NZ710447B2 - Fluorinated integrin antagonists - Google Patents

Abstract

The present invention relates to fluorinated compounds of formula I and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing the fluorinated compounds of the invention, and methods of treating macular degeneration, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO), by administering these compounds and pharmaceutical compositions to subjects in need thereof. (DR), macular edema, diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO), by administering these compounds and pharmaceutical compositions to subjects in need thereof.

Description

FLUORINATED INTEGRIN ANTAGONISTS CROSS-REFERENCE TO RELATEDAPPLICATIONS This application claims priority to and the benefit of U.S.S.N. 61/762,087, filed on February 7, 2013, and N. 61/900,706, filed on November 6, 2013, the ts of each of which are incorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION Age-related macular degeneration (AMD) is the leading cause of ess in people over the age of 55; and diabetic retinopathy (DR) is the leading cause in people under 55 (Klein, 1994; Williams, 2004). Both diseases are characterized by new blood vessel growth – choriodal neovascularization in AMD and retinal neovascularization in DR (Freund, 1993; Speicher, 2003; Zarbin, 2004). Macular edema occurs when fluid and protein deposits t on or under the macula of the eye (a yellow central area of the retina) and cause it to thicken and swell ). Diabetic macular edema (DME) is similarly caused by leaking macular capillaries. DME is the most common cause of visual loss in both proliferative and liferative DR. Thrombosis of central retinal vein (CRV) and its branches is the second most prevalent vascular pathology after DR, and results in abrupt decrease in visual acuity and is accompanied by macular edema. Thus, anti-angiogenesis treatments are useful in combating all these conditions. αv integrins have been shown to be ed in ocular angiogenesis. sion of αv integrins is upregulated in various diseases or ions, such as AMD and DR, and in mouse model of oxygen-induced pathy (OIR) or retinopathy of prematurity (ROP) model (Takagi, 2002). Also, αvβ3 is expressed in new vessels after photocoagulation, but not in normal choroidal vessels, in the laser-induced choroidal neovascularization model for AMD (Kamizuru, 2001). Administration of αv integrins antagonists, such as a cyclic RGD peptide, has been shown to inhibit retinal and choroidal neovascularization (Friedlander, 1996; Chavakis, 2002; Luna, 1996; Riecke, 2001; Yasukawa, 2004).

Angiogenesis inhibitors ing vascular endothelial growth factor (VEGF), other growth factors (e.g., fibroblast growth factor (FGF), platelet-derived growth factor (PDGF)), chemokines (e.g., IL8, SDF1, G-CSF), ors (e.g., CXCR1, FGF- R, PlGFR, PDGFR, Tie-receptors), intracellular mediators (e.g., c-kit kinase, PI3 kinase, PKC), and extracellular mediators (e. g., integrins, cadherins), as well as inhibitors of pro-angiogenic targets (e. g., phosphoinositide 3 kinase), have been investigated for the treatment ofAMD and DR.

However, application of these drugs is limited due to various concerns, such as toxicity and complexity of administration. Further, av integrins inhibitors tested or currently in clinical trials for treating AMD and DR are not being successfully developed due to poor ocular pharmacokinetics and/or high levels of excipient/carrier (e. g., benzalconium chloride and mannitol) known to cause damage to the eye.

Thus, there continues to be a need for improved compounds, compositions, and methods for treating AMD, DR, DME, and r edema following retinal vein ion, that are safe, effective, and conveniently administered. The present invention addresses the need.

Y OF THE INVENTION The present invention provides novel fluorinated compounds which are av integrin antagonists, having formula I: R R' / (I), or a pharmaceutically acceptable salt or solvate thereof.

The present invention provides a ceutical composition comprising a nd of the invention or a pharmaceutically acceptable salt or e thereof, and a pharmaceutically acceptable carrier or excipient.

The present invention also provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable r or excipient, and further an active ingredient selected from the group consisting of a) an antagonist of integrin @581, b) a xic/antiproliferative agent, c) an inhibitor of mal-derived, ast-derived, or platelet-derived growth factor, d) an inhibitor of VEGF, e) an inhibitor of Flk-l/KDR, Flt-l, Tck/Tie-2, or Tic-l, and f) an inhibitor of phosphoinositide 3-kinase, and a mixture thereof.

The present invention further provides a pharmaceutical ition comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and a ceutically acceptable carrier or excipient, and further an active ingredient selected from the group consisting of a) an antagonist of integrin @581, b) a xic/antiproliferative agent, c) an tor of epidermal-derived, fibroblast—derived, or platelet-derived growth WO 24302 factors, d) an inhibitor of VEGF, and e) an tor of phosphoinositide 3-kinase, and a mixture thereof.

The present invention provides a method of treating or preventing a disease or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof or a therapeutically effective amount of a pharmaceutical composition of the invention. In one aspect, the invention es treating a disease or ion. In one , the invention provides preventing a disease or condition. In one aspect, the compound or pharmaceutical ition ofthe invention is administered topically.

The present ion provides a method of treating or preventing a disease or condition mediated by an (xv integrin in a subject, sing administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof or a therapeutically effective amount of a pharmaceutical composition of the invention. In one aspect, the disease or condition is a disease or condition in which angiogenesis is involved. In a further aspect, the disease or condition is a disease or condition in which ocular enesis is ed.

The present invention also provides a method of treating or preventing an (va3 and/or (va5 integrin-mediated disease or condition in a subject, comprising administering to a subject in need thereof a eutically effective amount of a compound of the invention or a pharmaceutically able salt or e f or a therapeutically effective amount of a pharmaceutical composition of the invention. In one aspect, the disease or condition is a disease or condition in which ocular angiogenesis is involved. In one aspect, the disease or condition is macular degeneration. In one , the disease or condition is age-related macular degeneration (AMD). In one aspect, the e or condition is diabetic retinopathy (DR). In one aspect, the disease or condition is diabetic macular edema (DME). In one , the disease or condition is macular edema following retinal vein occlusion (RVO).

The present invention fiirther provides a method of treating or preventing AMD, DR, DME, or macular edema following RVO, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate f or a therapeutically effective amount of a pharmaceutical composition ofthe invention. In one aspect, the invention provides treating AMD, DR, DME, or macular edema ing RVO. In one aspect, the invention provides preventing AMD, DR, DME, or macular edema following RVO.

The present invention r provides a method of treating or preventing a e or condition in a subject, comprising stering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof or a therapeutically effective amount of a pharmaceutical composition of the ion, in combination with one or more therapies for treating or preventing the disease or condition. In one aspect, the disease or condition is mediated by an av integrin. In a further aspect, the disease or condition is mediated by an avB3 and/or avBS integrin. In one aspect, the disease or condition is a disease or condition in which enesis is ed. In a further aspect, the disease or condition is a disease or condition in which ocular angiogenesis is involved. In one aspect, the therapy is an anti-VEGF therapy. In a further aspect, the anti- VEGF therapy is intravitreally injected.

The present invention provides the use of a compound of the invention or a pharmaceutically acceptable salt or e thereof in ng or preventing a disease or condition in a subject. In one aspect, the use is for treating a disease or condition. In one aspect, the use is for preventing a disease or condition. In one aspect, the compound or ceutical composition of the invention is formulated for use in topical stration.

The t ion provides the use of a compound of the invention or a pharmaceutically able salt or solvate thereof in the manufacture of a medicament for the treatment or prevention of a disease or condition in a subject. In one aspect, the invention provides for the treatment of a e or condition. In one aspect, the invention provides for the prevention of a disease or condition. In one aspect, the medicament is formulated for topical administration.

Unless otherwise defined, 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. In the case of conflict, the present specification, including definitions, will control.

In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the t invention, suitable methods and materials are described below. All ations, patent applications, patents, and other nces mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

Other es and advantages of the invention will be apparent from the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. A bar graph showing blood vessel counts (score) in the chick CAM assay, Figure 2. A bar graph showing plasma and ocular distribution of Compound Al in rabbit « Figure 3. A bar graph showing plasma and ocular distribution of Compound A2 in rabbit , Figure 4. A bar graph showing plasma and ocular distribution of nd A3 in rabbit.

Figure 5. Representative Fluorescein raphy (FA) images of the eye on day 35 in animals following twice daily topical administration of (A) 50 uL Compound Al, (B) 50 uL Compound A2, (C) 50 uL vehicle , DETAILED DESCRIPTION OF THE INVENTION It is believed that a wide variety of diseases and conditions can be treated or ted by inhibiting processes mediated by ow integrins. Thus, ow integrin antagonists represent a useful class of drugs for treating or preventing those diseases and conditions. ins are heterodimeric embrane proteins through which cells attach and communicate with extracellular es and other cells. The ow integrins are key receptors involved in mediating cell migration and enesis. Antagonists ofthe integrins ocvli3 and ocvliS are useful for treating and preventing bone resorption, osteoporosis, vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, viral disease, tumor , and metastasis. ow integrins have also been found to be involved in ocular angiogenesis, a process that can lead to various ocular diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), diabetic macular edema (DME), and macular edema following retinal vein occlusion (RVO) d, 1993; Speicher, 2003; Zarbin, 2004). Pro-angiogenic growth factors, including VEGF and FGF, are up—regulated in AMD and DR, which, in turn, stimulate ow integrin sion. In the well-established mouse model of -induced retinopathy (OIR) or retinopathy of prematurity (ROP) model, ow integrins and the ligand osteopontin are pressed in neovascular endothelial cells during the peak time of retinal vessel growth (Takagi, 2002). Cyclic peptides mimicking the arginine-glycine-asparagine (RGD) binding motif, through which ow integrins bind to their extracellular matrix ligands, have been shown to inhibit retinal neo-vascularization in the mouse OIR model via various routes of administration (e. g. , subcutaneous, intraperitoneal, periocular, or topical) (Friedlander, 1996; Chavakis, 2002; Luna, 1996; Riecke, 2001). Also, in the laser-induced choroidal cularization model (rats), a well-accepted model for AMD, integrins ocvli3 WO 24302 and von Willebrand factor are expressed on elial cells ofnew vessels after photocoagulation, but not in normal dal s (Kamizuru, 2001). In this model, intravitreal injection of a cyclic RGD peptide significantly reduces the development of choroidal cularization (Yasukawa, 2004). In humans, expression of avB3 and avBS, which are not expressed in normal retinal tissue, is observed in vascular cells in the eyes of DR patients (Friedlander, 1996; Luna, 1996), and high levels of avBS expression is primarily observed in ocular tissues in AMD ts (Friedlander, 1996).

Diseases or conditions of the retina (which is located at the back of the eye), including macular degeneration, DR, DME, and macular edema following RVO, are very difficult to treat by ic administration (e. g., oral, intravenous, nasally, or inhalation) because the retina is difficult to access from the systemic circulation due to the blood—retinal r.

Therefore, currently ed treatments (e.g., anti-VEGF proteins or a chemically-modified anti-VEGF aptamer) for macular degeneration, DME, and macular edema following RVO must be repeatedly administered by intra-ocular injection (intravitreal administration).

Many angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) (e. g. the VEGF aptamer, pegaptanib, and the VEGF or VEGF receptor (VEGFR)-targeted monoclonal antibodies, bevacizumab, ranibizumab, aflibercept) have been investigated for the treatment ofAMD and DR. However, only pegatanib, ranibizumab, aflibercept are approved by the Food and Drug Administration. Further, all the VEGF-targeted drugs must be administered by itreal injection to treat AMD or DR. Intravitreal injection requires adequate anesthesia and a spectrum microbicide, and the insertion of a syringe needle into the eye using aseptic conditions, thus necessitating the administration to be performed in a physician’s office. For example, the dosage and administration section of the ranibizumab Package Insert describes the complex requirements for administering the drug in a safe and effective manner: all of the ranibizumab vial contents are withdrawn h a 5-micron, 19- the filter gauge filter needle attached to a 1—cc tuberculin syringe under aseptic technique; needle should be ded after withdrawal of the vial contents and should be replaced with a sterile 30-gauge x 1/2-inch needle for the intravitreal injection; the contents should be expelled until the r tip is aligned with the line that marks 0.05 mL on the syringe; the intravitreal injection procedure should be carried out under controlled aseptic conditions (e. g., using e gloves, a sterile drape, and a sterile eyelid speculum).

In addition to the practical limitations and strictures related to the need for intravitreal injection in the treatment of ocular es, VEGF-targeted drugs only address VEGF- promoted angiogenesis, but not angiogenesis promoted by other growth factors, including fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). Targeting angiogenic molecules other than, or in addition to VEGF, may reveal more effective and safer inhibitors of intraocular neovascularisation. Potential targets e growth factors (e. g., angiopoietin, FGF, HGF, lGF-l, PDGF-B, PlGF), chemokines (e. g., 1L8, SDF1, G—CSF), receptors (e.g., CXCRl, FGF- R, PlGFR, PDGFR, Tie-receptors), intracellular mediators (e. g., c—kit kinase, PI3 kinase, PKC), and extracellular mediators (e.g., integrins, cadherins).

Several drugs which do not selectively target VEGF have indeed shown anti-angiogenic efficacy in eyes: Pazopanib (which blocks PDGFRS, 0- Kit, FGFR, and c-fms) suppresses choroidal neovascularization in mouse models; and PKC412 (which blocks PKC, VEGF-R, PDGF-R and SCF-R isoforms) reduces r oedema in diabetics (Doukas, 2008; Takahashi, 2009; Campochiara, 2004). ents that combine the action of the VEGF- ed therapies with inhibition of one of these other growth factors have also been studied.

For e, a Phase 3 clinical trial is underway testing the combination of ranibizumab and the anti-PDGF antibody designed E10030 (ClinTrials.gov, NCT0194483 9). However, these therapies are limited by safety concerns and complexity of administration, such as liver toxicity observed following oral administration of PKC412, and intravitreal administration of ranibizumab and E10030. r approach for treating or ting ocular diseases is to selectively target a distinct pro—angiogenic target, such as PI3K. A broad-spectrum PI3K inhibitor LY294002 in rodents sses retinal or choroidal neovascularisation following intraocular injection (Yang, 2009). Additional alternative treatments for AMD and DR involving intravitreal administration of l small molecule inhibitors which prevent enesis (e. g., fibronectin receptor antagonists, JSM6427 (Clin Trials.gov, NCT00536016) and ATN—l61 (Wang, 2011), vascular endothelial protein tyrosine phosphatase inhibitors (ClinTrials.gov, NCT01702441), and mTOR inhibitors, sirolimus, and Palomar 529 (Jacot, 2011)) are being tested in animals or in clinical trials. Further, combination therapies involving multiple foci of pro-angiogenic pathways with several selective inhibitors (e. g., combining angiostatic therapy with a VEGF aptamer, an integrin antagonist, and a proteolytic fragment of tryptophan tRNA synthetase) have been shown to t ocular angiogenesis (Dorrell, 2007).

Despite these studies and clinical trials, no therapy with a favorable y and safety profile has been ed.

Recent advances in drug ry technology, including formulation, polymer chemistry, chnology, microdrug devices, and surgical advancements, have offered new s and opportunities for topical ocular drug administration. These logies include the use of hydrogels, mucoadhesive polymers, extrins, nanocomposite formulations, micellar and lipid nanoparticles, niosomes, microemulsion, microspheres, and prodrug tization. For instance, nanocomposites have been used to deliver Diclofenac (Cao, 2011), and topical administration of Nepafenac has been shown to reduce the extent of microangiopathy in animal models ofDR (Kern, 2007) and oxygen-induced retinopathy (Yanni, 2010). Also, nanoparticle technology has been employed to enhance the surface penetration of hydrophobic compounds such as glucocorticoids to posterior ocular structures (Diebold, 2010), and injection of nanoparticles into the vitreous has demonstrated intraretinal localization for l months after initial dosing and therefore can be used as a localized drug release depot (Bourges, 2003). Topical administration using eye drops (e.g., eye drop formulation comprising TG100572, which inhibits FGF, PDGF and VEGF (Doukas, 2008), or tyrosine kinase tors (TKIS) (e. g, sorafenib (WO2013/000909), bradykinin or antagonists (ClinTrials. gov, NCT013 l 9487), or an anti—microbial agent, squalamine (ClinTrials. gov, NCT01678963)) has been studied or is under investigation. However, none of these approaches have been shown to be suitable for replacing the current rd anti— VEGF treatments that require itreal injection.

Oral or topical stration of drugs that inhibit (xv integrins (e.g., cyclic penta- e inhibitor of OMB and ochS, RGDfV, cilengetide, and the non-peptide OMB and ochS antagonist, INJ-26076713 and EMD478761), for e, by means of a polyvinyl alcohol-based reservoir implant, has been tested or is currently in clinical trials for treating AMD and DR (Friedlander, 1996; Santulli, 2008; Fu, 2007). Cyclo-RGDfV was also tested in a mouse model of retinopathy of urity administered by topical administration e, 2000); however, the compound needed to be administered six times a day, due to the of the compound that poor ocular pharmacokinetics of the nd (116., the amount distributes to the retina after administration as eye drops, and then maintains an adequate retinal concentration between administrations). In addition, the peptide was formulated with high levels of conium chloride and mannitol, which are known to cause damage to the To date, the eye. As a result, topical administration has not been successfully developed. most recent approach to treating ocular angiogenesis is through intravitreal injection of ALG- 1001 (a synthetic oligo-peptide inhibitor of (va3, (vaS, and (1581), which cannot be administered topically.

The present invention relates to novel fluorinated compounds, which are antagonists of the av integrins, particularly integrins (va3 and/or (vaS. The compounds of the present invention or pharmaceutically acceptable salts or solvates thereof are useful in treating or preventing bone resorption, osteoporosis, ar restenosis, atherosclerosis, inflammation, viral disease, tumor growth, or metastasis. In particular, the compounds of the present invention or ceutically acceptable salts or solvates thereof and pharmaceutical composition comprising the compounds are effective in treating macular degeneration, DR, DME, and macular edema following retinal vein occlusion (RVO) when administered topically.

Prior ts to use small molecule integrin antagonists by topical administration have not succeeded because those compounds lack the appropriate physiochemical ties (e. g., lipophilicity, molecular size and polar surface area) to allow delivery of therapeutically effective amounts of those compounds by a convenient formulation and dosing regimen. The compounds of the present ion have been surprisingly shown to distribute to the retina after topical administration in therapeutically effective amounts to inhibit the function of integrins avB3 and avBS and thus treat or prevent retinal angiogenesis. The compounds of the present invention have advantages such as providing improved potency, selectivity, tissue penetration, half-life, and/or metabolic stability, and sfill distribution to the retina in therapeutically effective s via ient topical stration to the eyes.

