NZ743308B - Meta-azacyclic amino benzoic acid derivatives as pan integrin antagonists - Google Patents

Abstract

The present disclosure provides pharmaceutical agents of the formula (I): wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such pharmaceutical agents. Methods of using the pharmaceutical agents for the treatment of a variety of diseases and disorders are also provided, for example the biological activity of the compounds such as integrin receptor antagonists and for example, the disease or disorder is associated with fibrosis and/or angiogenesis. a variety of diseases and disorders are also provided, for example the biological activity of the compounds such as integrin receptor antagonists and for example, the disease or disorder is associated with fibrosis and/or angiogenesis.

Description

META-AZACYCLIC AMINO BENZOIC ACID DERIVATIVES AS PAN INTEGRIN ANTAGONISTS DESCRIPTION This application claims benefit of priority to US. Serial No. 62/273,246, filed December 30, 2015, the entire contents of which are hereby incorporated by reference.

BACKGROUND 1. Field of the Invention The present disclosure relates to the fields of pharmaceuticals, medicine and cell biology. More specifically, it relates to ceutical agents (compounds) which are useful as integrin receptor antagonists, with biological activity as antagonists of one or more ins that mediate the pathologic processes of enesis and fibrosis. As such, these nds may be used are useful in pharmaceutical compositions and in methods for treating diseases and disorders, including conditions mediated by one or more of such integrins. 11. Description of Related Art Integrins are a family of integral cytoplasmic membrane proteins that mediate cell interactions with other cells and with the extracellular matrix. Approximately one third of the members of the integrin family directly bind to a specific amino acid motif, arginine-glycine- aspartate (RGD), that is contained within the sequence of their cognate protein ligands. It has been established in the art that peptides containing the RGD sequence, and synthetic small molecule compounds that mimic the RGD sequence, are capable of binding to these integrin receptors with varying degrees of specificity, and thereby inhibit the binding to normal physiologic ligands (Millard, 2011, Sun et al., 2014). The ical effects of treatment with such agents is dependent on intrinsic molecular ties, reflected in the structure, that determine to what degree a particular in, or ation of ins, is inhibited in a body tissue over a period of time.

Many human diseases are characterized by either or both of two common contributing pathological mechanisms: angiogenesis and s. Different subsets of the RGD-binding integrins have predominant roles in driving these dual processes, so that simultaneous antagonism of angiogenesis and fibrosis requires agents capable of binding potently to several target integrins. This contrasts with agents designed cally for binding to a 2016/069511 single integrin which may be less effective in some applications due to their more restricted mechanism of action. ins which have been shown to have a role in promoting angiogenesis include 0tv[33, ochS, and OLSBI. 0tv[33 and ochS were initially described as mediators of bFGF- and VEGF-induced angiogenesis, respectively, in corneal or choriallantoic models. Subsequent data from studies using mice lacking these integrins also support an ant onal role for OLSBI. The integrin OLSBI (also known as VLA-S) is often referred to as the ‘classic fibronectin receptor’ ing its well characterized interaction with this ellular matrix protein. Cells expressing OLSBI bind to fibronectin in a region that incorporates the ninth and tenth type III fibronectin repeats, the latter of which contains the RGD motif critical for integrin binding. In addition to ectin, OLSBI has been reported to interact with other RGD-containing extracellular matrix proteins including ogen, denatured collagen, and fibrillin-l (Bax et al., 2003, Perdih, 2010, o et al., 2000). These ligands are components of the provisional matrix that is laid down by cells as part of the wound healing response in tissues. Key ents of this response are angiogenesis (new blood vessel formation) and fibrosis (scar formation) which are beneficial for healing of acute injuries, but can be deleterious in many disease contexts.

Antagonists of RGD-binding integrins should be useful for ent of human diseases having angiogenesis or fibrosis as a principal part of their pathology. In particular, the important role of OLSBI in angiogenesis is supported by numerous studies. For example, mice lacking this integrin exhibit embryonic lethality at day 10-11 with a phenotype that includes defects in both the nic and extraembryonic vasculature (Yang et al., 1993).

Angiogenic cytokines such as bFGF, IL-8, TGFB, and TNFoc upregulate OLSBI expression on endothelial cells in vitro and in vivo, and immunohistochemistry shows nated increases in both OLSBI and fibronectin staining in blood vessels from various types of human tumor biopsies and xenograft tumors in animals (Collo, 1999, Kim et al., 2000). Monoclonal antibodies that specifically inhibit OLSBI, and nds that have been described as OLSBI inhibitors, significantly reduce angiogenesis in a number of experimental models (Kim et al., 2000, Bhaskar et al., 2007, Livant et al., 2000, Zahn et al., 2009).

Because OLSBI expression is not confined to the endothelium, it has other functional roles in addition to angiogenesis. It is expressed to varying degrees in many cell types including fibroblasts, hematopoietic and immune cells, smooth muscle cells, epithelial cells, and tumor cells. Expression on tumor cells has been implicated in the progression of tumor growth and metastasis (Adachi et 61].; 2000; Blase’ et 61].; 1995; Danen et al.; 1994; Edward; 1995). In human fibroblasts; oc5[31 promotes motility and survival (Lobert et 61].; 2010). In pancreatic stellate cells; it cts with connective tissue growth factor to stimulate adhesion; migration; and fibrogenesis (Gao and Brigstock; 2006). It has been shown that pharmacologic antagonism of oc5l31 ts the ment migration; and proliferation of human retinal epithelial cells in vitro; and reduces retinal cell eration and scarring when administered intravitreally to rabbits with retinal detachment (Li et al.; 2009; Zahn et 61].; 2010) Besides a5[31; another RGD-binding integrin of the beta-1 family that is lated after organ injury is 0L8l31. Studies have shown that this integrin is co-eXpressed with markers of tissue myofibroblasts; the principal cellular ors of fibrosis (Levine et al.; 2000; Bouzeghrane et al.; 2004). Ectopic expression of a8l31 conferred to cells increased ing and adhesion on latent TGFB, a major pro-fibrotic cytokine; in a manner that was RGD- dependent (Lu et 61].; 2002).

RGD-binding integrins of the alpha v family have been implicated in ing the biological activation of the latent pro-fibrotic cytokine TGFB. This is mediated by binding to the y associated peptide (LAP); particularly by ocvl36 and ; but also by ochl; OMB, and ocvl35. Furthermore; the alpha v integrins mediate attachment; migration; eration and other functions in diverse cell types associated with the wound repair process. This onal redundancy; differential cellular expression; and the known fibrosis phenotypes of integrin knockout mice; all suggest that a highly potent antagonist of this entire subset may be particularly useful for therapeutic development. To achieve TGFB activation; these integrins are all critically dependent upon the amino acid sequence arg-gly-asp (RGD) contained in LAP. Indeed; mice containing a mutation in the RGD sequence of LAP are incapable of TGFB activation and recapitulate the phenotype of TGFB-null mice. Genetic on of the expression of alpha v integrins specifically from myofibroblasts in mice conferred protection against the development of fibrosis in several models of organ injury; and this efficacy was similarly provided by continuous infusion ent with a small molecule integrin antagonist of RGD-binding integrins known as CWHM-12 (Henderson 62‘ 611.; 2013). Such studies support the concept that simultaneous inhibition of le integrins may have particular utility to prevent or treat a range of fibrotic ions.

The multi-integrin receptor antagonist compounds previously described in the art generally lack either demonstrated broad spectrum potency against all of the RGD integrins described above, or the pharmacokinetic properties suitable for sustained activity with oral dosing, or both. Long plasma half-life at therapeutically significant concentrations following oral administration is a highly desirable property for development of drug formulations for al ents, allowing convenient administration usually without need for medical supervision.

SUMMARY The present disclosure provides novel integrin or antagonists, pharmaceutical compositions thereof, methods of manufacture thereof, and methods for their use.

In some aspects, the present disclosure provides compounds of the formula: N\ NH Y O \ N | HAWN B CO2R' / O X Y (I), wherein: A is C—H, C—OH, or N, R’ is hydrogen, alkyl(c:3), substituted alkyl(cs8), or a tuent tible in vivo to hydrogen, and X and Y are each independently cyano, halo, fluoroalkoxy(c1—2), alkyl(c1—2), or fluoroalkyl(c1.2), with the proviso that X and Y are not both cyano or alkyl(c1—2); or a pharmaceutically able salt or tautomer of the above formula.

In some embodiments, the compound is further defined as: N\ NH HN N l3 \ N CO R' I/ HAD“ 2 X Y (I), wherein: A is C—OH or N, R’ is hydrogen, alkyl(c:3), substituted alkyl(c:3), or a substituent convertible in vivo to hydrogen, and X and Y are each independently cyano, halo, lkoxy(c1—2), alkyl(c1—2), or fluoroalkyl(c1.2), with the proviso that X and Y are not both cyano or alkyl(c1- or a pharmaceutically acceptable salt or tautomer of the above formula.

In some embodiments, A is N. In other embodiments, A is C—OH. In some embodiments, R' is hydrogen.

In some embodiments, X is halo such as —F, —C1, or —Br. In some embodiments, X is —F. In other embodiments, X is —Cl. In other embodiments, X is —Br. In other embodiments, X is fluoroalkoxy(c1-2) such as —OCF3. In other embodiments, X is fluoroalkyl(c1-2). In some embodiments, X is —CHF2. In other embodiments, X is —CF3. In other embodiments, X is alkyl(c1.2) such as —CH3.

In some ments, Y is halo such as —F, —C1, or —Br. In some embodiments, Y is —F. In other embodiments, Y is —Cl. In other ments, Y is —Br. In other embodiments, Y is fluoroalkoxy(c1-2) such as —OCF3. In other ments, Y is fluoroalkyl(c1—2). In some embodiments, Y is —CHF2. In other embodiments, Y is —CF3. In other embodiments, Y is alkyl(c1.2) such as —CH3.

In some embodiments, X and Y are each independently selected from the groups consisting of F, Cl, Br, OCF3, CH3, CHF2, and —CF3, with the proviso that X and Y are not both —CH3.

In some embodiments, the carbon atom labeled B is in the S configuration. In some ments, the compounds are further defined as: OH OH ©HOHO N\NH HN N/\n’NEOE :sz YD»?HN COzH WO 17538 HO; HO; N\ NH N\ NH ”/7; COZH ”/7; COZH OH OH Cl CF2H Br CF2H HO; HO: N\ NH HI N\ NH n Y O HN N N0? 00 H2 my OH OH 0' CFs Cl Br , 3 HO; HO; N\ NH H\Nr N\ NH H Y O \ HN N | ”W COZH \ | NW COZH N N CI CF3 Cl Br , 3 HO: HO; N\ NH N\ NH | H/\fl/ COZH ”W COZH / O O Br CF3 F30 CF3 HO; HO; N\ NH N\ NH ”Ag COZH ”Ag COZH 0H 0H H30 Br H3O CI KO; HO; N\ NH Y ON/\[O]/N:3 £:OZH :NflkmN\NH HN ZI COZH Br Br N\NH N N/\n/NCOOEHE::IOZH YfiwHN COZH F3CO CI N\ NH ”W COZH F300 Br or a pharmaceutically acceptable salt or tautomer of any of the above formulas.

In some embodiments, the compounds are effective for inhibiting three or more RGD ins selected from the group consisting of (1531, (val, (1831, (va3, (vaS, (va6, and (va8, wherein the effectiveness of the compound corresponds to an ICso value of less than nM for each of the three or more RGD integrins as measured using a solid phase or assay (SPRA) for function of the respective integrin.

In some embodiments, the compounds possess pharmacokinetic properties that allow eutically significant plasma trations to be achieved and/or sustained in a patient for two or more hours after oral administration. In some embodiments, the compounds have a sustained plasma half-life of at least two hours as measured in a rat using an iv. bolus comprising 1 mg of compound per kg of rat.

In yet another aspect, the present sure provides pharmaceutical compositions comprising: a) a compound described herein, and 2016/069511 b) an excipient.

In still yet another aspect, the t disclosure es methods of treating and/or preventing a disease or a disorder in a patient in need thereof, comprising administering to the patient a compound or composition bed herein in an amount sufficient to treat and/or prevent the disease or disorder.

In some embodiments, the disease or disorder is associated with angiogenesis. In other embodiments, the e or disorder is associated with fibrosis. In some embodiments, the disease or disorder is associated with fibrosis and/or angiogenesis.

In some embodiments, the disease or disorder is pulmonary, liver, renal, cardiac, and pancreatic fibrosis, scleroderma, scarring, pathy of prematurity, familial exudative vitreoretinopathy, proliferative vitreoretinopathies, macular degeneration, diabetic retinopathy, cancer, osteoporosis, autoimmune diseases, humoral hypercalcemia of malignancy, Paget’s disease, periodontal disease, psoriasis, arthritis, restenosis, and infection.

In some ments, the disease or disorder is pulmonary fibrosis. In other embodiments, the disease or disorder is liver s. In other embodiments, the disease or disorder is cardiac fibrosis. In other ments, the disease or disorder is renal fibrosis. In other embodiments, the disease or disorder is pancreatic fibrosis.

In other embodiments, the disease or disorder is scleroderma. In other embodiments, the e or disorder is scarring. In some embodiments, the scarring is dermal scarring. In other embodiments, the scarring is retinal scarring. In other embodiments, the scarring is corneal scarring.

In other embodiments, the disease or disorder is retinopathy of prematurity. In other ments, the disease or disorder is al exudative vitreoretinopathy. In other ments, the disease or disorder is proliferative vitreoretinopathies. In other embodiments, the e or disorder is macular degeneration. In other embodiments, the disease or disorder is diabetic retinopathy.

In other embodiments, the disease or disorder is cancer. In some embodiments, the cancer includes solid tumor growth or neoplasia. In some embodiments, the cancer includes tumor metathesis. In some embodiments, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, lia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, te, skin, , small intestine, large intestine, stomach, testicle, or thyroid. In some embodiments, the cancer is a carcinoma, sarcoma, ma, leukemia, melanoma, mesothelioma, le myeloma, or seminoma.

In other embodiments, the disease or disorder is osteoporosis. In other embodiments, the disease or disorder is an mune disease. In some embodiments, the autoimmune disorder is multiple sis. In other embodiments, the disease or disorder is humoral hypercalcemia of malignancy. In other embodiments, the disease or disorder is Paget’s disease. In other embodiments, the e or disorder is periodontal e. In other embodiments, the disease or disorder is psoriasis. In other embodiments, the disease or disorder is arthritis. In some embodiments, the arthritis is rheumatoid arthritis. In other embodiments, the disease or er is restenosis. In other embodiments, the disease or disorder is an infection.

In some embodiments, the patient is a human, monkey, cow, horse, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In some embodiments, the patient is a monkey, cow, horse, sheep, goat, dog, cat, mouse, rat, or guinea pig. In some embodiments, the patient is a human.

In some aspects, the present disclosure contemplates the fact that the bond between the phenyl ring and the amino acid backbone on the B-amino acid is freely rotating. As such, in some aspects, it is contemplated that the structure may rotate such that the X group is on the oriented s the backbone and the Y is oriented away form the backbone as well as the manner drawn in most commonly in the specification showing the X group on the ed towards the backbone and the Y oriented away from the backbone as shown in the structures below. The structure: N\ NH is equivalent to the structure: 2016/069511 given the free rotation of the bond g the carbon label B in the backbone and the carbon labeled 1 in the aromatic ring.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed ption and the specific examples, while indicating specific embodiments of the disclosure, are given by way of ration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. Note that simply because a particular compound is ascribed to one particular generic formula doesn’t mean that it cannot also belong to another generic formula.

BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the present cation and are included to further demonstrate certain s of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

— Dot plots comparing potency of comparison nds (comparators) and es shown in Tables 1A & B for each integrin. Horizontal lines indicate group means.

Statistical analysis was performed using a two-tailed standard T test for comparison of group means.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Disclosed herein are new compounds and compositions with integrin receptor antagonists properties, s for their manufacture, and methods for their use, including for the ent and/or prevention of disease. 1. Compounds and tic s The compounds provided by the present disclosure may be made using the methods outlined below and further described in the Examples section. Comparison compounds shown in Table l and listed in Tables 3-5 were sized as disclosed in the literature.

Additionally, these ison compounds may also be readily synthesized by ing the methods and procedures described herein by those skilled in the art. General synthetic sequences for preparing the compounds useful in the present disclosure are outlined in Schemes I-VIII. Both an explanation of, and the actual procedures for, the various aspects of the present sure are described where appropriate. The following Schemes and Examples are ed to be merely illustrative of the present disclosure, and not limiting thereof in either scope or spirit. Those with skill in the art will readily understand that known variations of the conditions and processes described in the Schemes and Examples can be used to synthesize the compounds of the present disclosure. Starting materials and equipment employed were either commercially available prepared by methods previously reported and readily duplicated by those d in the art.

SchemeI H N2 (:0 H \ 2 NH4SCN,HCI,H20 H | H2N\n/N COZH A | A s A/ l Mel NH2 NH2 “Y“YYSMe COZH w / HN COZH A |\ 1.DMAorDMF A A 2. dilute HCI Scheme I illustrates general methodology which may be used for preparing the cyclic guanidine substituted left hand side aromatic acid portion of Formula I of the present disclosure which can then be coupled to a Gly-B-amino acid ester, or to Gly ester first, followed by (after ester hydrolysis) coupling to the appropriate B-amino acid ester. , in Scheme 1, the appropriate amino benzoic (or pyridine) acid is reacted with ammonium anate in hot dilute hydrochloric to give the resulting 3-thiourea benzoic (or pyridine) acid after normal work-up. The starting amino benzoic (or pyridine) acids are either commercially available or can be converted to such amino benzoic (or pyridine) acids via reduction of the corresponding nitro benzoic (or pyridine) acid, which can be ed commercially or synthesized by nitration of the appropriate benzoic (or pyridine) acid, followed by reduction to the desired amino c (or pyridine) acid, or by other reported methodologies that are known to those skilled in the art. This thiourea intermediate is converted to the S-methyl derivative by reaction with methyl iodide in ethanol at reflux. The appropriate 1,3-diaminohydroxy propane is d with this resulting intermediate in hot DMA (or DMF). Upon g, a precipitate forms and the zwitterionic product is isolated by tion. The HCl salt may be obtained by lyophilizing from dilute hydrochloric acid.

Alternatively, the product may be ed from the original reaction mixture by removing volatiles and concentrating. The resulting product is taken up in water and pH adjusted to about 5-7 where zwitterionic product precipitates and is isolated by filtration. The HCl salt may be ed as previously stated or by simply dissolving in dilute hydrochloric acid and concentrating to a solid and drying.

Scheme 11 HO COzH HZNOCOZH 1. NH4OH, NH4CI, 180 deg. c OH 2. 37% HCI, reflux OH MeNcs, DMF, 25 deg. c N 002“ —> s RH OH NYNH 1' HE NH NH M HN9 N 00 H2 2 2 HN COZH Y/ * HI 2 90 deg C 3. H20 4. HCI Scheme 11 illustrates methodology which may be used for preparing the ydropyrimidinobenzoic acid portion of Formula I of the present disclosure which can then be coupled to a amino acid ester, or to Gly ester first, followed by (after ester hydrolysis) coupling to the appropriate B-amino acid ester. Briefly, in Scheme 11, 3,5- dihydroxybenzoic acid is converted to 3-aminohydroxy-benzoic acid using the procedure described in Austr. J. Chem. 1981 or Becker et al., 1983. The product is d with methyl isothiocyanate in DMF at room temperature (Organic Process Research & Development, 2004) to give 3-N-methyl thioureahydroxybenzoic acid after normal work-up. This thiourea intermediate is converted to the S-methyl derivative by reaction with methyl iodide neat at below 40 °C. l,3-diaminohydroxypropane is reacted with this resulting intermediate in hot DMA (or DMF). Upon cooling, a precipitate forms and the zwitterionic product is isolated by filtration. The HCl salt may be obtained by lyophilizing from dilute hydrochloric acid. atively, the product may be isolated from the al reaction mixture by removing volatiles and concentrating. The resulting product is taken up in water and pH adjusted to about 5-7 where zwitterionic product itates and is isolated by filtration. The HCl salt may be obtained as previously stated or by simply dissolving in dilute hydrochloric acid and concentrating to a solid and drying.

Scheme III 0 1. malonic acid, ammonium acetate HZN x Y isopropyl l * HCI A x Y 2. EtOH / HCI resolve COzEt COZEt HZN HZN 1,.

X Y x Y Scheme III illustrates a general methodology which may be used for the synthesis of the beta amino acid ester portion of Formula I of the present disclosure, starting from an riate benzaldehyde. This beta amino acid ester can then be coupled to Boc-Glycine followed by (after removal of the Boc protecting group) ng to the appropriate ic acid described in Schemes I and II, or to the ic acid that has been coupled to e.

Briefly in Scheme III, to the appropriate benzaldehyde in isopropanol is added ammonium acetate followed by malonic acid. The reaction mixture is stirred at reflux, the resulting precipitate filtered and washed with hot isopropanol and dried to yield the desired racemic beta amino acid. The ethyl ester is synthesized by heating this acid in excess ethanol in the presence of excess HCl gas. These racemic beta amino acid esters can be resolved into the (R) and the (S) omers via chiral chromatographic separation, or via enzymatic resolution as described in Faulconbridge et al., 2000 or Landis et al., 2002, which are incorporated herein by reference. In some embodiments, the (S) enantiomer is the preferred enantiomer of the B-amino acid group.

Scheme IV >L i O HZN O >l\ N o/ 0 HCI / EtOH dioxane COZEt H2N/\n/ N * HCI x Y Scheme IV illustrates a general methodology which may be used for preparing the ethyl-N-Gly-beta amino acid n of Formula I of the present sure, which can be coupled to the ic acid portion of Formula I described in Schemes I and II. This method describes coupling a beta amino acid ester to Glycine. Briefly, the desired beta amino acid ester (described in Scheme 111 above) is treated with activated Boc Glycine. l of the Boc protective group (by treatment with ethanol/HCl, for example) affords the Glycine amide of the corresponding beta amino acid ester (the (S) enantiomer is afforded by utilizing the (S)—beta amino acid ester, described in the above scheme).

