NZ710173B2 - 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 I and related structures. of Formula I 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. o RELATED APPLICATIONS This application claims the benefit of United States ional 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 sure 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 (FPR2). 2. Summary of the related art The formyl peptide receptor (FPR) family is involved in host defense against pathogens, but also in sensing internal molecules that may provide signals of ar ction. This family includes 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 matory 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, Shimizu T, Yokomizo T, Brink, C. The lipoxin receptor ALX: Potent ligandspecific and stereoselective s in vivo. Pharmacological Reviews 2006; 58: 463-519). FPR2 is an ionally promiscuous receptor that responds to a large array of exogenous and endogenous ligands, including serum amyloid A (SAA), ine variant sCKβ8-1, the neuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4 (LXA4) and glucocotricoid-modulated protein annexin A1 (Chiang 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 experimental inflammation. Journal of Immunology 2010; 184: 2611-2619).

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

FASEB 2010; 24: 4240-4249; Reville K, Cream JK, Vivers S, ield I, Godson C. Lipoxin A4 redistributes Mysoin IIA and Cdc42 in macrophages: Implications for phagocytosis of apoptotic ytes. Journal of Immunology 2006; 176: 1878-1888). In on, FPR2 has been shown to inhibit NK xicity and e tion of T cells which further 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 pathways. Annual s of Immunology 2007; 25: 7; Medeiros R, Rodrigues GB, Figueiredo CP, Rodrigues EB, Grumman A Jr, Menezes-de-Lima O Jr, Passos GF, Calixto JB. Molecular mechanisms of topical nflammatory effects of lipoxin A(4) in endotoxin-induced uveitis.

Molecular Pharmacology 2008; 74: 1; Gronert K, Maheshwari N, Khan N, Hassan IR, Dunn M, Schwartzmann ML. A role for the mouse 12/15- lipoxygenase pathways in ing 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 injury. an Journal of ogy 2010; 176: 74-84; Gronert K. Lipoxins in the eye and their role in wound healing. glandins, 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 product. 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 effects as compared to more broad acting anti-inflammatories such as steroids or NSAIDs which have significant 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 ents an important novel pro-resolutionary molecular target for the development of new therapeutic agents in ocular es with excessive inflammatory responses.

SUMMARY OF THE INVENTION In a first aspect the present ion provides a use of a compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , and ; or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular inflammatory disease in a patient in need thereof.

In a second aspect the present invention es a use of the compound: or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular inflammatory disease in a patient in need thereof.

In a third aspect the present invention provides a use of the compound: or a ceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular inflammatory disease in a patient in need thereof.

BRIEF DESCRIPTION OF THE INVENTION The present disclosure pertains to the y of FPR2 agonists to exhibit ocular nflammatory activity with chemical stability and suitable 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 nds may also be administered directly or through a local drug ry device applied to ocular tissue, and via IV, intramuscularly, intrathecally, subcutaneously, , intravitreally or eritoneally. These compounds will be useful for the treatment of ocular matory diseases including, but not limited to, uveitis, dry eye, keratitis, 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, ions caused by photodynamic therapy, wet and dry age-related macular degeneration , , conditions ing the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal cularization, diabetic retinopathy (proliferative), retinopathy of prematurity (ROP), acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and ic macular edema; birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), ocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi and Harada syndrome; vasuclar diseases/ exudative diseases such as l arterial occlusive disease, central retinal vein occlusion, cystoids macular edema, inated intravascular coagulopathy, branch retinal vein ion, hypertensive fundus changes, ocular ic syndrome, retinal arterial microaneurysms, Coat’s disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch l artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, d streaks, familial exudative vitreoretinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, conditions caused by ynamic 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, ed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV ion, 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; c disorders such as retinitis pigmentosa, systemic disorders with accosiated retinal 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 lline dystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease ated with , 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 fundus, retinal astrocytoma, and intraocular id ; and miscellaneous other diseases affecting the ior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigment liitis, post-surgical corneal inflammation, ritis, MGD, glaucoma, branch vein occlusion, Best’s vitelliform macular degeneration, retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and any other degenerative diseases of either the eceptors 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, sepsis, matory bowel disease, cachexia, angina is, rheumatoid tis and related inflammatory disorders, alopecia, systemic inflammatory es 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 ers, 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 anti-inflammatory 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 nd 3, {[(2S,3S){[(4- bromophenyl)carbamoyl]amino}methylpentanoyl]amino}acetic acid.