Compounds of the Invention The present invention relates to novel fluorinated compounds of formula I: R R' / (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: gNJKNA; \ / Z is 5W2 or \_J ; R and R’ are each independently H or F, or R and R”, together with the carbon atom to which they are ed, form a 3- or ered carbocyclic or heterocyclic ring; if; no?R1 QiS N or R3 - X is CH or N; Y is CH or N; R1 is C1-C4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C1-C6 alkoxy substituted with O, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms; and R2 and R3 are each independently H, F, CH2F, CHF2, or CF3, provided that one of R2 and R3 is not H, provided that the compound of formula (I) contains at least one fluorine atom.

The compounds of the present invention contain at least one fluorine atom. In one aspect, the compounds of the present invention contain at least one fluorine atom in the R or R’ substituent. In another aspect, the compounds of the present invention n at least one fluorine atom in the R1 substituent. In another aspect, the compounds ofthe present invention contain at least one fluorine atom in the R2 or R3 substituent. Fluorination at any particular position, such as that t in the compounds of the ion, has not been taught or ted. mks: In one aspect, Z is Filmy In another , Z is L—J In one aspect, R and R’ are each H. In another aspect, R and R’ are each F. In another aspect, R is H and R’ is F.

In another aspect, R and R’, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring. In a further , R and R’, together with the carbon atom to which they are attached, form a 4-membered heterocyclic ring. In a fiirther embodiment, the 4-membered heterocyclic ring is an oxetane ring. For e, the oxetane ring is an oxetanyl ring or oxetanyl ring.

EffxYA In one aspect, Q is R1. In one aspect, X is N and Y is CH. In r aspect, X and Y are each CH. In another aspect, X and Y are each N.

In one aspect, R1 is straight chain C1-C4 or branched C3-C4 alkyl, and is substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms. In a fiirther aspect, R1 is , ethyl, propyl, or butyl, and is substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms. In a further aspect, R1 is methyl substituted with 1, 2, or 3 fluorine atoms. In a further aspect, R1 is CF3.

In another aspect, R1 is straight chain C1-C6 or branched C3-C6 , and is substituted with 0, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms. In a further aspect, R1 is methoxy, ethoxy, propoxy, or butoxy, and is substituted with O, 1, 2, 3, 4, 5, 6, or 7 fluorine atoms. In a fiirther aspect, R1 is y substituted with 0, 1, 2, or 3 fluorine atoms. In a further aspect, R1 is OCH3, OCH2F, OCHF2, or OCF3. In a further aspect, R1 is OCHF2.

In r aspect, Q is N R3 In one aspect, R2 is F. In a further aspect, R2 is F and R3 is H. In another aspect, R2 is CH2F, CHF2, 01‘ CF3.

In one aspect, R3 is F. In a further aspect, R3 is F and R2 is H. In another aspect, R3 is CH2F, CHF2, or CF3. In a r aspect, R3 is CF3. In a further aspect, R3 is CF3 and R2 is H.

In one aspect, R2 and R3 are each F.

In one aspect, Z1s \_/N}{ and Qis ACA In a further aspect, Z1s 51$ Q.fCAR1; and R and R’ are each H.

In a further aspect, Z1s z.& ,Q1s ACAR1; R and R’ are each H; and R1is OCH3, OCH2F, OCHF2, or OCF3. In a further aspect, X is N and Yis CH; and R11s OCHF2.

In one aspect, Z is fWi‘Z and Q is In a further aspect, Z is 5W2} Q1s ACAR1,and X and Y are each N. In a further aspect, R1 is methyl substituted with 1, 2, or 3 e atoms. In a further aspect, R1 is CF3.

In another further aspect, Z is f\/\}{; Qis ACAR1,and Xis N and Yis CH. In a further aspect, R1 is OCH3, OCH2F, OCHF2, or OCF3. In a further , R1is OCHF2. >3(AlR2\ In one aspect, Z is f\/\}{ and Q is N R3 In one aspect, a compound of present invention is of formula II: N N\ Z/‘\/COOH 1 R R, / (11), or a pharmaceutically acceptable salt or solvate f, wherein each of the variables are as defined above. Compounds of the present invention include compounds of formula 11, wherein the variables are rated in the s aspects of formula I above.

Representative compounds of the present invention include the compounds listed in Table 1.

Table 1 Cmpd # Chemical Structure Cmpd # Chemical Structure A1 OCHFz A8 OCHF2 o _/ o O ./ o H E H N le NJLNVkOH N le NJLNVkOHE \—/ \_/ / / A2 0 A9 OCHF2 H 1 :N \ / N O O I : / \NkCF H N\ NJLNVkOH 3 l / F F \—/ A3 0 A10 We a I L” \ / O _ O l I H NJLNVkOHE N / \N N\ OCHF2 l / F F \_/ A4 0 A11 iCHFz H Nl \N N N\ F / 0 K) o l l H § / \N |N\ NfiNVkOH A5 A12 iCHFZ A6 0 A13 2:1: N F / \ A7 0 A14 OCHFZ ZI N O E: O / \ . 1 l H / / N\ NANA/[L0H N CF3 i/FFL—J In one aspect, a compound of the present invention is selected from compounds Al, A2, and A3, or a pharmaceutically acceptable salt or solvate thereof. In a r aspect, a compound of the present invention is selected from compounds Al and A2, or a pharmaceutically acceptable salt or solvate thereof. In a further aspect, a compound of the present invention is compound Al, or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, a compound of the present invention is a pharmaceutically acceptable salt. In one aspect, a compound of the present ion is a solvate. In a further aspect, a compound of the present invention is a hydrate.

In one aspect, a nd of the present invention inhibits the activity of av integrins (e.g., avB3 and avBS) at a submicromolar concentration, e. g., below 1 uM, 0.8 uM, 0.6 uM, 0.5 uM, 0.2 uM, or 0.1 uM.

In one aspect, a compound of the present ion inhibits cellular adhesion to vitronectin through the OLV integrin (e. g., avB3 and avBS) at or below an ICso of 2.0E—07 M using a human dermal microvascular endothelial cell (HMVEC) assay. In a further aspect, a compound of the present invention inhibits cellular adhesion to vitronectin through the ocv integrin (e. g., avB3 and avBS) at or below an IC50 of 8 M using an HMVEC assay. In a further aspect, a compound of the present invention inhibits cellular adhesion to vitronectin through the ocv integrin (e.g., avB3 and avBS) at or below an ICso of 1.0E—08 M using an HMVEC assay. In one aspect, a compound of the present invention inhibits cellular adhesion to vitronectin through the ocv in (e. g., avB3 and avBS) at or below an IC50 of 2.5E—07 M using a rat lung microvascular endothelial cell (RLMVEC) assay. In a further aspect, a nd of the present invention inhibits cellular adhesion to vitronectin h the ocv in (e. g., avB3 and avBS) at or below an IC50 of 3.5E-08 M using an RLMVEC assay. In one aspect, a compound of the t invention inhibits cellular on to ectin through the ocv integrin (e. g., avB3 and avBS) at or below an IC50 of 2.0E—08 M using a rabbit aortic elial cell (RAEC) assay. In a further aspect, a compound of the present invention inhibits cellular adhesion to vitronectin through the ocv integrin (e.g., avB3 and avBS) at or below an ICso of 1.0E—08 M using an RAEC assay.

In one aspect, a compound of the present ion inhibits or decreases formation of blood vessels in a tissue or organ, in vivo or in vitro. In one aspect, a compound of the present invention decreases the ion of blood vessels below 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, or 5%, as compared to that in an untreated control. In a further aspect, a nd of the present invention decreases the formation of blood vessels below 60%, 50%, 40%, 30%, 20%, 10%, or 5%, as compared to that in an untreated control. In a r aspect, a compound of the present ion decreases the formation of blood vessels below 40%, 30%, 20%, 10%, or 5%, as compared to that in an untreated control. In one aspect, the tissue is a tissue from the eye, such as a retinal tissue. In one aspect, the organ is the eye.

In one aspect, a compound of the present ion is efficiently buted to the back of the eye, e.g., retina, after topical administration. In one aspect, a compound of the present invention is efficiently distributed to the retina within 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour, after topical administration to the eye. In a further aspect, a compound of the present invention is ntly distributed to the retina within 8 hours, 6 hours, 4 hours, 2 hours, or 1 hour, after topical administration to the eye.

Compounds of the present invention can be conveniently prepared by a variety of methods familiar to those skilled in the art. The compounds of each of the formulae described herein may be prepared according to the following procedures from commercially available starting materials or starting materials which can be prepared using ture procedures.

These procedures show the preparation of representative compounds of this ion. It is understood that compounds of the present invention other than those illustrated in the following schemes can be made using these schemes with modifications ly known in the art (e. g., using different ng material, changing reaction solvents, or adjusting reaction duration or temperature).

Scheme 1 OCHFZ OCHFZ OCHF2 OCHFZ O N \ OCHFZ fCOZtBu N \ N \ Pd/C—Hz I Pd(0AC)z. TEA l J: (Meobcmm / NH OZNa ' N \ Ph NHBn / 4095i 'r / “f \ 0 I -'————’ ——————> ————> ——————> ‘ _ _ / / Step-l / (o-tolyl)3P nBuLl E ‘ Step~4 0 Step-5 N/\/U\O(: Step-2 /\/CO B I / Step-3 BnN Br Br X HZN/K/lL0'3” J: co ‘B HCO OCH3 u 3 1 2 32 Ph $029 0an2 OCHF2 OCHFZ N \ N \ N \ 1/ I/ ah l/ NaCNBH3 O (CI3CO)2CO O O 0 : EI3N 0 z H2504 HN/\/U\O‘BUI C1)J\N/\/U\O‘BuI ‘—F S‘ep'fi 532:7 Step-8 N\ 5‘°P'9 | fi’U‘NNJLo‘Bu: kj/OMe OMe /, OMe OMe OMe OMe 8 9 ocmr2 ocx-IF2 N \ N \ I ‘ / / o o O O H H j: lLO‘Bu —’2 Pd/C-HZ H i TFA N N\ N N N\ N N\ NJLNK/lLO‘Bu I 777’ | __ mpm 3/ H22 ll 12 Step-ll A] DIPA O=(j—-—-——>(B0020 __—,Hexyllithium M20 9 DMAP 1'3 dimethylmethyl MeO’ S‘BP- 1 phosphonate Ia Step-2 CH0 NaOH __———> water, MeOH Step-3 6b Scheme 2 H 9 N N\ P—OMe I OMe / tBuOK ________—__> OHC\ H N / LiAlH4 \ Q ———-—-—-——'—> I THF 1. EtCOzH MeC((OEt)3 HO H N TFA, MeOH 1‘ Q 3. NaOH, H20 / MeOH /N NH2 acetone N N NCS l N N proline \ \ AIBN \ \ CI \ H —-» 1 —-» l EtOH / / CCI4 / / A B C BuLi + ———> DMPU 1. propane-1,3—diol EtO S 0E1 S 2. BOCZO, Et3N D E N N N N \ \ NHBoc Fluorlnatlon. _ \ \ NHBoc I S S -——> I / / V F F 1. H2,Pt02 2. Acid : n E i \ I NH2§ i F F / i H E Scheme4 NHB°C M60 MeO 2. 1,2-ethanedithiol P O \ nBuLi n=0,1 N N o (kw o A, NaOH \ \ NHBoc Fluorlna’uon. i S S ---—> Me0/,P”M *9NHBOC / / H20, EtOH MeO LM) R F n=0,1 N\ N\ 1 H2,Pt02 3 H N NHBOC I 2 \ NHZ; F F / / 2 ACId g I F F : Schemes O O OH O O ‘d l DMAP /N| N\ 1 ‘ Th‘Iocar onyb Id"um: azoe, N N H EtOJVBr /Nl N\ OEt / \ OEt _________________________________ , I F \ / ......._F__’_:____, \ / F \ / F F 2.BU3SnH,AIBN 8 T U EWH"""""""""""""""E 1_ LiBH4 /N N\ P102, H2 1 N N3 N\ NH2 E 2- szQPYr I """"""""" ’ F F : | \ / / F F 5 .............. .> . 3 NaN3 ; H Scheme6 . Me \/0 1‘ ”202 Me ['11 MeMgBr N02 N\ NH2 N02 --------- * MeO No2 --—--—-----» o + [ o 2. (00002; o / H MeONHMe O J K L .-:°.'.n.e.- /N [w ___“_2:_'°_‘_‘32_, s \ I s EtOH \ / / O E O i Scheme 7 o 0 B00 NH N Me 30620 MeMgBr NHBoc |N\ NH2 ——————————— -> -——-—-> O + O / H O O o ro ne /N N\ 1' H2,Pt02 ; g . ' _____1---, NHBoc NH2 I ------------- > : | : EtOH \ / / o 2‘ Acid E O ; Scheme 8 N NH2 HOWNHz 1 Soc 0 H 1' MeMgBr Me \ NHBoc l --------- -> WNHBOC --————------> + / H o 2. Swern Ox. 0 o 2 TPAP 0 T U R Pro meI n /N N‘ N ------ * ””300 l ..1__.H.2_-Pt0.2, NHz EtOH \ / / o 2. Acid 0 The compounds of the invention may contain one or more asymmetric s and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual reomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers. It is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of the invention. The invention is meant to comprehend all such isomeric forms of these compounds.

The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate ation of the methodology disclosed . Their absolute stereochemistry may be determined by the x— ray crystallography of crystalline products or lline intermediates which are tized, if necessary, with a reagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so that the individual omers are isolated. The separation can be carried out by methods well known in the art, such as contacting a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by rd methods, such as onal crystallization or chromatography.

The diasteriomeric mixture is often a mixture of diasteriomeric salts formed by contacting a c mixture of compounds with an enantiomerically pure acid or base. The diasteromeric derivatives may then be ted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which are well known in the art.

Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

Some of the compounds of the invention may exist in unsolvated as well as solvated forms such as, for example, hydrates.

“Solvate” means a solvent addition form that contains either a stoichiometric or non- stoichiometric amounts of the solvent molecules. Some compounds have a tendency to trap a fixed molar ratio of the solvent molecules in the crystalline solid state, thus forming a solvate.

If the solvent is water, the e formed is a hydrate. When the solvent is l, the solvate formed is an alcoholate. Hydrates are formed by the ation of one or more molecules of water with one of the substances (e. g. , a compound of the invention) in which the water retains its molecular state as H20, such ation being able to form one or more hydrate. In hydrates, the water molecules are attached through secondary ies by intermolecular forces, in particular hydrogen bridges. Solid hydrates contain water as so- called crystal water in stoichiometric ratios, where the water molecules do not have to be lent with respect to their g state. Examples of hydrates include sesquihydrates, monohydrates, dehydrates, and trihydrates. y le are the hydrates of salts of the compounds of the invention.

For use in medicine, the salts of the compounds of the invention refer to xic “pharmaceutically able salts”. Other salts may, however, be useful in the preparation of the compounds of the invention or pharmaceutically acceptable salts f. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of the invention which can be prepared by reacting the free base with a suitable organic or inorganic acid. Representativesalts include the ing: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, e, edisylate, estolate, e, fumarate, gluceptate, ate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, e, pamottle (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate. rmore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e. g., sodium or potassium salts; alkaline earth metal salts, e. g., calcium or magnesium salts; and salts formed with suitable organic ligands, e. g., quaternary ammonium salts which may be d from ammonia or organic , such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, oabietylamine, or methylpiperidine.

The invention includes within its scope prodrugs of the compounds of the invention.

In general, such prodrugs will be onal derivatives of the nds of the invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the invention, the term “administering” shall encompass the treatment of the various disease and conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after stration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for e, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of the invention into the biological milieu.

The invention also includes one or more metabolites of a compound of the invention.

The present invention also comprehends ium labeled compounds of a I or II or the compounds listed in Table 1, wherein a hydrogen atom is replaced by a deuterium atom. The deuterium labeled compounds comprise a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, e.g., 0.015%.

The term “deuterium enrichment factor” as used herein means the ratio between the deuterium nce and the natural abundance of a deuterium. In one aspect, a compound of the invention has a ium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each ium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% ium incorporation), at least 6333.3 (95% ium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). ium labeled compounds can be prepared using any of a variety of art- recognized techniques. For example, deuterium labeled compounds of formula I or II or the compounds listed in Table 1 can generally be prepared by carrying out the procedures disclosed in the Schemes and/or Examples described herein, by tuting a readily available deuterium d reagent for a non—deuterium d reagent.

A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the invention.

Further, substitution with deuterium, z'. e. can afford certain eutic advantages , 2H, resulting from greater metabolic stability, for example, increased in vivo half—life and/or reduced dosage requirements.

In one aspect, the present invention relates to a method of synthesizing a compound of the invention or a pharmaceutically acceptable salt or e thereof Pharmaceutical Compositions of the Invention The t invention relates to ceutical compositions sing a compound of the invention as an active ingredient. In one aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula I or II, or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable carriers or ents. In one aspect, the invention provides a pharmaceutical composition comprising at least one compound selected from Table 1. In a further aspect, the invention provides a pharmaceutical composition comprising at least one compound selected from compounds A1, A2, and A3. In a further , the invention provides a pharmaceutical ition comprising at least one compound selected from compounds A1 and A2. In a further aspect, the invention provides a pharmaceutical composition sing nd Al.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which s, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The compounds of the invention can be formulated for oral administration in forms such as tablets, capsules (each of which es sustained e or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions.

The compounds of the invention can also be formulated for intravenous (bolus or in—fusion), intraperitoneal, topical (e. g., ocular eye-drop), subcutaneous, intramuscular or transdermal (e. g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts. Preferably, compounds of the invention for the treatment of macular degeneration, DR, DME, or macular edema following RVO, are formulated for topical administration, for example, in the form of eye-drops.

For topical ocular administration, the compositions are provided as ophthalmic formulation comprising a compound of the t invention in concentration between about 0.01 and about 5 weight percent, preferably between about 0.1 and about 5.0 weight percent, more preferably n about 0.5 and about 5.0 weight percent, and most preferably between about 0.8 and about 3.0 weight percent.

The ophthalmic formulation of the present invention may be in the form of an aqueous solution comprising an aqueous vehicle.

