Drug treatment for macular degeneration

Abstract

The present disclosure relates to compounds and methods for preventing and treating macular degeneration, the methods comprising administering to the subject a compound of Formula (I). In some embodiments, the disclosure provides compounds and methods for treating cancer.

Description

[0001] Attorney Docket No. 204606-0204-00WO

[0002] TITLE OF THE INVENTION

[0003] Drug Treatment for Macular Degeneration

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This application claims priority to U.S. Provisional Application No. 63 / 734,404, filed December 16, 2024, the entire contents of which are hereby incorporated by reference in their entirety.

[0006] STATEMENT REGARDING GOVERNMENT SUPPORTED RESEARCH

[0007] This invention was made with government support under EY028167 and EY033192 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0008] REFERENCE TO A SEQUENCE LISTING SUBMITTED AS AN XML FILE The present application hereby incorporates by reference the entire contents of the Sequence Listing XML named 204606-0204-00WO_SequenceListing.xml” having a creation date of December 10, 2025, and a file size of 1,964 bytes.

[0009] BACKGROUND OF THE INVENTION

[0010] Age-related macular degeneration (AMD) and related macular dystrophies (MDs) like Sorsby’s fundus dystrophy (SFD), Doyne honeycomb macular dystrophy (DHRD) and autosomal dominant radial drusen (ADRD) show similar pathological manifestations and lead to irreversible blindness in affected adults (Capon et al., Ophthalmology. Dec 1989;96(12): 1769- 77; Marmorstein et al., Proc Natl Acad Set USA. Oct 1, 2002, 99(20): 13067-72; Fariss et al., Br J Ophthalmol. Nov 1998, 82(11): 1329-34). AMD / MDs show multi-tissue pathology in the eye with the primary disease manifestations localized to the retinal pigment epithelium (RPE)- choriocapillaris complex (McLeod et al., Invest Ophthalmol Vis Sci. Oct 2009, 50(10):4982-91). Furthermore, alterations of Bruch’s membrane, the extracellular matrix (ECM) underlying the RPE monolayer, are central to AMD / MD development (Bhutto et al., Mol Aspects Med. Aug 2012;33(4):295-317). Bruch’s membrane undergoes regulated turnover that involves protease- mediated degradation by matrix metalloproteinases (MMPs) and consistently several MMPs (e g., MMP2, MMP3, MMP9) have been linked to AMD / MD pathophysiology (Nita et al., Med Attorney Docket No. 204606-0204-00WO

[0011] Sci Monit. 2014, 20: 1003-16; Alge-Priglinger et al., Invest Ophthalmol Vis Sci. Nov 2009, 50(11):5495-503; Hussain et al., Invest Ophthalmol Vis Sci. Jun 23, 2011, 52(7):4459-66; Hongisto et al., J Pathol. October 2020, 252(2): 138-150).

[0012] Tissue inhibitor of metalloproteinase 3 (TIMP3) forms stable complexes with MMPs and is a negative regulator of several MMPs (e.g., MMP2, MMP3, MMP9) (Nagase et al., Cardiovasc Res. Feb 2006;69(3):562-73; Arpino et al., Matrix Biology . 2015;44-46:247-254). Genotype-agnostic proteomics and histopathologic studies have reliably shown increased levels of TIMP3 in Bruch’s membrane and drusen of AMD donor eyes (Kamei et al., Invest Ophthalmol Vis Sci. Sep 1999, 40(10):2367-75; Crabb et al., Proc Natl Acad Sci USA. Nov 12, 2002, 99(23): 14682-7; Gourier et al., J ClinMed. May 04, 2015, 4(5):874-83) and AMD patient- derived induced pluripotent stem cell RPE (iRPE) cultures (Senabouth et al., bioRxiv. 2021 :2021.08.19.457044). Similarly, increased levels of TIMP3 in RPE-Bruch’s membrane have been consistently documented in donor eyes and animal and cell culture models of AMD / MDs (Langton et al., Hum Mol Genet. Dec 1, 2005, 14(23):3579-86; Engel et al., Exp Eye Res. Feb 2022, 215: 108899; Senabouth et al., Nat Commun. Jul 26, 2022, 13(1):4233). Consistent with excess TIMP3 and consequently reduced activity of RPE-secreted MMPs (MMP2 / MMP9), ECM / Bruch’s membrane and drusen in relevant animal and cell culture models of MDs and AMD donor eyes have been reported to display reduced gelatinase (MMP2 / MMP9) activity (Leu et al., Exp Eye Res. Jan 2002;74(l): 141-54; Femandez-Godino et al., Hum Mol Genet. Oct 1, 2015, 24(19):5555-69). Consistently, collagen 4 (COL4), a major component of Bruch’s membrane that is proteolytically degraded by MMP2 and MMP9, aberrantly accumulates in AMD / MDs (Chong et al., Invest Ophthalmol Vis Sci. Mar 2000;41(3):898-902; Galloway et al., Proc Natl Acad Sci USA. Sep 26, 2017, 114(39):E8214-E8223; Sohn et al., Retina. Jan 2015, 35( 1 ):48-57). However, in contrast to the aforementioned studies, increased MMP2 / MMP9 activity in wet-AMD is well-supported by cellular, genetic, and histopathologic studies (Bandyopadhyay et al., Invest Ophthalmol Vis Sci. Apr 2012, 53(4): 1953-61 ; Chau et al., Eye (Land). Dec 2007, 21(12): 1511-5; Hoffmann et al., Retina. Apr 2006, 26(4):454-61; Steen et al., Invest Ophthalmol Vis Sci. Oct 1998, 39(11):2194-200; Lambert, The FASEB Journal, 17:2290- 2292). For example, MMP2 and MMP9 show prominent expression in choroidal neovascular membranes from wet-AMD patients. Similarly, mice lacking MMP2 and / or MMP9 were less prone to development of wet-AMD associated choroidal neovascularization (CNV) in a laser- Attorney Docket No. 204606-0204-00WO induced model of CNV (Berglin et al., Investigative Ophthalmology & Visual Science 2003, 44(l):403; Lambert et al., The American Journal of Pathology 2002, 161(4): 1247-1253).

[0013] Overall, consistent with optimal MMP(s) activity being necessary for matrix homeostasis and cell-matrix interaction, published literature supports a role of both decreased and increased levels of specific MMPs (e g., MMP2, MMP9) in AMD / MDs.

[0014] Thus, there is a need in the art for improved compositions and methods for treating and preventing macular degeneration. This invention satisfies this unmet need.

[0015] SUMMARY OF THE INVENTION

[0016] In one aspect, the present invention provides a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0017] Formula (I) wherein:

[0018] X1is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, and combinations thereof;

[0019] X2is selected from the group consisting

[0020] Z is selected from the group consisting of -OH, -ORZ, -NHz, -NHRN, and - N(RN)2; Attorney Docket No. 204606-0204-00WO

[0021] L is a divalent linking group selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof;

[0022] R1, R3, R4, and R5are each independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, -S-alkyl, S(=O)2alkyl, -C(=0)NHRN, -C(=O)N(R )2, -OC(=O)N(RN)2, -NHC(=0)NH(RN), -NHC(=O)alkyl, -N(RN)C(=O)(RN), -NHC(=0)(RN), -C(OH)(RN)2, -C(NH2)(RN)2, and combinations thereof;

[0023] R2is selected from the group consisting of hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy and combinations thereof; each occurrence of Rxand Rzis independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, "S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl, combinations thereof; wherein each occurrence of RNis independently selected from the group consisting of H, D, CH3, CD3, and CF3; each instance of n is independently an integer selected from 1-10, and

[0024] Ubiig is an E3 ubiquitin ligase ligand.

[0025] In some embodiments, the compound of Formula (I) is a compound of Formula (II) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Attomey Docket No. 204606-0204-00WO

[0026] Formula (II).

[0027] In some embodiments, Z is -NH2. In some embodiments, R1is selected from the group consisting of aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, fluoroalkyl, heteroalkyl, and combinations thereof. In some embodiments, R1is . In some embodiments, R2is alkyl. In some embodiments, R2is ethyl. In some embodiments, each of R3, R4, and R3are H.

[0028] In some embodiments, the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0029] Formula (III).

[0030] In some embodiments, L is selected from the group consisting of Attorney Docket No. 204606-0204-00WO wherein:

[0031] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3,

[0032] CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

[0033] In some embodiments, Ubiig is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2is mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H,

[0034] D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

[0035] In some embodiments, the compound of Formula (I) is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO wherein:

[0036] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3,

[0037] CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

[0038] In some embodiments, the compound of Formula (I) is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO and derivatives, prodrugs, and pharmaceutically acceptable salts and solvates thereof, wherein:

[0039] Y is selected from the group consisting of O, S, and NRL; and each instance of RLis independently selected from the group consisting of H, D, Attorney Docket No. 204606-0204-00WO

[0040] F, CH3, CD3, and CF3.

[0041] In one aspect, the present invention provides a method for treating macular degeneration or macular dystrophy in a subject, comprising administering to the subject a compound of the present invention. In some embodiments, the method further comprises administering an activator of MMP2 and / or an inhibitor of RAGE. In some embodiments, the activator of MMP2 comprises one or more selected from the group consisting of MMP2 protein and a nucleic acid molecule encoding MMP2.

[0042] In some embodiments, the inhibitor of RAGE comprises at least one selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomimetic, an antibody, an antibody fragment, a ribozyme, a small molecule chemical compound, a short hairpin RNA, RNAi, siRNA, miRNA, an antisense nucleic acid molecule, or a nucleic acid encoding an antisense nucleic acid molecule. In some embodiments, the inhibitor of RAGE comprises an antagonistic peptide comprising the amino acid sequence of ELKVLMEKEL (SEQ ID NO: 1). In some embodiments, the inhibitor of RAGE comprises one or more selected form the group consisting of FPS-ZM1, RBGO1, RAGE203, RAGE208, RAGE229, azeliragon, TTP488, GM- 1111, 4,6-disubstutuded 2-aminopyrimidines, 4-fluorophenoxy analogs, TTP-3000, and low- molecular weight heparin.

[0043] In some embodiments, the subject has age-related macular degeneration (AMD).