DETAILED DESCRIPTION OF THE INVENTION bed herein is 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 FPR2.

In another aspect, described herein 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.

In another aspect, described herein is a method for treating ocular inflammatory diseases, which comprises administering a pharmaceutical composition comprising a eutically 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 g activity at the FPR2 receptor.

In r aspect, described herein 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 nds have binding activity at the FPR2 receptor .

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

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

In another aspect, described herein 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.13/523,579, provided that the compounds have binding activity at the FPR2 or.

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

The compounds disclosed in U.S. patent application S.N. 13/523,579 are represented by Formula II: a 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 substituted C3-8 cycloalkyl, optionally substituted C6-10 aryl, optionally substituted C3-8 cycloalkenyl, - NR11R12 or -OR13; R2 is optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R3 is hydrogen, optionally substituted C1-8 alkyl, halogen, -COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 lkyl, optionally substituted C6-10 aryl or optionally substituted C3-8 cycloalkenyl; R4 is hydrogen, optionally substituted C1-8 alkyl, n, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally tuted C3-8 cycloalkyl, optionally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; 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 ally substituted C3-8 cycloalkenyl; R7 is en, ally tuted C1-8 alkyl, halogen, - COOR15, - OR13, - NR11R12, NO2, optionally substituted heterocycle, optionally substituted C3-8 cycloalkyl, ally substituted C6-10 aryl or optionally tuted C3-8 cycloalkenyl; 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 en, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R9a is hydrogen, optionally substituted C1-8 alkyl or optionally substituted C6-10 aryl; R10a is hydrogen, 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 ally substituted C1-8 alkyl; R15 is hydrogen or optionally substituted C1-8 alkyl; In another aspect, described herein 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. 13/673,800, provided that the compounds have binding activity at the FPR2 receptor..

In another aspect, described herein 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 ion mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor..

In another aspect, described herein is the use of at least a compound as sed 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 binding activity at the FPR2 receptor.

The nds disclosed in U.S. patent application S.N. 13/673,800 are represented by Formula III: a III R1 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, 0, 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, ally 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 ally substituted; R4 is hydrogen, optionally substituted C 1-8 alkyl, , ( )n O , , , OR17 , , , , , , , , , , , , , , , , , , , , , , , optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 cycloalkenyl, optionally substituted C 6-10 aryl, ally 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 tuted 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 optionally substituted or together with R3 forms a 5 or 6 member ring which is ally substituted; R6 is halogen, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or SO2R16; R7 is n, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, NR13R14, CN, SR15 or ; R8 is n, hydrogen, optionally substituted C 1-8 alkyl, OR9, C(O)R10, NO2, 4, CN, SR15 or SO2R16; R9 is en, 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 tuted C 1-8 alkyl; R13 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R14 is en, 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 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 ally substituted C 1-8 alkyl; R19 is hydrogen, C(O)(C1-8 alkyl), optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R20 is en, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; R21 is hydrogen, optionally substituted C 6-10 aryl or optionally substituted C 1-8 alkyl; n is 1, 2, 3, 4, or 5; m is 1, 2, 3, 4, or 5.

In another aspect, described herein 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 application S.N. 13/765,527, provided that the compounds have g activity at the FPR2 receptor.

In another aspect, described herein is the use of at least one compound as disclosed 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.

In another , bed herein is the use of at least one compound as disclosed in U.S. patent application S.N. ,527 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. 13/765,527 are represented by Formula IV: Formula IV wherein: R1 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, tuted or tituted C2-6 l, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C3-8 cycloalkenyl substituted or unsubstituted heterocycle or substituted or unsubstituted C6-10 aryl, or together with R2 can form an optionally tuted cyclobutyl; R2 is isopropyl or together with R3 can form a substituted or unsubstituted 3 to 6 member ring cycle or together with R1 can form an optionally substituted cyclobutyl, cyclopropyl; and R3 is hydrogen, tuted or unsubstituted C1-6 alkyl, substituted or unsubstituted C2-6 alkenyl, substituted or unsubstituted C2-6 alkynyl, tuted 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 unsubstituted 3 to 6 member ring heterocycle.