The s vehicle component of the ophthalmic formulation may comprise water and at least one ophthalmically acceptable excipient. Preferably, the aqueous vehicle comprises a on of the one or more ophthalmically acceptable excipients in water.

Suitable ophthalmically acceptable excipients include those selected from the group ting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, , and pH ing agent, and a mixture thereof.

Preferably, the ophthalmically able excipient is ed from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity/suspending agent, and pH modifying agent, and a mixture thereof Any suitable ophthalmically acceptable solubility enhancing agent can be used.

Examples of a solubility ing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-[3—cyclodextrin, methyl-[3-cyclodextrin, ly methylated—[3—cyclodextrin, ethylated-B-cyclodextrin, triacetyl—[3-cyclodextrin, peracetylated- [3-cyclodextrin, carboxymethyl-[3-cyclodextrin, hydroxyethyl—[3-cyclodextrin, 2-hydroxy—3- (trimethylammonio)propyl-[3—cyclodextrin, yl—[3—cyclodextrin, sulphated [3-cyclodextrin (S-B-CD), maltosyl-[3—cyclodextrin, [3-cyclodextrin sulfobutyl ether, branched-[3—cyclodextrin, ypropyl-y-cyclodextrin, randomly ated-y-cyclodextrin, and trimethyl—ycyclodextrin , and mixtures thereof. Preferably, solubility enhancing agent includes [3- cyclodextrin sulfobutyl ether, hyrdoxypropyl—[3-cyclodextrin, sulphated [3-cyclodextrin (S-[3- CD), and maltosyl-[3-cyclodextrin, and es thereof. [3-cyclodextrin sulfobutyl ether is a particularly preferred solubility enhancing agent. The solubility enhancing agent(s) may be added in an amount of about 1 to about 20 wt%, preferably about 1 to about 10 wt%, and more preferably about 5 to about 10_ wt%.

Any suitable ophthalmically acceptable chelating agent can be used. Examples of a suitable ophthalmically acceptable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, um edetate, trisodium edetate, and tetrasodium e, and mixtures thereof. Disodium edetate is a particularly preferred chelating agent. The chelating agent(s) may be added in an amount of about 0.001 to about 0.05 wt%, ably about 0.001 to about 0.02 wt%, more preferably about 0.002 to about 0.01 wt%, and most ably about 0.002 to about 0.005 wt%.

Preferably, the aqueous vehicle includes a preservative. Preferred vatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium s (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p— hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, sorbic acid, and mixtures thereof More preferably, the preservative is a quaternary ammonium salt such as benzalkonium halides rably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, potassium sorbate, sodium benzoate, ethyl p-hydroxybenzoate, butyl p-hydroxybenzoate, or propylaminopropyl biguanide, or mixtures thereof. Propylaminopropyl biguanide is an especially red preservative. The preservative(s) may be used in an amount of about 0.00001 to about 00001 wt%, preferably about 0.00001 to about 0.00008 wt%, and more preferably about 0.00002 to about 0.00005 wt%.

The aqueous vehicle may also include a ty agent to adjust the tonicity (osmotic pressure) in order to achieve an lmically compatible formulation. The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. Preferably, the tonicity agent is selected from the group consisting of glycerin, mannitol, ium chloride, and sodium chloride. More preferably mannitol and/or sodium chloride (and most preferably a mixture f) are employed. The tonicity agent(s) may be used in an amount of about 0.05 to about 8 wt%, preferably about 0.1 to about 6 wt%, more ably about 0.1 to about 4 wt%, and most preferably about 0.2 to about 4 wt%.‘ When a mixture of mannitol and sodium chloride is used as tonicity , preferably the weight ratio of ol : sodium chloride is about 4:1 to about 15:1, more preferably about 6:1 to about 14:1, or 8:1 to about 14:1 and particularly about 10:1 to about 12:1. If mannitol alone is used as the tonicity agent, it is preferably used in an concentration of about 4.5 to about 6.5 wt%, and more preferably in a concentration of about 5.0 to about 5.5 wt%.

If sodium chloride alone is used as the tonicity agent, it is used in a concentration of about 0.05 to about 8 wt%, preferably about 0.1 to about 6 wt%, more preferably about 0.1 to about 4 wt%, and most preferably about 0.2 to about 4 wt%.

The aqueous vehicle preferably also contains a viscosity/suspending agent. Suitable viscosity/suspending agents include those selected from the group ting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl ose, and cross—linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross—linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof. In preferred embodiments of the present invention, the viscosity/suspending agent is a carbomer, more preferably Carbopol 974P. The ity/suspending agent(s) may be t in an amount of about 0.05 to about 2 wt%, preferably 0.1 to about 1 wt%, more ably about 0.2 to about 0.8 wt%, and most preferably about 0.3 to about 0.5 wt%.

In order to adjust the formulation to an ophthalmically acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the ation may contain a pH modifying agent. The pH modifying agent is typically a l acid or metal hydroxide base, ed from the group of potassium hydroxide, sodium hydroxide, and hloric acid, and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH modifying agents are added to adjust the formulation to the target ophthalmically able pH range. Hence it may not be necessary to use both acid and base — ing on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof. The buffer s) may be present in an amount of about 0.05 to about 5 wt%, preferably 0.1 to about 5 wt%, more preferably about 0.2 to about 5 wt%, and most preferably about 0.5 to about 5 wt%.

The ophthalmic formulation for topical administration to the eye may further se a wetting agent. In any embodiment of the present invention the wetting agent is preferably a non-ionic g agent. More preferably, the g agent is water soluble or swellable. Most preferably the wetting agent is water soluble. “Water soluble” is to be understood in the manner used in stande texts such as the “Handbook of Pharmaceutical ents” (Raymond C Rowe, Paul J Sheskey and Sian C Owen, Fifth Edition, Pharmaceutical Press and American Pharmacists Association 2006). Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene- yethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid yl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof. c es of suitable g agents include those selected from the group consisting of: polyoxyethylene—p0lyoxypropylene block copolymers (poloxamers) such as: polyoxyethylene (160) ypropylene (30) glycol [Pluronic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol [Poloxamer 407, Pluronic F127], polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L44], yethylenated sorbitan esters (polysorbates) such as poly(oxyethylene)sorbitan monopalmitate (polysorbate 40), poly(oxyethylene)sorbitan monostearate (polysorbate 60), poly(oxyethylene)sorbitan tristearate (polysorbate 65), poly(oxyethylene) an monooleate (polysorbate 80), poly(oxyethylene) sorbitan monolaurate, poly(oxyethylene) sorbitan trioleate, polyethoxylated ethers of castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene enated castor oil 50 and polyoxyethylene liydrogenated castor oil 60, polyoxyl 40 stearate, sucrose fatty esters, and polyoxyethylene fatty , and mixtures thereof.

Preferably, the wetting agent is selected from the group consisting of: polyoxyethylene-p0lyoxypropylene block copolymers (poloxamers) such as: polyoxyethylene (160) polyoxypropylene (30) glycol nic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol [Poloxamer 407, Pluronic F127], and polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L44], polyoxyethylenated sorbitan esters (polysorbates) such as poly(oxyethylene)sorbitan monopalmitate (polysorbate 40), poly(oxyethylene)sorbitan monosteaxate (polysorbate 60), poly(oxyethylene)sorbitan tristearate (polysorbate 65), poly(oxyethylene) an monooleate (polysorbate 80), poly(oxyethylene) sorbitan monolaurate, and poly(oxyethylene) sorbitan trioleate and mixtures thereof.

More preferably, the wetting agent is a polyoxyethylene-polyoxypropylene block copolymer (poloxamer). Examples of suitable poloxamers include: polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F68], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol [Poloxamer 407, Pluronic F127] and polyoxyethylene (20) polyoxypropylene (20) glycol [Pluronic L44] or a mixture thereof.

Further preferred are wetting agents selected from the group consisting of polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic PI 23], polyoxyethylene (54) polyoxypropylene (39) glycol [Pluronic P85], polyoxyethylene (196) polyoxypropylene (67) glycol amer 407, Pluronic F127] and mixtures thereof.

An especially red g agent is polyoxyethylene (196) polyoxypropylene (67) glycol [Poloxamer 407, Pluronic F127].

Particularly preferred formulations for topical administration to the eye of the t invention comprise a compound of the t ion, a lity enhancing agent, a cheating agent, a preservative, a tonicity agent, a viscosity/suspending agent, a , and a pH modifying agent. More particularly preferred formulations are comprised of an aqueous solution of a B-cyclodextrin, a borate salt, boric acid, sodium chloride, disodium edetate, and propylaminopropyl biguanide.

In one aspect, the ophthalmic formulation of the present invention is in the form of a on, such as one of the following: on Comnosition a com nound ofthe ion Solution Composition a com ound of the invention a solubility enhancing agent a buffering a ent .05 mg on Composition I II III IV a compound of the invention 2.5 g 1.0 g g 10L 5 g 1.05 g 1.05 g fi—O 285 g 2.5 mg 2.5 mg 2.5 mg 0.03 mg 0.03 mg 0.03 mg 0.03 mg 100 ml 100 ml 100 nil 100 ml The ophthalmic formulation of the present invention may also be in the form of a gel or a semi—gel, or both; a jelly; a suspension; an on; an oil; an ointment; a cream; or a spray.

The ophthalmic gel, semi-gel, jelly, suspension, emulsion, oil, ointment, cream, or spray may contain various additives incorporated ordinarily, such as ing agents (e.g, phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, amino acids, sodium acetate, sodium citrate and the like), tonicity agents (e.g., saccharides such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, concentrated glycerin, PEG and propylene glycol, salts such as sodium chloride), preservatives or antiseptics (e. g., benzalkonium chloride, benzatkonium chloride, P-oxybenzoates such as methyl p- oxybenzoate or ethyl p-oxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid or its salt, thimerosal, chlorobutanol and the like), solubilizing enhancing agents (e. g. , cyclodextrins and their derivative, water-soluble polymers such as polyvinyl pyrrolidone, surfactants such as tyloxapol, polysorbates), pH modifiers (e.g, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like), thickening agents (e. g., HEC, hydroxypropyl cellulose, methyl cellulose, HPMC, carboxymethyl cellulose and their salts), chelating agents (e. g., sodium edetate, Ssdium citrate, condensed sodium phosphate) and the like. Each of these ves may be in the amount or concentration similar to those described for the ophthalmic formulation in the form of a solution above.

Furthermore the compounds of the invention may be formulated for l administration by oration into novel ophthamlic ations including but not limited to: microemulsions, liposomes, niosomes, gels, hydrogel, nanoparticles, and nanosuspension. 1. Microemulsions Microemulsions are dispersion of water and oil tated by a combination of surfactant and cosurfactant in a manner to reduce interfacial tension. These systems are y characterized by higher thermodynamic stability, small t size (approximately 100 nm) and clear appearance. Their transparent appearance is due to the high level of dispersion of the internal phase, and the size of it ranges from 100-1000 angstroms.

Processes for forming microemulsions le for use in ophthalmic formulations are descrived in Vandamne TF. Prog Retinal Eye Res 2002; 21 :15—34, which is incorporated by reference. 2. Liposomes Liposomes are lipid vesicles ning aqueous core and have been widely exploited in ocular delivery for various drug substances. Depending on the nature of the lipid composition selected, liposomes can provide extended release of the drug. 3. Niosomes Niosomes are bilayered structural es made up of ic surfactant and are capable of encapsulating both lipophilic and hydrophilic nds. They can release the drug independent of pH and enhance ocular bioavailability. Niosomes are microscopic lamellar structures that are formed on the admixture of nonionic surfactant of the alkyl or diakyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media.

Structurally niosomes are r to liposomes, in that they are also made up of a bilayer.

However, the bilayer in the case of nisomes is made up of nonionic surface—active agents rather than phospholipids as in the case of liposomes. Niosomes may be unilamellar or multilamellar depending on the method used to e them. They are e of entrapping hydrophilic and hydrophobic solutes. They s great stability and lack many disadvantages associate with mes such as high cost and the variable purity of phospholipids. The properties of niosomes and process for preparing them are well known in the art, see e.g., Wagh VD et al., J Pharm Res 2010; 3(7):1558—1563; Kaur H et 61]., Int J Pharm Sci Rev Res 2012; 15(1): 1 13——l20, each of which is incorporated by reference. 4. Gels Ophthalmic gels are composed of mucoadhesive polymers that e localized delivery of an active ingredient to the eye. Such polymers have a ty known as bioadhesion, meaning attachment of a drug carrier to a specific biological tissue. These polymers are able to extend the contact time of the drug with the biological s and thereby improve ocular bioavailability. The choice of the polymer plays a al role in the release kinetics of the drug from the dosage form. Several bioadhesive polymers are available with varying degree of mucoadhesive performance. Some examples are carboxymethylcellulose, carbopol, polycarbophil, and sodium alginate. The use of gel formulations in ocular drug deliver has been reviewed in Ali Y et 51]., Adv Drug Deliv Rev 2006; 58: 268, which is incorporated by reference.

. Hydrogels Hydrogels are three-dimensional, hydrophilic, polymeric networks capable of taking in large amounts of water or biological fluids. Residence time can be significantly enhanced with a hydrogel formulation. The gelation can be ed by changing ature and pH.

Poloxamers, the most widely used polymer, contains the hydrophobic part in the centre surrounded by a hydrophilic part. Though they are widely employed to enhance the residence time. Recent ctives in the use of hydrogels in ocular drug deliver are described by a R, Jwala J, Boddu SHS, Mitra AK. Pharm Res. 2009; 26(5):l 197—1216 which is incorporated by reference. 6. Nanoparticles Nanoparticles are defined as particles with a diameter of less than 1 um, comprising of various biodegradable or non biodegradable polymers, lipids, phospholipids or metals.

They can be classified as nanospheres or nanocapsules depending upon whether the drug has been uniformly dispersed or coated within polymeric material. The uptake and distribution of nanoparticles is dependent on their size. The use of nanoparticles in ocular drug delivery has WO 24302 recently been reviewed by Hing er al., Int. J. Ophthalmol 2013; 6:390—396, which is incorporated by reference. 7. Nanosuspensions Nanosuspensions are defined as sub—micron colloidal s that consist of poorly water soluble drugs suspended in an appropriate dispersion medium stabilized by tants.

Usually, spensions consist of colloidal carriers like polymeric resins which are inert in nature. Nanosuspensions enhance drug solubility and thus bioavailability. Unlike microemulsions, nanosuspensions are non—irritant. Charge on the surface of nanoparticles facilitates their adhesion to the cornea. The use of nanosuspensions in drug delivery is reviewed in Rabinow, Nature Rev Drug Disc 2004; 785—796, which is incorporated by reference.

The compounds of the present invention can also be administered in the form of a formulation suitable for ocular topical delivery. Detailed descriptions of formulation suitable for ocular topical delivery are bed in JD. Bartlett and S. D. Jaanus, “Clinical Ocular Pharmacology”, 2008, Elsevier Health Sciences, which is incorporated by reference.

The compounds of the ion may also be coupled with soluble polymers as targetable drug carriers. Such rs can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, and polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the nds ofthe invention may be coupled to a class of biodegradable polymers useful in ing lled release of a drug, for example, ctic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon actone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

The present ion also provides a pharmaceutical composition comprising a compound ofthe invention or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient, and further an active ingredient ed from the group ting of a) an antagonist of integrin OLSBI, b) a cytotoxic/antiproliferative agent, c) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth , d) an inhibitor of VEGF, e) an inhibitor of Flk—l/KDR, Flt—l, Tck/Tie-2, or Tic-l, and f) an inhibitor of phosphoinositide 3-kinase, and a mixture thereof The present invention further provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof, and a ceutically acceptable carrier or excipient, and further an active ingredient selected WO 24302 from the group consisting of a) an antagonist of integrin 0L5Bl, b) a xic/antiproliferative agent, c) an inhibitor of epidermal-derived, fibroblast—derived, or platelet-derived growth s, d) an inhibitor of VEGF, and e) an inhibitor of phosphoinositide 3—kinase, and a mixture f.

Nonlimiting examples of antagonists of integrin a5Bl are (S)—2—((R)—2—((S)—2-((S)—2- ((S)—l ~acetylpyrrolidine-2—carboxamido)—3—( l H—imidazol-5—yl)propanamido)—3— hydroxypropanamido)mercaptopropanamido)succinamide, and JSM6427, described in es, R. et 61]., J. Med. Chem. 2007, 50:3786—3794, herein incorporated by reference.

Nonlimiting examples of cytotoxic/antiproliferative agents are taxol, vincristine, vinblastine, and doxorubicin.

Nonlimiting examples of inhibitors of epidermal—derived, ast—derived, or platelet-derived growth s are pazopanib, and sunitinib, Nonlimiting examples of inhibitors of vascular endothelial derived growth factor (VEGF) 'are bevacizumab and ranibizumab, Nonlimiting examples of inhibitors of phosphoinositide se are indelalisib and 2— lin-4—yl—8—phenylchroman-4—one.

Methods of Use Compounds of the invention typically display submicromolar inhibitory activity for the integrins av, such as OMB and (WM. Inhibiting the function of OMB and aVBS integrins prevents endothelial cell proliferation. Endothelial cell proliferation can result in deleterious neovascularization or angiogenesis, particularly choroidal cularization in the choriocapillaris, through Bruch’s membrane, ultimately leading to blood and protein e below the macula. Bleeding, leaking, and scarring from these blood vessels eventually cause irreversible damage to the photoreceptors and rapid vision loss if left untreated.

Diabetic retinopathy, a closely related condition, is the result of microvascular retinal changes. Hyperglycemia-induced intramural pericyte death and thickening of the basement ne lead to incompetence of the vascular walls in the retina, which s the blood— retinal barrier and makes the retinal blood vessels more permeable. Damaged blood vessels leak fluid and lipids onto the macula, the part of the retina that provides us with detailed vision, causing the macula to swell. Eventually this can progress to develop a condition called macular edema.

Accordingly, AMD, DR, DME, and macular edema ing central retinal vein occlusion (thrombosis) can be treated or prevented through administration (e. g. , topical administration) of the compounds or pharmaceutical itions of the present invention.

The present ion provides a method of treating or preventing a disease or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof or a therapeutically effective amount of a pharmaceutical composition of the invention. In one aspect, the invention provides treating a disease or condition. In one aspect, the invention provides preventing a disease or condition.