[0044] In some embodiments, the subject has a macular dystrophy selected from the group consisting of: Sorsby’s fundus dystrophy (SFD), Doyne honeycomb macular dystrophy (DHRD) and autosomal dominant radial drusen (ADRD).

[0045] BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The following detailed description of embodiments of the invention will be better understood when read in conjunction with the appended drawings. It should be understood that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0047] Figure 1, comprising Figure 1A through Figure IF, depicts representative images of non- invasive retina imaging of human / animal eye, allowing visualization of drusen in early disease and advanced AMD / MD phenotypes. Figure 1A depicts a representative Fundus photograph of a Attorney Docket No. 204606-0204-00WO normal eye, in which the macula is outlined by a dashed circle. Figure IB depicts a representative Fundus image of an AMD patient showing arrows pointing to drusen, seen as spots of varying shape and size. Figure 1C depicts a representative Fundus image of an AMD patient showing arrows pointing to the boundary of a choroidal neovascularization (CNV) in the macula. Figure ID depicts a schematic representation of a normal retina showing Bruch’s membrane (BrM) and retinal pigment epithelium (RPE) cells. Figure IE depicts a schematic representation of a diseased retina showing soft drusen. Figure IF depicts a schematic representation of a diseased retina with advanced AMD phenotypes of geographic atrophy (GA, RPE cell loss) and CNV (aberrant neovascularization invading the RPE monolayer).

[0048] Figure 2, comprising figure 2A through Figure 2F, depicts representative confocal images demonstrating sPLA2-IIA is present in soft drusen in both AMD donor eye cells and AMD iRPE cultures. Figure 2A depicts a representative confocal image of a normal donor stained for CEP protein adducts (co-[2-carboxyethyl]pyrrole) and drusen protein APOE. Figure 2B depicts a representative confocal image of an AMD donor stained for CEP protein adducts (co-[2- carboxyethyl]pyrrole) and drusen protein APOE. Figure 2C depicts a representative confocal image of AMD iRPE cells stained for CEP protein adducts (co-[2-carboxyethyl]pyrrole) and drusen protein APOE. Figure 2D depicts a representative confocal image of a normal donor stained for sPLA2-IIA and drusen protein APOE. Figure 2E depicts a representative confocal image of an AMD donor stained for sPLA2-IIA and drusen protein APOE. Figure 2F depicts a representative confocal image of AMD iRPE cells stained for sPLA2-IIA and drusen protein APOE. For Figure 2A through Figure 2F, white arrows denote Bruch’s membrane and white arrowheads denote RPE nuclei; scale bar = 50 pm.

[0049] Figure 3 depicts a schematic representation of the mechanism for TIMP3 -mediated drusen deposition in AMD iRPE cells. Sub-RPE TIMP3 accumulation, and consequently decreased MMP2-mediated sterile inflammation, occur due to perturbation of MMP2-DAMP- RAGE-sPLA2-IIA axis in AMD / MDs in a genotype=-agnostic manner. TIMP3: Tissue Inhibitor of Metalloproteinases 3; MMP2: Matrix Metalloproteinase 2; DAMP: Damage Associated Molecular Pattern; HMGB1 : High Mobility Group Box 1 protein; RAGE: Receptor for Advanced Glycation End products; sPLA2-IIA: Secretory Phospholipase A2-IIA; C3: Complement Component 3; CFB: Complement Factor B. Attorney Docket No. 204606-0204-00WO

[0050] Figure 4 depicts representative sPLA2-IIA inhibition with a pan-sPLA2 small molecule inhibitor, LY315920, decreasing drusen accumulation in AMD / MD iRPE. Quantitative analysis was performed on >90-day cultures showing amount (count and area) of co-localized APOE and Nile Red or APOE and sPLA2-IIA drusen deposits in un-supplemented versus LY315920- supplemented cultures of Sorsby fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy (DHRD) and AMD iRPE cells; n = 3.

[0051] Figure 5 depicts representative confocal images of tissue sections demonstrating a lack of sPLA2-IIA in C5BL / 6J retina / RPE mouse cells, while human AMD cells and PLA2G2A (tg) mouse cells demonstrate significant localization of sPLA2-IIA. RPE nuclei are denoted by a white arrowhead; scale bar = 50 pm.

[0052] Figure 6, comprising Figure 6A through 6H, depicts representative images demonstrating that PLA2G2A (tg) mice show drusen and advanced AMD-like pathology. Figure 6A depicts a representative light microscopy image of tissue sections from age- and sex-matched C57BL / 6J and PLA2G2A (tg) mice showing drusen (arrowheads) in mice at 15-18-month age. Figure 6B depicts representative confocal microscopy images of tissue sections of mice as in Figure 6A showing Bruch’s membrane (BrM) thickening (APOE / COL4-positive; arrow). Figure 6C depicts representative confocal microscopy images of tissue sections of mice as in Figure 6A showing CNV (arrowhead). Figure 6D depicts representative confocal microscopy images of tissue sections of mice as in Figure 6A showing inflammation (GFAP / Ibal -positive microglia). Figure 6E depicts representative Fundus and fluorescein angiography images of PLA2G2A (tg) mice at 9-month age showing drusen (arrows). Figure 6F depicts representative confocal microscopy images of mice demonstrating AMD-associated drusen (asterisks) below RPE (arrows) preceding advanced AMD pathology of GA and CNV. Figure 6G depicts a representative confocal microscopy image demonstrating Bruch’s membrane thickening (arrow) in PLA2G2A (tg) mice, with a loss of outer segments and displaced photoreceptor nuclei (arrowhead). Figure 6H depicts representative ERG an amplitude showing a selective decline in photoreceptor function of aged PLA2G2A (tg) mice but not C57BL / 6J mice that lack sPLA2-IIA; n = 3. For Figure 6A through 6D, 6F, and 6G scale bar = 50 pm.

[0053] Figure 7 depicts the chemical structures of proteolysis targeting chimeras (PROTACs) UR-00059, UR-00060, UR-00061, and UR-00062. Attorney Docket No. 204606-0204-00WO

[0054] Figure 8, comprising Figure 8A and Figure 8B, depicts representative results of primary screening of PROTACs with molecular docking. Figure 8A depicts a representative image of UR-00059 docking with E3-ligase and sPLA2-IIA using Autodock Vina and UCSF-Chimera tools. Figure 8B depicts a representative image showing interaction types and distances of protein amino acid residues from UR-00059. The calculated AG was found to be -7.943 kcal / mol.

[0055] Figure 9, comprising Figure 9A through Figure 9D, depicts representative results demonstrating that UR-00059 degrades sPLA2-IIA. Figure 9A depicts a representative image of a Western blot demonstrating that UR-00059 potently induces degradation of sPLA2-IIA in iRPE cells. Figure 9B depicts representative quantification of UR-00059-induced sPLA2-IIA degradation with a DCso of 295.5 nM. Figure 9C depicts a representative image of a Western blot demonstrating that UR-00060 does not degrade sPLA2-IIA as potently as UR-00059. Figure 9D depicts representative quantification of UR-00060-induced sPLA2-IIA degradation with a DC50 of 4.274 pM.

[0056] Figure 10, comprising Figure 10A through Figure 10E, depicts representative results demonstrating that UR-00059 reduces drusen in iRPE cells. Figure 19A depicts a representative confocal image of untreated AMD iRPE cells. Figure 10B depicts a representative confocal image of AMD iRPE cells treated with UR-00059 (500 nM daily for 7 days). Figure 10C depicts representative quantification of drusen in AMD iRPE cells left untreated or treated with UR- 00059 (100 nM or 1 pM daily for 7 days). Figure 10D depicts representative transepi theli al resistance (TER) measurement of AMD iRPE cells treated with UR-00059, demonstrating no adverse effect. The threshold for RPE TER in vivo is 150 Q cm-2. Figure 10E depicts representative fluorescence microscopy images of AMD iRPE cells left untreated or treated with UR00059 (500 nM or 1 pM daily for 7 days), demonstrating no alteration in cell viability. For Figure 10A, Figure 10B, and Figure 10E, scale bar = 50 pm. For Figure 10C and Figure 10D, n = 3.

[0057] Figure 11, comprising Figure 11A and Figure 1 IB, depicts representative results demonstrating that UR-00059 degrades sPLA-IIA in RPE in vivo. Figure 11A depicts a representative image of a Western blot demonstrating decreased RPE sPLA2-IIA in PLPA2G2A (tg) mice 24 hours post-intravitreal injection. Figure 1 IB depicts representative quantification of sPLA2-IIA level in RPE of PLA2G2A (tg) mice 24 hours post-intravitreal injection. Attorney Docket No. 204606-0204-00WO

[0058] Figure 12 depicts a representative dose-response curve demonstrating the inhibitory activity of UR-00059 against sPLA2-IIa.

[0059] Figure 13, comprising Figure 13A and Figure 13B, depicts representative results of patient-derived acute AMD iRPE cultures treated with UR-00059. Figure 13 A depicts representative confocal microscopy images of sPLA2-IIa (green) in drusen deposits in patient- derived AMD iRPE cultures seven days after treatment with UR-00059. Scale bar = 50 pm. Figure 13B depicts quantification of PLA2-IIA in drusen deposits from Figure 13A. *, p < 0.05; ***, p < 0.005.

[0060] Figure 14, comprising Figure 14A and Figure 14B, depicts representative results of patient-derived acute AMD iRPE cultures treated with UR-00059. Figure 14A depicts representative confocal microscopy images of APOE+drusen in patient-derived AMD iRPE cultures seven days after treatment with UR-00059. Scale bar = 50 pm. Figure 14B depicts quantification of PLA2-IIA in drusen deposits from Figure 14 A. **, p < 0.01; ***, p < 0.005.