In r aspect, described herein 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.

In r aspect, described herein is the use of at least one compound as disclosed in U.S. patent application S.N. 13/409,228 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 herein 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 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. 13/409,228 are represented by a V: Formula V “ ” 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 lkenyl or hydroxyl; R2 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 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 lkenyl, 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 cycloalkenyl or H; Rb is n; 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 cycloalkenyl or C3-8 cycloalkyl; 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 cycloalkyl, or C3-8 cycloalkenyl ; R11 is H, hydroxyl, -C1-6 alkyl, C3-8 cycloalkyl or C3-8 cycloalkenyl; R12 is H, yl, -C1-6 alkyl, C3-8 lkyl, C3-8 cycloalkenyl, NR13R14 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, cycle 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.

In another aspect, described herein 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 sed in U.S. patent application S.N. 13/370,472, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, described herein 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 mediated by FPR2 in a mammal, provided that the compounds have binding activity at the FPR2 receptor.

In another aspect, described herein 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, ed that the compounds have binding activity at the FPR2 receptor.

The compounds as disclosed in U.S. patent ation S.N. 13/370,472 are represented by a 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, C(O)R12, 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 lkyl or hydroxyl; R3 is H, C1-6 alkyl or C3-8 cycloalkyl; R4 is H, C1-6 alkyl or C3-8 lkyl; 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, 4, C3-8 cycloalkyl or hydroxyl; R5b 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, 4, C3-8 cycloalkyl or hydroxyl; R5c is H, halogen, 15, -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, -(CH2)n 4, -(CH2)m heterocycle , 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 lkyl or hydroxyl; R9 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, 4, C3-8 lkyl 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 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 cycloalkyl, SO2R11 or C(O)R16; R14 is H, -C1-6 alkyl or C3-8 cycloalkyl; R15 is -C1-6 alkyl, or C3-8 cycloalkyl; R16 is H, -C1-6 alkyl or C3-8 cycloalkyl; n is 1-4; and m is 1-4.

In another aspect, described herein is a method for ng 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. 13/863,934, provided that the compounds have binding ty at the FPR2 receptor.

In another aspect, described herein 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 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 herein is the use of at least one compound as disclosed in U.S. patent application S.N. 13/863,934 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 compounds as disclosed in U.S. patent application S.N. 13/863,934 are represented by Formula VII: Formula VII wherein: n is 0 or 1; R1 is hydrogen, substituted or tituted C1-8 alkyl, halogen, -NR8R9, - NC(O)R20, -OR10, -OC(O)R21 -SR11 , 12, 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, tuted 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 S(O)2R16; R4 is hydrogen, tuted or unsubstituted C1-8 alkyl, halogen, - NR8R9, - NC(O)R20 , -OR10, -OC(O)R21 , -SR11 , -C(O)R12, CN or NO2; R5 is hydrogen, tuted or unsubstituted C1-8 alkyl, n, - NR8R9, - ,-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 unsubstituted heterocycle, -SR11, -NR8R9 , - N(H)C(O)N(H)S(O)2R19, -BR13R14, 15, -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 tuted or unsubstituted C3-8 cycloalkyl, substituted or tituted heterocycle, or substituted or unsubstituted C6-10 aryl; R9 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; 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 tuted or unsubstituted C1-8 alkyl; R16 is substituted or tituted C1-8 alkyl, -NR8R9 , -NHS(O)2R19 or hydroxyl; R17 is OR10 or NR8R9; R18 is OR10 or NR8R9; R19 is substituted or unsubstituted heterocycle, tuted or unsubstituted 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 unsubstituted C3-8 cycloalkyl, substituted or unsubstituted heterocycle, or substituted or unsubstituted C6-10 aryl; R22 is hydrogen, substituted or tituted 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 unsubstituted cycle, or substituted or unsubstituted C6-10 aryl.

The term ”alkyl”, as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations f 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, sulfate, sulfonate, amide, amide, by a nt C 3-8 lkyl, by a divalent heterocycle, or by a nt 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 groups, cyclic groups, aryl groups, carboxylic acid , phosphonic acid groups, sulphonic acid groups, phosphoric acid , nitro , amide groups, sulfonamide groups.