In one aspect, the compound or pharmaceutical composition of the invention is administered topically. In a further , the compound or pharmaceutical composition of the invention is administered as an ophthalmic on. In another aspect, the compound or ceutical composition of the invention is administered as an ophthalmic emulsion, suspension, gel, or semi-gel. In another aspect, the nd or pharmaceutical ition of the ion is administered as an ophthalmic jelly, oil, ointment, cream, or spray.

The compounds or pharmaceutical compositions of the invention are administered in dosages effective to inhibit the function of avB3 and/or avBS ins and thus treat or prevent a disease ion mediated by the avB3 and/or avBS integrin.

The present invention provides a method of treating or preventing a disease or condition mediated by an av integrin in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof or a therapeutically effective amount of a pharmaceutical composition of the invention. In one aspect, the disease or ion is a disease or ion in which angiogenesis is involved. In a further aspect, the disease or condition is a disease or condition in which ocular angiogenesis is involved.

The present invention also provides a method of treating or preventing an avB3 and/or avBS integrin—mediated disease or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically able salt or e thereof or a therapeutically effective amount of a ceutical ition of the ion. In one aspect, the disease or ion is a disease or condition in which ocular angiogenesis is involved. In one aspect, the disease or condition is macular degeneration. In one aspect, the disease or condition is age—related macular degeneration (AMD). In one aspect, the disease or condition is diabetic retinopathy WO 24302 (DR). In one aspect, the disease or condition is ic macular edema (DME). In one aspect, the disease or condition is macular edema following l vein occlusion (RVO).

The present invention further provides a method of treating or preventing AMD, DR, DME, or r edema following RVO, comprising administering to a subject in need thereof, a therapeutically ive amount of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof or a therapeutically effective amount of a pharmaceutical composition of the invention. In one aspect, the invention provides treating AMD, DR, DME, or macular edema following RVO. In one aspect, the ion provides preventing AMD, DR, DME, or macular edema following RVO.

The present invention further provides a method of treating or preventing a disease or condition in a subject, comprising stering to a subject in need thereof a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or e thereof or a therapeutically effective amount of a ceutical composition of the ion, in combination with a second therapy for treating or preventing the disease or condition. In one aspect, the disease or condition is mediated by an (iv integrin. In a further aspect, the disease or condition is mediated by an (va3 and/or ochS integrin. In one aspect, the disease or condition is a disease or condition in which angiogenesis is involved. In a further aspect, the disease or condition is a disease or condition in which ocular angiogenesis is involved. In one aspect, the second therapy comprises administration of one or more of the following: a) an antagonist of integrin (XSBI, b) a cytotoxic/antiproliferative agent, c) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factor, d) an inhibitor of VEGF, e) an inhibitor of Flk-l/KDR, Flt-l, Tck/Tie-2, or Tic-1, and f) an tor of phosphoinositide 3-kinase, and a mixture thereof. In a further aspect, the second therapy comprises administration of one or more of the following: a) an nist of integrin (XSBI, b) a cytotoxic/antiproliferative agent, c) an tor of epidermal-derived, fibroblast-derived, or platelet-derived growth factor, d) an inhibitor of VEGF, and e) an inhibitor of phosphoinositide 3-kinase, and a mixture thereof. In a further aspect, the second therapy comprises administration of an inhibitor of VEGF. In a further , the VEGF tor is zumab or ranibizumab.

The second therapy can be administered via any administration routes, including oral administration in forms such as tablets, es (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups emulsions, enous administration (bolus or in—fusion), intraperitoneal administration, topical administration (e.g, ocular eye-drop), subcutaneous administration, intramuscular administration, transdermal (e.g., patch) administration, and intravitreal administration. In one aspect, the second therapy is administered through intravitreal injection.

Administration of the second therapy in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). “Combination y” may be, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy ns that incidentally and arbitrarily result in the combinations of the present invention.

“Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential , wherein each therapeutic agent is administered at a different time, as well as administration of these eutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.

In accordance with the method ofthe invention, the individual ents of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimens of simultaneous or alternating treatment, and the term “administering” is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of the invention with other agents useful for treating (xv integrin-mediated ions includes in principle any combination with any pharmaceutical composition useful for treating macular ration, DR, DME, or macular edema following RVO. When the method of the invention is a combination treatment of a formulation of the present invention topically administered to the eyes and an anti-VEGF protein or aptamer, the procedures, dosages and frequencies of the anti-VEGF protein or aptamer are as described in the e s for those agents.

The dosage regimen utilizing the compounds of the invention is selected in accordance with a y of factors ing type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; and the particular compound or salt thereof employed. An ordinary skilled physician, veterinarian or clinician can readily ine and prescribe the effective amount of the drug ed to prevent, r or arrest the progress of the condition.

In the methods of the invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with le pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier”) ly selected with respect to the intended topical administration to the eye and consistent with tional pharmaceutical practices.

For purposes of the invention, the following definitions will be used (unless sly stated otherwise): “A nd of the invention3, ‘6 ‘6 , compounds of the invention9, a compound of the present invention”, or “compounds of the present invention” refers to a nd(s) disclosed herein, e.g, a compound(s) of the invention includes a compound(s) of any of the ae described herein including formula I and 11 and/or a compound(s) explicitly disclosed herein. Whenever the term is used in the context of the invention it is to be understood that the reference is being made to the free base and the corresponding pharmaceutically acceptable salts or solvates f, provided that such is possible and/or appropriate under the stances.

“Pharmaceutical” or “pharmaceutically acceptable” when used herein as an adjective, means substantially non-toxic and ntially non-deleterious to the recipient.

By “pharmaceutical composition” it is further meant that the carrier, diluent, solvent, excipient, and salt must be compatible with the active ingredient of the formulation (e.g., a compound of the invention). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.

“Solution” refers to a clear, homogeneous liquid dosage form that contains one or more chemical substances ved in a solvent or mixture of mutually miscible solvents.

Because les of a therapeutic agent nce in solution are uniformly dispersed, the use of solutions as dosage forms generally provides assurance of uniform dosage upon administration and good accuracy when the solution is diluted or ise mixed.

“Solution” as disclosed herein contemplates any ions based on the current state of the art or variations achieved by one skilled in the art.

“Suspension” refers to a liquid dosage form that ns solid particles dispersed in a liquid vehicle. “Suspension” as disclosed herein contemplates any variations based on the current state of the art or variations achieved by one skilled in the art. ient” is used herein to include any other compound that is not a therapeutically or biologically active compound and may be contained in or combined with one or more of the compounds of the present invention. As such, an excipient should be pharmaceutically or biologically acceptable or relevant (for e, an excipient should generally be non-toxic to the subject). “Excipient” includes a single such compound and is also intended to include a plurality of excipients. For the purposes of the present disclosure the term ient” and “carrier” are used interchangeably throughout the description of the t application.

“Therapeutically effective amount” refers to that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a cher or clinician.

“Treat,” “treating,” or “treatment” refers to decreasing the symptoms, markers, and/or any negative effects of a disease or ion in any appreciable degree in a subject who currently has the disease or ion. In some embodiments, treatment may be administered to a subject who exhibits only early signs of a e or condition for the purpose of decreasing the risk of developing the disease or condition. In some embodiments, “Treat,” “treating,” or “treatment” refers to amelioration of one or more symptoms of a e or condition. For example, amelioration of one or more ms of a disease or condition includes a decrease in the severity, frequency, and/or length of one or more symptoms of a disease or condition.

“Prevent,” “prevention,” or “preventing” refers to any method to partially or completely prevent or delay the onset of one or more symptoms or features of a e or condition. Prevention may be administered to a subject who does not exhibit any sign of a disease or condition.

“Subject” means a human or animal (in the case of an animal, more typically a mammal). In one aspect, the subject is a human.

The term “symptom” is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non-health-care professionals. “0w integrin antagonist” refers to a compound which binds to and ts or interferes with the function of either avB3 or avBS, or a compound which binds to and inhibits or interferes with the function of both (va3 and (vaS (i. e., a dual (va3/0LVB5 antagonist). The compounds bind to the receptors as antagonists, blocking or interfering with the binding of the native agonist, such as vitronectin, while not provoking a ical response themselves.

“Bone resorption” refers to the process by which osteoclasts degrade bone.

“Alkyl” refers to straight chain or branched alkyl of the number of carbon atoms specified (e. g., C1-C4 , or any number within this range (methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, etc).

“Alkoxy” refers to straight chain or branched alkoxides of the number of carbon atoms specified (e. g., C1-C6 alkoxy), or any number within this range (methoxy, , propoxy, i-propoxy, butoxy, i-butoxy, t-butoxy, etc.) cyclic ring” refers to saturated cycloalkyl of the number of carbon atoms specified (i.e., C3 or C4), such as cyclopropyl and cyclobutyl. ocyclic ring” refers to saturated heterocyclic ring of the number of carbon atoms specified (i.e., C3 or C4), further comprising one additional heteroatoms selected from N, O, and S.

The term “about” refers to a range of values which can be 15%, 10%, 8%, 5%, 3%, 2%, 1%, or 0.5% more or less than the specified value. For example, “about 10%” can be from 8.5% to 11.5%. In one embodiment, the term “about” refers to a range of values which are 5% more or less than the ed value. In another embodiment, the term “about” refers to a range of values which are 2% more or less than the ed value. In another embodiment, the term “about” refers to a range of values which are 1% more or less than the specified value.

EXAMPLES Example 1. Synthesis of (S)—3-(6-(difluoromethoxy)-pyridineyl)-3—(2—oxo(3—(5, 6, 7, 8— tetrahydro—1, 8—naphthyridin-2—yl)propyl)imidazolidin—1-yl) propanoic acid (Compound A1) Compound A1 is made using a convergent sis scheme as shown in Scheme 1: fragment 6b is reacted with nt 9 to form compound 10, which is further reacted in three steps to form Compound A1.

Synthesis of fragment 6b tert-butyl 2-oxopyrrolidine-l-carboxylate (2a): To a stirred solution of compound 1a (100 g, 117 mmol, 1.0 equiv.) in DCM, (Boc)20 (25.5 g, 117 mmol, 1.00 equiv.) and DMAP (0.022 g, 0.180 mmol, 0.001 ) were added at RT and stirred for 12 h. After consumption of the starting material (monitored by TLC), volatiles were removed under reduced pressure to afford compound 2a (196 g, 90.3%) as a brown syrup.

TLC: 50% EtOAc/Hexane (Rf: 0.40) 1H NMR (400 MHz, CDC13): 8 3.74 (t, J: 6.8 Hz, 2H), 2.50 (t, J= 8.0 Hz, 2H), 2.01 (t, J: 7.6 Hz,‘2H), 1.52 (s, 9H) tert—butyl (5—(dimethoxyphosphoryl)—4-oxopentyl)carbamate (321): To a stirred solution of iPerH (2.99 mL, 21.8 mmol, 1.35 equiv.) in THF, cooled to -10 0C, hexyl lithium (8.79 mL, 20.0 mmol, 1.24 equiv.) was slowly added. The on mixture was cooled to - 60 °C, dimethylmethyl phosphonate (2.20 mL, 20.9 mmol, 1.29 equiv.) was added and stirred for 1 h. Then the temperature was raised to —40°C, and compound Za (3.0 g, 16.2 mmol, 1.0 ) was uced to the reaction mixture and stirring was continued for further 1 h. After consumption of the starting material, 2N H2804 solution (20 mL) was added slowly to the reaction and stirred at 0°C for 15 minutes. The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (25 mL), brine (25 ml), dried over NaZSO4, filtered and evaporated under reduced re to afford compound 33 as a brown liquid (5.0 g, crude).

TLC: 80% EtOAc/Hexane (Rf: 0.30) 1H NMR (400 MHz, Z 6 4.85 (brs, 1H, Exc), 3.80-3.72 (m, 8H), 3.13-3.07 (m, 2H), 2.67 (t, J= 6.8 Hz, 2H), 1.87— 1.76 (m, 2H), 1.43 (s, 9H) LC—MS: m/z = 308.3 [M+H]+ at RT 2.67 (99.1% purity) tert-butyl (3-(1, 8-naphthyridin-2—yl)pr0pyl)carbamate (53): To a stirred solution of compound 421 (0.500 g, 4.09 mmol, 1.0 equiv.) and compound 3a ( 1.26 g, crude, 1.0 equiv.) in MeOH (9.17 mL), 50% NaOH solution (0.314 mL) was added and the reaction mixture was stirred at 50°C for 10 h. After consumption of the starting material (by TLC), volatiles were removed, crude residue was diluted with EtOAc (15 mL) and the organic layer was washed with water (2 x 15 mL). The separated c layer was dried over Na2804, filtered and concentrated under d pressure to afford brown syrup, which was purified by column chromatography on neutral alumina (80% EtOAc: Hexane) to provide compound 53 (0.980 g, 83.3%) as an off-white solid.

TLC: EtOAc 1H NMR (500 MHz, CDCl3)Z 6 9.09 (s, 1H), 8.17—8.15 (m,1H), 8.10 (d, J: 8.0 Hz, 1H), 7.45 (t, J: 8.0 Hz, 1H), 7.41 (t, J: 15.0, 1H), 4.76 (brs, 1H, Exc), 3.25-3.21 (m, 2H), 3.09 (t, J: .0 Hz, 2H), 2.14—2.08 (m, 2H), 1.42 (s, 9H) LC-MS: m/z = 288 [M—H]' at RT 2.86 (94.7 %) tert-butyl (3-(5,6,7,8-tetrahydr0-1,8-naphthyridin-Z-yl)pr0pyl)carbamate (S-024): To a stirred solution of compound 5a (0.25 g, 0.87 mmol, 1.00 equiv.) in MeOH (5 mL), Rh/C (catalytic, 5 wt %) was added under N2 atmosphere and stirred at RT for 8 h under en (balloon pressure) atmosphere. After completion of the starting material, the reaction mixture was filtered through pad of ®, washed with MeOH (5 mL). The filtrate was evaporated under reduced re to afford compound S-024 (0.18 g, 71.1%) as a white solid.

TLC: EtOAc 2014/015372 1H NMR (400 MHz, CDCl3): 6 7.05 (d, J= 7.6 Hz, 1H), 6.34 (d, J: 7.2 Hz, 1H), 5.44 (s, 1H), 4.78 (brs, 1H, Exc), 3.41-3.38 (m, 2H), 3.16 (d, J= 6.0 Hz, 2H), 2.68 (t, J: 6.0 Hz, 2H), 2.59 (t, J: 7.6 Hz, 2H), 1.93-1.81(m, 4H), 1.44 (s, 9H) LC-MS: m/z = 292.3 [M+H]+ at RT 3.41(97.9% purity) 3—(5, 6, 7, 8—tetrahydro-1, 8-naphthyridinyl)propan-1~amine (6b): To a stirred solution of S-024 (0.25 g, 0.85 mmol, 1.00 equiv.) in DCM (5 mL), cooled to 0°C, TFA (0.13 mL, 1.69 mmol, 2.00 equiv.) was added. The reaction was warmed to RT and d for 4 h.

After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure to afford crude compound 6b (0.30 g) as a thick syrup which was used in the next step without purification.

Synthesis of Fragment 9 and completion of the synthesis —bromo(difluoromethoxy)pyridine (2): To a stirred solution of compound 1 (4.50 g, 25.8 mmol, 1.0 equiv.) in ous MeCN (80 mL), sodium 2-chloro-2,2- difluoroacetate (4.89 g, 31.0 mmol, 1.20 equiv.) was added at RT and stirred at 70°C for 48 h.

After consumption of the starting al (by TLC), the reaction mixture was brought to RT and diluted with NH4Cl solution (30 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine on (2 x 50 mL), dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure to give the crude compound which was purified by column chromatography (2% EtOAc/hexane) to afford compound 2 (3.2 g, 57%) as pale yellow syrup.

TLC: 5°/o EtOAc/Hexane (Rf; 0.5) 2 1H NMR (400 MHz, CDCl3): 8 8.25 (d, J= 2.8 Hz, 1H), 7.82 (dd, J= 2.4, 6.4 Hz, 1H), 7.40 (t, J= 72.8 Hz, 1H), 6.83 (d, J= 8.8 Hz,1H) LC-MS: m/z = 224.7 [M+H]+ at RT 4.22 (98.2% purity) (E)—tert-butyl 3-(6-(difluoromethoxy)pyridin-3—yl)acrylate (3): To a stirred solution of tert—butyl acrylate (9.99 g, 78.1 mmol, 3.50 equiv.), Et3N (8.5 mL, 60.2 mmol, 2.70 equiv.), N-methyl pyrrolidine (20 mL), Tritolylphosphine (1.17 g, 3.52 mmol, 0.16 equiv.) followed by Pd(OAc)2 (0.50 g, 2.22 mmol, 0.09 ) were added. The temperature was gradually raised to 90°C and compound 2 (5.00 g, 22.3 mmol, 1.0 equiv.) in NMP (10 mL) was added drop wise and stirred at 90°C for 12 h. After consumption of the starting material (by TLC), the reaction e was filtered through pad of CELITE® and washed with EtOAc (50 mL). The combined filtrate was washed with cold water (2 x 50 mL) followed by NaOCl (50 mL), brine solution (50 mL). The organic layer was dried over ous , filtered and concentrated under reduced pressure to give the crude residue which was purified by column tography (3% EtOAc/hexane) to afford compound 3 (4.0 g, 66%) as yellow solid.

TLC: 5% Hexane (Rf: 0.5) 1H NMR (400 MHZ, CDCl3): 6 8.28 (d, J= 2.4 Hz, 1H), 7.88 (dd, J: 2.0, 6.4 Hz, 1H), 7.56 (d, J: 16.0 Hz, 1H), 7.55 (t, J: 45.6 Hz, 1H), 6.91 (d, J: 8.4 Hz, 1H), 6.34 (d, J: 16.0 Hz, 1H), 1.53 (s, 9H) LC-MS: m/z = 272 [M+H]+ at RT 4.16 (99.5% ) (S)—tert-butyl 3—(benzyl ((R)phenylethyl)amin0)-3—(6-methoxypyridin yl)pr0panoate (5): To a stirred solution of compound 4 (0.39 g, 1.85 mmol, 2.0 equiv.) in THF (5 mL), cooled to -30°C, n-BuLi (0.66 mL, 1.65 mmol, 1.79 equiv.) was added and then cooled to —78°C. Compound 3 (0.25 g, 0.92 mmol, 1.0 equiv.) dissolved in THF (3 mL) was added to the reaction mixture, stirred for 30 min and quenched with saturated ammonium chloride. The reaction mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with 10% AcOH, brine solution which was dried over anhydrous NaZSO4, filtered and concentrated under reduced pressure to give the crude compound (mixture of 3 and 5, 0.17 g) as thick syrup, which was directly used in the next step.