[0061] DETAILED DESCRIPTION

[0062] In one aspect, the present disclosure is directed to compositions and methods for treating macular degeneration and / or macular dystrophy in a subject. In some embodiments, the methods comprise administering to the subject a novel compound that degrades secretory phospholipase 2-IIA (sPLA2-IIA). In some embodiments, the degrader of sPLA2-IIA is a compound of Formula (I) , or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0063] Formula (I) wherein:

[0064] X1is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, and combinations thereof; Attorney Docket No. 204606-0204-00WO

[0065] X2is selected from the group consisting

[0066] R\ Rx

[0067] | X _j l-N JNH

[0068] Rr\X / ' rRr\X

[0069] Z is selected from the group consisting of -OH, -ORZ, -NH2, -NHRN, and - N(RN)2;

[0070] L is a divalent linking group selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof;

[0071] R1, R3, R4, and R5are each independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, -S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl, combinations thereof;

[0072] R2is selected from the group consisting of hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy and combinations thereof; each occurrence of Rxand Rzis independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, 'S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl, combinations thereof; wherein each occurrence of RNis independently selected from the group consisting of H, D, CH3, CD3, and CF3; each instance of n is independently an integer selected from 1-10, and Attorney Docket No. 204606-0204-00WO

[0073] Ubiig is an E3 ubiquitin ligase ligand.

[0074] Definitions

[0075] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0076] As used herein, each of the following terms has the meaning associated with it in this section.

[0077] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0078] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

[0079] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0080] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0081] A disease or disorder is “alleviated” if the severity of a sign or symptom of the disease or disorder, the frequency with which such a sign or symptom is experienced by a patient, or both, is reduced.

[0082] The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human.

[0083] As used herein, the term “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Attorney Docket No. 204606-0204-00WO

[0084] Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

[0085] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of pathology disease or disorder, for the purpose of diminishing or eliminating those signs or symptoms.

[0086] As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a disease or disorder contemplated herein, the signs or symptoms of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

[0087] As used herein, the terms “effective amount,” “pharmaceutically effective amount" and “therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and / or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0088] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0089] As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, Attorney Docket No. 204606-0204-00WO hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic. Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, paratoluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like. Furthermore, pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salts (e.g., sodium-dependent or potassium), and ammonium salts.

[0090] As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propyl glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are Attorney Docket No. 204606-0204-00WO compatible with the activity of the compound useful within the invention and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0091] As used herein, the term “potency” refers to the dose needed to produce half the maximal response (EDso).

[0092] As used herein, the term “efficacy” refers to the maximal effect (Emax) achieved within an assay.

[0093] By the term “modulating,” as used herein, is meant mediating a detectable increase or decrease in the level of a response in a subject compared with the level of a response in the subject in the absence of a treatment or compound, and / or compared with the level of a response in an otherwise identical but untreated subject. The term encompasses perturbing and / or affecting a native signal or response thereby mediating a beneficial therapeutic response in a subject, such as a human.

[0094] The phrase “inhibit,” as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and / or a protein’s expression, stability, function or activity by a measurable amount or to prevent entirely. Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate a protein, a gene, and an mRNA stability, expression, function and activity, e.g., antagonists.

[0095] The phrase “activate,” as used herein, means to increase a molecule, a reaction, an interaction, a gene, an mRNA, and / or a protein’s expression, stability, function or activity by a measurable amount. Activators are compounds that, e.g., bind to, increase stimulation, activation, activate, sensitize, or upregulate a protein, a gene, and an mRNA stability, expression, function, and activity, e.g., agonists.

[0096] As used herein, “activity” includes physiological activity, binding affinity, and / or the enzymatic activity of a molecule. Attorney Docket No. 204606-0204-00WO

[0097] As used herein, the term “potency” refers to the dose needed to produce half the maximal response (EDso).

[0098] As used herein, “MPP2” refers to matrix metalloproteinase 2.

[0099] As used herein, “DAMP” refers to damage-associated molecular pattern molecules.

[0100] As used herein, “RAGE” refers to receptor for advanced glycation end-products.

[0101] As used herein, “sPLA2-IIA” refers to secretory phospholipase 2-IIA.

[0102] As used herein, “associated” refers to coincidence with the development or manifestation of a disease, condition, or phenotype. Association may be due to, but is not limited to, genes responsible for housekeeping functions, those that are part of a pathway that is involved in a specific disease, condition, or phenotype and those that indirectly contribute to the manifestation of a disease, condition, or phenotype.

[0103] As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.

[0104] As used herein, the term “substituted alkyl” means alkyl as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OE1, alkoxy, -NH2, amino, azido, -N(CH3)2, -C(=O)OH, trifluoromethyl, -ON, -C(=O)O(Ci-C4)alkyl, -C(=0)NH2, -SO2NH2, -C(=NH)NH2, and -NO2. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxy cyclopentyl and 3 -chloropropyl.

[0105] As used herein, the term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quatemized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(=O)-CH3, and -CH2-CH2-S(=O)2-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CEI2-NH-O-CEI3 or Attorney Docket No. 204606-0204-00WO

[0106] -CH2-CH2-S-S-CH3.

[0107] “Alkyl” as used herein refers to a divalent hydrocarbyl group having the specified number of carbon atoms which can link two other groups together. Sometimes it refers to a group — (CH2)n — where n is 1-8, and preferably n is 1-4. Where specified, an alkyl can also be substituted by other groups and may include one or more degrees of unsaturation (i.e., an alkenyl or alkynyl moiety) or rings. The open valences of an alkyl need not be at opposite ends of the chain. Thus branched alkyl groups such as -CH(CH3)-, -CH2CH(CH3)-, and -C(CH3)2- are also included within the scope of the term ‘alkyls’, as are cyclic groups such as cyclopropan-l,l-diyl and unsaturated groups such as ethyl (-CH=CH-) or propyl (-CH2-CH=CH-). Where an alkyl group is described as optionally substituted, the substituents include those typically present on alkyl groups as described herein. Examples of substituents include oxo, fluorine, chlorine, bromine, iodine, CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -0CH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=0)NHCH3, -C(=O)CH3, -ON(O)2, or -C(=O)OH.

[0108] As used herein, heteroalkyl refers to an alkyl group as defined herein in which one or more of the carbon atoms is each independently replaced with the same or different heteroatom selected from O, S, N or C(O). In a preferred embodiment, heteroalkyl refers to an alkyl group as defined herein in which one or more of the carbon atoms is each replaced with an oxygen atom. In a preferred embodiment, heteroalkyl refers to an alkyl group as defined herein in which 1, 2, 3 or 4 of the carbon atoms is each replaced with an oxygen atom. Example of suitable C2-C6 heteroalkyl are -O-CH2, -O-CH2-CH2, -O-CH2-C(O), -O-CH2-C(O)-NH, -CH2-CH2-O-CH2-CH2, -O-CH2-CH2-O-CH2-CH2, -O-CH2-CH2-O-CH2-CH2-O-CH2-CH2, -O-CH2-CH2-(N-CH3)-CH2-CH2-O-CH2-CH2, -CH2-CH2-(N-CH3)-CH2-CH2, and -CH2-CH2-S-CH2-CH2.

[0109] As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.

[0110] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Attorney Docket No. 204606-0204-00WO

[0111] As used herein, the term “cycloalkyl” refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having from 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

[0112] Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalenyl. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.

[0113] As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N. In some embodiments, each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In some embodiments, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. A heterocycle may be aromatic or non- aromatic in nature. In some embodiments, the heterocycle is a heteroaryl. Attorney Docket No. 204606-0204-00WO

[0114] An example of a 3-membered heterocycloalkyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine and piperazine. Other non-limiting examples of heterocycloalkyl groups are:

[0115] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2, 3 -dihydrofuran, 2, 5 -dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,

[0116] 2.3 -dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine,

[0117] 1.3-dioxepane, 4,7-dihydro-l,3-dioxepin, and hexamethyloxide.

[0118] As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n + 2) delocalized 7t (pi) electrons, where n is an integer.

[0119] As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent Attorney Docket No. 204606-0204-00WO manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl.

[0120] As used herein, the term “aryl-(Ct-C3)alkyl” means a functional group wherein a one- to three-carbon alkyl chain is attached to an aryl group, e.g., -CFhCFb-phenyl. In some embodiments, aryl-(Ci-C3)alkyl is aryl-CH2- or aryl-CH(CH3)-. The term “substituted aryl-(Ci-C3)alkyl” means an aryl-(Ci-C3)alkyl functional group in which the aryl group is substituted. Similarly, the term “heteroaryl-(Ci-C3)alkyl” means a functional group wherein a one to three carbon alkyl chain is attached to a heteroaryl group, e.g., -CthCEb-pyridyl. The term “substituted heteroaryl-(Ci-C3)alkyl” means a heteroaryl-(Ci-C3)alkyl functional group in which the heteroaryl group is substituted.

[0121] As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character. A polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moieties:

[0122] Examples of heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1 ,3,4-oxadiazolyl.

[0123] Examples of polycyclic heterocycles and heteroaryls include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (particularly 3-, 4-, 5-, 6- and 7-benzofuryl), Attorney Docket No. 204606-0204-00WO

[0124] 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

[0125] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. The term “substituted” further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In some embodiments, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.

[0126] As used herein, the term “optionally substituted” means that the referenced group may be substituted or unsubstituted. In some embodiments, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0127] In some embodiments, the substituents are independently selected from the group consisting of oxo, halogen, -CN, -NH2, -OH, -NH(CHs), -N(CH3)2, alkyl (including straight chain, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoro alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -C(=O)N[H or alkyl]2, - OC(=O)N[substituted or unsubstituted alkyl]2, -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -N[substituted or unsubstituted alkyl]C(=O)[substituted or unsubstituted alkyl], -NHC(=O)[substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl]2, and -CXNH2) [substituted or unsubstituted alkyl]2. In another embodiment, by way of example, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CH(CH3)2, -CF3, -CH2CF3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, - OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3, -C(=O)CH3, -ON(O)2, and -C(=O)OH. In yet some embodiments, the substituents are independently selected from the group consisting of C1-6 Attorney Docket No. 204606-0204-00WO alkyl, -OH, Ct-6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of Ci-6 alkyl, Ct-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic.

[0128] Ranges: throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0129] Compounds

[0130] The compounds of the present disclosure may be synthesized using techniques well- known in the art of organic synthesis. The starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art.