Scheme V OH OH 1. IBCF, NMM, DMA; (or DIC, HOBt, DMF/DCM) RH NYNH N\ NH HN HN N (jCOZH \ 2. NMM, | NW A/ O COZEt A/ HZN/\n’ N x Y 0 *HCI 1. LI+OH (or NaOH), H20 x Y 2.H,H20 N NH Y o COZH HN N \ N I/ 0? x Y Scheme V illustrates a general ology which may be used for preparing various compounds of the present disclosure. Briefly, the cyclic guanidine substituted left hand side ic acid portion of Formula I (described in Schemes I and II) is activated for coupling using known methods. Thus, after dissolving in a suitable solvent such as DMA an equivalent of NMM is added. The reaction mixture is cooled to ice-bath temperatures and IBCF added. To the mixed anhydride intermediate is added the Gly-B-amino acid ester (described in Scheme IV) and NMM. Upon completion of the reaction the product is purified by preparative HPLC and the ester hydrolyzed to the acid by treating with a base, such as LiOH in a suitable solvent (dioxane/water or acetonitrile/water). Alternatively, a suitable acid, such as TFA can be used. The product is ed by preparative HPLC or by isolating the zwitterion at pH 5-7 and converting to the desired salt by standard ures. (The (S) enantiomer is afforded by utilizing the (S) — beta amino acid ester, bed in the above schemes).

Scheme VI NYNH 1. IBCF, NMM, DMA; RH (or Die, HOBt, DMF/DCM) NYNH HN COZH o COZEt : H HN N 2 NMM' ”/1: OH ’ COZEt H OH N x Y Hzmr 0 * HCI x Y 1. LiOH (or NaOH), H20 2. w, H20 NYNH o COZH HN MWN x Y Scheme VI illustrates a general methodology that may be used for preparing various compounds of the present disclosure. Briefly, 3-Hydroxy[(l,4,5,6-tetrahydrohydroxy- 2-py1imidinyl)amino]benzoic acid ibed in Scheme 11) is activated for ng using known s. Thus, after dissolving in a suitable solvent such as DMA an equivalent of NMM is added. The reaction mixture is cooled to ice-bath atures and IBCF added. To the mixed anhydride intermediate is added the Gly-B-amino acid ester (described in Scheme IV) and NMM. Upon completion of the reaction the product is purified by preparative HPLC and the ester hydrolyzed to the acid by treating with a base, such as LiOH in a suitable solvent (dioxane/water or acetonitrile/water). Alternatively, a suitable acid, such as TFA can be used. The product is isolated by preparative HPLC or by isolating the zwitterion at pH 5-7 and converting to the desired salt by standard procedures. (The (S) omer is afforded by utilizing the (S) — beta amino acid ester, described in the above schemes).

WO 17538 SchemeVII (O; 1. IBCF, NMM, DMA; H} ‘or DIC, HOBt, NMM, DMA’ N\YNH N\ N“ Y HN OH ethyl ate HCI, \ HN NW \ COZH I / o | 2. NaOH, H20 A A 3. H+, H20 COZEt 1. IBCF, NMM, DMA; (or DIC, HOBt, NMM, DMA) * HCI X Y NYNH o COZEt HN N \ N / U? x Y 1. LiOH (or NaOH), H20 2. H”, H20 NYNH o COZH HN N |\ N / O x Y Scheme VII illustrates a general methodology that may be used for preparing s compounds of the present disclosure. Briefly, the cyclic guanidine substituted left hand side aromatic acid portion of Formula I (described for example in Schemes I and II) is activated for coupling using known methods. Thus, after dissolving in a suitable t such as DMA an equivalent ofNMM is added. The reaction mixture is cooled to ice-bath temperatures and IBCF added. To the mixed anhydride intermediate is added ethyl glycinate HCl and NMM.

Upon completion of the reaction the product is purified by preparative HPLC and the ester hydrolyzed to the acid by treating with a base, such as NaOH in a suitable solvent (water, dioxane/water or acetonitrile/water), followed by acidification. This Gly adduct is then activated for coupling using known methods. Thus, after dissolving in a suitable solvent such as DMA an equivalent of NMM is added. The reaction mixture is cooled to ice-bath atures and IBCF added. To the mixed ide intermediate is added the appropriate beta amino acid ester salt (described in Scheme 111 above) and NMM. Upon completion of the reaction the product is purified by ative HPLC and the ester hydrolyzed to the acid by treating with a base, such as LiOH in a suitable solvent (dioxane/water or acetonitrile/water). Alternatively, a suitable acid, such as TFA can be used. The t is isolated by preparative HPLC or by isolating the zwitterion at pH 5-7 and converting to the desired salt by standard procedures (the (S) enantiomer is afforded by utilizing the (S) — beta amino acid ester, described in the above schemes).

Scheme VIII HO; 1. IBCF, NMM, DMA; H} ‘or DIC, HOBt, NMM, DMA’ NvNH NYNH HN ethy 9yI I cinate HCI HN N/\n/OH COZH H 2. NaOH, H20 3. H+, H20 OH COZEt 1. IBCF, NMM, DMA; (or DIC, HOBt, NMM, DMA) * HCI X Y NYNH o COZEt HN ufirN x Y 1. LiOH (or NaOH), H20 2. H”, H20 NYNH o COZH HN MWN x Y Scheme VIII illustrates a general methodology which may be useful for preparing various compounds of described herein. Briefly, 3-Hydroxy[(1,4,5,6-tetrahydro ypyrimidinyl)amino]benzoic acid (described in Scheme 11) is activated for coupling using known methods. Thus, after dissolving in a suitable solvent such as DMA, an lent of NMM is added. The reaction e is cooled to ice-bath temperatures and IBCF added. To the mixed anhydride intermediate is added ethyl glycinate HCl and NMM.

Upon completion of the reaction the product is purified by preparative HPLC and the ester hydrolyzed to the acid by ng with a base, such as NaOH in a suitable t , dioxane/water or acetonitrile/water), followed by acidification. This Gly adduct is then activated for coupling using known methods. Thus, after dissolving in a suitable solvent such as DMA an equivalent of NMM is added. The reaction mixture is cooled to ice-bath temperatures and IBCF added. To the mixed anhydride intermediate is added the appropriate beta amino acid ester salt (described in Scheme 111 above) and NMM. Upon completion of the reaction the product is purified by prep hplc and the ester hydrolyzed to the acid by treating with a base, such as LiOH in a suitable t (dioxane/water or acetonitrile/water).

Alternatively, a suitable acid, such as TFA can be used. The product is isolated by preparative HPLC or by isolating the zwitterion at pH 5-7 and converting to the desired salt by standard procedures (the (S) enantiomer is afforded by ing the (S) — beta amino acid ester, described in the above schemes).

In some embodiments, the compounds of the present disclosure are those described in Table 1A (below), the es, and the claims.

Table 1A: Example Compounds of the Present Disclosure Example Number Compound Structure N\ NH 1 HI n ”W COZH Br Br N\ NH 2 HI H ”W COZH Br CF3 e Number Compound Structure N NH Y 0 3 HN ”/71;N COZH CI CFZH NYNH 4 HN ”/1?N COZH Br CFZH NYNH HN ”/1?N COZH CI CF3 N NH Y 0 HN ”/71; N COZH Cl Br YNH 0 7 HN N \ H/YN 00 H | 2 / o CI CF3 WO 17538 Example Number Compound Structure NYNH 8 HN N \ N COH I 2 / HT Cl Br N NH Y 0 9 HN N \ N COH I H/Y 2 / o Br CF3 N NH Y 0 HN ”/71;N COZH F30 CF3 NYNH 11 HN ”11/N COZH H3O Br YNH O 12 HN ”/11:N COZH H30 CI 2016/069511 Example Number Com ound Structurep N\ NH 13 HI n ”W COZH F Br N\ NH 14 HI n \ Q?N 00 H I 2 Br Br N\ NH HI n ”W COZH CI CI N\ NH 16 IDN/ H ”/11: COZH F300 CI N\ NH 17 HI H ”W COZH F300 Br Table 1B: Comparison Compounds Comparison Number nd Structure N NH \Y 0 C1 HN NWN COZH O OH Cl Br N NH Y 0 C2 H HN ”/71;N COZH N NH NW COZH O OH CI CI HN NH C4 OM: H30 CH3 HN NH Y 2 0 HN(2%:N ison Number Compound Structure N NH Y 0 C6 HN ”WN COZH O OH N NH Y 0 C7 HN NWN COZH O OH Br Br HN NH2 Y o HN N/\n/N COZH C8 H O OH YNH2 0 HN N/\n/N CO H2 C9 H F30 F NYNH C10 HN N \\ N -‘ \COZH O OH Cl CH3 NYNH HN N H C11 m "\002H 0 OH Cl CH3 ison Number Compound Structure N NH Y 0 C12 HN ”/7;N COZH NYNH C13 HN ”WN COZH 0 OH C14 HO: N NH Y 0 HN NWN COZH 0 OH C15 HO: NYNH HN ”/7;N COZH Comparison Number nd Structure C16 HO; N NH Y 0 HN ”AgN COZH C17 HN NH YNH 0 fin:H HN N C19 HO; N NH Y 0 HN ”/7;N COZH C20 #0; NYNH HN ”/71; N COZH ison Number Compound Structure C21 HO; HN ”/7;N COZH C22 HO: N NH \Y 0 HN ”/71;N COZH C23 (a ”W o HN ”/71; N COZH C24 HO; N\ NH ”W COZH OH OH Comparison Number nd Structure C25 HO; N NH Y 0 HN ”/7;N COZH C26 KO; NYNH HN ”/7;N COZH C27 HO; NYNH HN ”/7;N COZH OH OH C28 HO: N NH Y 0 HN ”/71;N COZH CF2H Comparison Number Compound Structure C29 (0; N \ NH ”W COZH C30 OH N:NrNH o ”W COZH 0H NH2 All these methods described above can be further modified and optimized using the principles and techniques taught in US. Patents 6,013,651 and 223, which are incorporated herein by reference, as well as the ples and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March ’s Advanced Organic try: Reactions, Mechanisms, and Structure (2007), which is incorporated by nce herein.

Compounds employed in methods of the disclosure i'nay cei'itain one or mere asyniinetricelly—suhstilined C'irlioii er nitrogen atoms, and may be ed in optically active or receiiiii: forhi. Thus, all chiral, tliastereonieric, raceiriic form, epiineric form, and all geonieti'ic isomeric forms of a structure an: intended, unless the specific slereeeheinistiy or isomeric twin is specifically indicated. In some embodiments, the B-amino acid portion of formula I is in the (5) ration. In some embodiments, the (S) omer is the preferred enantiomer of the B-amino acid group. Compounds may occur as i'aceinates and raeeniic i'nizx‘iiires. single eiiaiitieinei's. diaslereeineric es and dual dieslei'eeinei‘s. in some eniliotliifneiits, a single diastereeiner is ij-lj‘taiiied. "the chiral centers cf the compounds of the present disclosure can have the S or the R configuration, as defined by the lUl’AC N74 RGCOU'li‘Tlei‘lilmilOHS. For example. i'nixtnres of stereolseinei's may be separated using the techniques taught in the. Emittiples section helow, as well its modifications theirenf. eric forms are also ed as well as pharmaceutically acceptable salts of such isomers and tautomers.

Atoms making up the compounds of the present disclosure are intended to include all isotopic forms of such atoms. Compounds of the present disclosure include those with one or more atoms that have been ically modified or enriched, in particular those with ceutically acceptable isotopes or those useful for pharmaceutically research. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of en include ium and tritium, and isotopes of carbon include 13C and 14C. Similarly, it is contemplated that one or more carbon atom(s) of a compound of the present disclosure may be replaced by a silicon atom(s). Furthermore, it is contemplated that one or more oxygen atom(s) of a compound of the present disclosure may be replaced by a sulfur or selenium atom(s).

Cenrpounds of the present disclosure may atse exist in prodrug fenn. Since prodrugs are known to enhance ntinten‘itis desirable qualities of pharmaceuticals teg, setubitity. bitmvaiiahiiity, manufacturing, ete}, tl' e (LOU'tpOt/ttidil. ei'npteyed in sente t'netheds of the disclosure may, if desired, be. detivered in predrug form. Thus, the disclosure contemplates predmgs ef cenipounds of the present disclosure as well as methods of delivering prodrugs, Predrtigs Of the commends ed in the disclosure may be prepared by modifying functional groups present in the compound in such a. way that the medifieations are cleaved, either in e manipulation or in viva, tn the parent compound. Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or y group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a hydroxy, amino, or carboxylic acid, respectively. it slinuld he recognize-:1 that the particular aninii or cation forming a part ef any salt of this sure is net al, se long as the salt, as a whole, is pharntneoiegicaliy acceptable.

Additiena} examples of eeuticatty acceptable salts and their methods of preparatien and use are presented in ok of Pharmaceutical Salts: Properties, and Use (2002), which is ineerporated herein by reference.

It should be further recognized that the compounds of the t disclosure include those that have been further modified to comprise substituents that are convertible to hydrogen in vivo. This includes those groups that may be convertible to a hydrogen atom by enzymological or chemical means including, but not d to, hydrolysis and hydrogenolysis. Examples include hydrolyzable groups, such as acyl groups, groups having an oxycarbonyl group, amino acid residues, peptide residues, 0-nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl, and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. es of groups having an oxycarbonyl group include carbonyl, tert—butoxycarbonyl (—C(O)OC(CH3)3, Boc), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, B-(p- toluenesulfonyl)ethoxycarbonyl, and the like. Suitable amino acid residues include, but are not limited to, residues of Gly (glycine), Ala (alanine), Arg ine), Asn (asparagine), Asp (aspartic acid), Cys (cysteine), Glu mic acid), His (histidine), Ile (isoleucine), Leu (leucine), Lys (lysine), Met (methionine), Phe lalanine), Pro (proline), Ser (serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Om (omithine) and B- Ala. Examples of suitable amino acid es also include amino acid es that are protected with a protecting group. Examples of suitable protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert—butoxycarbonyl groups (—C(O)OC(CH3)3, Boc), and the like. Suitable peptide es e peptide residues comprising two to five amino acid residues. The residues of these amino acids or es can be present in stereochemical configurations of the D-form, the L- form or mixtures thereof. In addition, the amino acid or peptide residue may have an asymmetric carbon atom. Examples of suitable amino acid residues having an asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr.

Peptide residues having an asymmetric carbon atom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom. Examples of suitable amino acid protecting groups include those typically employed in peptide synthesis, including acyl groups (such as formyl and acetyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert—butoxycarbonyl groups (—C(O)OC(CH3)3), and the like. Other examples of substituents “convertible to hydrogen in viva” e reductively eliminable hydrogenolyzable groups. Examples of suitable reductively eliminable enolyzable groups include, but are not limited to, arylsulfonyl groups (such as 0-toluenesulfonyl), methyl groups substituted with phenyl or benzyloxy (such as benzyl, trityl and benzyloxymethyl), thoxycarbonyl groups (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl), and hoxycarbonyl groups (such as B,B,B-trichloroethoxycarbonyl and B-iodoethoxycarbonyl).

Compounds of the disclosure may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g., higher oral ilability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise. 11. Biological Activity In some embodiments, the compounds of the present disclosure may be used to antagonize multiple RGD-binding integrins. In some of these embodiments, the compounds may be used to treat or prevent diseases in which more than one in promotes aberrant angiogenesis. For example, the compounds may be especially useful when a second disease process, which is either co-dependent or independent of angiogenesis, is mediated by RGD integrins that can be simultaneously affected with the anti-angiogenic antagonist. Tumors are known to be dependent on the formation of new blood vessels to sustain growth beyond a few millimeters in er. Aberrant angiogenesis in the retina is a teristic of many blinding disorders such as wet age-related macular degeneration, vitreoretinopathies, retinopathy of prematurity, and diabetic retinopathy. Angiogenesis has been associated with progression of pulmonary and liver fibrosis, and with growth of the synovial pannus in toid arthritis.

The integrins 0tv[33 and ochS have been ated in promoting angiogenesis (Avraamides et al., 2008), so that their antagonism in addition to other integrins may be predicted to provide superior blockade of this process. Integrin ocvl33 is also known to play a role in tumor cell metastasis, and in the elevated bone resorption associated with osteoporosis and some cancers. The antagonists of the disclosure possess varying activity against at least five integrins that have been reported to bind the latent cytokine TGFB complex in vitro: ochl, och3, ochS, ocv[36, and ocvl38. See (Asano et al., 2005, Mu et al., 2002, Munger et al., 1999, Wipff et al., 2007, and Munger et al., 1998), which are incorporated herein by reference. TGFB is ntly co-expressed with the enic cytokine VEGF and induces its synthesis (Ferrari 62‘ al., 2006). Aside from having vascular regulatory ty, TGFB is a powerful r of fibrosis in many tissues such as lung, liver, kidney, and skin mura, 2009). Virtually all TGFB is secreted from cells in a complex which contains the y associated peptide (LAP). The integrins ocvl33, ochS, and , interact with the RGD motif 2016/069511 contained within LAP, producing a conformational change in the complex which allows TGFB to bind cellular receptors that activate pro-fibrotic pathways. Integrin ocvl38 also activates TGFB in an RGD-dependent manner, but utilizes a protease-dependent mechanism distinct from the other integrins.

Latent TGFB is ubiquitously present in tissues, and is ted by integrins in a spatially and temporally restricted manner. ore, upregulation of the epithelial integrin 0tv[36 in the lungs or liver may promote zed collagen deposition and scarring, as has been observed in patients with idiopathic pulmonary fibrosis (Horan et al., 2008) or hepatic s (Popov et al., 2008). Similarly, ochS, and to a lesser extent , are present on mesenchymal cells and are able to activate hymal TGFB (Wipff et al., 2007, Scotton et al., 2009). Integrin 0tv[38 is expressed on subsets of epithelial, neural, immune, and mesenchymal cell types. In the skin, the TGFB activation that accompanies the wound healing process mediates matrix deposition and promotes the formation of scars. Compounds of the present disclosure, by virtue of their ability to simultaneously inhibit several TGFB- activating integrins, have the potential for greater efficacy in treatment of is than previously described compounds having more restricted tory profiles. Furthermore, the compounds provided herein, including, for example, those which have good OLSBI potency, may be used to treat and/or prevent diseases characterized by both aberrant angiogenic and fibrotic ogies.

TGFB is an important inducer of the formation of FoxP3+ regulatory T cells (Treg) (Yoshimura, 2011). In some embodiments, compounds of the present disclosure, including those that inhibit the activation of TGFB and/or reduce Treg activity may be used to relieve immune suppression in disease states such as cancer, when administered alone or in combination with existing therapies. Mitigation of Treg activity with such compounds also has the potential to enhance the activity of vaccines which are intended to prevent or treat cancer and infectious diseases. TGFB, in the ce of IL-6, es the conversion of naive T cells to TH17 cells mura, 2011). These cells promote a variety of autoimmune diseases. It has been reported that mice lacking all ocvl38 sion on dendritic cells have near complete protection from experimental autoimmune encephalitis, a model of multiple sclerosis (Melton et al., 2010). Therefore, compounds of the present disclosure, including those that inhibit the activation of TGFB and/or reduce Th17 activity, and be used in preventing or treating mune disease when administered alone or in combination with existing therapies.

Antagonism of the integrin ocIIbB3 (also known as the fibrinogen receptor), is known to block platelet aggregation as part of the blood coagulation process. Hence, to avoid increased bleeding when treating conditions or disease states mediated by integrin OLSBI and other integrins, it would be beneficial to utilize compounds which selectively spare OLIIbB3.

As discussed above, integrins are a family of integral cytoplasmic membrane proteins that mediate cell interactions with other cells and with the extracellular matrix (ECM). These proteins also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle. Not only do integrins perform “outside-in” signaling typical of receptors, but they also operate an e-out” mode. Thus, they transduce information from the ECM to the cell as well as reveal the status of the cell to the outside, allowing rapid and flexible responses to changes in the environment, for example to allow blood coagulation by platelets.

There are many types of integrin, and many cells have multiple types on their surface.

Integrins are of vital importance to all animals and have been found in all animals igated, from sponges to mammals. As such compounds which target ins have found us uses in different animals including companion animals, ock s, 200 animals as well as wild animals. ins have been extensively studied in humans.

Integrins work alongside other proteins such as cadherins, immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell—cell and cell—matrix ction and communication. ins bind cell surface and ECM ents such as fibronectin, vitronectin, collagen, and laminin.

Each integrin is formed by the non-covalent heterodimerization of alpha and beta glycoprotein subunits, the combination of which conveys distinct biological activities such as cell attachment, ion, proliferation, differentiation, and survival. Currently, 24 integrins have been described in mammals that are formed by pairing of 18 0t subunits and 8 B subunits, as set out in Table 2.

Table 2: Integrins ITGA4 CD49d VLA4 Alpha ITGAS CD49e VLAS Alpha ITGA6 CD49f VLA6 Alpha ITGAl 0 ITGAl 0 Alpha ITGAL CD1 la LFAlA Alpha In addition, variants of some of the ts are formed by differential splicing; for e, four variants of the beta-1 subunit exist. Through different combinations of these or and B subunits, some 24 unique integrins are generated, gh the number varies according to different studies.

III. Therapeutic Methods The present disclosure relates to the fields of pharmaceuticals, medicine and cell biology. More specifically, it relates to pharmaceutical agents (compounds) and pharmaceutical compositions thereof which may be used as integrin receptor antagonists, including in some embodiments, integrin receptor antagonists. As such, these compounds may be used in pharmaceutical compositions and in methods for treating conditions mediated by one or more of such integrins, for e, by inhibiting or antagonizing one or more of these integrins. In several aspects of the present sure, the compounds provided herein may be used in a variety of biological, prophylactic or 2016/069511 therapeutic areas, including those one or more the (15b1, a8Bl, ochl, ocvl33, ochS, avb6, and avb8 integrins plays a role.

In another aspect, this sure provides methods of inhibiting or nizing one or more of the OLSBI, oc8[31, ochl, ocv[33, ochS, ocv[36 and ocv[38 integrins using one or more of the compounds disclosed herein, as well as pharmaceutical compositions thereof. In some embodiments, these methods inhibit pathological conditions associated therewith, such as angiogenesis, including tumor angiogenesis, fibrosis and ic diseases, such as pulmonary, renal, cardiac, muscle, and liver fibrosis, scarring, such as retinal, corneal and dermal scarring, retinopathy, including diabetic retinopathy and macular degeneration, vitreoretinopathy, including pathy of prematurity (ROP) and familial exudative vitreoretinopathy (FEVR), osteoporosis, humoral hypercalcemia of malignancy, Paget’s disease, tumor metastasis, solid tumor growth (neoplasia), arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis, autoimmune disease, such as multiple sclerosis, and infectious pathogens by administering a eutically effective amount of a compound provided herein. In some embodiments, the compound is administered as part of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In some embodiments, the compounds and/or pharmaceutical compositions thereof may be administered orally, parenterally, or by tion spray, or topically in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes, for example, subcutaneous, intravenous, intramuscular, intrastemal, on ques or intraperitoneally. In some embodiments, the compounds of the present disclosure are administered by any suitable route in the form of a ceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to prevent or arrest the ss of or to treat a medical ion are readily ained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.