TLC: 5% EtOAc/Hexane (Rf: 0.5) LC-MS: m/z = 483 [M+H]+ at RT 4.66 (75.1% purity) Synthesis of (S)—tert-butyl 3—amin0-3—(6—(diflu0r0meth0xy)pyridin yl)pr0pan0ate (S—029): To a stirred solution of nd 5 (0.80 g, crude mixture) in EtOAc (5 mL) and AcOH (0.5 mL), 20% Pd(OH)2 (50 mg) was added under N2 atmosphere.

The reaction mixture was stirred under H2 atmosphere (40 psi) at RT for 2 h. After consumption of the starting material (monitored by TLC), the reaction mixture was filtered through a pad of CELITE®. Filtrate was concentrated under reduced re to afford crude compound which was purified by column chromatography (2% MeOH/DCM) to furnish S— 029 (0.3 g, 63%) as yellow syrup.

TLC: 5% CM (Rf: 0.3) 1H NMR (400 MHZ, : 6 8.17 (d, J= 2.8 Hz, 1H), 7.78 (dd, J= 2.4, 6.4 Hz, 1H), 7.44 (t, 73.2 Hz, 1H), 6.88 (d, J: 8.4 Hz, 1H), .40 (m, 1H), 2.65—2.56 (m, 2H), 1.42 (s, 9H) LC-MS: m/z = 274 [M+H]+ at RT 2.76 (99.8% purity) (S, E)—tert—Butyl 3-(6—(tert-but0xy) pyridin—3—yl)—3-((2, 2— dimethoxyethylidene)amino)pr0pan0ate (7): To a stirred on of dimethoxy acetaldehyde (0.44 mL, 2.50 mmol, 1.20 equiv., 60% in water) in DCM (10 mL), cooled to 0°C, anhydrous MgSO4 (10 g) was added followed by S-029 (600 mg, 2.08 mmol, 1.0 equiv.) in DCM (5 mL). The reaction was continued at RT for 2h and filtered through a pad of CELITE®, the filtrate was concentrated under reduced pressure to afford nd 7 (650 mg, crude) as a yellow liquid which was used in the next step without any purification.

TLC: 5% MeOH/DCM (Rf: 0.5) (S)-tert-butyl 3-(6-(diflu0romethoxy)pyridinyl)((2, 2—dimethoxyethyl) amino) oate (8): To a stirred solution of compound 7 (0.65 g, crude, 1.0 equiv.) in MeOH (7 mL), cooled to 0°C, NaBH(CN)3 (0.13 g, 2.09 mmol, 1.20 equiv.) was added and the reaction mixture was stirred at RT for 2 h. After consumption of the starting material (by TLC), MeOH was removed under reduced pressure to give the crude residue which was diluted with water (10 mL) and extracted with EtOAc (2 x10 ml). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under d pressure to give the crude material which was purified by column tography (2% MeOH/DCM) to afford nd 8 (0.52 g, 79%) as a thick syrup.

TLC: 5% MeOH/DCM (Rf: 0.7) 1H NMR (400 MHz, : 8 8.13 (d, J= 2.0 Hz, 1H), 7.75 (dd, J: 2.4, 6.0 Hz, 1H), 7.44 (t, J= 73.2 Hz, 1H), 6.87 (d, J: 8.4 Hz, 1H), 4.43-4.37 (m, 2H), .02 (m, 1H), 3.60- 3.54 (m, 2H), 3.35 (s, 3H) 3.31 (s, 3H), 2.66-2.57 (m, 2H), 1.39 (s, 9H) LC-MS: m/z = 377 [M+H]+ at RT 2.96 (92.3% purity) (S)-tert-butyl 3-(6-(diflu0r0methoxy) pyridin-S-yl)(1-(2, 2-dimeth0xyethyl) (3-(5, 6, 7, 8-tetrahydro-1, 8-naphthyridinyl)propyl)ureido)pr0panoate (10) : To a stirred solution of compound 8 (375 mg, 0.99 mmol, 1.0 equiv.) in dry DCM (5 mL), cooled to 0°C, triphosgene (1.50 mL, 2.99 mmol, 3.00 equiv., 20% in PhMe) followed by Et3N (0.30 mL, 2.09 mmol, 2.10 equiv) were added. The reaction mixture was slowly brought to RT and stirred for 2 h. After completion of the starting material, volatiles were evaporated to afford the crude compound 9, which was used directly in the next step without purification. A solution of nd 9 in DCE (2 mL) was added to a solution of compound 6b (400 mg, 1.32 mmol, 1.32 ) in DCM (5 mL), Et3N (0.55 mL, 3.98 mmol, 4.00 equiv) at 0°C and stirred at RT for 4 h. After consumption of the starting material ored by TLC), the reaction mixture was concentrated under reduced pressure to give the crude residue which was purified by column chromatography (2% MeOH/DCM) to afford compound 10 (0.40 g, 67%) as a thick syrup.

TLC: 5% MeOH/DCM (Rf: 0.2) 1H NMR (400 MHz, CDC13): 8 8.13 (d, J= 2.8 Hz, 1H), 7.79 (dd, J= 2.4, 6.4 Hz, 1H), 7.62 (tt, J= 72.8 Hz, 1H), 7.12 (d, J= 6.4 Hz,1H), 6.86 (d, J= 8.4 Hz, 1H), 6.36 (d, J: 3.6 Hz, 1H), 6.22 (t, J= 4.8 Hz, 1H), 5.75 (t, J= 7.6 Hz, 1H), 4.26 (t, J: 5.2 Hz, 1H), 3.45—3.38 (m, 8H), 3.27—3.13 (m, 3H), 2.99—2.93 (m, 2H), 2.71-2.59 (m, 5H), 1.93—1.83 (m, 5H), 1.39 (s, LC-MS: m/z = 594 + at RT 3.42 (88.1% purity) (S)-tert-Butyl 3-(6-(difluorometh0xy) nyl)(2-0x0(3-(5, 6, 7, 8- tetrahydro-l, 8~naphthyridinyl)pr0pyl)-2, 3-dihydr0-1H-imidazolyl)pr0pan0ate (11): To a stirred solution of compound 10 (0.20 g, 0.34 mmol, 1.0 equiv.) in THF (4 mL), at —10 °C, 1 M sulfuric acid (0.8 mL) was added. The reaction was slowly warmed to RT and stirred for 10 h. After ption of the starting material (monitored by LCMS), THF was removed and the crude residue was lized with sodium hydroxide (50 wt %) till pH ~7.

The aqueous layer was extracted with 5% MeOH/DCM (3 x 20 mL) and the combined organic ts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to furnish compound 11 (0.22 g, crude) as a syrup.

TLC: 10% CM (Rf: 0.5) LC—MS: m/z = 530 [Mi—H]+ at RT 4.06 (72.8% ) (S)-tert-Butyl 3-(6-(diflu0r0meth0xy) pyridinyl)(2-0x0(3-(5, 6, 7, 8- tetrahydro-l, 8-naphthyridinyl)propyl) imidazolidiny1)pr0pan0ate (12): To a stirred on of compound 11 (0.45 g, crude, 1.0 equiv.) in EtOH (8 mL), 20% Pd/C (200 mg) was added under N2 atmosphere. The on mixture was stirred under H2 atmosphere (40 psi) at RT for 36 h. After consumption of the starting material the reaction mixture was filtered through a pad of CELITE®, and the filtrate was concentrated under reduced pressure to afford crude compound 12, which was purified by chiral ative HPLC to afford compound 12 (450 mg, crude) as an off-white solid.

TLC: 10% MeOH/DCM (Rf: 0.5) LC-MS: m/z = 532.6 [M+H]+ at RT 3.99 (80.1% purity) (S)(6-(difluoromethoxy)pyridinyl)—3-(2—0x0(3-(5, 6, 7, 8-tetrahydr0-1, 8- naphthyridinyl)propyl) imidazolidinyl)propan0ic acid (Compound A1); To a stirred solution of compound 12 (0.40 g, crude, 1.0 equiv.) in DCM (2 mL), cooled to —10°C, TFA (0.5 mL) was added under N2 atmosphere. The reaction was slowly brought to RT and stirred for 2h; after consumption of the starting material, volatiles were evaporated to afford crude (400 mg) compound, which was purified by chiral preparative HPLC to afford compound A1 as an off—white solid.

TLC: 10% MeOH/DCM (Rf: 0.3) 1H NMR (400 MHz, CD30D): 6 8.20 (d, J: 2.4 Hz, 1H), 7.85 (dd, J= 2.4, 6.4 Hz, 1H), 7.53 (t, ,J= 2.4 Hz, 1H), 7.50 (d, J: 7.2 Hz, 1H), 6.98 (d, J: 8.4 Hz, 1H), 6.57 (d, J= 7.2 Hz, 1H), 5.51 (dd, J= 3.6, 8.0 Hz, 1H), 3.68—3.61 (m, 1H), 3.52—3.46 (m, 3H), 3.38 (m, 1H), 3.24- 3.17 (m, 1H), 3.07—2.98 (m, 2H), .62 (m, 6H), 2.09—1.81 (m, 4H).

LC-MS: m/z = 476 [M+H]+ at RT 2.78 (97.9% purity) HPLC purity: 96.4%; Chiral : 99% The compounds of the present invention described in Examples 2—7 in which Z is - CHzCHzCHz— were synthesized using the general reaction scheme shown in Scheme 2. yl (2-oxo(5,6,7,8-tetrahydro-1,8—naphthyridinyl)hexyl)phosphonate was added to the fluorinated nitrogen heterocycle (Q) aldehyde to form the hept-1—enone. The hept— 1-en—3-one was reduced to the corresponding heptenol using lithium aluminum hydride or sodium borohydride. The hepten-3ol was then reacted with proprionic acid in 1,1,1- triethoxyethane and the resulting crude rearrangement product was reduced with hydrogen and palladium on carbon catalyst to the corresponding olefin reduction product which was then reacted with aqueous base to form the final nonanoic acid compounds.

Example 2. Synthesis of 9—(5,6,7,8-tetrahydro-1,8-naphthyridin-2—yl)(2- oromethyl)pyrimidinyl)nonanoic acid (Compound A2) (E)-7—(5,6,7,8-tetrahydro-1,8-naphthyridin-Z-yl)-1—(2—(trifluoromethyl)pyrimidin- -yl)hept—1—en-3—one o o H n N N \ P\—OMe I OMe O / H __”—_,t-B OK N / + / N THF IN\ \NJ\CF31 / OHCfij: N CF3 Under nitrogen, to dimethyl (2-oxo(5,6,7,8-tetrahydro-1,8-naphthyridin yl)hexyl)phosphonate (3.40 g, 10.0 mmol, 1.00 equiv; n, P. J. et al., J. Med. Chem. 2004, 47:4829—4837) in THF (10 mL) at 23 °C was added fluoromethyl)pyrimidine—5- carbaldehyde (1.76 g, 10.0 mmol, 1.00 equiv) and t—BuOK (1.01 g, 9.00 mmol, 0.900 equiv).

After stirring for 10 min at 23 °C, the reaction mixture was ly loaded on silica gel and purified by column chromatography on silica gel g with CHzClz/MeOH to afford 2.10 g of the title compound (54% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 5): 9.03 (s, 2H), 7.50 (d, J= 16.2 Hz, 1H), 7.07 (d, J: 7.2 Hz, 1H), 6.93 (d, J= 16.2 Hz, 1H), 6.35 (d, J: 7.2 Hz, 1H), 5.17 (br s, 1H), 3.42—3.37 (m, 2H), .64 (m, 4H), 2.62—2.55 (m, 2H), 1.95—1.85 (m, 2H), 1.77—1.66 (m, 4H). 19P NMR (282 MHz, CDCl3, 23 °C, 5): —70.3 (s, 3F).

(E)-7—(5,6,7,8—tetrahydro-1,8-naphthyridinyl)(2-(trifluoromethyl)pyrimidin- -yl)hept—1—en—3—ol O OH H H N N / LIA1H4' N \ / j: 1N\ / I N THF \NJ\CF31 / \ / N 01:3 Under nitrogen, to (E)(5 ,6,7,8—tetrahydro— 1 ,8—naphthyridinyl)— 1 -(2- (trifluoromethyl)pyrimidinyl)hept-1—en-3—one (1.20 g, 3.07 mmol, 1.00 equiv) in THF (15 mL) at —78 °C was added LiAlH4 (1.0 M in THF, 3.07 mL, 307 mmol, 1.00 equiv). After stirring for 10 min at —78 °C, H20 (116 uL), 15% NaOH aq (116 uL) and H20 (348 uL) were added sequentially to the reaction mixture. The reaction e was warmed to 23 °C and filtered through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2Clz/MCOH to afford 560 mg of the title nd (46% yield). 1H NMR (300 MHz, CDC13, 23 °C, 5): 8.86 (s, 2H), 7.06 (d, J: 7.2 Hz, 1H), 6.66 (d, J: 16.2 Hz, 1H), 6.53 (dd, J= 16.2 Hz, 4.5 Hz, 1H), 6.34 (d, J: 7.2 Hz, 1H), 4.81 (br s, 1H), 4.50—4.40 (m, 1H), 3.42—3.37 (m, 2H), 2.70—2.50 (m, 4H), 1.96—1.40 (m, 8H). 19P NMR (282 MHz, CDC13, 23 °C, 5): —70.1 (s, 3F). 9—(5,6,7,8-tetrahydro—1,8—naphthyridin-Z-yl)(2-(trifluoromethyl)pyrimidin yl)n0nanoic acid (Compound A2) 1. ElCOZH O OH MeC(OEt)3 ZI 2. H2, Pd/C, HO \ H / \ z TFA, MeOH l N N \NJ\CF3l ——-——-—-—> \ / N 3. NaOH, H20 l / \ MeOH N CF3 Under nitrogen, to (5,6,7,8—tetrahydro—1,8-naphthyridin—2-yl)-l-(2- (trifluoromethyl)pyrimidinyl)hept—l—en—3—ol (560 mg, 1.43 mmol, 1.00 equiv) in MeC(OEt)3 (14 mL) at 23 °C was added EtCOzH (107 uL, 1.43 mmol, 1.00 equiv). After ng for 2 hr at 140 0C, the reaction mixture was ly loaded on silica gel and purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford a crude rearrangement product, which was used in the next step without further purification.

Under air, to the above obtained e in FA (10 mL—l mL) at 23 °C was added 10% Pd/C (103 mg, 0.0969 mmol, 6.78 mol%) and H2 was introduced with a balloon.

After stirring for 1 hr at 23 °C, the reaction mixture was filtered h a pad of CELITE®.

The filtrate was concentrated in vacuo to afford a crude olefin reduction product, which was used in the next step without further purification.

Under air, to the above obtained residue in MeOH (10 mL) at 23 °C was added 15% NaOH aq (2.7 mL). After stirring for 20 min at 60 °C, the reaction e was neutralized with 3N HCl and concentrated in vacuo to remove MeOH. The residual aqueous solution was ted with EtOAc (3 >< 10 mL) and the combined organic phases were washed with NaHC03 aq (2 X 5 mL) and dried (MgSO4). The filtrate was trated in vacuo and the residue was purified by column chromatography on silica gel eluting with CHzClz/MeOH to afford 280 mg of the title compound (45% yield over 3 steps). 1H NMR (300 MHz, CDCl3, 23 °C, 8): 8.79 (s, 2H), 7.24 (d, J: 7.2 Hz, 1H), 6.25 (d, J= 7.2 Hz, 1H), 3.48—3.40 (m, 2H), 3.38—3.32 (m, 1H), 2.75—2.52 (m, 4H), 1.95—1.80 (m, 4H), .58 (m, 4H), 1.40—1.18 (m, 6H). 19P NMR (282 MHz, CDCl3, 23 °C, 8): —70.1 (s, 3F).

Example 3. Synthesis of 3-(6-(difluoromethoxy)pyridin—3-yl)-9—(5,6,7,8-tetrahydro-l,8— naphthyridin-2—yl)nonanoic acid (Compound A3) 6-(difluoromethoxy)nicotinaldehyde an t-BuLi; DMF / THF CHOU/ N OCHF2 N OCHF2 Under nitrogen, to 5—bromo(difluoromethoxy)pyridine (448 mg, 2.00 mmol, 1.00 equiv; Ando, M. et al., Org. Lett. 2006, —3 808) in THF (10 mL) at —78 °C was added t-BuLi (1.7 M in pentane, 2.35 mL, 4.00 mmol, 2.00 equiv) dropwise over 5 min. After stirring for 20 min at —78 °C, DMF (0.54 mL, 7.0 mmol, 3.5 equiv) was added to the reaction mixture. After stirring for 20 min at —78 °C, 1N HCl aq (10 mL) was added to the reaction mixture and the reaction mixture was warmed to 23 °C. The phases were separated and the aqueous phase was extracted with EtOAc (3 X 5 mL). The combined organic phases were washed with brine (10 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 105 mg of the title compound (30% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 8): 10.05 (s, 1H), 8.69 (d, J= 2.1 Hz, 1H), 8.24 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 7.56 (t, J= 72.3 Hz, 1H), 7.04 (d, J: 8.4 Hz, 1H). ”P NMR (282 MHz, CDC13, 23 °C, 8): ~89.8 (d, J: 72.3 Hz, 2F).

(E)—1—(6—(difluoromethoxy)pyridin—3-yl)—7-(5,6,7,8—tetrahydro-1,8-naphthyridin- 2-yl)hept—1-en-3—one O O H [I N N \ R—OMe l OMe O _______.l LCI,DBU. N N\ / + / OHC N OCHF2 N OCHF2 Under nitrogen, to dimethyl (2-oxo—6—(5,6,7,8—tetrahydro—1,8-naphthyridin—2- yl)hexyl)phosphonate (1.57 g, 4.62 mmol, 1.00 equiv) in MeCN (11 mL) at 23 °C was added 6—(difluoromethoxy)nicotinaldehyde (800 mg, 4.62 mmol, 1.00 equiv), LiCl (196 mg, 4.62 mmol, 1.00 equiv) and DBU (0.725 mL, 4.85 mmol, 1.05 equiv). After stirring for 1 hr at 50 °C, the reaction mixture was cooled to 23 °C and was filtered through a pad of CELITE®.