[0131] In one aspect, the present invention relates to a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0132] Formula (I) wherein: Attorney Docket No. 204606-0204-00WO

[0133] X1is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, and combinations thereof;

[0134] X2is selected from the group consisting

[0135] R R

[0136] LxX _| rN Nd

[0137] Rx nRx5 •

[0138] Z is selected from the group consisting of -OH, -ORZ, -NH2, -NHRN, and - N(RN)2;

[0139] L is a divalent linking group selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof;

[0140] R1, R3, R4, and R5are each independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, -S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl, combinations thereof;

[0141] R2is selected from the group consisting of hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy and combinations thereof; each occurrence of Rxand Rzis independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, "S-alkyl, -NHC(=O)alkyl, -N(RN)C(=O)(RN), -NHC(=O)(RN), -C(OH)(RN)2, -C(NH2)(RN)2, and combinations thereof; Attorney Docket No. 204606-0204-00WO wherein each occurrence of RNis independently selected from the group consisting of H, D, CH3, CD3, and CF3; each instance of n is independently an integer selected from 1-10, and

[0142] Ubiig is an E3 ubiquitin ligase ligand. In some embodiments, X1is alkyl. In some embodiments, X1is -CH2-. In some embodiments, X2is heterocycloalkyl. In some embodiments, X2is

[0143] In some embodiments, the compound of Formula (I) is Formula (II) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Formula (II).

[0144] In some embodiments, R1is selected from the group consisting of aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, fluoroalkyl, heteroalkyl, and combinations thereof In some embodiments,

[0145] In some embodiments, R2is alkyl. In some embodiments, R2is ethyl. In some embodiments, R3, R4, and R? are independently selected from the group consisting of H, D, F, Cl, and Br. In some embodiments, R3, R4, and R5are all H.

[0146] In some embodiments, the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Attorney Docket No. 204606-0204-00WO wherein:

[0147] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3, CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

[0148] In some embodiments, Ubiig is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO stereoisomers thereof; wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl;

[0149] In some embodiments, the compound of Formula (I) is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO es, prodrugs, and pharmaceutically acceptable salts and solvates thereof; wherein:

[0150] L2is selected from the group consisting of

[0151] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3,

[0152] CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

[0153] In some embodiments, the compound of Formula (I) is selected from the group consisting of Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00 WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO and derivatives, prodrugs, and pharmaceutically acceptable salts and solvates thereof, wherein Y is selected from the group consisting of O, S, and NR1'; and each instance of RLis independently selected from the group consisting of H, D,

[0154] F, CH3, CD3, and CF3.

[0155] The compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. Tn some embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In some embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting Attorney Docket No. 204606-0204-00WO example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

[0156] The compounds described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound of the invention, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In another embodiment, the compounds described herein exist in unsolvated form.

[0157] In some embodiments, the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0158] In some embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In some embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In another embodiment, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound.

[0159] In some embodiments, sites on, for example, the aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize, or eliminate this metabolic pathway. In some embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.

[0160] Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,nC,13C,14C,36C1,18F,123I,125I,13N,15N,15O,170,180,32P, and35S. In some embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium Attorney Docket No. 204606-0204-00WO affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet another embodiment, substitution with positron emitting isotopes, such asnC,18F,15O and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent otherwise employed.

[0161] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0162] The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Suppiementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference in their entirety). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

[0163] Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources or are prepared using procedures described herein.

[0164] In some embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In another embodiment, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. Attorney Docket No. 204606-0204-00WO

[0165] In some embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethyl silyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.

[0166] In some embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidativelyremovable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates.

[0167] Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.

[0168] Typically blocking / protecting groups may be selected from:

[0169] Attorney Docket No. 204606-0204-00WO

[0170] Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure.

[0171] Methods

[0172] In some embodiments, the disclosure provides methods of degrading sPLA2-IIA in a cell. In some embodiments, the disclosure provides methods of degrading sPLA2-IIA in a cell comprising contacting the cell with a degrader of sPLA2-IIA.

[0173] In some embodiments, the disclosure provides a method of administering a composition comprising a degrader of sPLA2-IIA to a subject. In some embodiments, the subject has macular degeneration. In some embodiments, the macular degeneration is age-related macular degeneration (AMD). In some embodiments, the AMD is Wet AMD. In some embodiments, the AMD is Dry AMD. In some embodiments, the subject has macular dystrophy. In some embodiments, the macular dystrophy is selected from the group consisting of Sorsby’s fundus dystrophy (SFD), Doyne honeycomb macular dystrophy (DHRD) and autosomal dominant radial drusen (ADRD). Attorney Docket No. 204606-0204-00WO

[0174] In some embodiments, the disclosure provides a method of preventing or inhibiting the formation of drusen in a subject. In some embodiments, the method comprises administering to the subject a degrader of sPLA2-IIA.

[0175] In some embodiments, the disclosure provides a method of reducing the size and / or number of drusen in a subject. In some embodiments, the method comprises administering to the subject a degrader of sPLA2-IIA.

[0176] In some embodiments, the disclosure provides a method of preventing or inhibiting a subject from developing geographic atrophy (GA). In some embodiments, the method comprises administering to the subject a degrader of sPLA2-IIA.

[0177] In some embodiments, the disclosure provides a method of treating or reversing GA. In some embodiments, the method comprises administering to the subject a degrader of sPLA2-IIA.

[0178] In some embodiments, the disclosure provides a method of preventing or inhibiting a subject from developing choroidal neovascularization (CNV). In some embodiments, the method comprises administering to the subject a degrader of sPLA2-IIA.

[0179] In some embodiments, the disclosure provides a method of treating or reversing CNV. In some embodiments, the method comprises administering to the subject a degrader of sPLA2-IIA.

[0180] In some embodiments, the disclosure provides methods of treating macular degeneration and / or macular dystrophy in a subject. In some embodiments, the method comprises the step of administering to the subject a composition comprising a degrader of sPLA2-IIA. In some embodiments, the macular degeneration is age-related macular degeneration (AMD). In some embodiments, the AMD is Wet AMD. In some embodiments, the AMD is Dry AMD.

[0181] In some embodiments, the degrader of sPLA2-IIA is a compound of Formula (I), a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Attorney Docket No. 204606-0204-00WO wherein:

[0182] X1is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, and combinations thereof;

[0183] X2is selected from the group consisting

[0184] Z is selected from the group consisting of -OH, -ORZ, -NH2, -NHRN, and - N(RN)2;

[0185] L is a divalent linking group selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof;

[0186] R1, R3, R4, and R5are each independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, -S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl, combinations thereof;

[0187] R2is selected from the group consisting of hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy and combinations thereof; each occurrence of Rxand Rzis independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, "S-alkyl, Attorney Docket No. 204606-0204-00WO

[0188] -NHC(=O)alkyl, -N(RN)C(=O)(RN), -NHC(=O)(RN), -C(OH)(RN)2, -C(NH2)(RN)2, and combinations thereof; wherein each occurrence of RNis independently selected from the group consisting of H, D, CH3, CD3, and CF3; each instance of n is independently an integer selected from 1-10, and Ubiig is an E3 ubiquitin ligase ligand.

[0189] In some embodiments, the degrader of sPLA2-IIA is a compound of Formula (II) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0190] Formula (II).

[0191] In some embodiments, the degrader of sPLA2-IIA is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0192] In some embodiments, the degrader of sPLA2-IIA is a compound selected from the group consisting of is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO es, prodrugs, and pharmaceutically acceptable salts and solvates thereof; wherein:

[0193] L2is selected from the group consisting of

[0194] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3,

[0195] CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10. Attorney Docket No. 204606-0204-00WO

[0196] Admi ni strati on / Dosage / Formul ati on s

[0197] The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either before or after the onset of a disease or infection. Further, several divided dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0198] Administration of the compositions of the present invention to a patient or subject, such as a mammal, (e.g., human), may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or infection in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the subject; the age, sex, and weight of the subject; and the ability of the therapeutic compound to treat a disease in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 mg / kg to about 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.

[0199] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without generating excessive side effects in the subject.

[0200] In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, or materials used in combination with the compound, the age, sex, weight, condition, general health, and prior medical history of the subject being treated, and like factors well, known in the medical arts.

[0201] A medical professional, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition Attorney Docket No. 204606-0204-00WO required. For example, the physician or veterinarian could start with a dosage of the compound of the invention in the pharmaceutical composition at a level that is lower than the level required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.

[0202] In particular embodiments, it is advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. “Dosage unit form” as used herein refers to a physically discrete unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. The dosage unit forms of the invention can be selected based upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound for the treatment of a disease or infection in a patient.

[0203] In some embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In some embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier.

[0204] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propyl glycol, and liquid polyethylene glycol, and the like), vegetable oils, and suitable mixtures thereof. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some embodiments, it is useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In some embodiments, the pharmaceutically acceptable carrier is DMSO, alone or in combination with other carriers.

[0205] The therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the subject, the current medical condition of the subject Attorney Docket No. 204606-0204-00WO and the severity of the disease in the subject being treated. The skilled artisan is able to determine appropriate doses depending on these and other factors.

[0206] The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.

[0207] Doses of the compound of the invention for administration may be in the range of from about 1 pg to about 10,000 mg, from about 20 pg to about 9,500 mg, from about 40 pg to about 9,000 mg, from about 75 pg to about 8,500 mg, from about 150 pg to about 7,500 mg, from about 200 pg to about 7,000 mg, from about 3050 pg to about 6,000 mg, from about 500 pg to about 5,000 mg, from about 750 pg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments therebetween.

[0208] In some embodiments, the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

[0209] The compounds for use in the method of the invention may be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a Attorney Docket No. 204606-0204-00WO suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.

[0210] In some embodiments, the compositions of the invention are administered to the subject from about one to about five times per day or more. In various embodiments, the compositions of the invention are administered to the subject, 1-7 times per day, 1-7 times every two days, 1-7 times every 3 days, 1-7 times every week, 1-7 times every two weeks, and 1-7 times per month. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the invention will vary from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and other factors. Thus, the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any subject is determined by the medical professional taking all other factors about the subject into account.

[0211] In the case wherein the subject’s status does improve, upon the doctor’s discretion the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0212] Once improvement of the subject’s condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a subject may require intermittent treatment on a long-term basis, or upon any recurrence of the disease or disorder.