Based upon standard tory experimental techniques and procedures well known and appreciated by those skilled in the art, as well as comparisons with compounds of known usefulness, the compounds described above can be used in the treatment of ts suffering from the above pathological conditions. One skilled in the art will recognize that ion of the most riate compound of the disclosure is within the ability of one with ordinary skill in the art and will depend on a variety of s including assessment of results obtained in standard assay and animal models.

In another , the compounds provided herein may be used in a variety of biological, prophylactic or therapeutic areas, ing those in wherein one or more the (15b1, a8Bl, ochl, ocv[33, ochS, avb6, and avb8 ins play a role. The disclosure further es treating or inhibiting ogical conditions associated therewith such as angiogenesis, including tumor angiogenesis, fibrosis and fibrotic diseases such as ary fibrosis, renal, cardiac, muscle, and liver fibrosis, scleroderma, scarring, such as retinal, corneal and dermal scarring, retinopathy, including diabetic retinopathy and macular degeneration, vitreoretinopathy, including retinopathy of prematurity (ROP) and al exudative vitreoretinopathy (FEVR), osteoporosis, humoral hypercalcemia of malignancy, s disease, tumor metastasis, solid tumor growth (neoplasia), arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials. Further, such pharmaceutical agents are useful as immune system modulators via inhibition of TGF-B activation resulting from inhibiting or antagonizing the targeted integrins. Such immune modulation s the immune activity and functions of T regulatory and T effector cells, and as such can be useful in the treatment of immune related pathologies, including autoimmune diseases such as multiple sclerosis, as well as in the treatment of tumors and infectious pathogens.

IV. Pharmaceutical ations and Routes of Administration It is another object of the disclosure to provide pharmaceutical compositions comprising one or more of the compounds described herein. Such compositions are useful in inhibiting or antagonizing integrins, including, for examples, (XSBI, oc8[31, ochl, ocv[33, ocv[36, and ocv[38 integrins. In some embodiments, this disclosure es pharmaceutical itions comprising a compound that is ive in inhibiting or antagonizing one or more of the OLSBI, , ochl, , ochS, ocvl36 and ocv[38 integrins using one or more of the compounds disclosed herein, as well as pharmaceutical compositions thereof. In some of these ments, such pharmaceutical compositions further comprise one or more non- toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants.

For the purpose of administration to a patient in need of such treatment, pharmaceutical formulations (also referred to as a pharmaceutical preparations, pharmaceutical itions, ceutical products, nal products, medicines, medications, or medicaments) comprise a therapeutically effective amount of a compound of the present invention formulated with one or more excipients and/or drug carriers riate to the indicated route of administration. In some embodiments, the compounds of the present invention are ated in a manner amenable for the treatment of human and/or veterinary patients. In some embodiments, formulation comprises admixing or ing one or more of the compounds of the present invention with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and m salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol. In some ments, e.g., for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some ments, the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.

Pharmaceutical formulations may be subjected to conventional pharmaceutical operations, such as sterilization and/or may contain drug carriers and/or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as , dendrimers, polymers, proteins such as albumin, or nucleic acids, and buffers, etc.

The pharmaceutical itions useful in the present sure may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional ceutical carriers and excipients such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.

The compounds of the present disclosure may be administered by a variety of methods, e.g., orally or by injection (6. g. subcutaneous, intravenous, intraperitoneal, etc).

Depending on the route of administration, the active compounds may be coated in a material to protect the nd from the action of acids and other natural conditions which may inactivate the nd. They may also be administered by continuous perfusion/infusion of a disease or wound site.

To administer the therapeutic compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. For example, the eutic compound may be administered to a patient in an appropriate carrier, for example, mes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in- -water CGF emulsions as well as conventional liposomes.

The therapeutic compound may also be administered parenterally, eritoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may n a preservative to prevent the growth of microorganisms.

Pharmaceutical compositions may be suitable for able use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the oraneous preparation of sterile injectable solutions or dispersion. In all cases, the ition must be sterile and must be fluid to the extent that easy ability exists. It must be stable under the conditions of manufacture and storage and must be preserved t the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid hylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it may be useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or n.

Sterile injectable solutions can be prepared by incorporating the eutic compound in the required amount in an appropriate solvent with one or a combination of ingredients ated above, as required, followed by filtered ization. Generally, sions are prepared by incorporating the therapeutic compound into a sterile carrier which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of e s for the preparation of sterile injectable solutions, the methods of ation include vacuum drying and freeze-drying which yields a powder of the active ingredient (l'.e., the eutic compound) plus any additional desired ingredient from a previously sterile-filtered solution thereof.

The therapeutic compound can be orally administered, for example, with an inert diluent or an assimilable edible carrier. The eutic compound and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject’s diet. For oral therapeutic administration, the therapeutic compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

The percentage of the therapeutic compound in the compositions and preparations may, of course, be . The amount of the therapeutic compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

In some embodiments, it is ageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as y dosages for the subjects to be treated, each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired eutic effect in association with the required pharmaceutical carrier.

The specification for the dosage unit forms of the disclosure are ed by and directly dependent on (a) the unique teristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of nding such a therapeutic compound for the treatment of a selected condition in a patient.

In some embodiments, the therapeutic compound may also be administered topically to the skin, eye, or mucosa. Alternatively, if local delivery to the lungs is desired, the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation.

Active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal, such as the model systems shown in the examples and gs.

An effective dose range of a therapeutic can be olated from effective doses determined in animal studies for a variety of ent animals. In general a human equivalent dose (HED) in mg/kg can be calculated in ance with the following formula (see, e.g., Reagan-Shaw et 61]., 2008, which is orated herein by reference): HED (mg/kg) = Animal dose (mg/kg) X (Animal Km/Human Km) Use of the Km factors in conversion results in more accurate HED , which are based on body surface area (BSA) rather than only on body mass. Km values for humans and various animals are well known. For example, the Km for an average 60 kg human (with a BSA of 1.6 m2) is 37, whereas a 20 kg child (BSA 0.8 m2) would have a Km of 25. Km for some nt animal models are also well known, including: mice Km of 3 (given a weight of 0.02 kg and BSA of 0.007), hamster K111 of 5 (given a weight of 0.08 kg and BSA of 0.02), rat K111 of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey K111 of 12 (given a weight of 3 kg and BSA of 0.24).

Precise amounts of the therapeutic composition depend on the judgment of the tioner and are peculiar to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic ation.

The actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a subject may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of e being treated, us or concurrent therapeutic interventions, thy of the subject and on the route of administration. These factors may be determined by a d artisan. The practitioner responsible for stration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage may be adjusted by the dual physician in the event of any complication.

An effective amount typically will vary from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, from about 10.0 mg/kg to about 150 mg/kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges e 1 mg to 10000 mg per day, 100 mg to 10000 mg per day, 500 mg to 10000 mg per day, and 500 mg to 1000 mg per day. In some particular ments, the amount is less than 10,000 mg per day with a range of 750 mg to 9000 mg per day.

The effective amount may be less than 1 mg/kg/day, less than 500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day, less than 50 mg/kg/day, less than 25 mg/kg/day or less than 10 mg/kg/day. It may alternatively be in the range of 1 mg/kg/day to 200 mg/kg/day. For example, regarding treatment of diabetic patients, the unit dosage may be an amount that reduces blood glucose by at least 40% as compared to an untreated subject.

In another embodiment, the unit dosage is an amount that reduces blood glucose to a level that is :: 10% of the blood glucose level of a non-diabetic subject.

In other non-limiting examples, a dose may also comprise from about 1 micro- g/body weight, about 5 ram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body , about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body , about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body , about 350 ram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein. In miting examples of a derivable range from the numbers listed herein, a range of about 5 mg/kg/body weight to about 100 mg/kg/body weight, about 5 microgram/kg/body weight to about 500 milligram/kg/body weight, etc, can be administered, based on the numbers described above.

In certain embodiments, a pharmaceutical composition of the present disclosure may comprise, for example, at least about 0.1% of a nd of the present disclosure. In other embodiments, the compound of the present disclosure may se n about 1% to about 75% of the weight of the unit, or between about 25% to about 60%, for example, and any range derivable therein.

Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, subjects may be administered two doses daily at approximately 12 hour intervals. In some embodiments, the agent is administered once a day.

The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a y basis or any set number of days or weeks there- between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other ments, the disclosure es that the agent(s) may taken orally and that the timing of which is or is not dependent upon food . Thus, for example, the agent can be taken every morning and/or every evening, regardless of when the subject has eaten or will eat.

V. Combination Therapy In addition to being used as a monotherapy, the compounds of the present disclosure may also find use in combination therapies. Effective combination therapy may be achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition es a compound of this disclosure, and the other includes the second agent(s). Alternatively, the y may precede or follow the other agent ent by intervals ranging from minutes to months.

Non-limiting examples of such combination y include combination of one or more nds of the disclosure with r agent, for example, an anti-inflammatory agent, a chemotherapeutic agent, radiation therapy, an antidepressant, an antipsychotic agent, an anticonvulsant, a mood izer, an anti-infective agent, an antihypertensive agent, a cholesterol-lowering agent or other modulator of blood lipids, an agent for promoting weight loss, an rombotic agent, an agent for treating or preventing vascular events such as myocardial infarction or stroke, an antidiabetic agent, an agent for reducing transplant rejection or graft-versus-host disease, an anti-arthritic agent, an analgesic agent, an thmatic agent or other treatment for respiratory diseases, or an agent for treatment or prevention of skin disorders. Compounds of the disclosure may be combined with agents designed to e a patient’s immune se to cancer, including (but not limited to) cancer vaccines.

VI. Definitions When used in the context of a chemical group: “hydrogen” means —H, “hydroxy” means —OH, “oxo” means =0, “carbonyl” means —C(=O)—, “carboxy” means —C(=O)OH (also written as —COOH or —C02H), “halo” means independently —F, —Cl, —Br or —I, and “amino” means —NH2.

In the context of chemical formulas, the symbol “—” means a single bond, “=” means a double bond, and “E” means triple bond. The symbol “————” represents an optional bond, which if present is either single or double. The symbol “--—--” represents a single bond or a double bond. Thus, for example, the formula includes 0 O E: O and Q. And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol “”,— when connecting one or 2016/069511 two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol “m when drawn perpendicularly across a bond l—CH3 for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of ment. The symbol “‘ ” means a single bond where the group attached to the thick end of the wedge is “out of the page.” The symbol “""”| ” means a single bond where the group attached to the thick end of the wedge is “into the page”. The symbol “WVI ” means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are ore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom tes that the hydrogen attached to that carbon is oriented out of the plane of the paper.

For the chemical groups and compound s, the number of carbon atoms in the group or class is as indicated as follows: “Cn” defines the exact number (n) of carbon atoms in the group/class. “CSn” defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question, e.g., it is understood that the minimum number of carbon atoms in the group “alkenyl(css)” or the class “alkene(css)” is two. Compare with “alkoxy(Cg10)”, which ates alkoxy groups having from 1 to 10 carbon atoms. “Cn-n’” defines both the minimum (11) and maximum number (n’) of carbon atoms in the group. Thus, “alkyl(c2—10)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the al groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “C5 olefin”, “CS-olefin”, “olef1n(CS)”, and “olefincs” are all synonymous.

The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated , one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded. When the 2016/069511 term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution.

The term “aliphatic” when used without the “substituted” r signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic).

Aliphatic compounds/groups can be saturated, that is joined by single carbon-carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl).

The term “aromatic” when used to modify a compound or a chemical group refers to a planar unsaturated ring of atoms with 4n +2 electrons in a fully conjugated cyclic 7: system.

The term “alkyl” when used without the “substituted” modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic ure, and no atoms other than carbon and en. The groups —CH3 (Me), —CH2CH3 (Et), —CH2CH2CH3 (n-Pr or propyl), —CH(CH3)2 (i-Pr, l'Pr or isopropyl), —CH2CH2CH2CH3 (n-Bu), 3)CH2CH3 (sec-butyl), —CH2CH(CH3)2 (isobutyl), —C(CH3)3 (tert—butyl, t—butyl, t—Bu or fBu), and —CH2C(CH3)3 (neo-pentyl) are non-limiting es of alkyl . The term “alkanediyl” when used without the “substituted” modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups —CH2— (methylene), —CH2CH2—, —CH2C(CH3)2CH2—, and 2CH2— are non-limiting examples of alkanediyl groups. The term “alkylidene” when used without the ituted” modifier refers to the nt group =CRR’ in which R and R’ are independently hydrogen or alkyl.

Non-limiting examples of alkylidene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2.

An “alkane” refers to the class of compounds having the formula H—R, wherein R is alkyl as this term is defined above. When any of these terms is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH, —F, —Cl, —Br, —I, —NH2, —N02, —C02H, —C02CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —NHCH3, CH3, —N(CH3)2, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, —OC(O)CH3, —NHC(O)CH3, 0H, or —S(O)2NH2. The following groups are non-limiting examples of substituted alkyl groups: —CH20H, —CH2Cl, —CF3, —CH2CN, —CH2C(O)OH, —CH2C(O)OCH3, —CH2C(O)NH2, —CH2C(O)CH3, —CH20CH3, —CH20C(O)CH3, —CH2NH2, —CH2N(CH3)2, and —CH2CH2Cl. The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is d to halo (i.e. —F, —Cl, —Br, or —I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, —CH2Cl is a miting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups —CH2F, —CF3, and 3 are non-limiting examples of fluoroalkyl groups.

The term “alkoxy” when used without the “substituted” modifier refers to the group —OR, in which R is an alkyl, as that term is defined above. Non-limiting examples e: —OCH3 (methoxy), —OCH2CH3 (ethoxy), —OCH2CH2CH3, —OCH(CH3)2 (isopropoxy), —OC(CH3)3 (tert—butoxy), —OCH(CH2)2, —O—cyclopentyl, and —O—cyclohexyl. The term “fluoroalkoxy” when used without the “substituted” modifier, refers to groups, defined as —OR, in which R is fluoroalkyl. The term “alkylthio” and “acylthio” when used without the “substituted” modifier refers to the group —SR, in which R is an alkyl and acyl, respectively.

The term “alcohol” corresponds to an , as defined above, wherein at least one of the hydrogen atoms has been ed with a hydroxy group. The term “ether” corresponds to an , as defined above, wherein at least one of the hydrogen atoms has been ed with an alkoxy group. When any of these terms is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by OH, F, Cl, Br, I, NH2, —N02, —C02H, —C02CH3, —CN, —SH, —OCH3, —OCH2CH3, —C(O)CH3, —NHCH3, —NHCH2CH3, —N(CH3)2, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, —OC(O)CH3, —NHC(O)CH3, —S(O)2OH, or —S(O)2NH2.

The term “effective,” as that term is used in the specification and/or claims, means adequate to accomplish a desired, expected, or intended . “Effective amount,” “Therapeutically ive amount” or “pharmaceutically effective amount” when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.

As used herein, the term “ICso” refers to an tory dose which is 50% of the m se obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half.

An “isomer” of a first compound is a te compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs.

As used herein, the term “patient” or “subject” refers to a living ian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain ments, the patient or subject is a e. Non- limiting examples of human subjects are , juveniles, infants and s.

As generally used herein “pharmaceutically able” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and/or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications surate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salts” means salts of compounds of the present disclosure which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts e acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with organic acids such as hanedisulfonic acid, oxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, ethylenebis(3-hydroxyene-l-carboxylic acid), 4-methylbicyclo[2.2.2]octene- l-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic ic acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, ic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 0-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p—chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p—toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, hamine, N—methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this disclosure is not critical, so long as the salt, WO 17538 as a whole, is pharmacologically able. Additional examples of ceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002).

The term “pharmaceutically acceptable carrier,” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent.

“Prevention” or nting” es: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and/or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and/or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease.

“Prodrug” means a compound that is convertible in vivo metabolically into an inhibitor according to the present disclosure. The prodrug itself may or may not also have activity with respect to a given target protein. For example, a compound sing a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy compound. Suitable esters that may be ted in vivo into hydroxy nds include acetates, citrates, es, ates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-[3-hydroxynaphthoate, gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates, esters of amino acids, and the like.

Similarly, a compound comprising an amine group may be administered as an amide that is converted by hydrolysis in vivo to the amine nd.

A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the ration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral les contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In c compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose isomerism is due to tetrahedral stereogenic s (e.g., tetrahedral carbon), the total number of hypothetically possible isomers will not exceed 2“, where n is the number of edral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be omerically enriched so that one enantiomer is present in an amount greater than 50%. lly, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a e of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains S 15%, more preferably S 10%, even more preferably S 5%, or most preferably S 1% of another stereoisomer(s).

“Substituent convertible to hydrogen in viva” means any group that is convertible to a hydrogen atom by enzymological or chemical means including, but not limited to, hydrolysis and hydrogenolysis. Examples include hydrolyzable groups, such as acyl groups, groups having an oxycarbonyl group, amino acid residues, peptide residues, 0-nitrophenylsulfenyl, trimethylsilyl, tetrahydropyranyl, diphenylphosphinyl, and the like. Examples of acyl groups include formyl, acetyl, trifluoroacetyl, and the like. Examples of groups having an oxycarbonyl group include ethoxycarbonyl, utoxycarbonyl (—C(O)OC(CH3)3), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, B-(p- toluenesulfonyl)ethoxycarbonyl, and the like. Suitable amino acid residues include, but are not limited to, residues of Gly (glycine), Ala (alanine), Arg (arginine), Asn (asparagine), Asp tic acid), Cys (cysteine), Glu (glutamic acid), His (histidine), Ile ucine), Leu (leucine), Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser (serine), Thr nine), Trp (tryptophan), Tyr (tyrosine), Val (valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline), 5-Hyl (5-hydroxylysine), Om (omithine) and B- Ala. Examples of suitable amino acid residues also include amino acid es that are protected with a protecting group. Examples of suitable protecting groups include those typically employed in peptide sis, including acyl groups (such as formyl and acetyl), thoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert—butoxycarbonyl groups (—C(O)OC(CH3)3), and the like. Suitable peptide residues include peptide residues comprising two to five amino acid residues. The residues of these amino acids or peptides can be present in stereochemical configurations of the , the L- form or mixtures thereof. In addition, the amino acid or e residue may have an asymmetric carbon atom. Examples of suitable amino acid residues having an asymmetric carbon atom e residues of Ala, Leu, Phe, Trp, Nva, Val, Met, Ser, Lys, Thr and Tyr.

Peptide residues having an asymmetric carbon atom include peptide residues having one or more constituent amino acid residues having an asymmetric carbon atom. Examples of suitable amino acid protecting groups include those typically ed in peptide synthesis, including acyl groups (such as formyl and ), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl), tert—butoxycarbonyl groups (—C(O)OC(CH3)3), and the like. Other es of substituents “convertible to hydrogen in viva” include reductively eliminable enolyzable groups. Examples of suitable reductively eliminable hydrogenolyzable groups include, but are not limited to, arylsulfonyl groups (such as 0-toluenesulfonyl), methyl groups substituted with phenyl or oxy (such as benzyl, trityl and benzyloxymethyl), arylmethoxycarbonyl groups (such as benzyloxycarbonyl and o-methoxy-benzyloxycarbonyl), and haloethoxycarbonyl groups (such as B,B,B-trichloroethoxycarbonyl and ethoxycarbonyl). ment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (eg, arresting further development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatology), and/or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or matology of the disease.

Other abbreviations used herein are as follows: 1H NMR is proton nuclear magnetic resonance, AcOH is acetic acid, Ar is argon, ACN or CH3CN is acetonitrile, CHN analysis is carbon/hydrogen/nitrogen elemental analysis, CHNCl analysis is carbon/hydrogen/nitrogen/chlorine elemental analysis, CHNS is is carbon/hydrogen/nitrogen/sulfur elemental analysis, DI water is deionized water, DIC is ropyl carbodiimide, DMA is N,N—dimethylacetamide, DMAP is 4-(N,N- dimethylamino)pyridine, DMF is N,N—dimethylformamide, EDCl is l-(3- dimethylaminopropyl)ethylcarbodiimide hydrochloride, EtOAc is ethyl e, EtOH is ethanol, FAB MS is fast atom bombardment mass spectroscopy, g is gram(s), HOBT is 1- hydroxybenzotriazole hydrate, HPLC is high performance liquid chromatography, IBCF is isobutylchloroformate, KSCN is potassium thiocyanate, L is liter, LiOH is lithium hydroxide, MEM is methoxyethoxymethyl, MEMCl is methoxyethoxymethyl chloride, MeOH is methanol, mg is milligram, MgSO4 is magnesium sulfate, ml is milliliter, mL is milliliter, MS is mass spectroscopy, MTBE is methyl tert-butyl ether, N2 is nitrogen, NaHCO3 is sodium bicarbonate, NaOH is sodium hydroxide, Na2SO4 is sodium sulfate, NMM is N- morpholine, NMP is N—methyl pyrrolidinone, NMR is r magnetic resonance, P205 is phosphorous pentoxide, PTSA is para-toluenesulfonic acid, RPHPLC is reverse phase high performance liquid chromatography, RT is room temperature, TFA is roacetic acid, THF is tetrahydrofuran, TMS is trimethylsilyl, and A signifies heating the reaction mixture.

The above tions supersede any conflicting definition in any of the reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the disclosure in terms such that one of ordinary skill can iate the scope and practice the present disclosure.

VII. Examples The following examples are included to demonstrate preferred ments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques ered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many s can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

A. Instrumentation and General Methods.

Analytical HPLC analyses were performed on an Agilent 1100 system and LC-MS analyses were conducted on Agilent 1100 Series LC/MSD . Reverse-phase preparative HPLC purifications were med on a e SP4 HPFC system using a variable dual ngth UV detector on a Biotage KP-C18-HS 120 g SNAP column using acetonitrile/water gradient containing 0.05% TFA. All final compounds were analyzed by analytical HPLC and peaks were monitored at 210, 254 and 280 nM for purity. 1H and 19F NMR spectra were ed in DMSO-da on a Bruker Avance-III/400 MHz spectrometer 2016/069511 equipped with a Broad Band NMR probe. The signal of the deuterated solvent was used as an internal reference. The chemical shifts are expressed in ppm (6) and coupling constants (J) are reported in hertz (Hz). 19F NMR detects a signal for the TFA salt of final ts (~74 ppm) stemming from TFA in the prep HPLC solvents during final purification. Reactions were performed under an atmosphere of dry nitrogen unless otherwise stated.