The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2C12/MeOH to afford 1.27 g of the title compound (71% yield). 1H NMR (300 MHz, CDC13, 23 °C, 8): 8.32 (d, J: 2.4 Hz, 1H), 7.92 (dd, J: 8.4 Hz, 2.4 Hz, 1H), 7.49 (t, J: 72.3 Hz, 1H), 7.47 (d, J: 16.2 Hz, 1H), 7.06 (d, J: 7.2 Hz, 1H), 6.93 (d, J: 8.7 Hz, 1H), 6.70 (d, J: 16.2 Hz, 1H), 6.35 (d, J= 7.2 Hz, 1H), 4.89 (br s, 1H), 3.42—3.36 (m, 2H), 2.76—2.64 (m, 4H), .56 (m, 2H), 1.94—1.85 (m, 2H), .66 (m, 4H). 19F NMR (282 MHZ, CDC13, 23 °C, 8): —89.2 (d, J= 72.3 Hz, 2F).

(E)(6-(difluoromethoxy)pyridin—3-yl)—7—(5,6,7,8—tetrahydro-1,8—naphthyridin— 2-yl)hept—1-enol O OH LIAIH4.

N N\ / N N / / / I l -——————-—-—————> / \ THF l /\ l N OCHFz N oczHF2 Under en, to (E)—1-(6-(difluoromethoxy)pyridin—3-yl)—7—(5,6,7,8-tetrahydro-1 ,8— naphthyridinyl)hepten—3—one (1.27 g, 3.28 mmol, 1.00 equiv) in THF (33 mL) at 0 °C was added LiAlH4 (1.0 M in THF, 3.28 mL, 3.28 mmol, 1.00 equiv). After stirring for 10 min at 0 °C, H20 (124 uL), 15% NaOH aq (124 uL) and H20 (372 ML) were added sequentially to the reaction e. The reaction mixture was warmed to 23 °C and d through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2C12/MeOH to afford 1.05 g of the title compound (82% yield). 2014/015372 1H NMR (300 MHz, CDCl3, 23 °C, 8): 8.22 (d, J: 2.4 Hz, 1H), 7.84 (dd, J: 8.4 Hz, 2.4 Hz, 1H), 7.49 (t, J= 72.3 Hz, 1H), 7.05 (d, J= 7.2 Hz, 1H), 6.88 (d, J= 8.7 Hz, 1H), 6.66 (d, J: 16.2 Hz, 1H), 6.55 (dd, J: 16.2 Hz, 4.5 Hz, 1H), 6.33 (d, J: 7.2 Hz, 1H), 4.84 (br s, 1H), 4.52—4.43 (m, 1H), 3.40—3.37 (m, 2H), 2.72—2.51 (m, 4H), 1.95—1.40 (m, 8H). 19F NMR (282 MHz, CDClg, 23 °C, 8): —89.0 (d, J= 72.5 Hz, 2F). 3-(6-(difluoromethoxy)pyridin-3—yl)(5,6,7,8—tetrahydro-1,8-naphthyridin yl)nonanoic acid (Compound A3) 1. EtCOZH OH MeC(OEt)3 232 2. H2, Pd/C, /z \ \ TFA, MeOH I I ——-———> N OCHF2 3. NaOH, H20 MeOH OCHF2 Under nitrogen, to (E)—1-(6-(difluoromethoxy)pyridin-3 -yl)(5,6,7,8-tetrahydro~1,8- naphthyridin—2—yl)hept-1~enol (1.05 g, 2.70 mmol, 1.00 equiv) in MeC(OEt)3 (27 mL) at 23 °C was added EtCOzH (201 ML, 2.70 mmol, 1.00 equiv). After stirring for 2 hr at 140 °C, the reaction mixture was directly loaded on silica gel and purified by column tography on silica gel eluting with hexanes/EtOAc to afford a crude rearrangement product, which was used in the next step without further purification.

Under air, to the above obtained residue in MeOH—TFA (10 mL—l mL) at 23 °C was added 10% Pd/C (176 mg, 0.165 mmol, 6.11 mol%) and H2 was introduced with a n.

After stirring for 1 hr at 23 °C, the reaction mixture was filtered through a pad of CELITE®.

The filtrate was concentrated in vacuo to afford a crude olefin reduction product, which was used in the next step t further purification.

Under air, to the above obtained residue in MeOH (10 mL) at 23 °C was added 15% NaOH aq (4.4 mL). After stirring for 20 min at 60 °C, the reaction mixture was neutralized with 3N HCl and trated in vacuo to remove MeOH. The residual aqueous solution was extracted with EtOAc (3 X 10 mL) and the combined organic phases were washed with NaHC03 aq (2 X 5 mL) and dried (MgSO4). The filtrate was trated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2C12/MeOH to afford 400 mg of the title compound (34% yield over 3 steps). 1H NMR (300 MHz, CDClg, 23 °C, 8): 8.06 (d, J= 2.4 Hz, 1H), 7.66 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 7.43 (t, J= 72.3 Hz, 1H), 7.20 (d, J: 8.7 Hz, 1H), 6.84 (d, J: 7.2 Hz, 1H), 6.25 (d, J: 7.2 Hz, 1H), 3.46—3.40 (m, 2H), 3.38—3.28 (m, 1H), 2.79—2.40 (m, 4H), .80 (m, 4H), 1.75—1.62 (m, 4H), 1.40—1.20 (m, 6H). 19F NMR (282 MHz, CDCl3, 23 0C, 8): —88.3 (d, J= 72.5 Hz, 2F).

Example 4. Synthesis of 3-(6-fluoroquinolinyl)(5,6,7,8—tetrahydro-1,8-naphthyridin—2- anoic acid (Compound A4) 6-fluoroquinoline—3-carbaldehyde EtsN,HCOZH OHC F Pd(PPh3)4 OHC F /| /| C! \N \N Under nitrogen, to 2-chlorofluoroquinolinecarbaldehyde (2.03 g, 9.68 mmol, 1.00 equiv) in DMF (10 mL) at 23 °C was added triethylamine (16.2 mL, 116 mmol, 12.0 equiV), Pd(PPh3)4 (559 mg, 0.484 mmol, 5.00 mol%), and formic aid (1.29 mL, 34.2 mmol, .40 equiv). After stirring for 1 hr at 100 °C, the reaction mixture was cooled to 23 °C and water (40 mL) and EtOAc (30 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 X 30 mL). The ed organic phases were washed with brine (50 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 734 mg of the title compound (43% . 1H NMR (300 MHZ, CDCl3, 23 °C, 5): 10.27 (s, 1H), 9.34 (d, J= 2.1 Hz, 1H), 8.60 (d, J= 1.8 Hz, 1H), 8.21 (dd, J= 9.0 Hz, 4.8 Hz, 1H), 7.70—7.60 (m, 2H). 19F NMR (282 MHz, CDCl3, 23 °C, 5): —110.8 (m, 1F).

(E)—1—(6-fluoroquinolinyl)—7-(5,6,7,8-tetrahydro-1,8-naphthyridin-Z-yl)hept—1- enone H .0.

N N \ P\-OMe l OMe O / H LiCI,DBU N + [N\ / F MeCN I / \ OHC F N Under nitrogen, to yl (2-oxo(5,6,7,8-tetrahydro-1,8—naphthyridin yl)phosphonate (900 mg, 2.64 mmol, 1.10 equiv) in MeCN (22 mL) at 23 °C was added 6-fluoroquinolinecarba1dehyde (420 mg, 2.40 mmol, 1.00 , LiCl (101 mg, 2.40 mmol, 1.00 equiv) and DBU (0.377 mL, 2.52 mmol, 1.05 equiv). After stirring for 1 hr at 75 °C, the reaction mixture was cooled to 23 °C and was filtered through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CHZClz/MeOH to afford 900 mg of the title compound (96% yield). 1H NMR (300 MHZ, CDC13, 23 °C, 8): 9.06 (d, J= 2.4 Hz, 1H), 8.21 (d, J: 2.1 Hz, 1H), 8.11 (dd, J= 10.6 Hz, 5.7 Hz, 1H), 7.66 (d, J: 16.2 Hz, 1H), 7.58—7.43 (m, 2H), 7.06 (d, J: 7.2 Hz, 1H), 6.96 (d, J= 16.2 Hz, 1H), 6.37 (d, J= 7.2 Hz, 1H), 4.76 (br s, 1H), 3.43~3.35 (m, 2H), .65 (m, 4H), 2.63—2.56 (m, 2H), 1.94—1.85 (m, 2H), 1.82—1.66 (m, 4H). 19P NMR (282 MHz, CDC13, 23 °C, 8): ~111.9 (m, 1F). (6-flu0r0quinolinyl)(5,6,7,8-tetrahydr0-1,8-naphthyridin-Z-yl)hept—1- enol O OH H H N iN\ / F NaBH4 N F / N\ / \N MGOH l I / \N Under air, to (E)—1-(6—fluoroquinolin—3—yl)(5,6,7,8-tetrahydro—1,8—naphthyridin—2— yl)hept—1—en-3—one (490 mg, 1.26 mmol, 1.00 equiv) in MeOH (29 mL) at 0 °C was added NaBH4 (71.5 mg, 1.89 mmol, 1.5 equiv). After stirring for 1 hr at 0 °C, 1N HCl aq (10 mL) was added to the reaction e and concentrated in vacuo to remove MeOH. The residue was neutralized with NaHCO3 aq and EtOAc (10 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 X 20 mL). The combined organic phases were washed with brine (30 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2Clg/MCOH to afford 490 mg of the title compound (99% yield). 1H NMR (300 MHZ, CDC13, 23 °C, 8): 8.95 (s, 1H), 8.06 (dd, J= 10.6 Hz, 5.7 Hz, 1H), 7.99 (s, 1H), 7.50—7.40 (m, 2H), 7.06 (d, J2 7.2 Hz, 1H), 6.75 (d, J: 16.2 Hz, 1H), 6.49 (dd, J: 16.2 Hz, 4.5 Hz, 1H), 6.34 (d, J2 7.2 Hz, 1H), 4.94 (br s, 1H), 4.47—4.39 (m, 1H), 3.42—3.38 (m, 2H), 2.70—2.47 (m, 4H), 1.96—1.45 (m, 8H). 19P NMR (282 MHz, CDC13, 23 °C, 8): — 111.8 (m, 1F). 3-(6-flu0roquinolinyl)—9—(5,6,7,8-tetrahydro-1,8-naphthyridin—2—yl)n0nanoic acid (Compound A4) 1. EtCOZH OH MeC(OEt)3 2:: 2. H2, Pd/C, / \ TFA, MeOH l l ————-—-> N 3. NaOH, H20 MeOH Under nitrogen, to (E)(6—fluoroquinolinyl)—7—(5,6,7,8—tetrahydro—1 ,8- naphthyridin-2—yl)hept—1—en—3—ol (489 mg, 1.25 mmol, 1.00 equiv) in MeC(OEt)3 (12 mL) at 23 °C was added EtC02H (93.3 uL, 1.25 mmol, 1.00 equiv). After stirring for 2 hr at 140 °C, the reaction e was directly loaded on silica gel and purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford a crude ngement t, which was used in the next step without further purification.

Under air, to the above obtained residue in MeOH—TFA (10 mL—1 mL) at 23 °C was added 10% Pd/C (128 mg, 0.121 mmol, 9.68 mol%) and H2 was introduced with a balloon.

After stirring for 1 hr at 23 °C, the reaction mixture was filtered through a pad of CELITE®.

The filtrate was concentrated in vacuo to afford a crude olefin reduction product, which was used in the next step without further purification.

Under air, to the above obtained e in MeOH (10 mL) at 23 °C was added 15% NaOH aq (3.0 mL). After stirring for 20 min at 60 °C, the reaction mixture was neutralized with 3N HCl and concentrated in vacuo to remove MeOH. The residual aqueous solution was extracted with EtOAc (3 X 10 mL) and the combined organic phases were washed with NaHC03 aq (2 X 5‘mL) and dried (MgSO4). The e was trated in vacuo and the residue was purified by column chromatography on silica gel eluting with /MeOH to afford 500 mg of the title compound (92% yield over 3 steps). 1H NMR (300 MHz, CD301), 23 °C, 8): 8.78 (s,‘1H), 8.11 (s, 1H), 8.00—7.93 (m, 1H), 7.52— 7.42 (m, 2H), 7.31 (d, J= 7.2 Hz, 1H), 6.35 (d, J= 7.2 Hz, 1H), 3.38—3.20 (m, 3H), 2.77— 2.42 (m, 4H), 1.90—1.20 (m, 14H). 19F NMR (282 MHz, , 23 °C, 8): —110.9 (m, 1F).

Example 5. Synthesis of 3-(7-fiuoroquinolinyl)(5,6,7,8-tetrahydro-l,8-naphthyridin yl)nonanoic acid (Compound A5) (E)(7-flu0roquinolinyl)(5,6,7,8-tetrahydro-1,8-naphthyridinyl)hept—1- en0ne H 9 N N \ P\—OMe I OMe O / H BU N + |N\ / MeCN | / \ OHC N F N F Under nitrogen, to dimethyl (2—oxo-6—(5,6,7,8-tetrahydro-1,8—naphthyridin yl)hexyl)phosphonate (749 mg, 2.20 mmol, 1.10 equiv) in MeCN (22 mL) at 23 °C was added 7-fiuoroquinolinecarbaldehyde (350 mg, 2.00 mmol, 1.00 equiv; Sato, 1. et al., Synthesis 2004, 9: 1419—1428), LiCl (84.8 mg, 2.00 mmol, 1.00 equiv) and DBU (0.314 mL, 2.10 mmol, 1.05 equiv). After stirring for 1 hr at 75 °C, the reaction mixture was cooled to 23 °C and was filtered through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2C12/MCOH to afford 570 mg of the title compound (73% yield). 1H NMR (300 MHz, CDC13, 23 °C, 8): 9.10 (d, J= 2.4 Hz, 1H), 8.28 (d, J= 2.1 Hz, 1H), 7.87 (dd, J: 9.0 Hz, 6.0 Hz, 1H), 7.74 (dd, J= 9.9 Hz, 2.4 Hz, 1H), 7.69 (d, J: 16.2 Hz, 1H), 7.42—7.33 (m, 1H), 7.11 (d, J? 7.2 Hz, 1H), 6.94 (d, J: 16.2 Hz, 1H), 6.37 (d, J: 7.2 Hz, 1H), 5.41 (br s, 1H), 3.43—3.37 (m, 2H), 2.78—2.58 (m, 6H), 1.93—1.85 (m, 2H), 1.81—1.69 (m, 4H). ”P NMR (282 MHz, CDC13, 23 °C, 8): —107.0 (m, 1F).

(E)(7-fluoroquin01in-3—yl)—7—(5,6,7,8—tetrahydro-l,8-naphthyridin-Z-yl)hept enol H OH N N\ / NaBH4 N / N\ / | 1 | / MeOH l \N F / \N F Under air, to (E)-1—(7-fluoroquinolinyl)(5,6,7,8—tetrahydro-1,8-naphthyridin t—1-en—3—one (300 mg, 0.770 mmol, 1.00 equiv) in MeOH (8 mL) at 0 °C was added NaBH4 (87.4 mg, 2.31 mmol, 3.00 equiv). After stirring for 30 min at 0 °C, 1N HCl aq (10 mL) was added to the reaction mixture and concentrated in vacuo to remove MeOH. The residue was neutralized with NaHCO3 aq and EtOAc (10 mL) was added. The phases were separated and the aqueous phase was ted with EtOAc (3 X 20 mL). The combined organic phases were washed with brine (30 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CHzClz/MeOH to afford 210 mg of the title compound (70% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 5): 8.98 (s, 1H), 8.07 (s, 1H), 7.81 (dd, J= 9.0 Hz, 6.0 Hz, 1H), 7.78 (dd, J: 9.9 Hz, 2.4 Hz, 1H), 7.63 (br s, 1H), 7.39—7.28 (m, 1H), 6.78 (d, J: 16.2 Hz, 1H), 6.47 (dd, J: 16.2 Hz, 4.5 Hz, 1H), 6.36 (d, J: 7.2 Hz, 1H), 4.48—4.41 (m, 1H), 3.48—3.41 (m, 2H), 2.79~2.67 (m, 4H), 1.97—1.48 (m, 8H). 19P NMR (282 MHz, CDC13, 23 °C, 5): —109.9 (m, 1F). uoroquin01inyl)—9-(5,6,7,8-tetrahydro-1,8—naphthyridin-Z-yl)nonanoic acid (Compound A5) 1.EtC02H OH MeC(OEt)3 ZI 2. H2, Pd/C, N / / / OH | l —————-———-—————> / \N F 3. NaOH, H20 MeOH Under nitrogen, to (ID(7—fluoroquinolin—3—yl)—7—(5,6,7,8-tetrahydro—1 ,8— naphthyridinyl)heptenol (730 mg, 1.71 mmol, 1.00 equiv) in t)3 (17 mL) at 23 °C was added EtCOzH (128 uL, 1.71 mmol, 1.00 equiv). After stirring for 2 hr at 140 0C, the reaction mixture was directly loaded on silica gel and purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford a crude rearrangement t, which was used in the next step without further purification.

Under air, to the above obtained residue in MeOH—TFA (10 mL—1 mL) at 23 °C was added 10% Pd/C (125 mg, 0.117 mmol, 6.84 mol%) and H2 was introduced with a balloon.

After stirring for 1 hr at 23 °C, the reaction e was filtered through a pad of CELITE®.

The filtrate was concentrated in vacuo to afford a crude olefin ion product, which was used in the next step without further purification.

Under air, to the above ed residue in MeOH (10 mL) at 23 °C was added 15% NaOH aq (3.0 mL). After stirring for 20 min at 60 °C, the reaction mixture was neutralized with 3N HCl and concentrated in vacuo to remove MeOH. The residual aqueous solution was extracted with EtOAc (3 X 10 mL) and the combined c phases were washed with NaHC03 aq (2 X 5 mL) and dried (MgSO4). The e was concentrated in vacuo and the e was purified by column chromatography on silica gel eluting with CHzClz/MeOH to afford 480 mg of the title compound (64% yield over 3 steps).

IHNMR (300 MHz, CD3OD, 23 °C, 8): 8.79 (s, 1H), 8.21 (s, 1H), 8.00—7.91 (m, 1H), 7.62— 7.57 (m, 1H), 7.48—7.38 (m, 2H), 6.47 (d, J= 7.2 Hz, 1H), 3.48—3.30 (m, 3H), 2.80—2.52 (m, 4H), 1.90—1.20 (m, 14H). I9F NMR (282 MHz, CD3OD, 23 °C, 8): —111.9 (m, 1F).