The term “cycloalkyl”, as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms derived from a saturated cyclic hydrocarbon.

Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be independently substituted by halogen atoms, sulfonyl C1-8 alkyl , sulfoxide C1-8 alkyl groups, amide groups, nitro groups, cyano , - 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, 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 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 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 , 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, en, carbonyl, carboxyl, sulfonyl, sulfate, ate, 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 uration. 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 l having 2 to 6 carbon atoms, derived from a saturated alkyl, having at least one triple bond. One ene (-CH2-) group, of the alkynyl 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. 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 membered ring, which can be aromatic or non-aromatic, saturated or rated, containing at least one heteroatom selected form oxygen, nitrogen, sulfur, or combinations of at least two thereof, interrupting the carbocyclic ring ure. The heterocyclic ring can be interrupted by a C=O; the S and N heteroatoms can be ed.

Heterocycles can be monocyclic or polycyclic. cyclic 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 l groups , ketone , alkylamino groups, amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups.

The term “aryl” as used herein, refers to an organic moiety derived from an aromatic hydrocarbon ting 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 groups, aldehydes, alkylamino , amino groups, aryl groups, C3-8 cycloalkyl groups or hydroxyl groups. 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 , 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 ” 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 ”.

The term “sulfate” as used herein, represents a group of a “-OS (O)2-O-”.

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

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

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

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

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

The term horic acid” as used herein, represents a group of a “-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 hydrogen atom.

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

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

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

In another , agonists of FPR2 are compounds selected from Table Table 1 FPR2 IUPAC name Ga16-CHO Structure EC50 (efficacy) 2-({[(4- chlorophenyl)amino]carbonyl}amino) 110 nM phenylpropanoic acid (1.0) (2S)({[(4- methoxyphenyl)amino]carbonyl}amino) 1754 nM phenylpropanoic acid (0.90) H H (2S)phenyl[({[4- N N HO (trifluoromethyl)phenyl]amino}carbonyl) 120 nM O F amino]propanoic acid (0.97) (2S)({[(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) yl[({[4- (trifluoromethoxy)phenyl]amino}carbon 1572 nM yl)amino]propanoic acid (0.79) 2-({[(3,4- dimethoxyphenyl)amino]carbonyl}amin 2793 nM o)phenylpropanoic 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) 3-phenyl{[(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- henyl)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 7820673 disclose inhibitors of coagulation Factor Xa and can be ed for the prophylaxis and/or therapy of thromboembolic diseases and or the treatment of tumors. 2-({[(4- phenyl)amino]carbonyl}amino)phenylpropanoic acid, (2S)({[(4- methoxyphenyl)amino]carbonyl}amino)phenylpropanoic acid, (2S)phenyl- 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 46 discloses the resolution of N-(p-bromophenylcarbamyl) derivatives ((2S)({[(4-bromophenyl)amino]carbonyl}amino) phenylpropanoic acid, (2S,3S)({[(4-bromophenyl)amino]carbonyl}amino) methylpentanoic acid, 2-({[(4-bromophenyl)amino]carbonyl}amino)(1H-indol- 3-yl)propanoic acid, -({[(4-bromophenyl)amino]carbonyl}amino) methylbutanoic acid) on HPLC column with novel tographic chiral stationary phases.

Journal of Chromatography (1987), 404(1), 117-22 and Chromatographia (1987), 23(10), 727-30 describe the resolution of p-Bromophenylcarbamyl derivatives of enantiomeric protein amino acids ((2R)({[(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, c Acids and Protein Synthesis , 272(4), 667-71 describes compound (2S)({[(4- nitrophenyl)amino]carbonyl}amino)phenylpropanoic acid) in poly(uridylic acid)-dependent g of para nitrophenyl-carbamyl-phenylalanyl tRNA .