B. Preparation of Compounds Example A Preparation of 3-Hydroxy-S-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-Z- nobenz0ic acid NYN COZH OH 3-Hydroxy((5 -hydroxy- l ,4,5,6-tetrahydropyrimidinyl)aminobenzoic acid was synthesized according to literature procedures (see Organic Process ch & Development, 8:571-575, 2004, which is incorporated herein by reference).

Example B Preparation of ydroxy((5—hydroxy-1,4,5,6-tetrahydr0pyrimidin yl)amino)benzamido) acetic acid N N Y NH NH OH HO Hf OH 0 2-(3-Hydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid was prepared according to the following procedure: Coupling of 3-hydroxy((5—hydr0xy—1,4,5,6-tetrahydr0pyrimidin-2— yl)aminobenz0ic acid with glycine ethyl ester: O O N H “0' N H Y OH HZN/\n/002H5 DIC I \ NH NH + DMF/DCM 1:1 NH HO o HO 51/00sz OH OH 0 To a suspension of 3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)aminobenzoic acid (9.013 g, 35.87 mmol) in a 1:1 mixture of DMF (50.0 mL) and DCM (50.0 mL) was added glycine ethyl ester hydrochloride (5.02 g, 35.95 mmol) and the mixture WO 17538 was stirred at room temperature under nitrogen here. Neat N,N’- diisopropylcarbodiimide (6.75 mL, 43.60 mmol) was added to above reaction mixture and the mixture was stirred at room temperature ght to give a colorless suspension. The crude reaction mixture was used as such for the hydrolysis of the above ester.

Y NH 2.5 N NaOH NYN NH NH OC2H5 HO NH HO l\fl/OH OH 0 OH 0 The above crude reaction mixture was cooled to 10 °C (ice-bath) and a 2.5 N NaOH solution (90.0 mL) was added slowly with stirring, the solution temperature was kept below 0C, to give a pale yellow solution/suspension. The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was acidified with 5N HCl with stirring to pH 5 to give a colorless itate and the mixture was stirred at room temperature for another 15 min and filtered to give a colorless solid. The solid was washed with water (1X25 mL) and then with acetonitrile (1X25 mL). The solid was dried in-vacuo to give a colorless powder (9.686 g, yield 88%). 1H NMR (400 MHz, D20): 5 3.37 (dd, J = 12.7 and 3.1 Hz, 2H), 3.50 (dd, J = 12.7 and 2.8 Hz, 2H), 4.17 (s, 2H), 4.37 (m, 1H), 6.97 (t, J = 2.01 Hz, 1H), 7.17-7.26 (m, 2H). 1 NMR spectrum of the sample was consistent with the suggested structure of the product.

Example C Preparation of 5-((5-hydroxy-1,4,5,6-tetrahydr0pyrimidinyl)amino nicotinic acid N N COZH LE\ \ HO N -((5 -hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino nic acid was. prepared according to the following procedure: Step 1 HZNfiOl-l H H PhCONCS “\n/N \ OH CH3CN r.t 1h 0 s / 90% 2 A mixture of compound 1 (40 g, 0.3 mol) and benzoylisothiocyanate (95 g, 0.58 mol) in CH3CN (2.0 L) was stirred at room temperature for 12 h. TLC showed no starting al left. The precipitate was filtered and washed with CH3CN, dried to afford Compound 2 (80 g, 90%) as a light yellow solid.

Step2 O O H H HN H NTN 2 \ NaOMe \ OH OH l \n/ l O S N/ MeOH,r.t,1h s / 2 3 Into a stirred solution of compound 2 (80 g, 0.27 mol) in anhydrous CH3OH (500 ml) was added NaOMe (28.5 g, 0.53 mol) slowly at room ature. A clear solution resulted in 20 min, and the reaction mixture was stirred for l h. The solvent was removed and the residue was triturated with t-BuOMe to leave a light yellow powder. The powder was diluted with H20, acidified to pH=2-3. The yellow solid formed was filtered, dried to afford Compound 3 (33.7 g, 65%).

Step 3 H “N N H N Mel EtOH \ S / reflux, 5h S / \ N 3 4 l5 Into a stirred solution of compound 3 (33.7 g, 0.17 mol) in DMF (200 mL) was added CH3I (24.3 g, 0.17 mol) slowly at room temperature. The reaction mixture was stirred at RT for 1 h. TLC showed no ng al left. The solvent was removed, and Compound 4 (34.3 g, 95%) was obtained as ayellow oil. 2016/069511 Step 4 0 /—<_ o HN H HZN NH2 N H Y \ OH Y \ OH 8 / reflux, 6h | NH / \ N HO N 4 Example C A mixture of nd 4 (15.5 g, 0.074 mol) and the hydroxy diamino propane (20 g, 0.22 mol) in DMF (100 mL) was heated to reflux and stirred for 5 h. The solid formed was filtered and dried. Example C (5.2 g, 30%) was obtained as a white solid.

LC/MS (M+H =237) is consistent for the desired product. 1H NMR: DMSO-da 400MHz 8 13053(&11D,9881@,2ED,8783(&11D,8630(a11D,7897(a11D,5492(&11D,4112 (s, 1H), 3.410 (s, 2H), 3228-3190 (m, 2H).

Example D ation of 2-[[5-[(5-hydr0xy-1,4,5,6-tetrahydr0pyrimidin-2— yl)amino] pyridine-S-carbonyl]amin0]acetic acid H O N N OH r NW HO N/ 2-[[5- [(5 -hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino]pyridine carbonyl]amino] acetic acid was prepared according to the following procedure: Step 1 0 H H N N 00 H5 N N DIC \ 2 \{HW\ 0H + CIHH N 00sz Y 2 «6 | N/\[r DMF/DCM/1:1 NH / 0 HO N HO N To a suspension of 5-((5-Hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino)nicotinic acid (1.20 g, 5.08 mmol) in a 1:1 mixture of DMF (10.0 mL) and DCM (10.0 mL) was added glycine ethyl ester hydrochloride (0.798 g, 5.717 mmol) and the mixture was stirred at room temperature under nitrogen atmosphere for 10 min. Neat N,N’-diisopropylcarbodiimide (1.10 mL, 7.104 mmol) was added to above reaction mixture and the mixture was stirred at room ature overnight to give a colorless to cream suspension. The solvent was ated m-vacuo to afford a pale yellow viscous e. LC-MS analysis of the residue shows the desired product’s mass: m/z 322 (M+H), m/z 344 (M+Na) and m/z 643 (2M+H Calculated for C14H19N504z32133. The crude product was used as such in the next step for the saponification of the above ester.

Step2 H O N H OH I H NH O NH / 0 HO N’ HO N ExampleD The above crude product was dissolved in a mixture of M (1:1) (10 mL) and the solution was cooled to 10 °C (ice-bath) and a 2.5 N NaOH solution (10.0 mL) was added slowly with stirring, the solution temperature was kept below 20 0C, to give a pale yellow solution. The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 5N HCl with stirring to pH 5 to give a yellow-orange solution.

The mixture was diluted with DCM (25 mL) and the organic and the aqueous layers were separated. The aqueous layer was evaporated in-vacuo to afford a yellow gummy solid. The crude product was purified by reverse-phase HPLC with a gradient 10-40% CH3CN in water containing 0.05% TFA to give the desired product as a colorless to yellow gummy solid. The solid was triturated with itrile to give a colorless to pale yellow crystalline solid which was recrystallized from methanol to afford a cream solid (869.3 mg, yield 59%). LC-MS analysis of the solid shows the desired t’s mass: m/Z 294 (M+H), and m/Z 316 , Calculated for C12H15N504z29328. 1H NMR (400 MHz, D20): 5 3.19 (dd, J = 12.47 and 3.67 Hz, 2H), 3.37 (dd, J = 12.47 and 2.93 Hz, 2H), 3.96 (s, 2H), 4.11 (m, 1H), 8.12 (t, J = 2.20 Hz, 1H), 8.64 (d, J = 2.45 Hz, 1H), 8.90 (d, J = 1.96 Hz, 1H). 1H NMR spectrum of the nd was consistent with the suggested ure of the product as Example D.

Beta amino acids and their corresponding beta amino ester intermediates Beta amino acids and their ponding beta amino ester ediates used as starting materials and reagents in the synthesis of examples 1 — 17 can be synthesized as depicted in Scheme 111 above. Briefly, such beta amino acids and esters can be synthesized from the appropriate benzaldehyde and under the conditions depicted. Alternatively, the appropriate benzaldehyde can be reacted with mono-ethyl or methyl malonate to yield the racemic beta amino ethyl ester directly. Examples utilizing such an alternative method are described below. Unless otherwise exemplified, all relevant benzaldehydes are readily ble commercially or can be readily synthesized from the appropriate phenyl bromide, 12- BuLi and DMF by methods known to those skilled in the art. As noted in Scheme III, the corresponding c beta amino esters can be converted to the desired (5) enantiomer 2016/069511 either via supercritical fluid chiral chromatographic separation or via selective enzymatic cleavage of the (5) beta amino ester with Amano Lipase PS (Sigma Aldrich) to the readily isolated (S) beta amino acid, which can then be converted to the (S) ester and used as such for the synthesis of the examples 1-17 disclosed herein.

The following are representative s exemplifying a variety of general procedures used in various steps in the formation of all beta amino ester ediates utilized in the synthesis of examples 1-17 which follow, and are meant to rate the general utility of such methods: Example E Preparation of ethyl (3S)amino[3-chlor0 (trifluoromethyl)phenyl] propanoate hloride COZEt *HCI CI CF3 COZEt CH0 H2N HOOCCHZCOOEt NH4OAc,EtOH CI CF3 CI CF3 NH4OAc (1.33 g, 0.12 mol), HOOCCH2COOEt (4.5 g, 0.034 mol) and benzaldehyde 1 (3.6 g, 0.017 mol) in EtOH (30 mL) were stirred at 70 °C for 6 h. The e was concentrated and adjusted to pH=7.5 by addition of aq. NaHCO3. The mixture was extracted with EtOAc (3X50 mL). The organic layer was washed with brine, dried with NazSO4 and concentrated to dryness to give an oil. The crude product was purified via silica gel chromatography to give c compound 2 (1.5 g, 29.4%). The (S) enantiomer, Example E, was isolated using the enzymatic resolution procedures described for Example F (below).

Example F Preparation of ethyl (3S)amino[3-bromo-5— (trifluoromethyl)phenyl] propanoate hydrochloride H N2 COZEt *HCI Br CF3 Step 1 Preparation 0fraceml'c ethyl 3-amin0[3-br0m0-5—(trl'fluoromethyUphenyljpropanoate 0000sz Br CF3 Ethyl 3-amino[3-bromo(triflu0r0methyl)phenyl]propanoate was ed according to the method described for the preparation of Example E, substituting 3-br0mo trifluoromethyl benzaldehyde for 3-chlor0triflu0r0methyl benzaldehyde.

Step 2 Preparation of(3S)amtn0[3-br0m0-5—(trl'fluoromethyUphenyljpropanotc acid H N2 COZH Br CF3 Enzymatic resolution of the racemic mixture: A suspension of (rac)-ethyl 3-amin0- 3-[3-br0m0(tIiflu0romethyl)phenyl]propanoate (570.0 mg, 1.676 mmol) in 50 mM KH2PO4 solution (30.0 mL) was stirred at room temperature and the pH of the aqueous layer was adjusted to pH 8.32 by the addition of 1.0 N NaOH solution and 50 mM KH2PO4 solution. Amano Lipase PS (625.0 mg) was added to the above suspension and the reaction mixture was stirred at room temperature for 2 days. The e was diluted with MTBE (25 mL) and reaction mixture was stirred at room temperature for 1 h to extract the (R)-ester. The MTBE layer containing the (R)-ester was discarded after analyzing by LC-MS. Evaporation of the s layer tn-vacuo afforded a cream solid containing the (S)—acid as well as Amano Lipase and ate buffer salt. The above crude product was purified by e- phase HPLC with a gradient 10-60% CH3CN in water containing 0.05% TFA to give the desired product as a colorless glassy solid (231.0 mg). LC/MS analysis of the product shows the desired product's mass: m/z 312 (79BrM+H), m/z 314 (SlBrM+H), m/z 334 (79BrM+Na), and m/z 336 (SlBrM+Na), Calculated for C10H9BrF3N02: 312.08. The ed TFA salt of the (S)- acid was used as such for the preparation of the (S)—ester.

Step 3 Preparation ofethyl (3S)amino[3-bromo(trifluoromethyl)phenyl]propanoate hydrochloride (Example F) H N2 COZEt *HCI Br CF3 To a solution of (3S)amino[3-bromo(trifluoromethyl)phenyl]propanoic acid TFA salt from step 2 above (231.0 mg, 0.542 mmol) in absolute ethanol (3 mL) was added absolute ethyl alcohol saturated with dry HCl gas (10 mL) and the reaction mixture was stirred at room ature for 1.5 h. Evaporation of the solvent uo gave a colorless crystalline solid, (Example F) (198.5 mg, 97%). LC-MS analysis of the solid shows the desired product’s mass: m/z 340 (79BrM+H), m/z 342 (SlBrM+H), m/z 362 (79BrM+Na), and m/z 364 (SlBrM+Na), Calculated for C12H13BrF3N02: 340.14.

Example G ation of ethyl (3S)amino[3-chlor0 oromethoxy)phenyl] propanoate hydrochloride H N2 COZEt *HCI CI OCF3 Step 1 Preparation ofracemic ethyl 3-amino[3-chloro-5—(trifluoromethoxy)phenyl]propanoate H N2 COZEt CI OCF3 A solution of a mixture of 3-chloro(trifluoromethoxy)benzaldehyde (1.05 g, 4.676 mmol) mono-ethyl malonate (1.54 g, 11.69 mmol) and ammonium acetate (1.985 g, 25.75 mmol) in absolute l (30 mL) was heated at 80 °C overnight to give a colorless on.

The reaction mixture was cooled to room temperature and the solvent was evaporated in- vacuo to give a yellow viscous liquid. The residue was partitioned between aqueous saturated NaHCO3 solution (50 mL) and ethyl acetate (50 mL), the organic layer was removed, dried over anhydrous sodium sulfate, d and evaporated in-vacuo to give a yellow-brown viscous liquid (1.56 g). LC-MS is of the crude t shows the desired product's mass: m/Z 312 (35C1M+H), m/Z 314 (37C1M+H), m/Z 334 (35C1M+Na), and m/Z 336 (37C1M+Na), Calculated for C12H13ClF3NO3: 311.68. LC-MS also shows the uct: (E)-ethyl 3-(3- chloro(trifluoromethoxy) phenyl)acrylate’s mass: m/z 295 (35C1M+H), and m/z 297 (37C1M+H), Calculated for C12H10ClF3O3: 294.65. To a solution of the crude residue in absolute ethanol (2 mL) was added a 2.0 M solution of HCl in diethyl ether (10.0 mL) and the reaction mixture was stirred at room temperature for 1 h to give a yellow solution. The residue after evaporation of the solvents was partitioned between water (25 mL) and dichloromethane (50 mL). The organic and the aqueous layers were separated. The aqueous layer was evaporated in-vacuo to afford a colorless gummy residue. The residue was purified by reverse-phase preparative HPLC with a gradient 10-70% CH3CN in water containing 0.05% TFA. The pure fractions mixture was evaporated in-vacuo to afford the desired product as a colorless lline solid (347.2 mg, yield 24%). LC/MS analysis of the product shows the desired t's mass: m/z 312 (35C1M+H), m/z 314 (37C1M+H), m/z 334 (35C1M+Na), and m/Z 336 (37C1M+Na), Calculated for C12H13ClF3NO3: 311.68 Step 2 Preparation ofracemic ethyl 3-ammo[3-chloro(trl'fluoromethoxy)phenyl]propanoate hloride COZEt *HCI CI OCF3 To a solution of ethyl 3-amino[3-chloro (trifluoromethoxy)phenyl]propanoate TFA salt from above (347.2 mg, 0.816 mmol) in absolute ethanol (2 mL) was added absolute ethyl alcohol saturated with dry HCl gas (5 mL) and the reaction mixture was stirred at room temperature for 30 min. Evaporation of the solvent uo gave a colorless gummy solid. The solid was slurried with hexanes (2X10 mL), the solvent layer was decanted off and the residue was dried in-vacuo to afford a colorless crystalline solid (270.7 mg, yield 95%). LC-MS analysis of the solid shows the desired product’s mass: m/z 312 +H), m/z 314 (37C1M+H), m/z 334 +Na), and m/z 336 (37C1M+Na), Calculated for C12H13ClF3NO3: 311.68 1H NMR (400 MHz, DMSO-da): 5 1.08 (t, J :71 Hz, 3H, CH3-CH2-), 3.06 (dd, J = 16.1 and 8.8 Hz, 1H, CHH-C=o-), 3.20 (dd, J = 16.4 and 10.3 Hz, 1H, -CHH-C=O-), 4.01 (q, J = 7.1 and 2.0 Hz, 2H, CH3-CH2—), 4.72 ( m, 1H, -NH2-CH-CH2-C=O-), 7.62 (s, 1H, H-2), 7.64 (s, 1H, H-6), 7.80 (s, 1H, H-4), 8.87 (brs, 3H, -NH2.HCl). 1H NMR spectrum of the solid was consistent with the suggested structure of the t.

Step 3 Preparation of(3S)amino[3-chloro-5—(trifluoromeihoxy)phenyl]propanoic acid H N2 COZH CI OCF3 Enzymatic resolution of the racemic mixture: A suspension of (rac)-ethyl 3-amino- 3-[3-chloro(trifluoromethoxy)phenyl]propanoate hloride (185.30 mg, 0.532 mmol) in 50 mM KH2PO4 on (25.0 mL) was d at room temperature and the pH of the aqueous layer was adjusted to pH 8.32 by the addition of 1.0 N NaOH solution and 50 mM KH2PO4 on. Amano Lipase PS (201.0 mg) was added to above suspension and the on mixture was stirred at room temperature for 2 days. The mixture was diluted with MTBE (25 mL) and reaction mixture was stirred at room temperature for 1 h to extract the (R)-ester. The MTBE layer containing the (R)-ester was discarded after analyzing by LC-MS.

Evaporation of the aqueous layer in-vacuo afforded a cream solid containing the (S)-acid as well as Amano Lipase and Phosphate buffer salt. The above crude product was purified by e-phase HPLC with a gradient 10-70% CH3CN in water containing 0.05% TFA to give the desired product as a colorless glassy solid (83.1 mg). LC/MS analysis of the product shows the desired product's mass: m/z 284 (35C1M+H), m/z 286 (37C1M+H), m/z 306 (35C1M+Na), and m/z 308 (37C1M+Na), Calculated for C10H9ClF3NO3: 283.63. The isolated TFA salt of the (S)-acid was used as such for the preparation of the ter.

Step 4 Preparation ofethyl (3S)amino[3-chloro-5—(irifluoromeihoxy)phenyl]propanoaie hydrochloride (Example G) H N2 COZEt *HCI CI OCF3 To a solution of (S)amino[3-chloro(trifluoromethoxy)phenyl]propanoic acid TFA salt from Step 3 above (83.0 mg, 0.209 mmol), in absolute ethanol (2.0 mL), was added absolute ethyl alcohol saturated with dry HCl gas (5 mL) and the reaction mixture was d at room temperature for 1 h to give a colorless solution. LC-MS analysis of the on e after 1 h shows the desired product: ethyl (3S)—3-amino[3-chloro (trifluoromethoxy)phenyl]propanoate’s mass: m/z 312 (35C1M+H), m/z 314 +H), m/z 334 (35C1M+Na), and m/z 336 (37C1M+Na), Calculated for C12H13ClF3NO3: 311.68. The solvent was evaporated in-vacuo to afford the desired HCl salt of the ester (Example G) as a colorless crystalline solid (68.70 mg, yield 94%).

Example H Preparation of ethyl (3S)amino-3—[3—br0mo-5— (trifluoromethoxy)phenyl] propanoate hydrochloride H N2 COZEt *HCI Br OCF3 Step 1 Preparation afraceml'c ethyl 3-amm0[3-br0m0(trifluoromethoxy)phenyl]pr0pan0ate H N2 COZEt Br OCF3 A solution of a mixture of 3-bromo(trifluoromethoxy)benzaldehyde (1.05 g, 3.90 mmol) mono-ethyl malonate (1.31 g, 9.91 mmol) and ammonium acetate (1.68 g, 21.79 mmol) in absolute ethanol (25 mL) was heated at 80 °C for 5 h to give a colorless solution.

The reaction mixture was cooled to room ature and the solvent was evaporated in- vacuo to give a colorless viscous liquid. The residue was partitioned between aqueous saturated NaHCO3 solution (50 mL) and ethyl acetate (50 mL), the organic layer was removed, dried over anhydrous sodium sulfate, filtered and evaporated in-vacuo to give a pale yellow viscous liquid (1.40 g). LC-MS analysis of the crude t shows the desired product's mass: m/Z 356 +H), m/z 358 (SlBrM+H), m/z 378 (79BrM+Na), and m/z 380 (SlBrM+Na), Calculated for C12H13BrF3NO3: . LC-MS also shows the uct: (E)- ethyl 3-(3-bromo(trifluoromethoxy)phenyl)acrylate’s mass: m/Z 339 (79BrM+H), and m/Z 341 (SlBrM+H); Calculated for C12H10BrF3O3: 339.11. To a solution of the crude residue in absolute l (2 mL) was added a 2.0 M solution of HCl in diethyl ether (15.0 mL) and the reaction mixture was stirred at room ature for 30 min to give a pale yellow solution.

The residue after evaporation of the solvents was partitioned between water (25 mL) and dichloromethane (25 mL). The organic and the s layers were separated. The aqueous layer was evaporated in-vacuo to afford a colorless gummy residue. The residue was purified by reverse-phase preparative HPLC with a nt 10-70% CH3CN in water containing 0.05% TFA. The pure fractions mixture was evaporated in-vacuo to afford the desired product as a colorless crystalline solid (442.5 mg, yield 31%). LC/MS analysis of the product shows the desired product's mass: m/z 356 (79BrM+H), m/z 358 (SlBrM+H), m/z 378 (79BrM+Na), and m/z 380 +Na); Calculated for C12H13BrF3NO3: 356.14.

