.7 nM (trifluoromethyl)phenyl]carba (0.96) moyl}amino)pentanamide 237 {[(2S)methyl({[4- (trifluoromethyl)phenyl]carba 1.9 nM moyl}amino)pentanoyl]amino (0.99) }methanesulfonic acid 138 diethyl ({[(2S)methyl ({[4- 3.5 nM (methylsulfanyl)phenyl]carba (0.91) moyl}amino)pentanoyl]amino }methyl)phosphonate 139 2-methyl{[(2S)methyl ({[4- 2.5 nM (trifluoromethyl)phenyl]carba (0.92) moyl}amino)pentanoyl]amino }propanoic acid 140 tert-butyl (2S){[(4- bromophenyl)sulfamoyl]amin o}methylpentanoate NA 141 O methyl 2-[2-(1-{[(4- O H O HN N H bromophenyl)carbamoyl]ami N no}ethyl-2,5- 10.3 nM O O dioxoimidazolidin (0.92) yl)ethyl]benzoate 142 O HO H HN N H 2-[1-{[(4- HO N N bromophenyl)carbamoyl]ami 13.8 nM HN O O 5-dioxo(propan (0.92) O yl)imidazolidinyl]-N-(1,3- Br oxypropan yl)acetamide 143 O 2-[2-(1-{[(4- HO H O HN N N H bromophenyl)carbamoyl]ami N no}ethyl-2,5- 17.2 nM O O dioxoimidazolidin (1.0) Br yl)ethyl]benzoic acid 144 {[(2S){[(4- bromophenyl)carbamoyl]ami 6.3 nM no} (0.91) (methylsulfanyl)butanoyl]ami no}acetic acid 145 O 3-({[1-{[(4-bromo O H HO HN N N H fluorophenyl)carbamoyl]amin N o}-2,5-dioxo(propan 1.0 nM HN O O yl)imidazolidin (1.0) O yl]acetyl}amino)propanoic Br acid 146 O 2-[2-(1-{[(4-bromo HO H O HN N N H F fluorophenyl)carbamoyl]amin N o}ethyl-2,5- 11.1 nM O O dioxoimidazolidin (1.0) yl]benzoic acid 147 O 3-({[1-{[(4- O H HN N bromophenyl)carbamoyl]ami HO N H N no}-2,5-dioxo(propan 3.9 nM HN O O dazolidin (0.99) O yl]acetyl}amino)propanoic Br acid 148 O 2-[1-{[(4-bromo HN N N H phenyl)carbamoyl]amin HO F N o}-2,5-dioxo(propan 6.9 nM HN O O yl)imidazolidinyl]-N-(2- (0.98) O hydroxyethyl)acetamide 149 O ethyl 3-[1-{[(4- HN N N H bromophenyl)carbamoyl]ami O no}-2,5-dioxo(propan 6.6 nM O O yl)imidazolidin (0.94) Br yl]propanoate 150 {[2-{[(4- bromophenyl)carbamoyl]ami no}(1H-indol 1.4 nM yl)propanoyl]amino}acetic (0.98) acid 151 O 2-{2-[1-{[(4- HO H bromophenyl)carbamoyl]ami O HN N N H N no}-2,5-dioxo(propan 5.8 nM O O yl)imidazolidin (1.0) yl]ethyl}benzoic acid 152 O diethyl [2-({[1-{[(4- O H O P HN N N H bromophenyl)carbamoyl]ami O no}-2,5-dioxo(propan 11 nM HN O O yl)imidazolidin (1.0) O yl]acetyl}amino)ethyl]phosph Br onate 153 O ethyl 3-{[(4- HN bromophenyl)carbamoyl]ami N N H N no}-2,4-dioxo-1,3- 12 nM O O diazaspiro[4.5]decane (0.99) O carboxylate 154 tert-butyl {[(4- bromophenyl)carbamoyl]ami no} 12 nM methylpentanoyl](methyl)ami (0.85) no}acetate {[(2S){[(4- henyl)carbamoyl]ami 1.0 nM no} (1.0) methylpentanoyl](methyl)ami no}acetic acid Immunohistochemistry: Chromagenic DAB histochemistry with antibodies specific to FPR2 was used to determine localization in normal human, primate, and rat eyes. Anti-FPR2 antibody (Abcam) was used at a dilution of 1:200 to detect FPR2 protein in all species.