In another aspect, ts of FPR2 are compounds selected from Table 2: 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) yl)urea 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 2,5-dioxoimidazolidinyl)acetamide (0.98) HN N H N-(4-bromophenyl)(2,4-dioxo-1,3- N 738 nM piro[4.5]decyl)acetamide O (0.89) HN N H N-(4-bromophenyl)(2,4-dioxo-1,3- N 322 nM diazaspiro[4.4]nonyl)acetamide O (0.96) HN N H N N-(4-bromophenyl)(2,5-dioxo-4,4- 645 nM O dipropylimidazolidinyl)acetamide (0.98) HN N H N-(4-bromophenyl)(4-ethyl-2,5- N 523 nM 4-phenylimidazolidin O O (0.83) yl)acetamide 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 (0.96) HN N H N-(4-bromophenyl)(4-ethyl N 485 nM methyl-2,5-dioxoimidazolidin O (1.0) O yl)acetamide 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 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 r embodiment of the disclosure, described are 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 ning a eutically effective amount of at least one compound described herein.

Therapeutic utilities of the FPR2 are ocular inflammatory diseases including, but not limited to, wet and dry age-related macular degeneration (ARMD), s, dry eye, Keratitis, allergic eye disease and ions affecting the posterior part of the eye, such as pathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, dal neovascularization, diabetic retinopathy (proliferative), pathy of prematurity (ROP), acute macular neuroretinopathy, central serous retinopathy, cystoid macular edema, and diabetic macular edema; infectious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, uveitis, retinitis, and choroiditis such as acute ocal placoid pigment epitheliopathy, Behcet’s disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal is 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 ascular coagulopathy, branch retinal vein occlusion, ensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat’s disease, parafoveal telangiectasis, etinal vein occlusion, papillophlebitis, central l artery occlusion, branch retinal artery occlusion, d artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, 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, ions caused by photodynamic therapy, oagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and inal nes, 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 ate with HIV infection, uveitic disease associate with HIV ion, viral tis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, e unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic ers with accosiated retinal dystrophies, congenital stationary 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 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 pigmented epithelium, posterior uveal melanoma, dal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors; and miscellaneous other es affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal d pigment epitheliopathy, myopic retinal ration, 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 e, 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, sis, seborrheic dermatitis, actinic keratoses, viral warts, photoaging rheumatoid arthritis and related inflammatory ers, alopecia, glaucoma, branch vein occlusion, Best’s iform macular degeneration, retinitis tosa, proliferative vitreoretinopathy (PVR), and any other degenerative 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, ing humans, with a range of conditions and diseases that are ated by the modulation of FPR2 : including, but not limited to the treatment of wet and dry age-related macular degeneration (ARMD), diabetic retinopathy ferative), 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 retinopathy (PVR), and any other degenerative disease of either the photoreceptors or the RPE.

In still another embodiment of the disclosure, there are described methods for treating disorders associated with modulation of the FPRL-1 receptor. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically ive amount of at least one compound described herein, or any ation 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 physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the t’s general physical condition, the cause of the condition, and the route of administration.

The patient will be administered 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 e, without exception, transdermal, parenteral, subcutaneous, intranasal, via an implant 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 described are pharmaceutical compositions including at least one compound described herein in a pharmaceutically acceptable carrier f. The phrase "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not rious 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 e, a liposome, and the like, n the resulting composition contains one or more compounds bed , 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 carriers for tablets, pellets, capsules, itories, solutions, ons, suspensions, and any other form suitable for use. The carriers which can be used e glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides, ns, and other carriers suitable for use in manufacturing preparations, in solid, lid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes 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.

Pharmaceutical compositions containing the compounds described herein may be in a form suitable for oral use, for example, as s, troches, lozenges, aqueous or oily suspensions, dispersible 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 itions may n one or more agents selected from the group ting of a sweetening agent such as sucrose, e, or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry, coloring agents and ving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets containing the compounds described herein in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (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 stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For e, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

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

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

Pharmaceutical compositions containing nds 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 emulsions.

Pharmaceutical compositions may be prepared by combining a therapeutically effective amount of at least one compound described herein, or a pharmaceutically able salt thereof, as an active ient with conventional ophthalmically 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 ons should preferably be maintained between 4.5 and 8.0 with an appropriate buffer system, a l pH being red but not essential. The formulations may also contain tional pharmaceutically acceptable preservatives, stabilizers and surfactants.

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

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

Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor. s buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include e buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these ations as needed.

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

Other excipient components which may be included in the ophthalmic preparations are chelating agents. The preferred chelating agent is edentate um, 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 4.5-7.8 antioxidant as needed surfactant as needed purified water to make 100% The actual dose of the active compounds described herein depends on the ic compound, and on the condition to be d; the selection of the appropriate dose is well within the knowledge of the skilled artisan.