Step 2 Preparation ofracemic ethyl 3-ammo[3-bromo(trifluoromethoxy)phenyl]propanoate hydrochloride COZEt *HCI Br OCF3 To a solution of (rac)-ethyl o[3-bromo (trifluoromethoxy)phenyl]propanoate TFA salt from above (442.8 mg, 0.942 mmol) in absolute ethanol (2 mL) was added a 2.0 M HCl solution in diethyl ether (10 mL) and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the solvent m-vacuo gave a colorless gummy solid. The solid was slurried with hexanes (2X10 mL), the solvent layer was decanted off and the e was dried in-vacuo to afford a colorless crystalline solid (358.0 mg, yield 96%). LC-MS analysis of the solid shows the desired product’s mass: W2 356 (79BrM+H), m/Z 358 (SlBrM+H), m/Z 378 (79BrM+Na), and W2 380 (SlBrM+Na); Calculated for BrF3NO3: 356.14. 1H NMR (400 MHZ, g): 5 1.08 (t, J =7.1 Hz, 3H, CH3-CH2-), 3.095 (double AB q, J = 16.4 and 8.7 Hz, and J = 16.4 and 10.3 HZ, (each 1H), 2H, -CHH-C=O- and -CHH-C=O-; diastereotopic), 4.01 (dq, J = 7.1 and 2.0 Hz, 2H, CH3-CH2—), 4.72 ( dd, J = 8.3 and 6.1 Hz, 1H, -NH2-CH-CH2-C=O-), 7.65 (appt, J = 1.7 Hz, 1H), 7.73 (appt, J = 1.7 Hz, 1H), 7.90 (appt, J = 1.5 Hz, 1H), 8.74 (brs, 3H, -NH2.HC1). 1H NMR spectrum of the solid was consistent with the suggested structure of the product.

Step 3 Preparation of(3S)ammo[3-bromo-5—(trifluoromez‘hoxy)phenyljpropanol'c acia’ COZH Br OCF3 Enzymatic resolution of the racemic mixture: A suspension of (rac)—ethyl 3-amino[3-bromo (trifluoromethoxy)phenyl]propanoate hydrochloride from step 2 above (345.40 mg, 0.880 mmol) in 50 mM KH2PO4 solution (30.0 mL) was stirred at room temperature and the pH of the aqueous layer was adjusted to pH 8.32 by the addition of 1.0 N NaOH solution and 50 mM KH2PO4 solution. Amano Lipase PS (317.0 mg) was added to above suspension and the reaction e was stirred at room temperature overnight. The mixture was diluted with MTBE (25 mL) and on mixture was stirred at room temperature for 1 h to extract the (R)-ester. The MTBE layer containing the (R)-ester was discarded after ing by LC-MS.

Evaporation of the aqueous layer in-vacuo afforded a cream solid containing the (S)-acid as well as Amano Lipase and Phosphate buffer salt. The above crude product was d by reverse-phase HPLC with a gradient 10-70% CH3CN in water containing 0.05% TFA to give the desired product as a colorless glassy solid (201.3 mg). LC/MS analysis of the t shows the desired product's mass: m/z 328 (79BrM+H), m/z 330 (SlBrM+H), m/z 350 (79BrM+Na), and m/z 352 (SIBM+Na), Calculated for C10H9BrF3NO3: . The isolated TFA salt of the (S)-acid was used as such for the preparation of the (S)—ester.

Step 4 Preparation ofethyl (3S)amino[3-bromo-5—(trifluoromethoxy)phenyl]propanoate hydrochloride (Example H) H N2 COZEt *HCI Br OCF3 To a solution of (S)amino[3-bromo(trifluoromethoxy)phenyl]propanoic acid TFA salt from step 3 above (201.30 mg, 0.455 mmol) in absolute ethanol (2.0 mL) was added absolute ethyl alcohol saturated with dry HCl gas (5 mL) and the reaction mixture was stirred at room ature for 1.5 h to give a ess solution. LC-MS analysis of the reaction mixture after 1.5 h shows the desired product: (S)—ethyl 3-amino[3-bromo (trifluoromethoxy)phenyl]propanoate’s mass: m/Z 356 (79BM+H), m/Z 358 +H), m/Z 378 (79BrM+Na), and m/Z 380 (SlBrM+Na); Calculated for C12H13BrF3NO3: 356.14 The solvent was ated in-vacuo to afford the desired HCl salt of the ester (Example H) as a colorless lline solid (171.0 mg, yield 95%).

Example I Preparation of ethyl (3S)amino[3,5-dichlor0-phenyl]propanoate hydrochloride COzEt *HCI CI CI Step 1 Preparation 0f(iS)amm0[3, 5-dich10r0-phenyljpropanoic acid H N2 COZH CI CI Enzymatic resolution of the racemic mixture: A suspension of (rac)-ethyl 3-amino- 3-[3,5-dichlorophenyl]propanoate hydrochloride (synthesized according to procedures described herein starting from chlorophenyl benzaldehyde) (316.0 mg, 1.058 mmol) in 50 mM KH2PO4 solution (30.0 mL) was stirred at room ature and the pH of the aqueous layer was adjusted to pH 8.32 by the addition of 1.0 N NaOH solution and 50 mM KH2PO4 solution. Amano Lipase PS (295.0 mg) was added to above suspension and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with MTBE (25 mL) and reaction mixture was stirred at room temperature for 1 h to extract the (R)-ester. The MTBE layer containing the (R)-ester was ded after analyzing by LC-MS.

Evaporation of the aqueous layer in-vacuo afforded a cream solid containing the (S)-acid as well as Amano Lipase and Phosphate buffer salt. The above crude product was purified by e-phase HPLC with a gradient 10-50% CH3CN in water containing 0.05% TFA to give the desired product as a ess glassy solid (103.0 mg). LC/MS analysis of the product shows the desired product's mass: m/Z 234 (35C1M+H), m/Z 236 (37C1M+H), m/Z 256 (35C1M+Na), and m/Z 258 (37C1M+Na); Calculated for C9H9C12N02: . The isolated TFA salt of the (S)-acid was used as such for the preparation of the (S)-ester.

Step 2 Preparation ofethyl (3S)ammo[3,5-dl'chloro-phenyljpropanoate hydrochloride (Example I) H N2 COZEt *HCI CI CI To a suspension of (S)amino[3,5-dichlorophenyl]propanoic acid from step 1 above (103.0 mg, 0.440 mmol) in absolute ethanol (2.0 mL) was added absolute ethyl alcohol saturated with dry HCl gas (5 mL) and the reaction e was stirred at room temperature for 1 h to give a colorless solution. LC-MS analysis of the reaction mixture after 1.5 h shows the desired product: (S)—ethyl 3-amino[3,5-dichlorophenyl]propanoate’s mass: W2 262 (35C1M+H), m/Z 264 (37C1M+H), m/Z 284 (35C1M+Na), and W2 286 (37C1M+Na); Calculated for CiiHi3C12N02: 262.13. The solvent was evaporated in-vacuo to afford the desired HCl salt of the ester (Example I) as a colorless crystalline solid (131.20 mg, yield 99%).

Example J Preparation of racemic ethyl 3-amino[3,5-bromophenyl]propanoate hydrochloride COZEt *HCI Br Br Step 1 Preparation ofracemic 3-ammo[3,5-bromo-phenyljpropanol'c acia’ COZH Br Br A sion of bromo-benzaldehyde (50 g, 189.39 mmol), malonic acid (39.39 g, 378.78 mmol) and ammonium e (29.19 g, 378.78 mmol) in isopropanol (350 mL) was heated at reflux under en for 14 h to afford a thick colorless solid. The solid was filtered hot, washed with hot isopropanol (2 X 100 mL) and dried in vacuo to give the desired racemic t as a colorless solid (32.2 g).

Step 2 Preparation ofracemic ethyl 3-amiho[3,5-bromophehyljpropahoate hloride H N2 COZEt *HCI Br Br Absolute ethanol (500 mL, saturated with anhydrous HCl gas) was added to 3-amino- 3-(3,5-dibromo-phenyl)-propionic acid from step 1 above (32 g, 99.07 mmol) and the reaction mixture was heated to reflux for 1.5 h to give a pale yellow solution. The solvent was removed in vacuo to give a colorless solid. The solid was washed with hexane (2 X 100 mL). After the solvent layer was decanted off, the residue was dried in vacuo to give the racemic amino ester hydrochloride salt (Example J) as a white solid (38 g).

Example K Preparation of ethyl (3S)amino[3-bromo(di-fluoromethyl)phenyl]propanoate hydrochloride H N2 COZEt *HCI Br CFZH Step 1 HO/—\OH TsOH 1 2 3,5-dibromo benzaldehyde 1 (10 g, 37.8 mmol, 1.0 eq), ethane-1,2-diol (7.0 g,114 mmol, 3.0 eq) and TsOH (0.32g, 1.89 mmol) in toluene (20 mL) was stirred at 110 0C for 4 h.

The mixture was cooled to 23 °C and trated, ted with EtOAc. The organic layer was washed with brine, dried (NazSO4) and concentrated to dryness to give compound 2 (9.2 g, 83.6 %) as an oil.

Step2 O O O O BuLi Br Br Br CH0 2 3 Compound 2 (9.2 g, 29.8 mmol, 1.0 eq) in THF (100 mL) was stirred at -78 0C. n- BuLi (12 mL, 1.0 eq) was added se to above mixture at -78 °C. The mixture was stirred at -78 0C for 1 h. DMF (4.56 g, 1.5 eq) was added dropwise to above mixture at -78°C.

The e was stirred at -78 °C for 3 h then warmed to 25 °C. Water was added to the mixture and then extracted with ethyl acetate. The organic layer was washed with brine, dried (NazSO4) and trated to dryness to give crude product. The crude product was purified by silica gel chromatograph to give compound 3 (6.6 g, 86.8%) as a white solid.

Step 3 O O O O DAST Br CHO Br CF2H 3 4 Compound 3 (6.6 g, 0.026 mol) was added to DCM (50 mL), then DAST (8.3 g, 0.052 mol) was added to the solution and the reaction was stirred for 8h under N2. The solution was washed with aq. NaHCO3, and the e was extracted with DCM. The organic layer was washed with brine, dried (NazSO4) and concentrated. The crude material was purified by silica gel chromatograph to give compound 4 (4.2 g, 58.3 %).

Step 4 O 0 CH0 Br CFZH Br CFZH 4 5 Compound 4 (4.2 g, 0.026 mol) was added to a solution of THF (40 mL) and 3N HCl (20 mL) and the reaction was stirred for 6h. The mixture was concentrated and the crude product was purified by silica gel chromatography to give compound 5 (3.6 g, 76.9%).

Step 5 COzEt CH0 H2N Q HOOCCH2COOEt , NH4OAc Br CF2H Br CF2H NH4OAc (0.54 g, ol), HOOCCH2COOEt (2.9 g, 0.022mol) and compound 5 (3.6 g, 0.011 mol), in EtOH (30 mL) were stirred at 70 °C for 6h. The e was concentrated and adjusted to pH=7.5 by addition of aq. NaHCO3. The mixture was ted with EtOAc. The organic layer was washed with brine, dried (NazSO4) and concentrated to dryness to give oil. The crude was purified by silica gel chromatography to give compound 6 (0.6 g, 17.1 %). The (S) enantiomer, Example K, was isolated using the enzymatic resolution procedures described above.

Example L Preparation of ethyl (3S)amino[3-chloro(di-fluoromethyl)phenyl]propanoate hydrochloride H N2 COZEt *HCI CI CF2H Example L was synthesized as described in the procedure for Example K, but tuting 3-bromochloro benzaldehyde for 3,5-di-bromo benzaldehyde in Step 1.

Example 1 Preparation of (3S)(3,5-dibromophenyl)(2-(3-hydroxy-S-((5-hydroxy-1,4,5,6- tetrahydropyrimidin-Z-yl)amino)benzamido)acetamido)propanoic acid NYNH HN iii/\ll/ N COZH Br Br Step 1 Preparation ofethyl (31$) 3-[3, 5-dibr0m-phenyl)(2-(3-hydr0xy((5-hydr0xy—1,4, 5, 6- ydropyrimidin-Z—yl)amino)benzamid0)acetamidojpropanoaz‘e N\ NH ”W COZEt Br Br A e of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid le B) (513.80 mg, 1.667 mmol), ethyl (3S)amino- 3-(3,5-dibromophenyl) propanoate hydrochloride (the (S) ester of Example J formed via the enzymatic lipase cleavage method) (645.80 mg, 1.667 mmol) and 1-hydroxybenzotriazole hydrate (52.0 mg, 0.340 mmol) was dissolved in a mixture of DMF (6 mL) and dichloromethane (6 mL) and the reaction mixture was stirred under nitrogen atmosphere for min to give a cream suspension. Neat N,N’-diisopropylcarbodiimide (360.0 uL, 2.325 mmol) was added and the reaction e was d at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a colorless viscous residue of the product: ethyl (3S)—3-[3,5-dibromophenyl][[2-[[3-hydroxy[(5-hydroxy- 1,4,5,6-tetrahydropyrimidinyl)amino]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 640 (79Br=79BrM+H), m/z 642 (79Br=81Bri\/1+H), m/Z 644 (SIBLSIBFNHH), W2 662 (79Br=79Bri\/1+Na), m/Z 664 (79Br=81BrM+Na), and m/z 666 (SlBr=81BrM+Na); Calculated for C24H27Br2N506: 641.31. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation of (3S)(3, 5-a’l'br0m0phenyl)(2—(3-hydr0xy-5—((5-hya’r0xy-1, 4, 5, 6- tetrahydropyrimidmyl)amin0)benzamia’o)acetamia’o)pr0panoic acia’ NYNH HN I'll/\ll/ N COZH Br Br To a solution of crude ethyl (3S)[3,5-dibromophenyl][[2-[[3-hydroxy[(5- hydroxy-1,4,5 ,6-tetrahydropyrimidinyl)amino] benzoyl] amino] acetyl] amino]propanoate from step 1 above (1.667 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (10 mL) was added lithium ide monohydrate (350.0 mg, 8.341 mol) at room temperature and the reaction mixture was stirred at room ature for 1 h. The mixture was neutralized with TFA (1.0 mL in 10.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless gummy residue. The above crude product was purified by reverse-phase HPLC with a nt 10-70% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a ess lyophilized solid (Example 1) (684.2 mg, yield 67%). LC/MS analysis of the product shows the desired product's mass: m/z 612 (79Br=79BrM+H), m/z 614 ngrM+H), and m/z 616 ngrM+H), Calculated for C22H23Br2N506: 613.26. 1H NMR (400 MHZ, DMSO-a’6): 5 2.74 (d, J = 7.10 Hz, 2H), 3.16 (d, J = 12.23 Hz, 2H), 3.33 (d, J = 11.25 Hz, 2H), 3.86 (d, J = 5.87 Hz, 2H), 4.08 (brs, 1H), 5.14 (q, J = 7.34 Hz, 1H), 6.74 (appt, J = 2.0 Hz, 1H), 7.11 (appt, 1H), 7.14 (appt, J :17 Hz, 1H),7.56 (d, J =1.71 Hz, 2H), 7.71 (t, J = 1.7 Hz, 1H), 8.11 (s, 1H), 8.53 (d, J = 7.8 Hz, 1H), 8.64 (t, J = 6.0 Hz, 1H), 9.61 (s,1H), 10.01 (brs, 1H),12.40 (brs, 1H). 1H NMR spectrum of the sample was consistent with the proposed structure for Example 1. 2016/069511 Example 2 Preparation of (3S)(3-bromo(trifluoromethyl)phenyl)—3-(2-(3-hydr0xy((5— hydroxy—1,4,5,6-tetrahydropyrimidin-Z-yl)amin0)benzamid0)acetamid0)pr0pan0ic acid NYNH O HN u/\[O]/N COZH Br CF3 Step 1 Preparation ofethyl (3S) 3-(3-br0m0(trifluoromethyUphenyU-S-(Z-(3-hydr0xy((5- hydroxy-I, 4, 5, 6-z‘etrahydropyrimidin-Z—yl)ammo)benzamido)acetamid0)pr0pan0ate NI—TNrNH o ”W COzEt Br CF3 A mixture of 2-(3-hydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (83.0 mg, 0.269 mmol), ethyl (3S)amino (3-bromo(trifluoromethyl)phenyl)propanoate hydrochloride (Example F) (102.0 mg, 0.271 mmol) was ved in DMF (4 mL) and dichloromethane (4 mL) to give a cream suspension. Solid 1-hydroxybenzotriazole hydrate (8.7 mg, 0.057 mmol) was added to above reaction mixture and the reaction mixture was stirred under nitrogen here for 10 min.

N,N'—diisopropylcarbodiimide (60.0 uL, 0.387 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a colorless gummy e of the product: ethyl (3S)—3-[3- bromo(trifluoromethyl)phenyl][[2-[[3-hydroxy[(5-hydroxy-l,4,5,6- tetrahydropyrimidinyl)amino]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired t’s mass: m/z 630 (79BrM+H), m/z 632 (SlBrM+H), m/z 652 (79BrM+Na), and m/z 654 (SlBrM+Na), Calculated for C25H27BrF3N506: 630.41. The crude e was used as such for the saponification reaction in step 2.

Step 2 Preparation 0f(31$)(3-br0m0(trifluoromethyUphenyl)(2-(3-hydr0xy((5-hydr0xy- 1, 4, 5, 6—2‘6trahya’ropyrimia’in-Z—yl)am1770)benzaml'a’o)acetamia’o)pr0panoic acia’ N\ NH ”W COZH Br CF3 To a solution of crude ethyl (3S)—3-[3-bromo(trifluoromethyl)phenyl][[2-[[3- hydroxy[(5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate from step 1 above (0.344 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (4 mL) was added lithium hydroxide monohydrate (77.0 mg, 1.83 mol) at room temperature and the reaction mixture was stirred at room temperature for 1.5 h. The mixture was neutralized with TFA (1.0 mL in 10.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water ning 0.05% TFA to give the desired product, after lization, as a colorless lyophilized solid (Example 2) (124.0 mg, yield 60%). LC/MS analysis of the product shows the desired product's mass: m/Z 602 (79BrM+H), and m/Z 604 H), Calculated for C23H23BrF3N506: . 1H NMR (400 MHz, DMSO-a’g): 5 2.78 (d, J = 7.3 Hz, 2H), 3.16 (d, J = 12.2 Hz, 2H), 3.33 (d, J = 12.2 Hz, 2H), 3.87 (d, J = 5.8 Hz, 2H), 4.08 (appt, J = 3.07 Hz, 1H), 5.23 (q, J = 7.3 Hz, 1H), 6.74 (t, J = 2.1 Hz, 1H), 7.11 (t, J = 1.8 Hz, 1H), 7.14 (t, J = 1.8 Hz, 1H), 7.72 , 7.85 (s,1H), 7.87 (s, 1H), 8.10 (brs, 2H), 8.61 (d, J = 7.9 Hz, 1H), 8.64 (t, J = 5.9 Hz, 1H), 9.60 (s,1H), 10.02 (brs, 1H),12.41 (brs, 1H, -COOH). 1H NMR spectrum of the t was consistent with the proposed structure for Example 2. 19F NMR (376 MHz, DMSO-a’g): 8 -61.09 (s), and -73.82 (s).

Preparation of (3S)[3-chloro-S-(difluoromethyl)phenyl)(2-(3-hydroxy-5—((5- hydroxy-1,4,5,6-tetrahydr0pyrimidin-Z-yl)amin0)benzamid0)acetamid0] oic acid NYNH O HN u/\g/N COZH Cl CF2H Step 1 ation 0f(3§)-ethyl 3-[3-ch10r0(dl'flu0r0methyUphenyl)(2-(3-hydr0xy-5—((5- hydroxy-I, 4, 5, 6-z‘etrahydropyrimidin-Z—yUammo)benzaml'do)acetamidojpropanoate N\ NH ”W COZEt CI CFZH A mixture of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (27.0 mg; 0.088 mmol), (S)—ethyl 3-amino (3-chloro(1-(difluoromethyl)phenyl)propanoate hydrochloride (Example L) (27.51 mg, 0.088 mmol) was ved in DMF (1 mL) and dichloromethane (1 mL) to give a colorless suspension. Solid 1-hydroxybenzotriazole hydrate (3.0 mg, 0.020 mmol) was added to above reaction mixture and the reaction mixture was stirred under nitrogen atmosphere for 10 min.

N,N'—diisopropylcarbodiimide (20.0 uL, 0.129 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a pale yellow viscous residue of the product: (3S)—ethyl 3-(3- chloro(difluoromethyl)phenyl)(2-(3-hydroxy((5-hydroxy-1,4,5,6- tetrahydropyrimidinyl)amino)benzamido)acetamido)propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 568 (35C1M+H), m/z 570 +H), m/z 590 +Na), and m/z 592 (37C1M+Na); Calculated for C25H28C1F2N506: 567.97. The crude residue was used as such for the saponification reaction in Step 2.

WO 17538 Step 2 Preparation 0f(31$)[3-ch10r0(difluoromethyUphenyZ)(2—(3-hydr0xy((5-hya’r0xy- 1,4,5, 6-z‘etrahydropyrimidm-Z-yl)ammo)benzaml'a’o)acetamia’ojpropanoic acia’ YNH 0 HN ”WN COZH Cl CF2H To a suspension of crude (3S)—ethyl 3-(3-chloro(difluoromethyl)phenyl)(2-(3- hydroxy-5 -((5-hydroxy-l ,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetamido)propanoate from step 1 above (0.088 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (4 mL) was added lithium ide drate (20.0 mg, 0.477 mol) at room temperature and the reaction mixture was stirred at room temperature overnight. The mixture was lized with TFA (1 mL in 10.0 mL CH3CN) and the mixture was evaporated uo to give a yellow gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water ning 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 3) (41.2 mg, yield 87%). LC/MS analysis of the product shows the desired product's mass: m/Z 540 (35C1M+H) and m/z 542 (37C1M+H), Calculated for C23H24ClF2N506: 539.92. 1H NMR (400 MHz, DMSO-a’g): 5 2.76 (d, J = 7.34 Hz, 2H, -CH2-COOH), 3.16 (d, J = 12.23 Hz, 2H), 3.33 (d, J = 10.76 Hz, 2H), 3.87 (dd/m, 3H), 4.08 (t, J = 3.18 Hz, 1H), 5.21 (q, J = 7.34 Hz, 1H, -NH-CH-CH2-COOH), 6.74 (t, J = 2.08 Hz, 1H), 7.03 (s, 1H), 7.11 (t, J =1.71 Hz, 1H), 7.13 (apt, 1H), 7.53 (brs, 1H), 7.59 (s, 1H), 8.14 (brs, 2H), 8.63 (t, J = 5.87 Hz, 1H), 9.67 (brs,lH), 10.02 (brs, 1H), 12.44 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 3. 19F NMR (376 MHz, DMSO-a’g): 6 -74. 12 (s), and -110.28 (d, J = 56.0 Hz).