Endotoxin-induced uveitis in rats: s is a harmful ocular inflammatory condition in humans. Anterior uveitis is a recurrent inflammatory disease and may have potentially blinding consequence.

The pathogenesis of the disease is poorly understood, and the flammatory therapy used is ecific and is associated with significant complications. Animal models are key to tanding the disease and testing novel therapies. A single low dose of lipopolysaccaride (LPS) in the footpad s anterior uveitis in rats.

This model known as endotoxin-induced uveitis serves as a useful paradigm of human anterior uveitis. Male Lewis rats (260 ± 25 grams) were purchased from Charles River Laboratory. Rats were footpadinjected (hind left side) with 100 μl of 1 mg/ml LPS (List Biological Labs) solution (in e 0.9% saline). Test nds were formulated in the e consisting of sodium phosphate, dibasic heptahydrate, salts, CMC and sterile water. Compounds were topically (0.1-1%) or subcutaneously (10mg/kg) dosed 2 hr after LPS. Animals were sacrificed at 24 hours following LPS injection. Aqueous humor was collected and analyzed to determine inflammatory cell counts and total protein concentrations.

Alkali burn in s: Corneal epithelium plays an important role in the maintenance of corneal function and integrity. Prolonged corneal epithelial defects causes corneal opacity, neovascularization, bacterial infection and visual loss. Corneal epithelial healing is a complex process involving matory response to injury, cell proliferation and migration.

Animal models of l injury are every useful to test new antiinflammatory and pro-wound healing therapies. New Zealand White rabbits weighing between 2.1 and 2.5 kg were anesthetized systemically with Ketamine/Xylazine (35/5 mg/kg) subcutaneously and topically with proparacaine (0.5%). The l epithelial wound in one eye was induced with a NaOH saturated filter paper containing 1.0 N NaOH for seconds. The eyes were rinsed with sterile PBS. The corneal wound was confirmed by fluorescein staining with 10% sodium fluorescein (Science Lab Com) and slit lamp photography. Test compounds were formulated in the vehicle bed above. For initial studies compounds were topically dosed three times a day. fication of corneal wound areas was done using Image J software where fluorescing stain green part was traced and converted to total pixel.

The nds below would be expected to have significant s in many different types of ocular inflammation, but have been exemplified by demonstrating anti-inflammatory activity in endotoxin-induced uveitis in rats (Figures 1 and 2). Anti-inflammatory activity in this model has been exemplified with the following FPR2 agonists: In this model the compounds show a strong anti-inflammatory activity in ng the infiltration of neutrophils and protein into the or chamber. In addition FPR2 agonists show accelerated healing and thelialization in mouse models of corneal wound as exemplified by compound {[(2S,3S){[(4- bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid in (Figure 3). These data demonstrate that FPR2 agonists are potent and efficacious anti-inflammatory agents suitable for ocular use in different models of ocular inflammation.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention.

Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any iction, are prior art, or form part of the common general knowledge in the art.

In the description in this ication reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person d in the art and may assist in putting into practice the invention as defined in the claims of this application.

Claims (18)

What is claimed is:

1. A use of at least one formyl peptide receptor 2 (FPR2) agonist of Formula III, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular disease in a patient in need thereof: Formula III R1 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, 4, CN, SR15 or SO2R16; R2 is halogen, optionally tuted C 1-8 alkyl, CF3, OR9, C(O)R10, NO2, 10 NR13R14, CN, SR15 or SO2R16; R3 is en, optionally tuted C1-8 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 5 forms a 10- 6-10 aryl, optionally substituted heterocycle, or together with R or 11- membered polycyclic ring which is optionally tuted; 15 R4 is hydrogen, optionally substituted C 1-8 alkyl, , , , , , , , , , , , , , 5 , , , , , , , , , , ,optionally substituted C3-8 lkyl, optionally substituted C3-8 cycloalkenyl, optionally tuted C 6-10 aryl, optionally 5 substituted heterocycle, or together with R5 forms a spiro monocyclic or polycyclic, carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted; R5 is hydrogen, optionally substituted C 1-8 alkyl, ally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally tuted C 10 4 forms a spiro 6-10 aryl, optionally substituted heterocycle, or together with R monocyclic or polycyclic carbocyclic or heterocyclic, saturated or unsaturated 5 to 10 member ring which is optionally substituted or together with R3 forms a 5 or 6 member ring which is optionally substituted; R6 is halogen, hydrogen, ally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, 15 NR13R14, CN, SR15 or SO2R16; R7 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, 0, NO2, NR13R14, CN, SR15 or SO2R16; R8 is halogen, en, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R9 is hydrogen, C(O)(C1-8 alkyl) or optionally substituted C 1-8 alkyl; R10 is hydrogen, optionally substituted C 1-8 alkyl, O(C 1-8 alkyl), NR11R12 or 5 OH; R11 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R12 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; 10 R13 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R14 is hydrogen, optionally substituted C 6-10 aryl, optionally substituted C 1-8 alkyl, C(O)(C 1-8 alkyl) or SO2(C 1-8 alkyl); R15 is hydrogen, ally substituted C 1-8 alkyl or O(C 1-8 alkyl); 15 R16 is OH, O(C 1-8 alkyl), (C 1-8 alkyl) or NR11R12; R17 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R18 is en, C(O)(C1-8 alkyl), optionally substituted C 6-10 aryl, or optionally substituted C 1-8 alkyl; 20 R19 is hydrogen, 1-8 , optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R20 is hydrogen, optionally substituted C 6-10 aryl or optionally tuted C 1-8 alkyl; R21 is hydrogen, ally substituted C 6-10 aryl or optionally substituted C 1-8 25 alkyl; n is 1, 2, 3, 4, or 5; and m is 1, 2, 3, 4, or 5; wherein the substituent on the optionally substituted C1-8 alkyl is one or more tuents selected from halogen atoms, hydroxyl , C3-8 cycloalkyl 5 groups, amino groups, C3-10 heterocyclic groups, C6-10 aryl groups, carboxylic acid groups, phosphonic acid , sulphonic acid groups, phosphoric acid groups, nitro groups, amide groups, and sulfonamide groups; the substituent on the optionally substituted C3-8 cycloalkyl is one or more 10 substituents selected from halogen atoms, sulfonyl C1-8 alkyl groups, sulfoxide C1-8 alkyl groups, sulfonamide groups, nitro groups, cyano groups, -OC1-8 alkyl groups, -SC1-8 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, alkylamino groups, amino groups, C6-10 aryl , C3-8 cycloalkyl groups and hydroxyl groups; 15 the substituent on the optionally substituted heterocycle is one or more substituents selected from halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano , -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-8 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups , ketone groups, alkylamino groups, amino , C6-10 aryl groups, C3-8 cycloalkyl 20 groups and/or hydroxyl groups; the substituent on the optionally substituted C6-10 aryl is one or more substituents selected from halogen atoms, sulfonyl C1-6 alkyl groups, sulfoxide C1-6 alkyl groups, amide groups, carboxylic acid groups, C1- 6 alkyl ylate ester groups, amide groups, nitro groups, cyano groups, - 25 OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl groups, ketone groups, aldehydes, alkylamino , amino groups, C6-10 aryl groups, C3-8 cycloalkyl groups and yl groups; and the tuent on the optionally substituted C3-8 cycloalkenyl is one or more substituents selected from halogen atoms, sulfonyl groups, sulfoxide groups, nitro groups, cyano groups, -OC1-6 alkyl groups, -SC1-6 alkyl groups, -C1-6 alkyl groups, -C2-6 alkenyl groups, -C2-6 alkynyl , ketone , 5 alkylamino groups, amino groups, C6-10 aryl groups, C3-8 cycloalkyl groups and hydroxyl groups; wherein the ocular inflammatory disease is selected from the group consisting of uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, 10 choroiditis, acute multifocal placoid pigment epitheliopathy, ’s e, post-surgical corneal wound healing, wet age-related macular degeneration (ARMD) and dry ARMD, and wherein a therapeutically efficient amount of the FPR2 agonist is between about 0.001 and about 5% (w/v) in a liquid ation. 15 2. The use according to claim 1, wherein the FPR2 agonist is selected from: romophenyl)[4-ethyl-2,5-dioxo(2-phenylethyl)imidazolidin yl]urea; 1-(4-bromophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidinyl]urea; 1-(4-bromophenyl)(4,4-diethyl-2,5-dioxoimidazolidinyl)urea; 20 1-(4-bromofluorophenyl)(4,4-diethyl-2,5-dioxoimidazolidinyl)urea; 1-(4-bromophenyl)(2,4-dioxo-1,3-diazaspiro[4.5]decyl)urea; romophenyl)[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidin yl]urea; 1-(4-bromophenyl)[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidin 25 yl]urea; 1-(4-bromofluorophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidin- 1-yl]urea; 1-(4-bromophenyl)[2,5-dioxo-4,4-di(propanyl)imidazolidinyl]urea; 1-(4-bromophenyl)(4,4-dicyclopropyl-2,5-dioxoimidazolidinyl)urea; 1-(4-bromophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidinyl]urea; 1-(4-bromophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidinyl]urea; 5 1-(4-bromofluorophenyl)[4-ethyl-2,5-dioxo(2- phenylethyl)imidazolidinyl]urea; 1-(4-bromophenyl){4-[2-(furanyl)ethyl]methyl-2,5-dioxoimidazolidin- 1-yl}urea; 1-(4-bromophenyl){4-[2-(4-fluorophenyl)ethyl]methyl-2,5- 10 dioxoimidazolidinyl}urea; 1-(4-bromophenyl){4-[2-(3-fluorophenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; 1-(4-bromophenyl){4-[2-(4-hydroxyphenyl)ethyl]methyl-2,5- midazolidinyl}urea; 15 1-(4-bromophenyl){4-methyl-2,5-dioxo[2-(thiophen yl)ethyl]imidazolidinyl}urea; 1-(4-bromofluorophenyl){4-[2-(4-hydroxyphenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; 1-(4-bromophenyl){4-methyl[2-(5-methylfuranyl)ethyl]-2,5- 20 midazolidinyl}urea; 1-(4-bromofluorophenyl){4-[2-(3-fluorohydroxyphenyl)ethyl] methyl-2,5-dioxoimidazolidinyl}urea; 1-(4-bromophenyl){4-[2-(3-fluorohydroxyphenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; 1-(4-bromofluorophenyl){4-[2-(2-hydroxyphenyl)ethyl]methyl-2,5- midazolidinyl}urea; 1-(4-bromofluorophenyl){4-[2-(3-hydroxyphenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; 5 1-(4-bromophenyl){4-[2-(3-hydroxyphenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; 1-(4-bromophenyl){4-[2-(2-hydroxyphenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; 1-(4-bromophenyl)[4-(hydroxymethyl)-2,5-dioxo(propan 10 yl)imidazolidinyl]urea; 2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]-N-(2-hydroxyethyl)acetamide; methyl 2-[2-(1-{[(4-bromophenyl)carbamoyl]amino}ethyl-2,5- dioxoimidazolidinyl)ethyl]benzoate; 15 2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]-N-(1,3-dihydroxypropanyl)acetamide; 1-{[(4-bromophenyl)carbamoyl]amino}ethyl-2,5-dioxoimidazolidin yl)ethyl]benzoic acid; 2-[2-(1-{[(4-bromofluorophenyl)carbamoyl]amino}ethyl-2,5- 20 dioxoimidazolidinyl)ethyl]benzoic acid; 3-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]acetyl}amino)propanoic acid;