The ophthalmic formulations described herein are conveniently ed in forms suitable for d application, such as in ners equipped with a dropper, to facilitate application to the eye. Containers suitable for dropwise application are y made of suitable inert, non-toxic plastic al, and generally n between about 0.5 and about 15 ml solution. One package may n one or more unit doses. ally 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 injectable suspension. This sion may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or t, for example, as a solution in 1,3-butanediol. Sterile, fixed oils are conventionally employed as a solvent or ding medium. 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 required.

The compounds described herein may also be administered 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 individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the tion of the practitioner.

The compounds and pharmaceutical compositions described herein are useful as medicaments in s, including , for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of FPR2. Thus, in further embodiments described are methods for treating a disorder associated with modulation of FPR2. Such s 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 ition that will elicit the biological or medical se of a subject in need thereof that is being sought by the researcher, narian, medical doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human.

Materials and Methods FPR2 agonists would be expected to have significant effects 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 ified with the FPR2 agonists described in Table 4.

FLIPR: HEK-Gα16 cells stably expressing the human FPR2 or was utilized. Cells were plated into ll poly-D-lysine coated plates at a density of 18,000 cells per well one day prior to use. The growth media was DMEM medium mented with 10% fetal bovine serum (FBS), 1% antibioticantimycotic , 50 µg/ml hygromycin, 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 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 (Fluorometric Imaging Plate Reader, Molecular s). 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 {[(2S){[(4- bromophenyl)carbamoyl]ami 2 no}pentanoyl]amino}acetic (0.91) acid 3 3S){[(4- O O bromophenyl)carbamoyl]ami H 1.98 N 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 phenyl)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 methylpentanoic acid (0.77) - 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 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 1-(4-acetylphenyl){3-(4- O cyanophenyl)[2-(1H- 11 nM O imidazolyl)ethyl]oxo- N 4-tetrahydroisoquinolin- (0.80) N N H H NH O N 7-yl}urea 14 rel-(2R,3S)[(4- bromophenyl)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 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 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 1-{3-(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 1-{3-(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 F 1-{3-(5-fluoropyridinyl) O O S [2-(1H-imidazolyl)ethyl] O N 10.5 nM N oxo-1,2,3,4- N N (1.0) H H NH tetrahydroisoquinolinyl} O N (methylsulfonyl)phenyl]urea 26 N-(4- bromophenyl)spiro[bicyclo[2. 4.8 nM 2.1]heptane-7,1'- (0.91) cyclopropane]ene-2,3- oxamide 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- (methylsulfanyl)phenyl]urea 28 Cl 1-{3-(6-chloropyridinyl) S N O [2-(1H-imidazolyl)ethyl] N oxo-1,2,3,4- 6.3 nM N N H H NH O N ydroisoquinolinyl} (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 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 [4- (methylsulfonyl)phenyl]urea 34 N-(4-bromophenyl)-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) 7-yl][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- iodophenyl)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) ydroisoquinolinyl] [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'- spiro[bicyclo[2.2.1]hep N tane-7,1'-cyclopropane]-2,3- 8.5 nM O dicarboxamide (1.0) O N Br 47 N-(4-bromophenyl)-N'- H piro[bicyclo[2.2.1]hepta N ne-7,1'-cyclopropane]-2,3- 9.3 nM O 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 N H 1-(4-bromo N F N fluorophenyl)(4,4-diethyl- 15.7 nM O O 2,5-dioxoimidazolidin (1.0) yl)urea 51 -{[(4- iodophenyl)carbamoyl]amino} 14.5 nM phenylpropanoic acid (1.0) 52 O romophenyl)(2,4- HN dioxo-1,3-diazaspiro[4.5]dec- N N H N 3-yl)urea 15.1 nM (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 yl]urea (0.87) 55 {[(2S){[(4- bromophenyl)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 henyl)carbamoyl]ami (0.86) no}-N-(2-hydroxyethyl) phenylpropanamide 59 {[(2S,3S){[(4-bromo fluorophenyl)carbamoyl]amin .5 nM o} (0.95) pentanoyl]amino}aceti c acid 60 (2S,3S)-N-(2-amino oxoethyl){[(4- 4.6 nM bromophenyl)carbamoyl]ami (0.91) no}methylpentanamide 61 O 1-(4-bromofluorophenyl)- HN N H thyl-2,5-dioxo N F N (propanyl)imidazolidin 9.2 nM O yl]urea (0.97) (2S,3S)-N-(2-amino .3 nM oxoethyl){[(4-bromo (1.0) fluorophenyl)carbamoyl]amin o}methylpentanamide 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 