[0213] Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the Attorney Docket No. 204606-0204-00WO D50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.

[0214] In some embodiments, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or prevent a disease or infection in a patient.

[0215] Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.

[0216] Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual, or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intratumoral, intrapulmonary, intraduodenal, intragastrical, intrathecal, intravitreal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

[0217] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for parenteral administration and the Attorney Docket No. 204606-0204-00WO like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

[0218] Oral Administration

[0219] For oral administration, suitable forms include tablets, dragees, liquids, drops, suppositories, or capsules, caplets, and gel caps. The compositions formulated for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated, or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

[0220] For oral administration, the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fdlers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets may be coated using suitable methods and coating materials such as OPADRY™ film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K 18400). Liquid preparation for oral administration may be in the form of solutions, syrups, or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid). Attorney Docket No. 204606-0204-00WO

[0221] Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient. The powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a “granulation.” For example, solvent-using “wet” granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.

[0222] Melt granulation involves the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents. The low melting solids, when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium. The liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together. The resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form. Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.

[0223] U.S. Patent No. 5,169,645 discloses directly compressible wax-containing granules having improved flow properties. The granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture. In certain embodiments, only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.

[0224] The present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of G-protein receptor-related diseases or disorders. Using a wax / pH-sensitive polymer mix, a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.

[0225] Parenteral Administration

[0226] For parenteral administration, the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular, intravitreal, or subcutaneous Attorney Docket No. 204606-0204-00WO injection or infusion, or for administration in a bolus dose and / or continuous infusion.

[0227] Suspensions, solutions, or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used.

[0228] Controlled Release Formulations

[0229] In some embodiments, the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release, and pulsatile release formulations.

[0230] The term sustained release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period. The period of time may be as long as a day, a week, or a month or more and should be a release which is longer than the same amount of agent administered in bolus form. The term delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.

[0231] For sustained release, the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds. As such, the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.

[0232] In some embodiments of the invention, the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.

[0233] The term pulsatile release refers to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profdes of the drug after drug administration.

[0234] The term immediate release refers to a drug formulation that provides for release of the drug immediately after drug administration.

[0235] As used herein, short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration. Attorney Docket No. 204606-0204-00WO

[0236] As used herein, rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.

[0237] Those skilled in the art recognize, or are able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

[0238] Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053; 20030044466; 20030039688; and 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Applications Nos. WO 03 / 35041; WO 03 / 35040; WO 03 / 35029; WO 03 / 35177; WO 03 / 35039; WO 02 / 96404; WO 02 / 32416; WO 01 / 97783; WO 01 / 56544; WO 01 / 32217; WO 98 / 55107; WO 98 / 11879; WO 97 / 47285; WO 93 / 18755; and WO 90 / 11757.

[0239] EMBODIMENTS

[0240] Embodiment 1 is a compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof Attorney Docket No. 204606-0204-00WO

[0241] Formula (I) wherein:

[0242] X1is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, and combinations thereof;

[0243] X2is selected from the group consisting

[0244] R Rx

[0245] I-N -I

[0246] RxxX Rfx•

[0247] Z is selected from the group consisting of -OH, -ORZ, -NH2, -NHRN, and - N(RN)2;

[0248] L is a divalent linking group selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof;

[0249] R1, R3, R4, and R5are each independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, -S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl, combinations thereof;

[0250] R2is selected from the group consisting of hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy and combinations thereof; each occurrence of Rxand Rzis independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, "S-alkyl, S(=O)2alkyl, -C(=O)NHRN, -C(=O)N(R )2, -OC(=O)N(RN)2, -NHC(=O)NH(RN), Attorney Docket No. 204606-0204-00WO

[0251] -NHC(=O)alkyl, -N(RN)C(=O)(RN), -NHC(=O)(RN), -C(OH)(RN)2, -C(NH2)(RN)2, and combinations thereof; wherein each occurrence of RNis independently selected from the group consisting of H, D, CH3, CD3, and CF3; each instance of n is independently an integer selected from 1-10, and Ubiig is an E3 ubiquitin ligase ligand.

[0252] Embodiment 2 is the compound of embodiment 1, wherein the compound of Formula (I) is a compound of Formula (II) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:

[0253] Formula (II).

[0254] Embodiment 3 is the compound of embodiment 1 or 2, wherein Z is -NH2.

[0255] Embodiment 4 is the compound of any one of embodiments 1-3, wherein R1is selected from the group consisting of aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, fluoroalkyl, heteroalkyl, and combinations thereof.

[0256] Embodiment 5 is the compound of any one of embodiments 1-4, wherein R1is

[0257] Embodiment 6 is the compound of any one of embodiments 1-5, wherein R2is alkyl.

[0258] Embodiment 7 is the compound of any one of embodiments 1-6, wherein R2is ethyl.

[0259] Embodiment 8 is the compound of any one of embodiments 1-7, wherein each of R3, R4, and R are H.

[0260] Embodiment 9 is the compound of any one of embodiments 1-8, wherein the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof: Attorney Docket No. 204606-0204-00WO

[0261] Formula (III).

[0262] Embodiment 10 is the compound of any one of embodiments 1-9, wherein L is selected from the group consisting of wherein:

[0263] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3, CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

[0264] Embodiment 11 is the compound of any one of embodiments 1-10, wherein Ubiig is selected from the group consisting of: Attorney Docket No. 204606-0204-00WO wherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2is mono to the maximum allowable substitution, or no substitution; Attorney Docket No. 204606-0204-00WO and each occurrence of RA2is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, 0CH3, 0CD3, and OCF3.

[0265] Embodiment 12 is the compound of any one of embodiments 1-11, wherein the compound of Formula (I) is selected from the group consisting of:

[0266] Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3, CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10. Attorney Docket No. 204606-0204-00WO

[0267] Embodiment 13 is the compound of any one of embodiments 1-12, wherein the compound of Formula (I) is selected from the group consisting of:

[0268] Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO Attorney Docket No. 204606-0204-00WO and derivatives, prodrugs, and pharmaceutically acceptable salts and solvates thereof, wherein:

[0269] Y is selected from the group consisting of O, S, and NRL; and each instance of RLis independently selected from the group consisting of H, D,

[0270] F, CH3, CD3, and CF3.

[0271] Embodiment ! 4 is a method for treating macular degeneration or macular dystrophy in a subject, comprising administering to the subject a compound of any one of embodiments 1-13.

[0272] Embodiment 15 is the method of embodiment 14, wherein the method further comprises administering an activator of MMP2 and / or an inhibitor of RAGE. Attorney Docket No. 204606-0204-00WO

[0273] Embodiment 16 is the method of embodiment 15, wherein the activator of MMP2 comprises one or more selected from the group consisting of MMP2 protein and a nucleic acid molecule encoding MMP2.

[0274] Embodiment 17 is the method of embodiment 15, wherein the inhibitor of RAGE comprises at least one selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomimetic, an antibody, an antibody fragment, a ribozyme, a small molecule chemical compound, a short hairpin RNA, RNAi, siRNA, miRNA, an antisense nucleic acid molecule, or a nucleic acid encoding an antisense nucleic acid molecule.

[0275] Embodiment 18 is the method of embodiment 17, wherein the inhibitor of RAGE comprises an antagonistic peptide comprising the amino acid sequence of ELKVLMEKEL (SEQ ID NO: 1).

[0276] Embodiment 19 is the method of embodiment 17, wherein the inhibitor of RAGE comprises one or more selected form the group consisting of FPS-ZM1, RBG01, RAGE203, RAGE208, RAGE229, azeliragon, TTP488, GM-1111, 4,6-disubstutuded 2-aminopyrimidines, 4-fluorophenoxy analogs, TTP-3000, and low-molecular weight heparin.

[0277] Embodiment 20 is the method of any of embodiments 14-19, wherein the subject has age- related macular degeneration (AMD).

[0278] Embodiment 21 is the method of any of embodiments 14-20, wherein the subject has a macular dystrophy selected from the group consisting of: Sorsby’s fundus dystrophy (SFD), Doyne honeycomb macular dystrophy (DHRD) and autosomal dominant radial drusen (ADRD).

[0279] EXPERIMENTAL EXAMPLES

[0280] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0281] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the present invention and practice the claimed methods. The following working examples, therefore, Attorney Docket No. 204606-0204-00WO specifically point out certain embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

[0282] Example 1: Novel sPLA2-IIA Degraders for Treatment of Macular Degeneration and Macular Dystrophy

[0283] AMD and related MDs lead to irreversible vision loss in adults. Notably, AMD is the leading cause of irreversible vision loss in adults >50 years of age. It is estimated that AMD is at least responsible for -8.7% of the global blindness and its incidence is rising exponentially with increased life-expectancy (Gehrs, K. M., et al., 2006, Ann Med, 38(7):450-471). In the United States of America (USA) alone, AMD is estimated to account for 54% of all blindness (Congdon, N., et al., 2004, Arch Ophthamol, 122(4):477-485).

[0284] AMD / MDs primarily affects the retinal pigment epithelium-choriocapillaris (RPE-CC) complex in the eye and according to the Macular Research Classification Committee 2013, the first symptom of the disease in early AMD are yellowish lipid-protein deposits, drusen (> 63 to < 125 pm in size), beneath the RPE monolayer (Ferris, F. L., et al., 2013, Ophthalmology, 120(4):844-851). The next stage of the disease, intermediate AMD, is associated with larger drusen (> 125 pm in size) and pigmentary abnormalities. Ultimately, advanced forms of AMD / MDs can present in two forms, i) geographic atrophy (GA / dry form) and ii) choroidal neovascularization (CNV / wet form) (Parravano, M., et al., 2013, Ophthalmology, 120(4):844- 851). From a drug testing and therapeutic perspective, both drusen (early / intermediate AMD) and GA / CNV can be visualized by non-invasive retina imaging (Figure 1).