Example 6. Synthesis of 3-(6,7-difluoroquinolin-3—yl)(5,6,7,8—tetrahydro—1,8— naphthyridin—2-yl)nonanoic acid (Compound A6) 6,7-difluoroquinolinecarbaldehyde EtsN, HCOZH OHC F / Pd(PPh3)4 1 OHCWF CI \N DMF F \N F Under en, to 2—chloro-6,7-difluoroquinoline-3—carbaldehyde (1.44 g, 6.33 mmol, 1.00 equiv) in DMF (6.3 mL) at 23 CC was added triethylamine (10.6 mL, 76.0 mmol, 12.0 equiv), Pd(PPh3)4 (366 mg, 0.317 mmol, 5.00 mol%), and formic aid (1.29 mL, 34.2 mmol, .40 equiv). After stirring for 1 hr at 100 °C, the reaction mixture was cooled to 23 °C and water (30 mL) and EtOAc (20 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (3 X 20 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 500 mg of the title compound (41% yield).

WO 24302 1H NMR (300 MHz, CDCl3, 23 °C, 5): 10.26 (s, 1H), 9.35 (d, J: 1.2 Hz, 1H), 8.60 (d, J: 1.5 Hz, 1H), 7.97 (dd, J: 10.8 Hz, 7.5 Hz, 1H), 7.97 (dd, J= 9.0 Hz, 8.7 Hz, 1H). 19F NMR (282 MHz, CDCl3, 23 °C, 5): ~125.3 (m, 1F), —132.3 (m, 1F).

(E)(6,7-diflu0roquinolinyl)(5,6,7,8-tetrahydr0-1,8-naphthyridin yl)heptenone o o H II N N \ P\-OMe I OMe O / H LiCl,DBU N / F + N\ / MeCN l l / \ OHC F N F N F Under nitrogen, to dimethyl (2—oxo—6-(5,6,7,8—tetrahydro-1,8—naphthyridin—2— y1)hexy1)phosphonate (599 mg, 1.76 mmol, 1.10 equiv) in MeCN (5 mL) at 23 °C was added 6,7—difluoroquinoline—3-carbaldehyde (310 mg, 1.60 mmol, 1.00 equiv), LiCl (67.8 mg, 1.60 mmol, 1.00 equiv) and DBU (0.251 mL, 1.68 mmol, 1.05 equiv). After stirring for 1 hr at 75 °C, the reaction mixture was cooled to 23 °C and was filtered through a pad of CELITE®.

The filtrate was concentrated in vacuo and the residue was purified by column tography on silica gel eluting with CH2C12/MeOH to afford 570 mg of the title compound (84% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 8): 9.07 (d, J: 2.4 Hz, 1H), 8.20 (d, J= 2.1 Hz, 1H), 7.87 (dd, J= 10.8 Hz, 7.5 Hz, 1H), 7.66 (d, J= 16.2 Hz, 1H), 7.62—7.53 (m, 1H), 7.06 (d, J: 7.2 Hz, 1H), 6.93 (d, J: 16.2 Hz, 1H), 6.36 (d, J: 7.2 Hz, 1H), 4.77 (br s, 1H), .38 (m, 2H), 2.79—2.58 (m, 6H), 1.96—1.85 (m, 2H), 1.81—1.69 (m, 4H). 19F NMR (282 MHz, CDCl3, 23 °C, 8): —129.1 (m, 1F), —133.6 (m, 1F).

(E)(6,7-difluoroquinolinyl)(5,6,7,8-tetrahydr0-1,8-naphthyridin yl)heptenol O OH H H N N / F LiAIH / F \ /| ”—‘3‘6 | THF N1N\ /1 / \N / F \N F Under en, to (E)- 1 ~(6,7—difluoroquinolin~3-y1)(5,6,7,8—tetrahydro~ 1 ,8— naphthyridin—2—yl)hept-1—en—3—one (1.03 g, 2.53 mmol, 1.00 equiv) in THF (25 mL) at 0 °C was added LiAlH4 (1.0 M in THF, 2.53 mL, 2.53 mmol, 1.00 equiv). After ng for 10 min at 0 °C, H20 (96 uL), 15% NaOH aq (96 uL) and H20 (288 uL) were added sequentially to the reaction mixture. The reaction mixture was warmed to 23 °C and filtered through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2Clg/MeOH to afford 780 mg of the title compound (75% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 5): 8.95 (d, J: 2.4 Hz, 1H), 8.00 (d, J: 2.1 Hz, 1H), 7.81 (dd, J: 10.8 Hz, 7.5 Hz, 1H), 7.52 (d, J= 16.2 Hz, 1H), 7.21 (d, J: 7.2 Hz, 1H), 6.76 (d, J= 16.2 Hz, 1H), 6.48 (dd, J: 16.2 Hz, 4.5 Hz, 1H), 6.34 (d, J: 7.2 Hz, 1H), 4.48—4.42 (m, 1H), 3.47—3.41 (m, 2H), .67 (m, 4H), 1.97~1.47 (m, 8H). 19F NMR (282 MHz, CDCl3, 23 °C, 5): ~132.1 (m, 1F),—135.1 (m, 1F). 3-(6,7-difluoroquinolinyl)(5,6,7,8-tetrahydro-1,8—naphthyridin—2- yl)nonanoic acid (Compound A6) 1. EtCOzH 0H MeC(OEt)3 ZI 2. H2, Pd/C, N / F / / TFA, MeOH 1 I _——————.

/ \N F 3. NaOH, H20 MeOH Under nitrogen, to (E)—1—(6,7-difluoroquinolin—3-yl)—7—(5,6,7,8-tetrahydro-1 ,8- naphthyridin—2—yl)hept—1—enol (780 mg, 1.90 mmol, 1.00 equiv) in MeC(OEt)3 (19 mL) at 23 °C was added EtCOgH (142 uL, 1.90 mmol, 1.00 equiv). After stirring for 2 hr at 140 °C, the reaction mixture was directly loaded on silica gel and ed by column chromatography on silica gel eluting with hexanes/EtOAc to afford a crude rearrangement product, which was used in the next step without further purification.

Under air, to the above obtained residue in MeOH—TFA (10 mL—l mL) at 23 °C was added 10% Pd/C (127 mg, 0.119 mmol, 6.26 mol%) and H2 was uced with a balloon.

After ng for 1 hr at 23 °C, the on mixture was ed through a pad of CELITE®.

The filtrate was concentrated in vacuo to afford a crude olefin reduction product, which was used in the next step without further purification.

Under air, to the above obtained residue in MeOH (10 mL) at 23 °C was added 15% NaOH aq (3.2 mL). After stirring for 20 min at 60 °C, the reaction mixture was neutralized with 3N HCl and concentrated in vacuo to remove MeOH. The residual aqueous solution was extracted with EtOAc (3 X 10 mL) and the combined organic phases were washed with NaHCO3 aq (2 X 5 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2C12/MeOH to afford 500 mg of the title compound (58% yield over 3 steps). 1H NMR (300 MHz, CDCl3, 23 °C, 5): 8.79 (s, 1H), 7.97 (s, 1H), .81 (m, 1H), 7.58— 7.47 (m, 1H), 7.24 (d, J= 7.2 Hz, 1H), 6.23 (d, J: 7.2 Hz, 1H), 3.48—3.32 (m, 3H), 2.80— 2.57 (m, 4H), .20 (m, 14H). 19F NMR (282 MHz, CDCl3, 23 °C, 6): —l32.3 (m, 1F), — 135.5 (m, 1F).

Example 7. Synthesis of 9—(5,6,7,8-tetrahydro-1,8—naphthyridin—2-yl)-3—(7- (trifluoromethyl)quinolin-3—yl)nonanoic acid (Compound A7) 2-chloroiodoquinoline—3-carbaldehyde i o / Me N I \l H Cl N l Under nitrogen, to POC13 (14.9 mL, 160 mmol, 7.00 equiv) at 0 °C was added DMF (4.40 mL, 57.1 mmol, 2.50 equiv). After stirring for 10 min at 0 OC, N—(3- iodopheny1)acetamide (5.96 g, 22.8 mmol, 1.00 equiv; Pialat, A. et al, Org. Lett. 2013, :1764—1767) was added to the on mixture. After stirring for 17 hr at 75 0C, the on mixture was poured into iced. The phases were separated and the aqueous phase was extracted with CH2C12 (3 X 50 mL). The combined organic phases were washed with brine (100 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CH2C12/MeOH to afford 2.9 g of the title compound (40% yield). 1H NMR (300 MHz, CDC13, 23 °C, 6): 10.55 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 7.93 (dd, J= 8.4 Hz, 1.5 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H). 2-chloro(trifluoromethyl)quinoline—3-carbaldehyde OHC FSOZCFZCOZMe 0H0 / / | ——-———————> | \N WP Cl | CI \N CF3 Under nitrogen, to 2-chloroiodoquinolinecarbaldehyde (2.90 g, 9.13 mmol, 1.00 equiv) in DMF (18 mL) at 23 °C was added CuI (4.35 g, 22.8 mmol, 2.50 equiv) and 2C02Me (11.6 mL, 91.3 mmol, 10.0 equiv). After stirring for 2 hr at 95 °C, the reaction mixture was cooled to 23 °C and d through a pad of CELITE®. The filtrate was trated in vacuo and the residue was purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford 1.5 g of the title compound (63% yield). 1H NMR (300 MHz, CDC13, 23 °C, 6): 10.60 (s, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 8.14 (d, J: 8.4 Hz, 1H), 7.84 (d, J: 8.4 Hz, 1H). 19F NMR (282 MHZ, CDC13, 23 °C, 6): ~63.2 (s, 3F). 7-(trifluoromethyl)quinolinecarbaldehyde EtSN, HCOZH 0H0 0H0 / Pd1PPh3)4 / I ——-———————> l Cl \N DMF CF3 \N CFS Under nitrogen, to 2-chloro(trifluoromethyl)quinolinecarbaldehyde (1.50 g, 5.78 mmol, 1.00 equiv) in DMF (5.8 mL) at 23 °C was added triethylamine (9.67 mL, 69.4 mmol, 12.0 equiv), Pd(PPh3)4 (334 mg, 0.289 mmol, 5.00 mol%), and formic aid (1.18 mL, 31.2 mmol, 5.40 equiv). After stirring for 1 hr at 100 °C, the on e was cooled to 23 °C and water (30 mL) and EtOAc (20 mL) was added. The phases were separated and the aqueous phase was ted with EtOAc (3 X 20 mL). The combined organic phases were washed with brine (50 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography onsilica gel eluting with s/EtOAc to afford 412 mg of the title compound (32% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 8): 10.32 (s, 1H), 9.48 (d, J= 1.5 Hz, 1H), 8.71 (d, J: 1.5 Hz, 1H), 8.51 (s, 1H), 8.15 (d, J: 8.4 Hz, 1H), 7.86 (d,J= 8.4 Hz,1H). 19F NMR (282 MHz, CDC13, 23 °C, 8): —63.1 (s, 3F).

(E)(5,6,7,8-tetrahydr0-1,8-naphthyridinyl)(7-(triflu0romethyl)quinolin- 3-yl)heptenone O O H II N N \ P\-OMe I OMB O / LCI,.l DBU N / + N\ / OHC N CFS N CF3 Under nitrogen, to yl (2-oxo—6-(5,6,7,8-tetrahydro-1,8-naphthyridin y1)hexyl)phosphonate (685 mg, 2.01 mmol, 1.10 equiv) in MeCN (9 mL) at 23 °C was added 7-(trifluoromethyl)quinoline-3—carbaldehyde (412 mg, 1.83 mmol, 1.00 equiv), LiCl (77.6 mg, 1.83 mmol, 1.00 equiv) and DBU (0.287 mL, 1.92 mmol, 1.05 equiv). After stirring for 1 hr at 75 °C, the reaction mixture was cooled to 23 °C and was filtered through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CHZClz/MeOH to afford 706 mg of the title compound (88% yield). 1H NMR (300 MHz, CDC13, 23 °C, 8): 9.19 (d, J: 2.4 Hz, 1H), 8.42 (d, J= 2.1 Hz, 1H), 8.31 (d, J: 2.1 Hz, 1H), 8.00 (d, J= 9.0 Hz, 1H), 7.79 (d, J: 9.0 Hz, 1H), 7.69 (d, J= 16.2 Hz, 1H), 7.04 (d, J= 7.2 Hz, 1H), 6.99 (d, J: 16.2 Hz, 1H), 6.37 (d, J=‘ 7.2 Hz, 1H), 4.78 (br s, 1H), 3.41—3.37 (m, 2H), 2.80—2.58 (m, 6H), 1.93—1.85 (m, 2H), 1.81—1.69 (m, 4H). 19F NMR (282 MHz, CDC13, 23 °C, 8): —62.8 (s, 3F).

(E)(5,6,7,8-tetrahydr0-1,8-naphthyridinyl)(7-(triflu0r0methyl)quinolin- 3-yl)heptenol 0 OH H .

. H N N / LIAIH4 N N\ / \ / / | l l I Under nitrogen, to (E)(5,6,7,8-tetrahydro-1,8-naphthyridin—2-yl)—1-(7- (trifluoromethyl)quinolin—3—yl)hept-l-en—3-one (705 mg, 1.60 mmol, 1.00 equiv) in THF (16 mL) at 0 °C was added LiAlH4 (1.0 M in THF, 1.60 mL, 1.60 mmol, 1.00 equiv). After ng for 10 min at 0 °C, H20 (54 uL), 15% NaOH aq (54 uL) and H20 (162 uL) were added sequentially to the reaction mixture. The reaction mixture was warmed to 23 °C and filtered through a pad of CELITE®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with /MeOH to afford 515 mg of the title compound (73% yield). 1H NMR (300 MHz, CDCl3, 23 °C, 8): 9.08 (d, J= 2.4 Hz, 1H), 8.37 (d, J= 2.1 Hz, 1H), 8.08 (d, J: 2.1 Hz, 1H), 7.91 (d, J: 9.0 Hz,1H), 7.71 (d, J: 9.0 Hz, 1H), 7.06 (d, J: 7.2 Hz, 1H), 6.79 (d, J= 16.2 Hz, 1H), 6.53 (dd, J: 16.2 Hz, 4.5 Hz, 1H), 6.34 (d, J= 7.2 Hz, 1H), 4.89 (br s, 1H), .40 (m, 1H), 3.43—3.37 (m, 2H), 2.75—2.57 (m, 4H), .42 (m, 8H). ”P NMR (282 MHz, CDCl3, 23 °C, 5): —62.6 (s, 3F). 9-(5,6,7,8-tetrahydr0-1,8-naphthyridin-Z-yl)(7-(triflu0r0methyl)quinolin yl)n0nan0ic acid (Compound A7) 1. EtCOZH OH MeC(0Et)3 ZI 2. H2, Pd/C, /Z \ \ TFA, MeOH l | N CF3 3. NaOH, H20 MeOH Under nitrogen, to (E)(5 ,6,7,8-tetrahydro— 1 ,8—naphthyridinyl)(7- (trifluoromethyl)quinolinyl)heptenol (515 mg, 1.17 mmol, 1.00 equiv) in MeC(OEt)3 (12 mL) at 23 °C was added EtCO2H (87.3 uL, 1.17 mmol, 1.00 equiv). After stirring for 2 hr at 140 0C, the reaction mixture was directly loaded on silica gel and purified by column chromatography on silica gel eluting with hexanes/EtOAc to afford a crude rearrangement product, which was used in the next step without further ation.

Under air, to the above obtained residue in MeOH—TFA (10 mL—l mL) at 23 °C was added 10% Pd/C 66.6 mg, 0.0626 mmol, 5.35 mol%) and H2 was introduced with a balloon.

After ng for 1 hr at 23 °C, the reaction mixture was filtered through a pad of CELITE®.

The filtrate was concentrated in vacuo to afford a crude olefin reduction product, which was used in the next step without further purification.

Under air, to the above obtained e in MeOH (10 mL) at 23 °C was added 15% NaOH aq (4.4 mL). After stirring for 20 min at 60 °C, the reaction mixture was neutralized with 3N HCl and concentrated in vacuo to remove MeOH. The residual aqueous solution was ted with EtOAc (3 X 10 mL) and the combined organic phases were washed with NaHC03 aq (2 X 5 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with CHzClz/MeOH to afford 300 mg of the title compound (53% yield over 3 . 1H NMR (300 MHz, CDC13, 23 °C, 5): 8.93 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.91 (d, J: 9.0 Hz, 1H), 7.70 (d, J: 9.0 Hz, 1H), 7.24 (d, J= 7.2 Hz, 1H), 6.23 (d, J: 7.2 Hz, 1H), 3.48—3.40 (m, 3H), 2.80—2.59 (m, 4H), 1.95—1.20 (m, 14H). 19F NMR (282 MHz, CDCl3, 23 °C, 5): ~62.7 (s, 3F).

Example 8. Synthesis of (SD(6-(difluoromethoxy)pyridin—3-yl)(2—oxo—3-((3—((5,6,7,8— ydro— l ,8-naphthyridin-2—yl)methyl)oxetan—3—yl)methyl)imidazolidin- l —yl)propanoic acid The synthetic route is the same as Example 1 except for substituting at Step-8: (3— 7,8—tetrahydro— l ,8-naphthyridin—2-yl)methyl)oxetan-3—yl)methanamine for compound 6b and continuing the synthetic scheme using the same reaction conditions.

Example 9. Synthesis of (53(3—(2,2-difluoro(5,6,7,8-tetrahydro—l,8-naphthyridin-2— yl)propyl)—2-oxoimidazolidin- l -yl)—3—(6-(difluoromethoxy)pyridin-3 —yl)propanoic acid OCHF2 o (ZNr o N N\ NAN¢OH / F F \__/ The synthetic route is the same as Example 1 except for tuting at Step-8: 2,2- difluoro~3-(5,6,7,8-tetrahydro-1,8~naphthyridinyl)propanamine for compound 6b and continuing the synthetic scheme using the same reaction ions.

The synthesis of 2,2-difluoro(5,6,7,8—tetrahydro-1,8—naphthyridinyl)propan amine is performed as shown in Scheme 3.