N N H 3-[4-ethyl-2,5-dioxo(2- 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 henyl)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 fluorophenyl)carbamoyl]amin 4.1 nM o}pentanoyl]amino}acetic (0.91) acid 75 (2S){[(4- bromophenyl)carbamoyl]ami 13.5 nM no}-N-(2-hydroxyethyl) (0.76) pentanamide 76 O 1-(4-bromophenyl){4-[2- HN N N H (furanyl)ethyl]methyl- N 2,5-dioxoimidazolidin 5.2 nM O a (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)- - 2.5 nM henyl)carbamoyl]ami (0.97) no}pentanamide 80 O 1-(4-bromophenyl){4-[2-(2- F HN N N H fluorophenyl)ethyl]methyl- N 2,5-dioxoimidazolidin 14.3 nM O O yl}urea (99) 81 (2S)-N-(2-aminooxoethyl)- 2-{[(4-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 oxoimidazolidin 16.3 nM F O O yl}urea (1.0) 83 O 1-(4-bromophenyl){4-[2-(3- HN N H fluorophenyl)ethyl]methyl- 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 fluorophenyl)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){[(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 methylpentanamide 93 (2S){[(4- bromophenyl)carbamoyl]ami 2.5 nM no}-N-(2-hydroxy (0.93) methylpropyl) pentanamide 94 (2S){[(4- bromophenyl)carbamoyl]ami 7.4 nM no}-N-(1,3-dihydroxypropan- (0.96) 2-yl)methylpentanamide 95 (2S){[(4- henyl)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 N H methyl[2-(5-methylfuran N yl)ethyl]-2,5- 3.5 nM O O dioxoimidazolidinyl}urea (0.95) 98 O romofluorophenyl)- F HN 2-(3-fluoro N N H F 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- H fluoro F HN N N H N hydroxyphenyl)ethyl] 8.0 nM HO O O -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 bromophenyl)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) methylpentanoyl]amino}meth yl)phosphonate 106 O romofluorophenyl)- 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 hydroxyphenyl)ethyl] N methyl-2,5-dioxoimidazolidin- 2.1 nM O O 1-yl}urea (1.0) HO Br 109 O romophenyl){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 no}-2,4-dimethylpentanoic (0.98) acid 111 [(2-{[(4- henyl)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- bromophenyl)carbamoyl]ami 2.7 nM no} (0.88) methylpentanoyl]amino}meth yl)phosphonate 116 (2S){[(4- bromophenyl)carbamoyl]ami 12.0 nM no}-N-[(3-hydroxy-1,2-oxazol- (1.0) ethyl] methylpentanamide 117 diethyl ({[(2S){[(4- bromophenyl)carbamoyl]ami 0.27 nM no}pentanoyl]amino}methyl)p (1.0) hosphonate 118 l ({[(2S){[(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] methylpentanamide 121 -{[(4- iodophenyl)carbamoyl]amino} 4.0 nM methylpentanoic acid (0.93) 122 (2R,3R){[(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 {[(2S)methyl({[4- uoromethyl)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) nate 126 ethyl en ({[(2S){[(4- bromophenyl)carbamoyl]ami 16.0 nM no} (1.0) phenylpropanoyl]amino}meth yl)phosphonate 127 {[(2S){[(4- henyl)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 no}pentanoyl)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 ({[(2S){[(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 N H bromophenyl)carbamoyl]ami HO N N 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 ({[(2S) methyl({[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) mino)pentanoyl]amino }methyl)phosphonate 139 2-methyl{[(2S)methyl ({[4- 2.5 nM uoromethyl)phenyl]carba (0.92) moyl}amino)pentanoyl]amino }propanoic acid 140 tert-butyl -{[(4- bromophenyl)sulfamoyl]amin o}methylpentanoate NA 141 O methyl 2-[2-(1-{[(4- O H O HN N 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 HO HN N N H 2-[1-{[(4- N henyl)carbamoyl]ami 13.8 nM HN O O no}-2,5-dioxo(propan (0.92) O yl)imidazolidinyl]-N-(1,3- Br dihydroxypropan yl)acetamide 143 O 2-[2-(1-{[(4- HO H O HN N N H henyl)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) lsulfanyl)butanoyl]ami no}acetic acid 145 O 3-({[1-{[(4-bromo O H HN N H fluorophenyl)carbamoyl]amin HO N F 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)ethyl]benzoic acid 147 O 3-({[1-{[(4- O H HN N N H bromophenyl)carbamoyl]ami N no}-2,5-dioxo(propan 3.9 nM HN O O yl)imidazolidin (0.99) O yl]acetyl}amino)propanoic Br acid 148 O 2-[1-{[(4-bromo HO HN N N H phenyl)carbamoyl]amin 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 N 6.6 nM O no}-2,5-dioxo(propan 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 O HN N N H bromophenyl)carbamoyl]ami 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 HN N H bromophenyl)carbamoyl]ami O P N O 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 N N H bromophenyl)carbamoyl]ami N no}-2,4-dioxo-1,3- 12 nM O O diazaspiro[4.5]decane (0.99) O carboxylate 154 tert-butyl {[(2S){[(4- bromophenyl)carbamoyl]ami no} 12 nM methylpentanoyl](methyl)ami (0.85) no}acetate {[(2S){[(4- bromophenyl)carbamoyl]ami 1.0 nM no} (1.0) methylpentanoyl](methyl)ami no}acetic acid Immunohistochemistry: Chromagenic DAB immunohistochemistry with dies specific to FPR2 was used to determine localization in normal human, primate, and rat eyes. PR2 antibody ) was used at a dilution of 1:200 to detect FPR2 protein in all species.