[0285] There are limited treatment options for advanced neovascular wet- AMD and FDA has recently approved complement pathway inhibitors, avacincaptad pegol and pegcetacoplan, for late-stage dry-AMD (GA) (Parravano, M., et al., 2021, BioDrugs, 35(6):673-692; Cruz-Pimentel, M., et al., 2023, J Clin Med, 12(15):5131). The currently available treatment options for advanced AMD (both dry- and wet- AMD) are inadequate in their therapeutic impact and are linked with several undesirable side-effects particularly with long-term usage. For example, although complement inhibitors, avacincaptad pegol and pegcetacoplan, have been shown to reduce the progression of GA in advanced dry-AMD, there has been no improvement of vision in patients treated with these drugs. Furthermore, both avacincaptad pegol and pegcetacoplan are associated with increased susceptibility to CNV (advanced wet-AMD) in treated patients(Cruz- Attorney Docket No. 204606-0204-00WO

[0286] Pimentel, M., et al., 2023, J Clin Med, 12(15):5131 ; Liao, D. S., et al., 2020, Ophthalmology, 127(2): 186-195; Patel, S. S., et al., 2023, Eye, 37(17):3551-3557). Similarly, monthly intravitreal injection of anti-VEGFA drug, the most commonly used treatment option for advanced wet- AMD, has limited success and is associated with photoreceptor degeneration after long-term use (Xu, M., et al., 2022, Drug Des Devel Ther, 16:3241-3262).

[0287] In contrast to advanced AMD, there is currently no treatment option for early / intermediate AMD (Garcia-Layana, A., et al., 2017, 12: 1579-1587). There is an urgent unmet need for therapeutics for early / intermediate AMD due to the high prevalence and elevated risk of progression to advanced AMD (Ferris, F. L., et al., 2013, Ophthalmology, 120(4):844 — 851; Garcia-Layana, A., et al., 2017, 12:1579-1587). A 2019 population study estimated that there are currently 18.34 million adults (prevalence rate of 11.64%) with intermediate AMD and 1.49 million adults (prevalence rate of 0.94%) with advanced AMD (Rein, D. B., et al., 2022, JAMA Ophthalmol, 140(12): 1202-1208). Although AMD-related MDs are not as prevalent as AMD, because they show the same pathological manifestations and disease progression, some MDs can be misdiagnosed with AMD (Saksens, N. T., et al., 2014, Prog Retin Eye Res, 39:23- 57). Importantly, there are several AMD-related MDs, e.g., Sorsby’s fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy (DHRD), autosomal dominant radial drusen (ADRD), that like AMD at initial stage of the disease are characterized by soft drusen (> 125 pm in size) (Saksens, N. T., et al., 2014, Prog Retin Eye Res, 39:23-57; Rahman, N., et al., 2020, Br J Ophthalmol, 104(4) :451-460). Therefore, targeting cellular pathways that contribute to drusen accumulation would be of high therapeutic value for targeting both AMD and several related MDs.

[0288] There are several therapeutic development efforts for AMD / MDs in progress, both in academia and the industry (e.g., Table 1, 2). The pipeline database Cortellis lists more than 400 products under clinical and preclinical active investigations for macular degenerations. Numerous large companies are represented including Abb Vie; Alcon; Amgen; Astellas; AstraZeneca; Bausch; Pfizer; Genentech; Janssen; and Novartis. The cell-based therapy for AMD / MDs that have been pursued in pre-clinical studies and clinical trials have mainly focused on use of stem cell RPE cells and have evidence of safety and some efficacy (Kashani, A. H., 2022, Curr Opin Ophthalmol, 33(3):211-218; Khateb, S., et al., 2021, Adv Exp Med Biol, Attorney Docket No. 204606-0204-00WO

[0289] 1256:265-293). There are also several gene therapy strategies being tested. In particular, gene therapies in clinical trials for neovascular wet-AMD are primarily targeting VEGF signaling (e.g., ADVM-022: Adverum Biotechnologies, RGX-314: REGENXBIO., AbbVie). Similarly, gene therapy clinical trials targeting GA in dry-AMD are targeting complement pathway (GT- 005: Gyroscope Therapeutics, JNJ-1887: Janssen). Apart from cell and gene therapy, the therapeutic pipeline for dry-AMD (that affects 80-90% of patients) includes strategies to i) prevent photoreceptor and RPE cell loss (e.g., neuroprotection, visual cycle modulators), ii) suppress inflammation (e.g., complement and inflammasome inhibition) and iii) regulation of extracellular matrix (e.g. matrix modulation and HtRAl inhibition). Drusen drives later stage pathologies of AMD and therefore there are several anti-drusen approaches (e.g., complement, apoptosis inhibitors) that are being developed and tested for AMD (Table 1, Table 2).

[0290] Table 1: Anti-drusen approaches in clinical development Attorney Docket No. 204606-0204-00WO

[0291] Table 2: Select anti-drusen approaches in patents and patent applications

[0292] To develop a rationale drug therapy for AMD / MDs, secretory phospholipase A2-IIA (sPLA2-IIA), a pro-inflammatory enzyme, has been identified as a novel key molecule driving drusen and subsequent pathological changes (e.g., GA and CNV) in AMD / MDs. No sPLA2-IIA inhibitors are currently under investigation for AMD / MDs in the Cortellis clinical and preclinical pipelines, however there are pan-sPLA2 inhibitors being considered for ocular applications (Table 3). Attorney Docket No. 204606-0204-00WO

[0293] From a drug development perspective, it is important to emphasize that previously pursued pan-PLA2 / sPLA2 inhibitors for other inflammatory diseases (e.g., arthritis and atherosclerosis) have failed in clinical trials, likely due to lack of specificity in targeting a specific sPLA2 family member (e.g., sPLA2-IIA) (Murakami, M., et al., 2023, Immunol Rev, 317(l):42-70; Bowton, D. L., et al., 2005, J Asthma, 42(1):65-71; Bradley, J. D., et al., 2005, J Rheumatol, 32(3):417-423; Nicholls, S. J., et al., 2014, JAMA, 311(3):252-262). Proteolysis targeting chimera (PROTAC) drugs provide an innovative strategy for specific targeting of a particular sPLA2 family member like sPLA2-IIA.

[0294] Biological Rationale and Compound Profile (Significance)

[0295] Previous work, and additional work herein (Figure 2 through Figure 6), has identified “genotype-agnostic molecular alteration” that contributes to drusen and subsequently late-stage pathologies in AMD and 3 distinct MDs (SFD, DHRD, ADRD) (Dalvi, S., et al., 2024, Developmental Cell, 59:1-16; Galloway, C. A., et al., 2017, Proc Natl Acad Sci USA, 114(39):E8214-E8223).

[0296] To understand the pathogenesis of drusen, patient-derived iPSCs from AMD / MD patients were differentiated to iPSC-RPE (iRPE) cells. Importantly, like human AMD / MD patients, “ageing” (> 12-16 weeks in culture) AMD / MD iRPE-cultures led to large drusen (Figure 2) associated with intermediate AMD / MDs but not observed with “ageing” in normal human eye, a disease phenotype previously not observed in either cell culture or animal model of macular degeneration. Note that the pharmacological target sPLA2-IIA was present in soft drusen in both AMD donor eyes and AMD iRPE cultures (Figure 2).

[0297] Mechanistically, this data shows that sub-RPE accumulation of Tissue Inhibitor of Metalloproteinase 3 (TIMP3), a well-described and consistent pathological feature of AMD / MDs, promotes drusen biogenesis by instigating sterile inflammation (Kamei, M., et al., 1999, Invest Ophthalmol Vis Sci, 40(10):2367-2375; Crabb, J. W., et al., 2002, Proc Natl Acad Attorney Docket No. 204606-0204-00WO

[0298] Sci USA, 99(23): 14682-14687; Courier, H C., et al., 2015, J Clin Med, 4(5):874-883; Fariss, R. N., et al., 1998, Br J Ophthalmol, 82(11): 1329-1334; Langton, K. P., et al., 2005, Hum Mol Genet, 14(23):3579-3586; Engel, A. L., et al., 2022, Exp Eye Res, 215: 108899). Specifically, these results show that sub-RPE TIMP3 accumulation, and consequently decreased activity of RPE-secreted matrix metalloproteinase 2 (MMP2), promotes pro-maculopathy changes including drusen by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation endproducts (RAGE) and consequently increased sPLA2-IIA (Figure 3) (Dalvi, S., et al., 2024, Developmental Cell, 59: 1-16).

[0299] Importantly, a small molecule pan-sPLA2 inhibitor (LY315920, Varespladib) that antagonizes sPLA2-IIA led to reduced drusen in AMD / MD iRPE cultures (Figure 4). Furthermore, while investigating AMD / MD pathobiology in an iPSC-derived human cell model, it was discovered that a crucial molecule, sPLA2-IIA, linking MMP2 to inflammation and dysregulated lipid metabolism is absent in several inbred strains of mice, including the C57BL / 6 and 129 / Sv, that have been extensively used for developing AMD mouse model(s) (Figure 5). The lack of sPLA2-IIA potentially explains “why” rodent models of macular degeneration on C57BL / 6 and 129 / Sv background have thus far failed to recapitulate the human disease phenotype. In fact, BALB / c mice, one of the few mice strains that express Pla2g2a, have recently shown drusen and CNV (Xu, J., et al., 2021, Am J Pathol, 191(10): 1787-1804).

[0300] To corroborate a direct role of sPLA2-IIA in instigating AMD / MD pathology in vivo, a genetic approach was used to evaluate the impact of human PLA2G2A (sPLA2-IIA) overexpression in C57BL / 6J mice. Consistently, and in agreement with the iPSC model data (Figure 3 and Figure 4), overexpression of sPLA2-IIA led to pathological features (e.g., drusen, matrix thickening, RPE thinning, CNV) and visual deficits reminiscent of human AMD / MDs in PLA2G2A transgenic (tg; human gene expressed) mice (Figure 5 and Figure 6).