Example 4 Preparation of (3S)[3-br0mo(difluor0methyl)phenyl)—3—(2-(3-hydr0xy((5- hydroxy-1,4,5,6-tetrahydr0pyrimidin-Z-yl)amin0)benzamid0)acetamid0] propanoic acid NYNH O HN u/\g/N COZH Br CF2H Step 1 ation 0f(3§)-ethyl 3-[3-br0m0(diflu0r0methyUphenyl)(2-(3-hydr0xy((5- hydroxy-I, 4, 5, 6—z‘etrahydropyrimidin-Z—yUammo)benzaml'do)acetamidojpropanoate N\ NH ”W COZEt Br CFZH A e of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (25.0 mg; 0.081 mmol), ethyl (3S)amino (3-bromo(1-(difluoromethyl)phenyl)propanoate hloride (Example K) (29.08 mg, 0.081 mmol) was dissolved in DMF (1 mL) and romethane (1 mL) to give a colorless suspension. Solid 1-hydroxybenzotriazole hydrate (3.0 mg, 0.020 mmol) was added to above reaction mixture and the reaction mixture was d under nitrogen atmosphere for 10 min.

N,N'—diisopropylcarbodiimide (20.0 uL, 0.129 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a yellow orange s residue of the product: (3S)—ethyl 3-(3- bromo-S-(difluoromethyl)phenyl)(2-(3-hydroxy-5 -((5-hydroxy-1,4,5 ,6- tetrahydropyrimidinyl)amino)benzamido)acetamido)propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 612 (79BrM+H), m/z 614 (SlBrM+H), m/z 634 (79BrM+Na), and m/z 636 (SlBrM+Na); Calculated for C25H28BrF2N506; 612.42. The crude residue will be used as such for the saponification reaction in Step 2.

WO 17538 Step 2 Preparation of(31$)[3-br0m0-5—(dij‘luoromethyUphenyl)(2-(3-hya’r0xy((5-hya’r0xy- 1, 4, 5, 6—z‘etrahydropyrimidm-Z-yl)ammo)benzaml'a’o)acetamia’ojpropanoic acia’ NYNH HN ”WN COZH Br CF2H To a suspension of crude ethyl -(3-bromo(difluoromethyl)phenyl)(2-(3- hydroxy-5 -((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetamido)propanoate from step 1 above (0.080 mmol) in a e of a 1:1 mixture of acetonitrile/water (4 mL) was added lithium hydroxide monohydrate (18.0 mg, 0.429 mol) at room temperature and the reaction mixture was stirred at room temperature overnight. The mixture was lized with TFA (500 uL in 5.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a yellow gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 4) (33.4 mg, yield 71%). LC/MS analysis of the product shows the desired product's mass: m/Z 584 (79BrM+H), m/Z 586 (SlBrM+H), m/Z 606 (79BrM+Na), and m/Z 608 (SlBrM+Na), Calculated for C23H24BI'F2N506: 584.37. 1H NMR (400 MHz, DMSO-a’a): 5 2.76 (d, J = 7.34 Hz, 2H, -CH2-COOH), 3.16 (d, J = 12.47 Hz, 2H), 3.33 (d, J = 10.76 Hz, 2H), 3.87 (dd/m, 3H), 4.08 (t, J = 2.90 Hz, 1H), 5.21 (q, J = 7.34 Hz, 1H, -NH-CH-CH2-COOH), 6.74 (t, J = 2.08 Hz, 1H), 7.02 (appt, 1H), 7.14 (appt, 1H), 7.56 (s, 1H), 7.66 (s, 1H), 7.72 (s, 1H), 8.13 (brs, 1H), 8.58 (s, 1H), 8.62 (t, J = 5.99 Hz, 1H), 9.65 (brs,1H), 10.02 (brs, 1H), 12.40 (brs, 1H, -COOH). 1H NMR spectrum of the t was consistent with the proposed structure for Example 4. 19F NMR (376 MHz, DMSO-a’g): 6 -73.81 (s), and -110.23 (d, J = 56.0 Hz).

Example 5 Preparation of (3S)[3-chloro—S-(trifluoromethyl)phenyl)(2-(3-hydr0xy((5- hydroxy-1,4,5,6-tetrahydr0pyrimidin-Z-yl)amin0)benzamid0)acetamid0] propanoic acid NYNH O HN u/\[O]/N COZH Cl CF3 Step 1 Preparation 0f(3§)-ethyl 3-[3-ch10r0(tifluoromethyUphenyl)(2—(3-hydr0xy((5- hydroxy-I, 4, 5, 6—z‘etrahydropyrimidin-Z—yUammo)benzaml'do)acetamidojpropanoate N\ NH ”AW COzEt CI CF3 A mixture of ydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin no)benzamido)acetic acid (Example B) (43.0 mg; 0.139 mmol), ethyl (3S)amino (3-chloro(l-(trifluoromethyl)phenyl)propanoate hydrochloride (Example E) (46.33 mg, 0.139 mmol) was dissolved in DMF (1 mL) and dichloromethane (1 mL) to give a colorless suspension. Solid oxybenzotriazole hydrate (4.40 mg, 0.029 mmol) was added to above reaction mixture and the reaction mixture was stirred under en atmosphere for 10 min. N,N'—diisopropylcarbodiimide (32.0 uL, 0.207 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen here overnight. The solvent was evaporated in-vacuo to give a colorless gummy residue of the product: (3S)—ethyl 3-(3- chloro(trifluoromethyl)phenyl)—3-(2-(3 -hydroxy((5 -hydroxy- 1 ,4,5,6- tetrahydropyrimidinyl)amino)benzamido)acetamido)propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/Z 586 (35C1M+H), m/z 588 (37C1M+H), m/z 608 (35C1M+Na), and m/z 610 (37C1M+Na); Calculated for C25H27C1F3N506: 585.96. The crude e was used as such for the saponification reaction in step 2.

Step 2 Preparation )[3-chlor0(triflu0r0methyUphenyl)(2-(3-hydr0xy-5—((5-hya’r0xy- 1, 4, 5, 6-z‘etrahydropyrimidm-Z-yl)ammo)benzaml'a’o)acetamia’ojpropanoic acia’ YNH 0 HN ”WN COZH Cl CF3 To a sion of crude ethyl (3S)—3-(3-chloro(tiifluoromethyl)phenyl)(2-(3- hydroxy-5 -((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetamido)propanoate from step 1 above (0.139 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (4 mL) was added lithium hydroxide monohydrate (30.0 mg, 0.715 mol) at room temperature and the reaction mixture was stirred at room ature overnight. The mixture was neutralized with TFA (1 mL in 10.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a cream gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water containing 0.05% TFA to give the desired product, after lization, as a colorless lyophilized solid (Example 5) (63.2 mg, yield 81%)). LC/MS analysis of the product shows the desired t's mass: m/z 558 (35C1M+H) and m/z 560 (37C1M+H), Calculated for C23H23ClF3N506: . 1H NMR (400 MHZ, DMSO-a’6): 5 2.79 (d, J = 7.09 Hz, 2H, -CH2-COOH), 3.16 (d, J = 11.98 Hz, 2H), 3.33 (d, J = 11.00 Hz, 2H), 3.87 (d, J = 5.87 Hz, 2H), 4.08 (t, J = 3.18 Hz, 1H), 5.24 (q, J = 7.09 Hz, 1H, -NH-CH-CH2-COOH), 6.75 (s, 1H), 7.11 (s, 1H), 7.13 (t, J = 2.00 Hz, 1H), 7.69 (s, 1H), 7.74 (s, 1H), 8.12 (brs, 1H), 8.61 (d, J = 8.07 Hz, 1H), 8.65 (t, J = 5.75 Hz, 1H), 9.66 (brs,1H), 10.02 (brs, 1H), 12.43 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 5. 19F NMR (376 MHz, DMSO-a’g): 8 -61.11 (s), and -73.94 (s).

Example 6 Preparation of (3S)[3-bromo-5—ch10r0-phenyl)(2-(3-hydr0xy—5-((5—hydroxy-1,4,5,6- tetrahydr0pyrimidin-Z-yl)amino)benzamid0)acetamid0]propanoic acid N\ NH ”W COZH Cl Br Step 1 Preparation of(359-62102] 3-[3-br0m0ch10r0-phenyl)(2-(3-hydr0xy—5-((5-hydr0xy- 1, 4, 5, mhydropyrimidin-Z—yUammo)benzamid0)acetamidojpropanoate N\ NH ”W COZEt Cl Br A mixture of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (82.0 mg; 0.266 mmol), ethyl (3S)amino (3-bromochloro-phenyl)propanoate hydrochloride ( sized as in the methods described above starting from 3-bromochloro benzaldehyde) (91.40 mg, 0.266 mmol) was dissolved in DMF (1.5 mL) and dichloromethane (1.5 mL) to give a cream-orange suspension. Solid 1-hydroxybenzotriazole hydrate (9.0 mg, 0.059 mmol) was added to above reaction e and the reaction mixture was stirred under en atmosphere for 10 min.

N,N'—diisopropylcarbodiimide (60.0 uL, 0.387 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a dirty yellow-orange gummy residue of the product: thyl 3-(3-bromochloro-phenyl)(2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin no)benzamido)acetamido)propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 596 (35C1=79BFM+H), m/z 598 (35cm1Br=37C1=79BrM+H), m/z 600 (37C1,81BrM+H)3 m/Z 618 (35C1,79BrM+Na)3 m/Z 620 (35Cl,81Br,37Cl,79BrM+Na) and m/Z 622 (37C1=SlBrM+Na), Calculated for C24H27BrClN506:596.86. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation )[3-br0m0-5—ch10r0-phenyl)(2—(3-hydr0xy—5-((5-hydr0xy-1, 4, 5, 6- tetrahya’ropyrimidin-Z—yUammo)benzamia’o)acetamia’ojpropanoic acia’ NYNH HN Iii/YN COZH Cl Br To a suspension of crude ethyl (3S)(3-bromochloro-phenyl)(2-(3-hydroxy droxy-1,4,5,6-tetrahydropyrimidinyl)amino)benzamido)acetamido)propanoate from step 1 above (0.266 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (4 mL) was added lithium hydroxide drate (56.0 mg, 0.1.334 mol) at room temperature and the reaction mixture was d at room temperature for 4 h to give an orange-yellow solution.

The mixture was neutralized with TFA (1 mL in 10.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 6) (88.7 mg, yield 59%). LC/MS analysis of the product shows the desired product's mass: m/Z 568 79BM+H), m/z 570 (35C1=81Br=37C1=79Br1\/I+H), and m/z 572 SlBrM+H), Calculated for C22H23BI'ClN506: 568.80. 1H NMR (400 MHz, DMSO-a’a): 5 2.74 (d, J = 7.34 Hz, 2H, -CH2—COOH), 3.16 (d, J = 12.23 Hz, 2H), 3.34 (d, J = 11.74 Hz, 2H), 3.87 (d, J = 5.87 Hz, 2H), 4.08 (appt, 1H), 5.15 (q, J = 7.42 Hz, 1H, -NH-CH—CH2- COOH), 6.75 (t, J = 1.96 Hz, 1H), 7.11 (s, 1H), 7.14 (s, 1H), 7.43 (s, 1H), 7.52 (s, 1H), 7.60 (s, 1H), 8.13 (brs, 1H), 8.84 (d, J = 8.07 Hz, 1H), 8.64 (t, J = 5.87 Hz, 1H), 9.65 (brs,1H), .03 (brs, 1H), 12.45 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 6.

Example 7 Preparation of (3S)[3-chloro-5—(trifluoromethyl)phenyl]-3—[[2-[[5-[(5—hydroxy—1,4,5,6- tetrahydropyrimidin-Z-yl)amino]pyridine-S-carbonyl]amino]acetyl]amin0]pr0pan0ic acid HN N \ N CO H | HW 2 Cl 01:3 Step 1 Preparation ofethyl (3S)[3-ch10r0(trifluoromethyUphenylj[[2-[[5-[(5—hydr0xy— 1,4,5, 6-tetrahydropyrimidin-Z—yl)aminojpyridme carbonyljaml'nojacelyljaml'nojpropanoate N NH Y 0 HN N \ N CO Et I/ 93 2 CI CF3 A mixture of 2-[[5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino]pyridine carbonyl]amino]acetic acid (Example D) (56.0 mg,0.115 mmol), ethyl (3S)amino[3- chloro(trifluoromethyl)phenyl)propanoate hydrochloride le E) (38.05 mg, 0.115 mmol) and 1-hydroxybenzotriazole hydrate (3.5 mg, 0.023 mmol) was dissolved in DMF (3 mL) and dichloromethane (3 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N'—diisopropylcarbodiimide (25 uL, 0.161 mmol) was added and the reaction mixture was stirred at room temperature under en atmosphere overnight. The solvent was evaporated uo to give a colorless gummy solid of the intermediate product: ethyl (3S)—3-[3-chloro(trifluoromethyl)phenyl][[2-[[5-[(5- hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino]pyridine carbonyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude e shows the desired product’s mass: m/z 571 +H), m/z 573 (37C1M+H); m/z 593 (35C1M+Na), and m/z 595 (37C1M+Na); Calculated for C24H26ClF3N605: 570.95. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation 0f(31$)[3-ch10r0(trifluoromethyUphenylj[[2—[[5-[(5-hydr0xy—1, 4, 5, 6- z‘etrahydropyrl'mia’m-Z-yl)ammojpyridme-S-carbonyljammojacetyljammojpropanoic acia’ \ N I/ Q? COZH Cl CF3 To a suspension of ethyl (3S)—3-[3-chloro(trifluoromethyl)phenyl][[2-[[5-[(5- hydroxy-1,4,5 ,6-tetrahydropyrimidinyl)amino]pyridine carbonyl]amino]acetyl]amino]propanoate from step 1 above (0.115 mmol) in a e of a 1:1 mixture of acetonitrile/water (4 mL) was added lithium hydroxide monohydrate (25.0 mg, 0.596 mmol) and the reaction mixture was d at room temperature for 1 h. The reaction mixture was neutralized with TFA (250 uL in 5 mL CH3CN) and the mixture was ated in-vacuo to give a colorless residue. The crude product was purified by e-phase HPLC with a gradient 10-70% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid le 7) (46.4 mg, yield 74%).

LC/MS analysis of the product shows the desired product’s mass: m/z 558 (35C1M+H), and m/z 560 (37C1M+H); Calculated for C22H22ClF3N605: 542.90. 1H NMR (400 MHz, DMSO-a’a): 5 2.79 (d, J = 7.34 Hz, 2H, -CH2—COOH), 3.17 (d, J = 11.98 Hz, 2H), 3.36 (d, J = 11.98 Hz, 2H), 3.94 (d, J = 5.87 Hz, 2H), 4.11 (brt, 1H), 5.25 (q, J = 7.09 Hz, 1H, -NH-CH-CH2- COOH), 7.70 (s, 1H), 7.75 (s, 2H), 8.02 (s, 1H), 8.43 (brs, 2H), 8.59 (brs, 1H), 8.66 (d, J = 8.07 Hz, 1H), 8.90 (brs, 1H), 9.04 (t, J = 5.75 Hz, 1H), 9.92 (s,1H), 12.41 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 7. 19F NMR (376 MHz, DMSO-a’g): 8 -61.12 (s), and -74.31 (s).

Example 8 Preparation of (3S)(3-bromo-S-chloro—phenyl)—3—[[2-[[5—[(5-hydr0xy-1,4,5,6— tetrahydropyrimidin-Z-yl)amino]pyridine-S-carbonyl]amino]acetyl]amin0]pr0pan0ic acid HN N Cl Br Step 1 Preparation ofethyl (3S)(3-br0m00ch10r0-phenyl)[[2-[[5-[(5—hydr0xy—1,4, 5, 6- retrahydropyrl'midm-Z-yl)amino]pyridme-S-carbonyljammojacelyljammojpropanoaz‘e \ N COEt I/ We 2 Cl Br A mixture of 2-[[5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino]pyridine carbonyl]amino]acetic acid (Example D) (80.0 mg,0.164 mmol), ethyl -amino[3- bromochlorophenyl)propanoate hydrochloride (synthesized as in the s bed above starting from 3-bromochloro benzaldehyde) (56.15 mg, 0.164 mmol) and 1- hydroxybenzotriazole hydrate (6.0 mg, 0.039 mmol) was dissolved in DMF (3 mL) and dichloromethane (3 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N'—diisopropylcarbodiimide (35.0 uL, 0.226 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a colorless solid of the intermediate product: ethyl (3S)[3-bromochloro-phenyl][[2-[[5-[(5-hydroxy-1,4,5,6- tetrahydropyrimidinyl)amino]pyridinecarbonyl]amino]acetyl] amino]propanoate. LC- MS is of the crude residue shows the desired product’s mass: m/z 581 79BFM+H), m/Z 583 (35Cl,81Br,37Cl,79BrM+H)3 m/Z 585 (37Cl,81BrM+H)3 m/Z 603 (35C1=79BrM+Na), m/Z 605 (35C1=81Br=37C1=79Br1\/I+Na) and m/z 607 (37C1=81BrM+Na); Calculated for C23H26lBrClN6Os; .

The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation of (3S)(3-br0m0-5—chlar0-phenyl)[[2-[[5—[(5-hydr0xy-1, 4, 5, 6- z‘etrahydropyrl'midm-Z-yl)ammojpyridme-S-carbonyljammojacetyljammojpropanoic acid HN PrN \ I 004* Cl Br To a suspension of ethyl (3S)—3-[3-bromochloro-phenyl][[2-[[5-[(5-hydroxy- 1,4,5,6-tetrahydropyrimidinyl)amino]pyridinecarbonyl]amino] acetyl]amino]propanoate from step 1 above (0.164 mmol) in a mixture of a 1:1 e of acetonitrile/water (6 mL) was added m hydroxide monohydrate (35.0 mg, 0.834 mmol) and the reaction mixture was stirred at room temperature for 2 h. The on mixture was neutralized with TFA (250 uL in 5 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless crystalline solid. The crude product was purified by reverse-phase HPLC with a gradient 10-50% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 8) (55.0 mg, yield 61%).

LC/MS analysis of the product shows the desired product's mass: m/z 553 (35C1=79BTM+H), m/z 555 (35C1=81Br=37C1=79BrM+H), and m/z 557 (37C1=81BFM+H); Calculated for C21H22BrClN605: 553.79. 1H NMR (400 MHz, DMSO-dg): 5 2.75 (d, J = 7.34 Hz, 2H, OOH), 3.17 (d, J = 12.23 Hz, 2H), 3.36 (d, J = 11.00 Hz, 2H), 3.94 (d, J = 5.62 Hz, 2H), 4.11 (t,J = 3.20 Hz, 1H), 5.16 (q, J = 7.42 Hz, 1H, -NH-CH-CH2-COOH), 7.44 (t, J = 1.47 Hz, 1H), 7.53 (apt, 1H), 7.60 (t, J = 1.83 Hz,1H), 8.03 (t, J = 2.08 Hz, 1H), 8.42 (brs, 2H), 8.59 (d, J =7.82 Hz, 1H), 8.90 (brs, 1H), 9.03 (t, J = 5.87 Hz, 1H), 9.90 (s,1H), 12.42 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 8.

Example 9 Preparation of (3S) [3-brom0-5—(trifluoromethyl)phenyl] [ [2- [ [5- droxy- 1,4,5,6-tetrahydr0pyrimidin-2—yl)amino]pyridine carbonyl]amin0]acetyl]amin0]pr0pan0ic acid | HAWN \ N CO H2 Br CF3 Step 1 Preparation ofethyl (35)[3-br0m0-5—(trifluoromethyUphenylj[[2-[[5-[(5—hydr0xy— 1, 4, 5, 6—2‘6trahydropyrimidin-Z—yl)aminojpyridme carbonyljaml'nojacelyljaml'nojpropanoate N NH \Y 0 HN N \ N CO Et l/ Hfir 2 Br CF3 A e of 2-[[5-[(5-hydroxy-1,4,5,6-tetrahydropyrimidinyl)amino]pyridine yl]amino]acetic acid (Example D) (64.0 mg,0.131 mmol), ethyl (3S)amino(3- bromo(trifluoromethyl)phenyl)propanoate hydrochloride (Example F) (49.31 mg, 0.131 mmol) and 1-hydroxybenzotriazole hydrate (5.0 mg, 0.033 mmol) was dissolved in DMF (3 mL) and dichloromethane (3 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N'—diisopropylcarbodiimide (30.0 uL, 0.194 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a colorless gummy solid of the ediate product: ethyl (359[3-bromo(trifluoromethyl)phenyl][[2-[[5-[(5- y-1,4,5 ,6-tetrahydropyrimidinyl)amino] pyridine-3 -carbonyl] amino] acetyl]amino]propanoate. LC-MS analysis of the crude e shows the desired product’s mass: m/Z 615 (79BrM+H), m/Z 617 (SlBrM+H), m/Z 637 (79BrM+Na), and m/Z 639 (SlBrM+Na); Calculated for BrF3N605: 615.40. The crude residue was used as such for the saponification on in Step 2.

Step2 Preparation of (3S)[3-br0m0-5—(trifluoromethyUphenyl][[2—[[5-[(5-hydr0xy—1, 4, 5, 6- hya’ropyrl'mia’m-Z-yl)ammojpyria’me-S-carbonyljammojacetyljammojpropanoic acia’ NI—jN/NH O \ 01N I/ COZH Br CF3 To a suspension of ethyl (3S)[3-bromo(trifluoromethyl)phenyl][[2-[[5-[(5- hydroxy-1,4,5 ,6-tetrahydropyrimidinyl)amino] pyridine-3 -carbonyl] amino] acetyl]amino]propanoate from step 1 above (0.131 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide monohydrate (30.0 mg, 0.715 mmol) and the reaction e was stirred at room temperature for 1 h. The reaction mixture was neutralized with TFA (250 uL in 5 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless crystalline solid. The crude t was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 9) (69.6 mg, yield 90%).