Endotoxin-induced s in rats: Uveitis is a harmful ocular matory 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 anti- inflammatory therapy used is non-specific and is associated with significant complications. Animal models are key to understanding the disease and testing novel therapies. A single low dose of lipopolysaccaride (LPS) in the footpad induces 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 sterile 0.9% saline). Test compounds were formulated in the vehicle consisting of sodium phosphate, dibasic heptahydrate, salts, CMC and e water. Compounds were lly %) 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 rabbits: Corneal epithelium plays an important role in the maintenance of corneal function and integrity. Prolonged corneal epithelial defects causes corneal y, neovascularization, bacterial infection and visual loss. Corneal epithelial healing is a complex s involving inflammatory se to injury, cell proliferation and migration.

Animal models of l injury are every useful to test new flammatory and und 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 described above. For initial studies compounds were topically dosed three times a day. Quantification of corneal wound areas was done using Image J re where fluorescing stain green part was traced and converted to total pixel.

The nds below would be expected to have significant effects in many different types of ocular inflammation, but have been exemplified by trating 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 blocking the infiltration of neutrophils and protein into the anterior chamber. In addition FPR2 agonists show accelerated healing and re-epithelialization 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 cious anti-inflammatory agents suitable for ocular use in ent models of ocular inflammation.

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 statement or claim may also be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

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

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

In the description in this specification 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 skilled in the art and may assist in g into practice the invention as defined in the claims of this application.

Claims (6)

What is d is:

1. A use of a compound selected from the group consisting of: , , , , , , , , 10 , , , , , , , , , , , , and ; 5 or a ceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular inflammatory disease in a patient in need thereof.

2. A use of the compound: or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular inflammatory e in a patient in need 15 thereof.

3. A use of the compound: or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an ocular inflammatory disease in a patient in need f. 5

4. The use of any one of claims 1 to 3, wherein the ocular inflammatory disease is selected from: uveitis, dry eye, keratitis, allergic eye disease, ious keratitis, herpetic keratitis, corneal angiogenesis, lymphangiogenesis, retinitis, choroiditis, acute multifocal placoid pigment epitheliopathy, Behcet’s disease, urgical corneal wound healing, wet and dry age-related macular 10 degeneration (ARMD).

5. The use of any one of claims 1 to 4, n the ocular inflammatory disease is dry eye. 15

6. The use of any one of claims 1-5 substantially as herein described and with reference to any example thereof.