[0301] From a drug development perspective, sPLA2-IIA is an ideal drug target as lack of sPLA2-IIA in several in-bred strains of mice (e.g., C57BL / 6 and 129 / Sv) does not lead to any noticeable effect on animal health or behavior (Kennedy, B. P., et al., 1995, J Biol Chem, 270(38):22378-22385). In contrast, from a therapeutic perspective, targeting TIMP3 and MMP2, key extracellular matrix regulators, is not suitable because both increased and decreased TIMP3 and MMP2 levels can adversely affect the cell matrix and cell health (Fariss, R. N., et al., 1998, Attorney Docket No. 204606-0204-00WO

[0302] Br J Ophthalmol, 82(11): 1329-1334; Weber, B. H., et al., 2002, Invest Ophthalmol Vis Sci, 43(8):2732-2740; Jomary, C., et al., 1995, J Neurochem, 64(5):2370-2373; Jones, S. E., et al., 1994, 352(2): 171-174; Black, R. A., 2004, Nat Genet, 36(9):934-935; Qi, J. H., et al., 2015, Apoptosis, 20(4):523-534; Fu, L„ et al., 2007, Hum Mol Genet, 16(20):2411-2422; Mahmoodi, M., et al., 2005, Am J Pathol, 166(6): 1733-1740; Martignetti, J. A., et al., 2001, Nat Genet, 28(3):261-265; Hussain, A. A., et al., 2011, Invest Ophthalmol Vis Sci, 52(7):4459-4466; Hardy, E., et al., 2018, Am J Physiol Heart Circ Physiol, 315(5):H1332-H1340; Zhao, F., et al., 2018, Am J Pathol, 188(8): 1754-1767). Furthermore, elevated TIMP3 levels and MMP2 knockdown (in the absence of sPLA2-IIA) does not lead to AMD / MD associated pathological changes in C57BL / 6 and 129 / Sv mice that lack functional sPLA2-IIA (Dalvi, S., et al., 2024, Developmental Cell, 59:1-16; Weber, B. H. F., et al., 1994, Nat Genet, 8(4):352-356; Ohno- Matsui, K., et al., 2003, Invest Ophthalmol Vis Sci, 44(12):5370-5375). Similarly, complement pathway inhibitors, including FDA approved drugs, avacincaptad pegol and pegcetacoplan, increase susceptibility for advanced wet-AMD in treated patients (Cruz-Pimentel, M., et al., 2023, J Clin Med, 12(15):5131; Liao, D. S., et al., 2020, Ophthalmology, 127(2): 186-195; Patel, S. S., et al., 2023, Eye, 37(17):3551-3557).

[0303] Overall, this data provides a “rational drug target” for AMD / MDs (Figure 3 through Figure 6) and provides a thus far elusive rodent model of macular degeneration (Figure 6) for proposed in vivo toxicity and efficacy studies. UR-00059 optimization, in vivo efficacy studies, non-GLP ADMET of UR-00059 and analogs, and finally IND-enabling GLP toxicology studies provide a novel drug for AMD and MDs that will pharmacologically target drusen (Figure 1 and Figure 6), thereby preventing the progression of the disease to the advanced form that leads to irreversible blindness in affected patients. Importantly, drusen, quantifiable via non-invasive imaging, will serve as surrogate biomarker of drug response in proposed studies and future clinical trials (Klein, M. L., et al, 2008, Ophthalmology, 115(6): 1026-1031).

[0304] PROTACs targeting sPLA2-IIA

[0305] PROTAC technology has revolutionized drug development by utilizing the ubiquitin proteasome system to degrade specific intracellular proteins (Zhu, X., et al., 2023, J Neuroinflammation, 20(1): 119; Keumper, S., et al., 2024, Front Mol Neurosci, 17: 1370509; Xie, H., et al., 2024, Eur J Med Chem, 267: 116168; Liu, H. Y., et al., 2024, Nat Commun, Attorney Docket No. 204606-0204-00WO

[0306] 15(1):5179; Brodermann, M H., et al., 2024, J Pathol, 263:403-417; Jin, J., et al., 2020, Theranostics, 10(22): 10141-10153; Xie, X., et al., 2023, Signal Transduct Target Ther, 8( 1 ): 335). PROTACs offer superior targeting capabilities through well-designed Protein of Interest (POI) ligands and E3 ligases specifically expressed in certain cells or tissues, providing an additional targeting mechanism compared to traditional drugs. PROTACs are effective at low doses because their pharmacologic mechanism is akin to that of a catalyst in a chemical reaction; they will degrade the target protein (e.g., sPLA2-IIA) without being consumed, reducing the risk of off-target toxicity associated with high-dose drugs. The event-driven pharmacological mechanism of PROTAC ensures a longer effective period, as the presence of PROTACs does not need to be continuously maintained above a certain level. Furthermore, PROTACs enable the development of drugs against targets traditionally considered undruggable or difficult to target with conventional inhibitors. This novel approach efficiently degrades sPLA2-IIA, avoiding drug resistance caused by overexpression or mutations of the target protein. Additionally, the PROTACs designed can bind to or near the target sPLA2-IIA, making them less affected by certain amino acid mutations.

[0307] A series of structurally diverse PROTACs (Figure 7) were developed. In silico docking enabled optimum diversity in PROTAC compounds targeting sPLA2-IIA by having variations in the E3L ligands and the length / conformational constraints of linkers, the critical factors for effective E3 ligase interactions and optimum protein degradation (Figure 8). This docking platform is able to predict binding energies of new analogs to select the most effective E3-ligase binder and the chain length. Based on in silico molecular docking of the small molecule PROTACs and sPLA2-IIA (Figure 8) and subsequent Western blotting (Figure 9), a ‘lead’ PROTAC (UR-00059) was identified with strong binding affinity and interaction with sPLA2- IIA (AG=-7.943 kcal / mol) and a half-maximal degradation concentration (DCso) for sPLA2-IIA of 295.5 nM (Figure 8 and Figure 9). In contrast, DCso of UR-00060, the second most efficacious PROTAC was 4.274 pM. Furthermore, UR-00059 showed selectivity for sPLA2-IIA when compared to another sPLA2 family member, sPLA2X, with a higher AG of -7.581 kcal / mol and no degradation of sPLA2X up to a concentration 5 pM. This is a major improvement over the small molecule LY315920 that is a pan-sPLA2 inhibitor that shows broad and potent inhibition of all group I / II / V / X sPLA2 and thus can cause off-target engagement orchestrated toxicities in Attorney Docket No. 204606-0204-00WO the eyes and elsewhere in the body (Murakami, M., et al., 2023, Immunol Rev, 317(1 ):42-70;

[0308] Oslund, R. C , et al., 2008, J Med Chem, 51(15):4708-4714).

[0309] In vitro and in vivo PROTAC activity

[0310] From the perspective of pharmacologically targeting drusen, a well-established cellular iRPE assay for drusen accumulation showed that UR-00059 treatment daily at 500 nM and 1 pM reduced drusen area by 56.5% (p<0.0001) and 59.1% (p<0.0001) respectively after 7 days of daily treatment (Figure 10) (Galloway, C. A., et al., 2017, Proc Natl Acad Sci USA, 114(39):E8214-E8223). From the perspective of toxicity, UR-00059 did not adversely affect retinal pigment epithelium (RPE) barrier integrity as measured by transepithelial resistance / TER, a key measure of RPE cell health and cell viability (as measured by Calcein-AM staining) after 7 days of daily treatment with up to 1 pM drug concentration (Figure 10) (Singh, R., et al ., 2023, Invest Ophthalmol Vis Sci, 54(10):6767-6778; Sonoda, S., et al., 2009, Aging, 2(l):28-42; Sonoda, S., et al., 2009, Nat Protoc, 4(5):662-673; Manimishkis, A., et al., 2006, Invest Ophthalmol Vis Sci, 47(8):3612-3624).

[0311] From the perspective of targeting macular degeneration in vivo, UR-00059 has a topological polar surface area (tPSA) of 191.3 and cLogP of 2.2 that would pose challenges for systemically targeting the retina via oral or intravenous routes of administration. However, from the perspective of using PROTACs as a therapy, the eye offers a significant advantage as drugs administered intravitreally or topically can target retinal cells. Furthermore, UR-00059 by nature carries catalytic activity, significantly extending the drug's duration of action compared to the classical sPLA2-IIA inhibitor, LY315920. While LY315920 is cleared from the system in a dose-time dependent manner necessitating repeated dosing, leading to additive toxicities, a single dose of UR-00059 can continuously degrade sPLA2-IIA over a longer period due to its catalytic nature, resulting in much lower toxicity.

[0312] In a proof-of-concept experiment, intravitreal injection of UR-00059 was investigated for targeting the retina / RPE in a mouse model of AMD / MD, PLA2G2A (tg) mice (Figure 6). Intravitreal injection (803.8 ng / mL equivalent to 1 pM in vitro dose) of UR-00059 to PLA2G2A (tg) mice led to decreased PLA2G2A (sPLA2-IIA) levels in RPE cells 24 h after administration as determined by quantitative Western blotting analyses (Figure 11). Note that because the C57BL / 6J mice used in these studies express the human PLA2G2A gene in the retina / RPE, this Attorney Docket No. 204606-0204-00WO rodent model provides a suitable platform to assess the impact of UR-00059 and subsequent analogs on human PLA2G2A (sPLA2-IIA) expression in the retina in vivo. Furthermore, because a lack of sPLA2-IIA does not have any noticeable effect on animal health or behavior, it is an ideal drug candidate for both intraocular and systemic administration (Kenney, B. P., et al., 1995, J Biol Chem, 270(38):22378-22385).

[0313] Based on molecular docking (Figure 8), in vitro cellular screening and target engagement (Western blotting and drusen quantification; Figure 9 and Figure 10), and in vivo AMD / MD modeling (Figure 11), it is clear that UR-00059 has significant promise as a therapeutic for the treatment of AMD and MD.

[0314] The activity of UR-00059 was further examined for its activity in additional sPLA2-IIa degradation studies, demonstrating a degradation DCso of 64.39 nM (Figure 12 and Table 4).

[0315] Table 4; UR-00059 sPLA2 -Ila Degradation Activity

[0316] UR-00059 was further tested for activity in decreasing sPLA2-lla accumulation and APOE+drusen in patient-derived AMD iRPE cultures. AMD iRPE cultures were treated with a single dose of UR-00059 at 500 nM or 1 pM, or left untreated, and cultured for seven days.