LC/MS analysis of the product shows the desired product's mass: m/z 587 (79BrM+H), m/z 589 +H), m/z 609 (79BrM+Na), and m/z 611 (SlBrM+Na), Calculated for C22H22BrF3N605: 587.35. 1H NMR (400 MHz, DMSO-a’g): 5 2.79 (d, J = 7.34 Hz, 2H, -CH2—COOH), 3.17 (d, J = 12.47 Hz, 2H), 3.36 (d, J = 11.74 Hz, 2H), 3.94 (d, J = 5.87 Hz, 2H), 4.11 (brt, 1H), 5.24 (q, J = 7.25 Hz, 1H, -NH-CH-CH2-COOH), 7.73 (s, 1H), 7.85 (s, 1H), 8.02 (t, J =2.08 Hz, 1H), 8.43 (brs, 2H), 8.59 (d, J = 1.96 Hz, 1H), 8.66 (d, J = 8.07 Hz, 1H), 8.90 (s, 1H), 9.05 (t, J = 5.75 Hz, 1H), 9.92 (s,1H), 12.43 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 9. 19F NMR (376 MHz, DMSO-a’a): 6 -61.10 (s), and -74.47 (s). e 10 Preparation of (3S)[3,5-bis(trifluoromethyl)phenyl)(2-(3-hydr0xy((5-hydroxy- 1,4,5,6-tetrahydropyrimidin-Z-yl)amin0)benzamido)acetamid0] propanoic acid N\ NH ”W COZH F3C CF3 Step 1 Preparation ofethyl -[3,5-bis(tifluoromethyUphenyl)(2-(3-hydr0xy—5-((5-hydr0xy- 1, 4, 5, 6—z‘elmhydropyrimidin-Z—yUammo)benzamid0)acetamidojpropanoate N\ NH NAH/ COzEt F3C CF3 A mixture of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (65.50 mg; 0.212 mmol), ethyl (3S)amino (3,5-bis(1-(trifluoromethyl)phenyl)propanoate hydrochloride (synthesized as in the methods described above starting from 3,5-bis romethyl benzaldehyde) (77.70 mg, 0.212 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) to give a ess suspension.

Solid 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol) was added to above on mixture and the reaction mixture was stirred under nitrogen atmosphere for 10 min. N,N'— diisopropylcarbodiimide (45.0 uL, 0.291 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated m-vacuo to give a colorless gummy residue of the product: ethyl (3S)(3,5- bis(trifluoromethyl)phenyl)(2-(3 -hydroxy((5 -hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetamido)propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 620 (M+H), and m/z 642 (M+Na); Calculated for C26H27F6N506: 619.51. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation of(31$)[3, 5-bis (trifluoromethyl)phenyl)(2-(3-hya’r0xy((5—hya’r0xy- 1,4,5, 6—z‘etrahydropyrimidm-Z-yl)ammo)benzaml'a’o)acetamia’ojpropanoic acia’ NYNH HN ”WN COZH F3C CF3 To a suspension of crude ethyl (3S)—3-(3,5-bis(trifluoromethyl)phenyl)(2-(3- hydroxy-5 -((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetamido)propanoate from step 1 above (0.212 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide drate (45.0 mg, 1.072 mol) at room ature and the reaction mixture was stirred at room temperature for 1 h. The e was neutralized with TFA (250 uL in 5.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-60% CH3CN in water containing 0.05% TFA to give the d product, after lyophilization, as a colorless lyophilized solid (Example 10) (69.2 mg, yield 55%). LC/MS analysis of the product shows the desired product's mass: m/Z 592 (M+H) and m/z 614 (M+Na), Calculated for C24H23F6N506: 591.46. 1H NMR (400 MHz, DMSO-a’g): 5 2.83 (d, J = 7.34 Hz, 2H, -CH2-COOH), 3.15 (d, J = 12.23 Hz, 2H), 3.33 (brd, J = 10.67 Hz, 2H), 3.87 (d, J = 5.62 Hz, 2H), 4.08 (d,J = 3.18 Hz, 1H), .33 (q, J = 7.09 Hz, 1H, -NH-CH-CH2-COOH), 6.74 (t, J = 2.08 Hz, 1H), 7.10 (appt, 1H), 7.13 (appt, 1H), 7.85-8.22 (m, 4H), 8.48-8.93 (m, 2H), 9.64 , 10.02 (brs, 1H), 12.45 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed ure for Example 10. 19F NMR (376 MHz, DMSO-a’g): 6 -61. 14 (s),and -73.73 (s).

Example 11 Preparation of (3S)[3-bromo-S-methyl-phenyl)(2-(3-hydr0xy((5-hydroxy- 1,4,5,6-tetrahydropyrimidin-Z-yl)amin0)benzamid0)acetamid0)pr0pan0ic acid NYNH O HN MEN COZH Br CH3 Step 1 Preparation ofmethyl (3S) 3-[3-br0m0methyl-phenyl)(2-(3-hydr0xy((5-hydr0xy- 1, 4, 5, 6-z‘elmhydropyrimidin-Z—yUammo)benzamid0)acetamidojpropanoate N\ NH ”W COzMe Br CH3 A mixture of ydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (94.70 mg, 0.307 mmol), methyl -amino- 3-(3-bromomethyl-phenyl)propanoate hydrochloride esized as in the methods described above starting from 3-bromomethyl benzaldehyde) (94.80 mg, 0.307 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) to give a cream suspension. Solid 1- hydroxybenzotriazole hydrate (10.20 mg, 0.067 mmol) was added to above reaction mixture and the reaction mixture was stirred under nitrogen atmosphere for 10 min. N,N'— diisopropylcarbodiimide (70 uL, 0.452 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere ght. The solvent was evaporated in- vacuo to give a colorless gummy residue of the product: methyl (3S)—3-[3-bromomethyl- phenyl][[2-[[3-hydroxy[(5-hydroxy-l,4,5,6-tetrahydropy1imidin yl)amino]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the d product’s mass: m/z 562 (79BrM+H), m/z 564 (SlBrM+H), m/z 584 (79BrM+Na), and m/z 586 (SlBrM+Na), Calculated for C24H28BrN506: 562.41. The crude e was used as such for the saponification reaction in Step 2.

Step 2 Preparation of (3S)[3-br0m0-5—methyl-phenyl)(2-(3-hydr0xy—5-((5—hydr0xy-1, 4, 5, 6- ydropyrimidmyl)amin0)benzamia’o)acetamia’o)pr0panoic acid N\ NH NW COZH Br CH3 To a solution of crude methyl (3S)—3-[3-bromomethyl-phenyl][[2-[[3-hydroxy- -[(5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate from step 1 above (0.307 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide monohydrate (65 mg, 1.55 mol) at room temperature and the reaction mixture was stirred at room temperature for l h. The mixture was neutralized with TFA (500 uL in 5.0 mL CH3CN) and the e was evaporated in-vacuo to give a colorless gummy residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-50% CH3CN in water containing 0.05% TFA to give the d product, after lyophilization, as a colorless lyophilized solid le 11) (105.3 mg, yield 62%). LC/MS analysis of the product shows the d product's mass: m/Z 548 (79BrM+H), and m/Z 550 (81BM+H), Calculated for C23H26BI‘N5062 548.39. 1H NMR (400 MHz, DMSO-a’g): 5 2.28 (s, 3H, CH3-), 2.70 (d, J = 7.34 Hz, 2H, -CH2—COOH), 3.16 (d, J = 12.23 Hz, 2H), 3.34 (d, J = 11.98 Hz, 2H), 3.86 (d, J = 5.87 Hz, 2H), 4.09 (t,J = 2.90 Hz, 1H), 5.13 (q, J = 7.50 Hz, 1H, -NH-CH-CH2-COOH), 6.74 (t, J = 1.96 Hz, 1H), 7.11 (s, 1H), 7.14 (appt, 1H), 7.28 (apt, 1H), 7.31 (apt, 1H), 8.13 (brs, 1H), 8.48 (d, J = 8.31 Hz, 1H), 8.61 (t, J = 5.87 Hz, 1H), 9.64 (s,lH), 10.02 (brs, 1H), 12.37 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 1 1.

Example 12 ation of (3S)[3-chloro-S-methyl-phenyl)(2-(3-hydr0xy((5-hydroxy— 1,4,5,6-tetrahydropyrimidin-Z-yl)amin0)benzamid0)acetamido)pr0pan0ic acid NYNH O HN ”EN COZH CI CH3 Step 1 Preparation ofethyl (3S) 3-(3-ch10r0methyl-phenyl)(2-(3-hydr0xy-5—((5-hydr0xy— 1, 4, 5, 6-z‘etrahydropyrimidin-Z—yl)amin0)benzamido)acetamid0)pr0pan0ate N\ NH NAH/ COzEt CI CH3 A mixture of 2-(3-hydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (81.80 mg, 0.265 mmol), (S)-ethyl 3-amino (3-chloromethyl-phenyl)propanoate hydrochloride (synthesized as in the methods described above starting from 3-chloromethyl benzaldehyde) (73.81 mg, 0.265 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) to give a cream suspension. Solid 1- hydroxybenzotriazole e (8.4 mg, 0.055 mmol) was added to above reaction mixture and the reaction mixture was stirred under nitrogen atmosphere for 10 min. N,N'— diisopropylcarbodiimide (60 uL, 0.390 mmol) was added and the on mixture was d at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in- vacuo to give a colorless gummy residue of the product: ethyl (3S)[3-chloromethylphenyl ][[2-[[3-hydroxy[(5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the d product’s mass: m/z 532 (35C1M+H), m/z 534 (37C1M+H), m/z 554 (35C1M+Na), and m/z 556 (37C1M+Na), ated for C25H30ClN506: 531.99. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation of (3S)[3-ch10r0methyl-phenyl)(2-(3-hydr0xy((5—hydr0xy-1, 4, 5, 6- tetrahydropyrimidmyl)amin0)benzamia’o)acetamia’o)pr0panoic acid N\ NH NW COZH CI CH3 To a solution of crude ethyl (3S)[3-chloromethyl-phenyl][[2-[[3-hydroxy [(5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate from step 1 above (0.265 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium ide drate (56 mg, 1.334 mmol) at room temperature and the reaction mixture was stirred at room temperature for 1 h. The mixture was neutralized with TFA (500 uL in 5.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless viscous residue. The above crude product was purified by e-phase HPLC with a gradient 10-50% CH3CN in water containing 0.05% TFA to give the desired t, after lyophilization, as a colorless lyophilized solid (Example 12) (89.4 mg, yield 67%). LC/MS analysis of the product shows the desired product's mass: m/z 504 (35C1M+H), m/z 506 (37C1M+H), m/z 526 (35C1M+Na), and m/z 528 +H), Calculated for C23H26ClN506: 503.94. 1H NMR (400 MHz, DMSO-a’a): 2.29 (s, 3H, CH3-), 2.70 (d, J = 7.34 Hz, 2H, -CH2-COOH), 3.16 (d, J = 11.98 Hz, 2H), 3.34 (d, J = 11.00 Hz, 2H), 3.86 (d, J = 5.87 Hz, 2H), 4.09 (appt/m, 1H), 5.14 (q, J = 7.25 Hz, 1H, -CH2-COOH), 6.74 (t, J = 1.96 Hz, 1H), 7.11 (d, J = 1.47 Hz, 2H), 7.14 (appt, 2H), 7.18 (s, 1H), 8.14 (br s, 2H), 8.48 (d, J = 8.31 Hz, 1H), 8.61 (t, J = 5.99 Hz, 1H), 9.67 (s,1H), .03 (brs, 1H), 12.32 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 12.

Example 13 ation of (3S)[3-bromo-S-fluoro-phenyl)(2-(3-hydr0xy((5-hydroxy-1,4,5,6- ydr0pyrimidin-Z-yl)amino)benzamid0)acetamid0)pr0pan0ic acid N\ NH NW COZH F Br Step 1 Preparation ofethyl (3S) 3-[3-br0m0flu0r0-phenyl)(2—(3-hydr0xy((5-hydr0xy- 1, 4, 5, 6—z‘elmhydropyrimidin-Z—yUammo)benzamid0)acetamidojpropanoate N:NrNH o ”W COZEt F Br A e of 2-(3-hydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (79.50 mg, 0.258 mmol), ethyl (3S)amino- 3-(3-bromofluoro-phenyl)propanoate hydrochloride (synthesized as in the methods described above starting from 3-bromofluoro benzaldehyde) (84.22 mg, 0.258 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) to give a cream suspension. Solid 1- hydroxybenzotriazole hydrate (8.0 mg, 0.052 mmol) was added to above reaction mixture and the reaction mixture was stirred under en atmosphere for 10 min. N,N'— diisopropylcarbodiimide (60 uL, 0.387 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere ght. The solvent was evaporated in- vacuo to give a colorless gummy residue of the product: ethyl (3S)[3-bromofluoro- phenyl][[2-[[3-hydroxy[(5-hydroxy-l,4,5,6-tetrahydropy1imidin yl)amino]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 580 (79BrM+H), m/z 582 (SlBrM+H), m/z 602 (79BrM+Na), and m/z 604 (SlBrM+Na), Calculated for C24H27BrFN506: 580.40. The crude e was used as such for the saponification reaction in Step 2.

Step 2 Preparation of (3S)[3-br0m0flu0r0-phenyl)(2—(3-hydr0xy-5—((5-hydr0xy-1, 4, 5, 6- tetrahydropyrimidmyl)amin0)benzamia’o)acetamia’o)pr0panoic acid NYNH HN ”WN COZH F Br To a solution of crude ethyl (3S)[3-bromofluoro-phenyl][[2-[[3-hydroxy [(5-hydroxy-l -tetrahydropyrimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate from step 1 above (0.258 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide monohydrate (55 mg, 1.32 mol) at room temperature and the reaction mixture was stirred at room temperature overnight. The mixture was neutralized with TFA (250 uL in 5.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless gummy residue. The above crude product was purified by reverse-phase HPLC with a nt 10-50% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 13) (110.3 mg, yield 77%). LC/MS analysis of the product shows the desired product's mass: m/Z 552 (79BrM+H), and m/Z 554 (81BM+H), Calculated for C22H23BrFN506: 552.35. 1H NMR (400 MHZ, DMSO-a’6): 5 2.74 (d, J = 7.58 Hz, 2H, -CH2— COOH), 3.16 (d, J = 12.23 Hz, 2H), 3.34 (d, J = 10.80 Hz, 2H), 3.87 (d, J = 5.87 Hz, 2H), 4.08 (t, J = 3.18 Hz, 1H), 5.17 (q, J = 7.34 Hz, 1H, -NH-CH-CH2-COOH), 6.75 (t, J = 1.96 Hz, 1H), 7.11 (t,J = 1.47 Hz, 1H), 7.14 (appt, 1H), 7.21 (t, J = 1.71 Hz, 1H), 7.24 (appt, 1H), 7.41 (m, 2H), 8.13 (brs, 1H), 8.53 (d, J = 8.07 Hz, 1H), 8.64 (t, J = 5.75 Hz, 1H), 9.66 (brs,lH), 10.03 (brs, 1H), 12.40 (brs, 1H, -COOH). 1H NMR spectrum of the t was consistent with the proposed structure for Example 13. 19F NMR (376 MHz, ’a): 6 - s), and -llO.57 (t, J = 8.85 Hz).

Example 14 Preparation of (3S)(3,5-dibromophenyl)-3—[[2-[[5-[(5-hydroxy-1,4,5,6- tetrahydropyrimidin-Z-yl)amino]pyridine-S-carbonyl]amino]acetyl]amino]propanoic acid NYNH HN N \ N COH I/ 0! 2 Br Br Step1 Preparation ofethyl (3S)(3, 5-dibr0m0phenyU[[2-[[5-[(5-hydr0xy-1, 4, 5, 6- retrahydropyrl'midin-Z—yl)ammojpyridme-S-carbonyljammojacelyljammojpropanoaz‘e _< O HN 2:: \ N I COZEt / 0; Br Br A e of [(5-hydroxy-l,4,5,6-tetrahydropyrimidinyl)amino]pyridine carbonyl]amino]acetic acid (Example D) (78.0 mg,0.266 mmol), ethyl (3S)amino(3,5- dibromophenyl)propanoate hydrochloride (the (S) ester of Example J formed via the tic lipase cleavage ) (103.06 mg, 0.266 mmol) and 1-hydroxybenzotriazole hydrate (8.15 mg, 0.053 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N'—diisopropylcarbodiimide (60.0 uL, 0.387 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was evaporated in-vacuo to give a colorless crystalline solid of the intermediate product: ethyl (3S)—3- [3,5 -dibromophenyl] -3 -[[2- [ [5 - [(5 -hydroxy- l ,4,5,6-tetrahydropyrimidin yl)amino]pyridinecarbonyl]amino] acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired t’s mass: m/z 625 (79Br=79BrM+H), m/z 627 (79BF=SIBYI\/I+H), m/z 629 ngrM+H), m/Z 647 (79Br=79BrM+Na), m/Z 649 (79Br=SIBrM+Na), and W2 651 (SlBr=SIBrM+Na); Calculated for C23H26Br2N605: 626.30. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 ation of(3S)(3, 5-dibr0m0phenyU[[2-[[5-[(5-hya’roxy-1, 4, 5, 6- z‘etrahya’ropyrl'mia’m-Z-yl)ammojpyria’me-S-carbonyljammojacetyljammojpropanoic acia’ \ N I/ 01 COZH Br Br To a suspension of ethyl (3S)[3,5-dibromophenyl][[2-[[5-[(5-hydroxy-1,4,5,6- tetrahydropyrimidinyl)amino]pyridinecarbonyl]amino] acetyl]amino]propanoate from step 1 above (0.266 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide monohydrate (56.0 mg, 0.1.334 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was neutralized with TFA (250 uL in 5 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless lline/gummy solid. The crude product was purified by reverse-phase HPLC with a nt 10-50% CH3CN in water containing 0.05% TFA to give the desired product, after lization, as a colorless lyophilized solid (Example 14) (825mg, yield 52%). LC/MS analysis of the product shows the desired product's mass: m/z 597 (79Br=79BrM+H), m/z 599 (79Br=81BrM+H), and m/z 601 81BrM+H); Calculated for C21H22Br2N605: 598.24. 1H NMR (400 MHz, DMSO-a’g): 5 2.74 (d, J = 7.34 Hz, 2H, -CH2-COOH), 3.17 (d, J = 12.23 Hz, 2H), 3.36 (d, J = 11.0 Hz, 2H), 3.93 (d, J = 5.62 Hz, 2H), 4.11 (t, J =3.06 Hz, 1H), 5.15 (q, J = 7.42 Hz, 1H, -NH-CH-CH2-COOH), 7.57 (d, J = 1.71 Hz, 1H), 7.72 (s, 1H), 8.03 (t, J = 2.20 Hz, 1H), 8.42 (brs, 1H), 8.59 (m, 2H), 8.90 (d, J = 1.71 Hz, 1H), 9.03 (t, J = 5.75 Hz, 1H), 9.88 (s,1H), 12.42 (hrs, 1H, -COOH). 1H NMR um of the product was consistent with the proposed structure for Example 14.

Example 15 Preparation of (3S)[3,5-dichloro-phenyl)(2—(3-hydr0xy((5-hydr0xy—1,4,5,6- tetrahydr0pyrimidin-Z-yl)amino)benzamid0)acetamid0)pr0pan0ic acid NYNH O HN ”El/N COZH CI CI Step 1 Preparation ofethyl (3S) 3-(3, 5-dich10r0phenyl)(2-(3-hydr0xy((5-hydr0xy-1,4, 5, 6- tetrahydropyrimidin-Z—yUammo)benzamido)acetamid0)pr0pan0ate N\ NH ”W COZEt CI CI A mixture of 2-(3-hydroxy((5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (87.0 mg, 0.282 mmol), ethyl (3S)amino (3,5-dichlorophenyl)propanoate hydrochloride (Example I) (84.26 mg, 0.282 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) to give a cream suspension. Solid 1- hydroxybenzotriazole hydrate (9.0 mg, 0.059 mmol) was added to above reaction mixture and the reaction mixture was stirred under nitrogen here for 10 min. N,N'— diisopropylcarbodiimide (65 uL, 0.420 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere ght. The solvent was evaporated in- vacuo to give a colorless gummy residue of the product: ethyl (3S)[3,5-dichlorophenyl] [[2-[[3-hydroxy[(5-hydroxy-l,4,5,6-tetrahydropyrimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 552 (35C1M+H), m/z 554 (37C1M+H), m/z 574 (35C1M+Na), and m/z 576 (37C1M+Na), Calculated for C24H27C12N506: 552.41 The crude e was used as such for the saponification reaction in Step 2.

Step 2 Preparation )[3, 5-dich10r0-phenyl)(2-(3-hya’r0xy((5—hya’r0xy—1 , 4, 5, 6- tetrahydropyrimidmyl)amin0)benzamia’o)acetamia’o)pr0panoic acia’ NYNH HN ”WN COZH CI CI To a solution of crude ethyl (3S)—3-[3,5-chlorophenyl][[2-[[3-hydroxy[(5- hydroxy-1,4,5 ,6-tetrahydropyrimidinyl)amino] benzoyl] amino] acetyl] amino]propanoate from step 1 above (0.282 mmol) in a mixture of a 1:1 e of acetonitrile/water (6 mL) was added lithium ide monohydrate (60 mg, 1.43 mol) at room temperature and the reaction mixture was stirred at room temperature for 2 h. The mixture was neutralized with TFA (100 uL in 5.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless viscous residue. The above crude product was purified by reverse-phase HPLC with a nt 10-50% CH3CN in water containing 0.05% TFA to give the d product, after lyophilization, as a colorless lyophilized solid (Example 15) (101.2 mg, yield 68%). LC/MS analysis of the product shows the desired product's mass: m/z 524 (35C1M+H), and m/z 526 (37C1M+H), Calculated for C22H23C12N506: 524.35. 1H NMR (400 MHz, DMSO-a’a): 5 2.75 (d, J = 7.34 Hz, 2H, OOH), 3.16 (brd, J = 11.98 Hz, 2H), 3.33 (brd, J = 12.23 Hz, 2H), 3.87 (d, J = 5.87 Hz, 2H), 4.08 (brs, 1H), 5.15 (q, J = 7.17 Hz, 1H, -NH-CH-CH2- COOH), 6.75 (t, J =2.08 Hz, 1H), 7.11 (appt, 1H), 7.14 (appt, 1H), 7.40 (d, J =1.96 Hz, 1H), 7.49 (appt, 1H), 8.12 (s, 2H), 8.54 (d, J = 8.07 Hz, 1H), 8.64 (t, J = 5.87 Hz, 1H), 9.64 (s,1H), 10.02 (brs, 1H), 12.40 (brs, 1H, -COOH). 1H NMR spectrum of the product was consistent with the proposed structure for Example 15. 2016/069511 Example 16 Preparation of (3S)[3-chlor0(triflu0r0meth0xy)phenyl)(2-(3-hydroxy-S-((5- hydroxy-1,4,5,6-tetrahydropyrimidin-Z-yl)amino)benzamid0)acetamido)pr0pan0ic acid NYNH O HN ”EN COZH CI OCF3 Step 1 Preparation l (3S) 3-(3-ch10r0(z‘rl'flu0r0methoxy)phenyl)(2—(3-hydr0xy((5- hydroxy-I, 4, 5, rahydropyrimidin-Z—yl)ammo)benzamido)acetamid0)pr0pan0ate N\ NH ”W COzEt CI 00F3 A mixture of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin yl)amino)benzamido)acetic acid (Example B) (61.0 mg, 0.198 mmol), ethyl (3S)amino (3-chloro(trifluoromethoxy)phenyl)propanoate hydrochloride (Example G) (68.89 mg, 0.198 mmol) was dissolved in DMF (2 mL) and romethane (2 mL) to give a cream suspension. Solid 1-hydroxybenzotriazole hydrate (6.1 mg, 0.040 mmol) was added to above reaction mixture and the reaction mixture was stirred under nitrogen atmosphere for 10 min.