2-[1-{[(4-bromofluorophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]-N-(2-hydroxyethyl)acetamide; 25 2-{2-[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]ethyl}benzoic acid; diethyl [2-({[1-{[(4-bromophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]acetyl}amino)ethyl]phosphonate; 1-(4-bromophenyl){4-[2-(2-fluorophenyl)ethyl]methyl-2,5- dioxoimidazolidinyl}urea; and 5 3-({[1-{[(4-bromofluorophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]acetyl}amino)propanoic acid.

3. The use according to claim 1, n the FPR2 agonist is a compound selected from: romophenyl)[4-ethyl-2,5-dioxo(2-phenylethyl)imidazolidin 10 yl]urea; 1-(4-bromophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidinyl]urea; 1-(4-bromophenyl)(4,4-diethyl-2,5-dioxoimidazolidinyl)urea; 1-(4-bromofluorophenyl)(4,4-diethyl-2,5-dioxoimidazolidinyl)urea; 1-(4-bromophenyl)(2,4-dioxo-1,3-diazaspiro[4.5]decyl)urea; 15 1-(4-bromophenyl)[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidin yl]urea; 1-(4-bromofluorophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidin- 1-yl]urea; 1-(4-bromophenyl)[2,5-dioxo-4,4-di(propanyl)imidazolidinyl]urea; and 20 1-(4-bromophenyl)(4,4-dicyclopropyl-2,5-dioxoimidazolidinyl)urea.