[0317] Cultures were then imaged for sPLA2-IIa and APOE (Figure 13 and Figure 14). Treatment of the AMD iRPE cultures with UR-00059 significantly reduced the number and area of sPLA2-IIa drusen deposits at both concentrations tested, and treatment with 1 pM UR-00059 significantly reduced the number and area of EPOE+drusen (Figure 13 and Figure 14).

[0318] PROTAC Structures Attorney Docket No. 204606-0204-00WO

[0319] HPLC Conditions:

[0320] Column: Altin Cl 8 (250 mm)

[0321] Solvent: CH3CN:H2O (80:20 v / v); 0.1% TFA in H2O

[0322] Flow Rate: 1 mL / min

[0323] Run Length: 22 min

[0324] US-000059

[0325] 1H NMR (400 MHz, D6-DMSO): 811.02 (s, 1H), 9.81 (s, 1H), 8.51 (s, 1H), 7.86 - 7.83 (m, 2H), 7.51 - 7.48 (m, 2H), 7.36 -7.25 (m, 3H) 7.07 - 7.02 (m, 3H), 6.62 (d, J = 6.4 Hz, 1H),

[0326] 5.52 (s, 2H), 5.14 (dd, J = 8.0, 5.2 Hz, 1H ), 4.80 (s, 2H), 4.36 (q, J = 17.6 Hz, 2H), 4.10 (d, J = 5.2 Hz, 1H), 3.53 - 3.38 (m, 8H), 3.17 (d, J = 5.2 Hz , 2H), 2.96 - 2.87 (m, 3H), 2.46 -2.41 (m, 4H), 2.08-2.02 (m,lH), 1.85 - 1.81 (m, 2H), 1.07 (t, J = 7.2, 3H).

[0327] Mass Spectrometry: m / z 804.8 [M+H]+Detection Wavelength: 235 nm

[0328] Retention Time: 11.836 min

[0329] Peak Area: 99.18% Attorney Docket No. 204606-0204-00WO

[0330] UR-00060

[0331] ‘HNMR(400 MHz, D6-DMSO): 811.10 (s, 1H), 8.24 (t, J = 5.6 Hz,lH), 8.06 (s, 1H), 7.75 (t, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.49 -7.43 (m, 2H), 7.33 - 7.25 (m, 3H), 7.10 -7.02 (m, 4H), 6.60 (d, J = 7.6 Hz, 1H), 5.53 (s, 2H), 5.10 - 5.06 (m, 1H), 4.58 (s, 2H), 4.28 (t, J = 6 Hz, 2H), 3.60 -3.53 (m, 2H), 2.96 -2.83 (m, 3H), 2.67 -2.59 (m, 2H), 2.09 -1.99 (m, 1H), 1.06 (t, 7.6 Hz, 3H).

[0332] Mass Spectrometry: m / z 680.7 [M+H]+

[0333] Detection Wavelength: 220 nm

[0334] Retention Time: 13.185 min

[0335] Peak Area: 99.95%

[0336] UR-00061

[0337] 1H NMR (400 MHz, D6-DMSO): 810.81 (s, 1H), 7.82 (s, 1H), 7.38 (s, 1H), 7.32 - 7.23 (m, 3H), 7.08 -7.06 (m, 2H), 7.04 -6.96 (m, 2H), 6.70 -6.64 (m, 3H), 5.52 (s, 2H), 4.84 (s, 2H), 4.28 (s, 1H), 4.00 -3.45 (s, 8H), 3.17 - 3.13 (m, 4H), 2.93 -2.87 (m, 2H), 2.73 -2.67 (m ,1H), 2.10 -2.06 (m, 1H), 1.87 - 1.85 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H).

[0338] Mass Spectrometry: m / z 651.7 [M+H]+

[0339] Detection Wavelength: 220 nm

[0340] Retention Time: 11.117 min

[0341] Peak Area: 99.29% Attorney Docket No. 204606-0204-00WO

[0342] UR-00062

[0343] ‘HNMR(400 MHz, D6-DMSO): 511.03 (s, 1H), 9.86 (s, 1H), 7.85 - 7.83 (m, 2H), 7.51 - 7.48 (m, 2H), 7.38 - 7.37 (m, 1H), 7.33 -7.30 (m, 2H), 7.27 - 7.25 (m, 1H), 7.07 - 7.03 (m, 4H), 6.64 (s, 1H), 5.52 (s, 2H), 5.15 (dd, J = 8.4, 5.2 Hz, 1H ), 4.80 (s, 2H), 4.36 (q, J = 18 Hz,

[0344] 2H), 3.57 - 3.44 (m, 8H), 2.95 - 2.88 (m, 3H), 2.67 -2.60 (m, 6H), 2.05-2.03 (m,lH), 1.08 (t, J = 7.2, 3H, CH3).

[0345] Mass Spectrometry: m / z 790.7 [M+H]+Detection Wavelength: 235 nm Retention Time: 12.046 min

[0346] Peak Area: 98.58%

[0347] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

Attorney Docket No. 204606-0204-00WOCLAIMSWhat is claimed is:

1. A compound of Formula (I), or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (I) wherein:X1is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, and combinations thereof;X2is selected from the group consistingZ is selected from the group consisting of -OH, -ORZ, -NH2, -NHRN, and - N(RN)2;L is a divalent linking group selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, silyl, amine, amide, ester, ether, carbonyl, carbamate, sulfamate, sulfonic ester, sulfoximine, sulfonamide, thioether, thioester, disulfide, hydrazine, urea, thiourea, phosphate, phosphonate ester, poly(alkyl ether), heteroatom, and combinations thereof;Attorney Docket No. 204606-0204-00WOR1, R3, R4, and R5are each independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, -S-alkyl, S(=O)2alkyl, -C( -NHC(=O)alkyl,combinations thereof;R2is selected from the group consisting of hydrogen, deuterium, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy and combinations thereof; each occurrence of Rxand Rzis independently selected from the group consisting of hydrogen, deuterium, halogen, -CN, -NH2, -OH, -NH(RN), -N(RN)2, aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, "S-alkyl, S(=O)2alkyl, -C(=O)NHRN, -C(=O)N(R )2, -OC(=O)N(RN)2, -NHC(=O)NH(RN), -NHC(=O)alkyl, -N(RN)C(=O)(RN), -NHC(=O)(RN), -C(OH)(RN)2, -C(NH2)(RN)2, and combinations thereof; wherein each occurrence of RNis independently selected from the group consisting of H, D, CH3, CD3, and CF3; each instance of n is independently an integer selected from 1-10, and Ubiig is an E3 ubiquitin ligase ligand.

2. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (II) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (II).

3. The compound of claim 1 or 2, wherein Z is -NH2.Attorney Docket No. 204606-0204-00WO4. The compound of any one of claims 1-3, wherein R1is selected from the group consisting of aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, fluoroalkyl, heteroalkyl, and combinations thereof.

5. The compound of any one of claims 1-4, wherein R1is6. The compound of any one of claims 1-5, wherein R2is alkyl.

7. The compound of any one of claims 1-6, wherein R2is ethyl.

8. The compound of any one of claims 1-7, wherein each of R3, R4, and R5are H.

9. The compound of any one of claims 1-8, wherein the compound of Formula (I) is a compound of Formula (III) or a derivative, prodrug, or pharmaceutically acceptable salt or solvate thereof:Formula (III).

10. The compound of any one of claims 1-9, wherein L is selected from the groupAttorney Docket No. 204606-0204-00WOwherein:Y is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3, CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

11. The compound of any one of claims 1-10, wherein Ubiig is selected from theAttorney Docket No. 204606-0204-00WOwherein A2is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, and imidazolyl; wherein RA2is mono to the maximum allowable substitution, or no substitution; and each occurrence of RA2is independently selected from the group consisting of H, D, F, CH3, CD3, CF3, OCH3, OCD3, and OCF3.

12. The compound of any one of claims 1-11, wherein the compound of Formula (I)ted from the group consisting of:Attorney Docket No. 204606-0204-00WOY is selected from the group consisting of O, S, and NRL; each instance of RLis independently selected from the group consisting of H, D, F, CH3, CD3, and CF3; each instance of p is independently an integer selected from 1 to 10; and q is an integer selected from 1 to 10.

13. The compound of any one of claims 1-12, wherein the compound of Formula (I) is selected from the group consisting of:Attorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOAttorney Docket No. 204606-0204-00WOand derivatives, prodrugs, and pharmaceutically acceptable salts and solvates thereof, wherein: Y is selected from the group consisting of O, S, and NRL; and each instance of RLis independently selected from the group consisting of H, D, F, CH3, CD3, and CF3.

14. A method for treating macular degeneration or macular dystrophy in a subject, comprising administering to the subject a compound of any one of claims 1-13.1 . The method of claim 14, wherein the method further comprises administering an activator of MMP2 and / or an inhibitor of RAGE.

16. The method of claim 15, wherein the activator of MMP2 comprises one or more selected from the group consisting of MMP2 protein and a nucleic acid molecule encoding MMP2.Attorney Docket No. 204606-0204-00WO17. The method of claim 15, wherein the inhibitor of RAGE comprises at least one selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomimetic, an antibody, an antibody fragment, a ribozyme, a small molecule chemical compound, a short hairpin RNA, RNAi, siRNA, miRNA, an antisense nucleic acid molecule, or a nucleic acid encoding an antisense nucleic acid molecule.

18. The method of claim 17, wherein the inhibitor of RAGE comprises an antagonistic peptide comprising the amino acid sequence of ELKVLMEKEL (SEQ ID NO: 1).

19. The method of claim 17, wherein the inhibitor of RAGE comprises one or more selected form the group consisting of FPS-ZM1, RBG01, RAGE203, RAGE208, RAGE229, azeliragon, TTP488, GM-1111, 4,6-disubstutuded 2-aminopyrimidines, 4-fluorophenoxy analogs, TTP-3000, and low-molecular weight heparin.

20. The method of claim 14-19, wherein the subject has age-related macular degeneration (AMD)21. The method of claim 14-20, wherein the subject has a macular dystrophy selected from the group consisting of: Sorsby’s fundus dystrophy (SFD), Doyne honeycomb macular dystrophy (DHRD) and autosomal dominant radial drusen (ADRD).

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