Example 10. sis of (S)(3-(2,2~difluoro(5,6,7,8-tetrahydro-l,8-naphthyridin yl)propyl)oxoimidazolidinyl)(6~methoxypyridinyl)propanoic acid O CN=/ O N |N\ NAN/"$OH F F \—/ The synthetic scheme is the same as Example 9, except the synthesis in Step 1 uses sodium 2~chloroacetate instead of sodium 2-chloro-2,2-difluoroacetate. The synthesis proceeds under the same conditions as Example 3. e 10-1. Scheme 3 Scheme3 /N NH2 acetone N N NCS N N I proline \ \ AIBN \ \ CI \ H ———> | —> | EtOH / / col4 / / A B C BuLi + ~————> DMPU 1. propane-1,3-diol BOW/\NH2 s BFSOEtz NANHBoc DE 2. 80020. EtaN D E N N N N \ \ NHBoc Fluorination \ \ NHBoc l S S ——*———* I K/l F F / / / / 1, H2, Pto2 2, Acid .......................................

The preparation of intermediates C and E is detailed in the literature and is depicted above (for C; W02011150156 and for E; Seebach, D. et al., Liebigs Arm. Chem, 1994, 701- 717). The formation of the dianion of E has been described, and it was used to displace substituted benzylic chlorides (Bradshaw, B. er al., Org. Biomol. Chem, 2008, 6:2138— 2157.). This event similarly affords complex dithiane F. Fluorodesulfiirization of thioketals has been described with several reagents (Sondej, S. C. et aZ., J. Org. Chem, 1986, 8— 13.); intermediate G is d and deprotected as described in the literature (US2004003 8963). Fragment H is inserted into the known route to e the target compounds.

Example 11. Testing of the compounds of present invention in cell adhesion assays The ability of compounds to block adhesion of three primary cell es: human dermal microvascular endothelial (HMVEC), rat lung microvascular endothelial (RLMVEC), and rabbit aortic endothelial (RAEC) cells, to ectin coated plates was determined using the following ure. This test demonstrates inhibition of the interaction of ow integrin on the cell surface with the ligand, vitronectin.

Adhesion plates preparation. 96-well plates were coated with vitronectin in PBS, pH7.4 by ting 50 uL of the solution (10 ug/ml) for 1.5 h at room temperature or overnight at 4°C. The plates then were blocked with 1% BSA in PBS (30 min at room temperature) and washed with PBS.

Cell culturing and g. HMVEC cells (passages (p)9-14) (from Lonza, Allendale, NJ) RLMVEC cells (p4—14) (from Vec Technology, Rensselaer, NY) and RAEC cells (p4-14) (from CellBiologics, Chicago, IL) were used for the compound testing. Cells were grown in T175 tissue culture flasks and dislodged by gentle 3 min treatment with Accutase (Life Technologies). After washing, the cells in suspension in RPMI-1640 (Life Technologies) were loaded with calcein-AM (5 uM) (Life Technologies) for 30 min at 37 °C and re-suspended into RPMI w/o phenol red medium containing 10 % FBS.

Adhesion assay. The cell suspension was aliquoted into the wells at a density of 1.0x105 cells/well (RLMVEC) and 5.0x104 (HMVEC, and RAEC). The test compounds are added at the same time with the cells. The plates are incubated for 1.5 h at 37 °C. The cells that did not adhere during this incubation were removed by gentle g. The wash was med by 2 cycles of aspiration of the supernatant and addition of 100 uL of the pre- warmed fresh DPBS (Life Technologies). A fluorescence of the remaining cells is measured using multimode plate reader r 2V, Elmer) at an excitation/emission wavelengths of 485/535 nm. The compounds were tested starting with maximal tration of 1 uM with half—log dilution schedule. IC50 values were calculated with Prism 5 (GraphPad, CA) by fixing the bottom of the curves to a value of blank for empty wells fluorescence.

As shown in Table 2, all the ated (xv antagonists are active in inhibiting cellular adhesion to vitronectin through the av integrin. orinated reference antagonist, L- 845704, is shown for ison.

Table 2. Potencies of test compounds to block adhesion of different cell cultures to vitronectin.

IC50 (M) C("“0“d # RLMVEC L-845704 _A5 2.5m 3.7m 2.0E-08 4,413-08 5.5E—09 4.4E—08 A7 1.3E-07 4.0E—07 2.1E—07 Example 12. Anti—angiogenic activity using chick chorioallantoic membrane (CAM) assay CAM surfaces were grafted with gelatin sponges impregnated with the concentrations of test compounds and 50 ng VEGF dissolved in PBS. Untreated CAM ed only VEGF and PBS. Error bars represent SEM, N = 5, P values for the d groups were calculated by comparing with the untreated group (*p<0.05, **p<0.01, ***p<0.001).

Test Substance ation: Test samples and standards were dissolved in PBS and sterilized by passing through a syringe filter(0.22 um). hVEGF(SIGMA) 50 ng/ul was prepared in sterile PBS.

Grafting: n sponge (Abogel) was cut in approximately 2 mm3 pieces and loaded with required test substance or PBS and VEGF. The graft was placed on the CAM.

Eggs: e hen eggs were procured from a hatchery and were cleaned and decontaminated using alcohol. 1 ml of albumin was removed using a syringe and incubated for 8 days. Grafts were placed on developing CAMs and r incubated to day12. On day12, CAMs were fixed with 4% formaldehyde in PBS, dissected and imaged.

Imaging: Fixed CAMS were imaged under constant illumination and magnification under a microscope fitted with a digital camera (CANON).

Image analysis: Images were ed on MS PowerPoint keeping the image size constant. A ring was drawn around the graft and the size was kept constant. Blood vessels ng the ring were counted for each test group.

Statistical Analysis: Data were analyzed on l 2007.

As shown in Figure 1, Compounds Al and A2 each shows anti-angiogenic activity in the chick CAM assay, and significantly decreases the number of blood vessels, as compared to the untreated control.

Example 13. Distribution in plasma, aqueous humor, vitreous humor, and retina after topical ocular administration in Dutch Belted rabbits The plasma concentrations and ocular distribution (aqueous humor, vitreous humor, and retina) of nds Al, A2, and A3 were determined following topical ocular administration in Dutch Belted rabbits. The test compounds were administered in each eye at a volume of 50 uL/eye at a concentration of 1.0 - 2.5 mg/mL (compound A2, 1.0 mg/mL; compounds A1 and A3 at 2.5 mg/mL). Plasma and different ocular tissue samples were collected at pre-determined time points (1.0 and 8.0 hours for compound A1; 0.5 and 8 hours for compounds A2 and A3). Aqueous humor, vitreous humor, and retina were ted from each eye at each time point post-dose. Also, weights were recorded. Plasma and ocular sample concentrations of the compounds were determined by LC-MS/MS.

Animal Dosing: The exposure of compounds Al, A2, and A3 was ted in Dutch Belted rabbits. The study was not blinded. Each compound was dosed as n=3/time point for a total of nine s. Rabbits were housed one per cage. Animals were not fasted, and food and water were supplied ad libitum.

Animals were anesthetized following the l3lA5 IACUC protocol for the dosing.

Each rabbit ed a bolus dose of test formulation via topical ocular stration into both eyes at time zero on the day of . Plasma and ocular samples were collected at pre-determined time points. Animals for the 30-minute and l-hour time points were anesthetized for the entire duration of the study. The animals for the 8-hour time point were recovered after dosing and then euthanized for sampling purposes.

At each time point, approximately 0.5 mL of blood was collected and placed into chilled Na-heparin tubes containing citric acid. Blood samples were centrifuged at a speed of 3,000 g for 5 minutes to obtain plasma as quickly as possible. Samples were stored frozen at -80°C until is. Animals were euthanized per the l3IA5 IACUC protocol and both eyes were enucleated immediately. Following enucleation, each eye was rinsed with PBS. Ocular samples from both eyes of each animal were collected and weights were recorded. All the samples were frozen immediately on dry ice, and stored at -60 to —80°C for analysis.

Analysis of Plasma and Ocular Samples: An LC—MS/MS method was ped for the determination of Compounds Al, A2, and A3 in rabbit plasma and ocular samples. A pre—study standard curve was analyzed to determine the specificity, range, and lower limit of quantitation of the method.

As shown in Figures 2, 3, and 4, Compounds A1, A2, and A3 are each efficiently distributed to the retina.

The following examples of ophthalmic formulations are given by way of illustration: Example 14. Ophthalmic formulation of Compound Al Solution Cwosition III I Compound A1 2. 5 g I B—cyclodextrin sulfobutyl ether 10 g 1200g I Boric acid 1. 05 g 1. 05 g 1. 05 g I Disodium orate 0.285 g 0.285 g 2085 g I I Sodium Chloride 025 g 0.25 g 025 g I I Edetate um 25 mg 2. 5 mg I 25 mg I I Propylaminopropyl biguanide 0. 03 mg 0.03 mg I 0.03 mg I Water for ion q.s. 100 ml 100 ml I 100 ml The active compounds were addedI to a solution of borate buffered saline containing the B-cyclodextrin sulfobutyl ether, edetate disodium, and propylamino idate dissolved in sterile water for ion in a tared sterile vessel. The pH of the on was ed to 7.5 by the addition of hydrochloric acid. The composition is sterilized by filtration through a 0.45 micron filter.

Example 15. Ophthalmic formulation of Compound A1 I Solution Commsition I II III I 2.5 g I 2.0 I 1.0 “I I Hyrdoxypropyl B—cyclodextrin I 10 g I 10 g I 5 g Boric acid I 1.05 g 1.05 g 1.05 g Disodium tetraborate 0.285 g 0.285 g 0.285 g Sodium Chloride 0.25 g 0.25 g 025 g__I Edetate disodium 2.5 mg 2.5 mg I 2. 5 mg I Propylaminopropyl biguanide 0.03 mg I 0.03 mg I Water for ion q.s. I 100 ml _I 100 ml I_ 0.03 mg100 ml The active compounds were added to a solution of borate buffered saline containing the hydroxylpropyl—B-cyclodextrin, edetate disodium, and amino biguanidate dissolved in sterile water for injection in a tared sterile vessel. The pH of the solution was adjusted to 7.5 by the addition of hydrochloric acid. The composition is sterilized by filtration through a 0.45 micron filter. e 16. Ophthalmic formulation of Compound A2 on Com osition Compound A2 2.0 g 1.5 l B-cyclodextrin sulfobutyl ether 10 g 10 g i Boric acid 1.05_L 1.05L l .

Disodium tetraborate 0.285 g I 0.285 g .

Sodium Chloride 0.25 0.25 g .

Edetate disodium 2.5 m 2.5 mg . l Propylaminopropyl biguanide 0.03 mg 0.03 mg . 1 Water for injection q.s. 100 ml 100 ml The active compounds were added to a solution of borate buffered saline containing the B—cyclodextrin sulfobutyl ether, edetate disodium, and propylamino biguanidate dissolved in sterile water for injection in a tared sterile vessel. The pH of the solution was adjusted to 7.5 by the addition of hydrochloric acid. The composition is sterilized by ion through a 0.45 micron filter. e 17. Ophthalmic formulation of Compound A3 on Composition I II III Compound A3 2.5 g 2.0 l 1.0 B—cyclodextrin sulfobutyl ether 10 g 10 g 5 g Boric acid 1.05 g l.05_g_ 1.05 g Disodium tetraborate 0.285 g 0.285 g 0.285 g Sodium Chloride 0.25 g 0.25 g 0.25 g Edetate disodium 2.5 mg l 2.5 mg i 2.5 mg Propylaminoplgpyl biguanide 0.03 mg l 0.03 mg i 0.03 mg Water for injection q.s. 100 ml l 100 ml l 100 ml The active compounds were added to a solution of borate buffered saline containing the B-cyclodextrin sulfobutyl ether, edetate disodium, and propylamino biguanidate dissolved in sterile water for injection in a tared sterile vessel. The pH of the on was adjusted to 7.5 by the addition of hloric acid. The composition is sterilized by filtration through a 0.45 micron filter.

Example 18. Evaluation of the safety and efficacy of topically applied test compounds in the laser—induced choroidal neovascularization (CNV) model in Dutch Belted rabbits y male animals weighing between 1.5 and 2.0 kg were used in these studies.

Animals were d prior to dosing and at euthanasia, and more often if needed. Baseline fundus photography and cein angiography was performed on each animal prior to CNV induction.

Animals were anesthetized with an intramuscular ion of ketamine hydrochloride (20 mg/kg) and xylazine (2 mg/kg) for CNV induction, fundus photography, fluorescein angiography, and itreal (lVT) injections. Rabbits were maintained on ane (approximatelyl to 3%) in oxygen (approximately 1 to 2 L/min) as necessary. One drop of topical proparacaine hloride anesthetic (0.5%) was placed in each eye before procedures. Additional topical ocular esia was utilized during the procedure if needed.

CNV was induced by laser photocoagulation treatment. An external diode laser was applied to the retina using a laser contact lens and a slit lamp biomicroscope. On Day 1, both the ing laser eyes of each animal underwent laser photocoagulation treatment using settings: Number of Spots: 12-15 spots per eye Power Range: 50-200 mW Spot Size: 20-100 um Time: 0.05 — 0.1 seconds ing laser treatment, 50 uL of a 25-ug/mL VEGF solution (1.25 ug dose) was intraVitreally injected into each eye. Daily gross ocular exams were performed throughout the study period.

Clinical ophthalmic exams lamp biomicroscopy and indirect ophthalmoscopy), fundus photography, and fluorescein angiography were performed at baseline and then weekly for up to 6 weeks post-induction. Exams were scored using the McDonald-Shadduck Score System. Optical Coherence Tomography OCT imaging was med weekly for diagnostic imaging during the exams.

On the last day of the study, blood sampling was performed just prior to administration of the AM dose and at 2 hours post dosing. Blood samples were centrifuged at a speed of 3,000 g for 5 minutes to obtain plasma as quickly as le. Samples were stored frozen at -80°C until analysis. At the conclusion of the study, animals were euthanized per the 13C232Q3 lACUC protocol and both eyes enucleated immediately. Following enucleation, each eye was rinsed with phosphate-buffered saline. Ocular samples (aqueous humor, Vitreous humor retina and choroid) from both eyes of each animal were ted and weights were recorded. All the samples were frozen immediately on dry ice, and stored at - 60 to -80°C for analysis.

As shown in Figure 5, Compound Al or Compound A2 effectively reduced laser- induced choroidal neovascularization, as compared to the vehicle control.

EQUIVALENTS Those skilled in the art will ize, or be able to ain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present invention.

All patents, patent applications, and literature references cited herein are hereby expressly incorporated by reference.

Claims (22)

1. A compound of formula I: (I), or a pharmaceutically able salt or e thereof, wherein: Z is ; R and R’ are each independently H or F, or R and R’, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or heterocyclic ring; Q is ; X is CH or N; Y is CH or N; R1 is methoxy substituted with 0, 1, 2, or 3 fluorine atoms; and provided that the compound of formula (I) contains at least one fluorine atom.

2. The nd of claim 1, wherein R and R’ are each H.

3. The compound of claim 1, wherein X is N and Y is CH.

4. The compound of claim 1, wherein X and Y are each CH.

5. The compound of claim 1, wherein X and Y are each N.

6. The compound of claim 1, wherein R1 is OCHF2.

7. The compound of claim 1, having formula II: (II), or a pharmaceutically able salt or solvate thereof.

8. The compound of claim 1, selected from the group consisting of: , , , and or a pharmaceutically acceptable salt or solvate thereof.

9. The compound of claim 8, wherein the compound is or a pharmaceutically acceptable salt or e thereof.

10. A compound of formula (I): (I), or a pharmaceutically acceptable salt or solvate thereof, wherein: Z is ; R and R’ are each H; or R and R’, together with the carbon atom to which they are attached, form a 3- or 4-membered carbocyclic or cyclic ring; Q is or ; X is CH or N; Y is CH or N; R1 is C1-C4 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, or C1-C6 alkoxy substituted with 1, 2, 3, 4, 5, 6, or 7 ne atoms; and R2 and R3 are each independently H, F, CH2F, CHF2, or CF3, provided that one of R2 and R3 is not H, provided that the compound of formula (I) contains at least one fluorine atom.

11. The compound of claim 10, wherein R and R’ are each H.

12. The nd of claim 10, wherein Q is , preferably wherein X is N and Y is CH, or preferably wherein X and Y are each CH, or preferably wherein X and Y are each N.

13. The compound of claim 12, wherein R1 is ht chain C1-C4 or branched C3-C4 alkyl, and is substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 fluorine atoms, preferably wherein R1 is methyl substituted with 1, 2, or 3 fluorine atoms, more preferably wherein R1 is CF3.

14. The compound of claim 12, wherein R1 is straight chain C1-C6 or branched C3-C6 alkoxy, and is substituted with 1, 2, 3, 4, 5, 6, or 7 fluorine atoms, preferably wherein R1 is methoxy tuted with 1, 2, or 3 fluorine atoms, more preferably wherein R1 is OCHF2.

15. The compound of claim 12, wherein R and R’ are each H; and R1 is methyl tuted with 1, 2, or 3 fluorine atoms or methoxy substituted with 1, 2, or 3 fluorine atoms, preferably wherein X is N and Y is CH and R1 is OCHF2, or wherein X and Y are each N and R1 is CF3.

16. The compound of claim 10, wherein Q is .

17. The compound of claim 10, having formula (II): (II), or a pharmaceutically acceptable salt or solvate thereof.

18. The nd of claim 10, selected from the group consisting of: and , or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 18, selected from the group consisting of: and , or a pharmaceutically able salt or solvate thereof.

20. A pharmaceutical composition comprising a compound ing to any one of the preceding claims or a ceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutical composition optionally comprises a further active ingredient selected from the group consisting of a) an antagonist of integrin α5β1, b) a cytotoxic/antiproliferative agent, c) an inhibitor of epidermal- derived, fibroblast-derived, or et-derived growth factor, d) an inhibitor of VEGF, e) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tic-1, and f) an inhibitor of oinositide 3- kinase, and a mixture thereof.

21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically able salt or solvate thereof, optionally in combination with one or more therapies, or a composition according to claim 20 in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by an αv integrin in a subject.

22. The use according to claim 21, wherein the disease or condition is selected from the group consisting of r degeneration, diabetic retinopathy (DR), macular edema, ic macular edema (DME), and macular edema following retinal vein occlusion (RVO). #59: wocoo mmmmmmmmmmo Time (hr)