4. The use of claim 1, wherein the FPR2 agonist is 1-(4-bromophenyl)[4-ethyl- 2,5-dioxo(2-phenylethyl)imidazolidinyl]urea.

5. The use of claim 1, n the FPR2 agonist is 1-(4-bromophenyl)[4-ethyl- 2,5-dioxo(propanyl)imidazolidinyl]urea.

6. The use of claim 1, wherein the FPR2 agonist is 1-(4-bromophenyl)(4,4- diethyl-2,5-dioxoimidazolidinyl)urea.

7. The use of claim 1, wherein the FPR2 agonist is 1-(4-bromofluorophenyl) (4,4-diethyl-2,5-dioxoimidazolidinyl)urea. 5

8. The use of claim 1, wherein the FPR2 agonist is romophenyl)(2,4- dioxo-1,3-diazaspiro[4.5]decyl)urea.

9. The use of claim 1, n the FPR2 agonist is 1-(4-bromophenyl)[4- methyl-2,5-dioxo(2-phenylethyl)imidazolidinyl]urea.

10. The use of claim 1, wherein the FPR2 agonist is 1-(4-bromofluorophenyl) 10 [4-ethyl-2,5-dioxo(propanyl)imidazolidinyl]urea.

11. The use of claim 1, n the FPR2 agonist is 1-(4-bromophenyl)[2,5- dioxo-4,4-di(propanyl)imidazolidinyl]urea.

12. The use of claim 1, wherein the FPR2 agonist is 1-(4-bromophenyl)(4,4- dicyclopropyl-2,5-dioxoimidazolidinyl)urea. 15

13. The use according to claim 1, wherein the FPR2 agonist is a compound selected from: 1-(4-chlorophenyl)(2,4-dioxo-1,3-diazaspiro[4,5]decanyl) urea; 1-(4-chlorophenyl)(4-ethylmethyl-2,5-dioxoimidazolidinyl)urea; and 1-(8-methyl-2,4-dioxo-1,3-diazaspiro[4,5]decanyl)(p-tolyl)urea. 20

14. The use according to claim 1, n the FPR2 agonist is a compound selected from: (+) 1-(4-bromophenyl)[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidin yl]urea; (+)1-(4-bromophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidin 25 yl]urea; (-)1-(4-bromophenyl)[4-ethyl-2,5-dioxo(propanyl)imidazolidin yl]urea; and ethyl [(4-bromophenyl)carbamoyl]amino}-2,5-dioxo(propan yl)imidazolidinyl]propanoate. 5 15. A use of at least one formyl peptide receptor 2 (FPR2) agonist in the manufacture of a medicament for treating an ocular inflammatory disease in a t in need of such treatment; wherein the ocular inflammatory disease is selected from the group ting of uveitis, dry eye, keratitis, allergic eye disease, infectious keratitis, herpetic keratitis, 10 corneal angiogenesis, lymphangiogenesis, retinitis, ditis, acute multifocal placoid pigment epitheliopathy, Behcet’s disease, post-surgical corneal wound healing, wet age-related macular degeneration (ARMD) and dry ARMD; wherein the FPR2 agonist is a compound selected from the group consisting of: ethyl 3-{[(4-bromophenyl)carbamoyl]amino}-2,4-dioxo-1,3-

15 diazaspiro[4.5]decanecarboxylate; 1-[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidinyl]phenylurea; and 1-(2-fluorophenyl)[4-methyl-2,5-dioxo(2-phenylethyl)imidazolidin yl]urea, and wherein a therapeutically efficient amount of the FPR2 agonist is between about 20 0.001 and about 5% (w/v) in a liquid formulation.

16. The use of claim 1, wherein the ocular inflammatory disease is dry eye.

17. The use of claim 15, wherein the ocular matory disease is dry eye.

18. A use as claimed in any one of claims 1-17 substantially as herein bed and with reference to any example thereof.