N,N'—diisopropylcarbodiimide (46 uL, 0.297 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen here overnight. The solvent was evaporated m-vacuo to give a cream gummy residue of the product: ethyl (3S)—3-[3-chloro (trifluoromethoxy)phenyl][[2-[[3-hydroxy[(5-hydroxy-1,4,5,6-tetrahydropyrimidin no]benzoyl]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/Z 602 (35C1M+H), m/z 604 (37C1M+H), m/z 624 (35C1M+Na), and m/z 626 (37C1M+Na), Calculated for C25H27C1F3N507z60196. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation of -[3-ch10r0(trifluoromethoxy)phenyl)(2—(3-hydr0xy—5-((5-hydr0xy- 1, 4, 5, 6—2‘6trahya’ropyrimia’in-Z—yl)am1770)benzaml'a’o)acetamia’o)pr0panoic acia’ NYNH HN ”WN COZH CI 00F3 To a solution of crude ethyl (3S)[3-chloro(trifluoromethoxy)phenyl][[2-[[3- hydroxy[(5-hydroxy-1,4,5,6-tetrahydropyiimidin yl)amino]benzoyl]amino]acetyl]amino]propanoate from step 1 above (0.198 mmol) in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide drate (42 mg, 1.10 mol) at room temperature and the reaction mixture was stirred at room ature for 1 h. The mixture was neutralized with TFA (100 uL in 5.0 mL CH3CN) and the mixture was evaporated uo to give a colorless viscous residue. The above crude product was purified by reverse-phase HPLC with a gradient 10-70% CH3CN in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 16) (69.50 mg, yield 61%). LC/MS analysis of the product shows the desired product's mass: m/Z 574 (35C1M+H), m/z 576 (37C1M+H), m/z 596 (35C1M+Na), and m/Z 598 (37C1M+Na), Calculated for C23H23ClF3N507: 57391. 1H NMR (400 MHZ, DMSO- a’6): 5 2.76 (d, J = 7.34 Hz, 2H, -CH2—COOH), 3.17 (d, J = 12.47 Hz, 2H), 3.34 (d, J = 12.72 Hz, 2H), 3.88 (d, J = 5.87 Hz, 2H), 4.09 (t, J = 3.20 Hz, 1H), 5.21 (q, J = 7.17 Hz, 1H, -NH- CH-CHz-COOH), 6.76 (t, J = 2.08 Hz, 1H), 7.12 (t, J = 1.59 Hz, 1H), 7.14 (t, J = 1.00 Hz, 1H), 7.35 (s, 1H), 7.45 (d, J = 0.73 Hz, 1H), 7.49 (t, J = 1.47 Hz, 1H), 8.13 (brs, 1H), 8.58 (d, J = 7.82 Hz, 1H), 8.65 (t, J = 5.87 Hz, 1H), 9.64 (s,1H), 10.03 (hrs, 1H), 12.44 (hrs, 1H, - COOH). 1H NMR spectrum of the product was consistent with the proposed structure for e 16. ”P NMR (376 MHz, DMSO-a’g): 5 -56.83 (s), and -73.70 (s).

Example 17 Preparation of (3S)(3-bromo(trifluoromethoxy)phenyl)(2—(3-hydroxy((5— y-1,4,5,6-tetrahydropyrimidin-Z-yl)amino)benzamido)acetamido)propanoic acid N\ NH ”W COZH Br ocr=3 Step 1 Preparation ofethyl (35) 3-(3-br0m0(triflu0r0methoxy)phenyl)(2—(3-hydr0xy-5—((5- hydroxy-I, 4, 5, 6—2‘6trahydropyrimidin-Z—yl)ammo)benzamido)acetamid0)pr0pan0ate NI—TNrNH o ”W COzEt Br ocr=3 A mixture of 2-(3-hydroxy((5-hydroxy-1,4,5,6-tetrahydropyrimidin y1)amino)benzamido)acetic acid (Example B) (65.0 mg, 0.211 mmol), (S)-ethy1 3-amino (3-bromo(trifluoromethoxy)pheny1)propanoate hydrochloride (Example H) (82.75 mg, 0.211 mmol) was dissolved in DMF (2 mL) and dichloromethane (2 mL) to give a colorless sion. Solid 1-hydroxybenzotriazole hydrate (7.0 mg, 0.046 mmol) was added to above reaction mixture and the reaction mixture was stirred under en atmosphere for 10 min.

MN'-diisopropy1carbodiimide (50 uL, 0.323 mmol) was added and the on mixture was stirred at room ature under nitrogen atmosphere overnight. The solvent was evaporated m-vacuo to give a cream gummy residue of the product: ethyl (3S)—3-[3-bromo (trifluoromethoxy)pheny1][[2-[[3-hydroxy[(5-hydroxy-1,4,5,6-tetrahydropyrimidin y1)amino]benzoy1]amino]acetyl]amino]propanoate. LC-MS analysis of the crude residue shows the desired product’s mass: m/z 646 (79BrM+H), m/z 648 +H), m/z 668 (79BrM+Na), and m/z 670 (SlBrM+Na), Calculated for C25H27BrF3N507:646.41. The crude residue was used as such for the saponification reaction in Step 2.

Step 2 Preparation 0f(3S)(3-br0m0(trifluoromethoxy)phenyl)(2—(3-hydr0xy((5-hya’r0xy- 1,4,5, rahya’ropyrimia’in-Z—yl)am1770)benzaml'a’o)acetamia’o)pr0panoic acia’ NYNH HN ”WN COZH Br ocr=3 To a solution of the crude product (0.211 mmol) from step 1 above in a mixture of a 1:1 mixture of acetonitrile/water (6 mL) was added lithium hydroxide monohydrate (48 mg, 1.144 mol) at room temperature and the reaction mixture was d at room temperature for 1 h. The mixture was neutralized with TFA (0.1 mL in 5.0 mL CH3CN) and the mixture was evaporated in-vacuo to give a colorless viscous residue. The above crude t was purified by reverse-phase HPLC with a gradient 10-70% CH3CN in water ning 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized solid (Example 17) (83.2 mg, yield 64%). LC/MS analysis of the product shows the desired product's mass: m/Z 618 (79BrM+H), m/Z 620 (81BFM+H), m/Z 640 (79BrM+Na), and m/Z 642 (SlBrM+Na), Calculated for C23H23BrF3N507: 618.36. 1H NMR (400 MHz, DMSO-a’a): 5 2.75 (d, J = 7.09 Hz, 2H, -CH2-COOH), 3.16 (d, J = 12.23 Hz, 2H), 3.33 (d, J = 11.25 Hz, 2H), 3.87 (d, J = 5.87 Hz, 2H), 4.08 (t, J = 3.20 Hz, 1H), 5.19 (q, J = 7.42 Hz, 1H, -NH-CHCHz-COOH ), 6.75 (t, J = 1.96 Hz, 1H), 7.11 (appt, 1H), 7.14 (t, J = 1.70 Hz, 1H), 7.38 (s, 1H), 7.55 (s, 1H), 7.61 (s, 1H), 8.12 (brs, 1H), 8.58 (d, J = 7.82 Hz, 1H), 8.64 (t, J = 5.87 Hz, 1H), 9.63 (brs,1H), 10.02 (brs, 1H), 12.42 (brs, 1H, -COOH). 1H NMR spectrum of the t was consistent with the proposed structure for Example 17. 19F NMR (376 MHz, ’g): 5 —56.81 (s), and —73.81 (s).

C. Biological Assay Results The activities of the compounds of the present disclosure and comparison compounds were tested in the following assays and experimental studies. The results are presented in Tables 2, 3, and 4, and '1. Solid Phase Receptor Assay (SPRA) for dfifii Function Purified human frbronectin (R&D Systems, 1918-FN) diluted to 2 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, lmM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 l) of a 96-well half-well transparent rnicrotiter plate (Greiner 675061) and incubated overnight at 4 °C. Wells were washed 3 times with 150 uL TBS+ and 150 uL of blocking buffer (TBS+ with 1% bovine serum n, Sigma A7906) were added. The plate was incubated for 1 hr at 37 °C and then washed 3X with TBS+ buffer. Recombinant human integrin (15B1 (R&D Systems, 3230-A5) was diluted to 0.1 ug/mL in TBS+/0.1% bovine serum albumin. Compounds were diluted 1:100 into the integrin solution and then 50 uL added to empty wells of the washed frbronectin-coated plate according to a standard template with each sample repeated in triplicate. After incubation for two hours at room temperature, the plate was washed 3X with 150 uL of TBS+ buffer. To each well, 50 uL of biotinylated anti-0L5 antibody (R&D Systems, BAF1864) at 0.5 ug/mL in TBS+/0.1% BSA were added and the plate d and incubated for 1 hr at room temperature. After washing the plate 3X with 150 uL of TBS+ buffer, 50 uL of avidin- conjugated adish peroxidase (R&D Systems, DY998) diluted in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room temperature. The plate was washed 3X with TBS+ buffer followed by 50 uL of room ature TMB substrate (Sigma, T444) added to each well and the plate incubated for 20 min at room temperature.

Plates were read by colorimetric detection at 650 nm wavelength using a Tecan Safrre 11 plate reader. Concentration-response curves were constructed by non-linear regression (best fit) analysis, and ICso values were calculated for each compound. 2. Solid Phase Receptor Assay (SPRA) for avBl Function Purified human frbronectin (R&D Systems, 1918-FN) d to 5 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, lmM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 uL/well) of a 96-well half-well transparent rnicrotiter plate (Greiner ) and incubated overnight at 4 °C. Wells were washed 3 times with 150 uL TBS+ and 150 uL of ng buffer (TBS+ with 1% bovine serum albumin, Sigma A7906) were added. The plate was incubated for 1 hr at 37 °C and then washed 3X with TBS+ buffer. Recombinant human integrin del (R&D Systems. 6579-AV) was diluted to 2.0 ug/mL in TBS+/0.1% bovine serum n. Compounds were diluted 1:100 into the integrin solution and 50 uL added to empty wells of the washed frbronectin-coated plate according to a standard te with each sample repeated in triplicate. After incubation for two hours at room temperature, the plate was washed 3X with 150 uL of TBS+ . To each well, 50 uL of biotinylated anti-ocv antibody (R&D Systems, BAF1219) at 1 ug/mL in TBS+/0.1% BSA were added and the plate covered and incubated for 1 hr at room temperature. After washing the plate 3X with 150 uL of TBS+ , 50 uL of streptavidin- conjugated horseradish peroxidase (R&D Systems, DY998) diluted in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room ature. The plate was washed 3X with TBS+ buffer followed by 50 uL of TMB substrate (Sigma, T4444) added to each well and the plate incubated for 20 min at room temperature. Plates were read by metric detection at 650 nm wavelength using a Tecan Safire 11 plate reader.

Concentration-response curves were constructed by non-linear regression (best fit) analysis, and ICso values were calculated for each compound. 3. Solid Phase Receptor Assay (SPRA) for (WM on Recombinant human vitronectin (R& D Systems, 2308-VN) diluted to 1 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, lmM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 uL/well) of a 96-well half-well transparent microtiter plate (Greiner 675061) and incubated overnight at 4 °C. Wells were washed 3 times with 150 uL TBS+ and 150 uL of blocking buffer (TBS+ with 1% bovine serum albumin, Sigma A7906) were added. The plate was incubated for 1 hr at 37 °C and then washed 3X with TBS+ buffer. Recombinant human integrin (va3 (R&D Systems, V) was diluted to 1 ug/mL in TBS+/0.1% bovine serum albumin. Compounds were diluted 1:100 into the integrin on and then 50 uL added to empty wells of the washed vitronectin-coated plate according to a standard template with each sample repeated in triplicate. After incubation for two hours at room ature, the plate was washed 3X with 150 uL of TBS+ buffer. To each well, 50 uL of biotinylated anti-ocv antibody (R&D Systems, BAF1219) at 0.5 ug/mL in TBS+/0.1% BSA were added and the plate covered and incubated for 1 hr at room ature. After washing the plate 3X with 150 uL of TBS+ buffer, 50 uL of streptavidin- conjugated horseradish peroxidase (R&D Systems, DY998) diluted in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room temperature. The plate was washed 3X with TBS+ buffer followed by 50 uL of TMB substrate (Sigma, T4444) added to each well and the plate was incubated for 20 min at room temperature. Plates were read by metric detection at 650 nm wavelength using a Tecan Safire 11 plate reader.

Concentration-response curves were constructed by non-linear regression (best fit) analysis, and ICso values were calculated for each compound. 4. Solid Phase or Assay (SPRA) for aVBS Function Recombinant human ectin (R& D Systems, 2308-VN) at 0.25 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1 mM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 uL/well) of a 96-well half-well transparent microtiter plate (Greiner ) and incubated overnight at 4 °C. Wells were washed 3 times with 150 “L TBS+ and 150 “L of blocking buffer (TBS+ with 1% bovine serum albumin, Sigma A7906) were added. The plate was incubated for 1 hr at 37 °C and then washed 3X with TBS+ buffer. Recombinant human integrin (va5 (R&D Systems, 2528-AV) was diluted to 0.1 ug/mL in TBS+/0.1% bovine serum albumin. Compounds were diluted 1:100 into the integrin solution and then 50 “L added to empty wells of the washed vitronectin-coated plate according to a standard template with each sample repeated in triplicate. After tion for two hours at room temperature, the plate was washed 3X with 150 “L of TBS+ buffer. To each well, 50 ul of biotinylated cv antibody (R&D Systems, BAF1219 ) at 0.5 ug/mL in TBS+/0.1% BSA at 0.5 ug/mL were added and the plate covered and incubated for 1 hr at room temperature. After washing the plate 3X with 150 uL of TBS+ buffer, 50 “L of streptavidin-conjugated horseradish peroxidase (R&D sm DY998) diluted in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room temperature. The plate was washed 3X with TBS+ buffer followed by 50 “L of TMB substrate (Sigma T4444) added to each well and the plate incubated for 20 min at room temperature. Plates were read by colorimetric ion at 650 nm wavelength using a Tecan Safire 11 plate . Concentration-response curves were constructed by non-linear sion (best fit) analysis, and ICso values were calculated for each compound.

. Solid Phase Receptor Assay (SPRA) for aVBG Function Recombinant human LAP (R&D Systems, 246-LP) diluted to 0.25 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1 mM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 uL/well) of a 96-well half-well transparent microtiter plate (Greiner 675061) and incubated overnight at 4 °C. Wells were washed 3 times with 150 “L TBS+, and 150 “L of blocking buffer (TBS+ with 1% bovine serum albumin, Sigma A7906) were added. The plate was ted for 1 hr at 37 OC, and then washed 3X with TBS+ buffer. Recombinant human integrin (va6 (R&D Systems, 3817-AV) was diluted to 0.1 ug/mL in TBS+/0.1% bovine serum n. Compounds were diluted 1:100 into the integrin solution and then 50 “L added to empty wells of the washed LAP-coated plate according to a standard template with each sample repeated in triplicate. After incubation for two hours at room temperature, the plate was washed 3X with 150 uL of TBS+ buffer. To each well, 50 uL of ylated anti-ocv antibody (R&D Systems, BAF1219) at 0.5 ug/mL in TBS+/0.1% BSA were added and the plate was covered and incubated for 1 hr at room temperature. After washing the plate 3X with 150 uL of TBS+ buffer, 50 uL of streptavidin- conjugated horseradish peroxidase (R&D Systems, DY998) diluted in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room temperature. The plate was washed 3X with TBS+ buffer followed by 50 uL of TMB substrate (Sigma T4444) added to each well and the plate ted for 20 min at room ature. Plates were read by colorimetric detection at 650 nm wavelength using a Tecan Safire 11 plate reader. tration-response curves were constructed by non-linear sion (best fit) analysis, and ICso values were calculated for each compound. 6. Solid Phase Receptor Assay (SPRA) for (WM Function Recombinant human LAP protein (R&D s, Inc, 246-LP) diluted to 0.5 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1mM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 ul/well) of a 96-well half-well transparent microtiter plate (Greiner 675061), and incubated overnight at 4 °C. Wells were washed 3 times with 150 uL TBS+ and 150 uL of blocking buffer (TBS+ with 1% bovine serum albumin, Sigma A7906) were added. The plate was incubated for 1 hr at 37 °C and then washed 3X with TBS+. Recombinant human integrin (vaS (R&D Systems,4135-AV) was diluted to 0.1 ug/mL in TBS+/0.1% bovine serum albumin. Compounds were diluted 1:100 into the integrin on and 50 uL added to empty wells of the washed LAP-coated plate according to a standard template with each sample repeated in triplicate. After incubation for two hours at room temperature, the plate was washed 3X with 150 uL of TBS+. To each well, 50 uL of ylated anti-ocv antibody (R&D Systems, BAF1219) at 1 ug/mL in TBS+/0.1% BSA were added and the plate was covered and incubated for 1 hr at room ature. After washing the plate 3X with 150 uL of TBS+ buffer, 50 uL of streptavidin- conjugated horseradish peroxidase (R&D s, DY998) diluted in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room temperature. The plate was washed 3X with TBS+ followed by 50 uL of TMB substrate (Sigma T4444) added to each well and the plate incubated for 20 min at room temperature. Plates were read by colorimetric detection at 650 nm wavelength using a Tecan Safire 11 plate reader.

Concentration-response curves were ucted by non-linear regression (best fit) analysis, and ICso values were calculated for each compound. 7. Solid Phase Receptor Assay (SPRA) for (1831 Function Recombinant mouse nephronectin protein (R&D Systems, Inc, 4298-NP) diluted to 1 ug/mL in TBS+ buffer (25 mM Tris pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1 mM CaClz, 1 mM MgC12, 1 mM MnClz) was added to wells (50 ul/well) of a 96-well half-well transparent microtiter plate (Greiner 675061), and incubated overnight at 4 °C. Wells were washed 3 times with 150 “L TBS+ and 150 “L of blocking buffer (TBS+ with 1% bovine serum albumin, Sigma A7906) were added. The plate was incubated for 1 hr at 37 °C and then washed 3X with TBS+. Recombinant human in (18B1 (R&D Systems, pre—launch) was diluted to 0.25 pg/mL in TBS+/0.1% bovine serum albumin. Compounds were diluted 1: 100 into the integrin solution and 50 pL added to empty wells of the washed nephronectin-coated plate ing to a standard template with each sample repeated in triplicate. After incubation for two hours at room temperature, the plate was washed 3X with 150 pL of TBS+. To each well, 50 “L of biotinylated anti-B1 antibody (R&D Systems, BAF1778) at 0.5 pg/mL in TBS+/0.1% BSA were added and the plate was covered and incubated for 1 hr at room temperature. After washing the plate 3X with 150 uL of TBS+ buffer, 50 “L of streptavidin-conjugated horseradish peroxidase (R&D Systems, DY998) d in TBS+ blocking buffer were added to the wells and the plate incubated for 20 min at room temperature. The plate was washed 3X with TBS+ followed by 50 pL of TMB substrate (Sigma T4444) added to each well and the plate incubated for 20 min at room ature.

Plates were read by colorimetric detection at 650 nm ngth using a Tecan Safire 11 plate reader. tration-response curves were constructed by non-linear regression (best fit) analysis, and ICso values were ated for each compound.

D. Pharmacokinetic Analysis 1. ais A lly sufficient volume of dimethylsulfoxide (DMSO) was added to each test compound to achieve solubilization. For intravenous (IV) delivery, compounds were then formulated as solutions in glycerol formal: saline r 20:80 or 40:60 v/v) (Sigma Chemicals, St. Louis). For oral (PO) administration, nds were formulated with 0.5% methylcellulose. Five to siX compound solutions were combined into a singled mixed solution for IV and PO cassette administration with final DMSO concentrations < 0.6% or < 1.2%, for the IV and PO cassettes, respectively. Analytes were detected in test samples using an LC/MS/MS (liquid chromatography/mass spectrometry) system consisting of an LC- 20AD pump (Shimadzu, Kyoto, Japan), an HTC PAL autosampler (Leap technologies, ro, NC), and a Sciex API-4000 mass spectrometer in ESI mode (AB Sciex, Foster City, CA.). An Amour C18 reverse phase column (Analytical Sales and Services, Pompton Plains, NJ.) was used for chromatographic separation. 2. Experimental ois Pharmacokinetic (PK) studies conducted at Saint Louis University used male Sprague-Dawley rats with an initial body weight of 200 to 220 g. IV PK studies were performed with the following compounds: Examples 1-3 and 5-17 and comparison compounds C12-C18, C29, and C30. Animals were allowed free access to food and water.

Rats were individually housed and connected to jugular vein catheters. Each cassette ation was administered intravenously to two rats (1 mL/kg body weight). Each cassette formulation contained 5-6 compounds at 1 mg/kg in either 20:80 or 40/60 glycerol formal/saline (v/v). Blood was collected manually via the catheter into lithium-heparin tubes at 0.017, 0.083, 0.5, 1, 2, 4, 6 and 24 hours post-dose. Animals were euthanized with C02 at the end of the experiment.

Oral PK studies were conducted with the following compounds: Examples 1-3 and 5- 17 and comparison compounds C12, C14-16 and C29-30. The P0 cassette formulations were administered via oral gavage to two rats (10 mL/kg body weight) containing 5-6 nds per cassette. The oral dose was administered at 2 mg/kg/compound in 0.5% methylcellulose.

Blood collection time points were 0.25, 0.5, 1, 2, 4, 6 and 24 hours post-dose into lithium- heparin tubes. Animals were euthanized with C02 at the end of the experiment. al standard was added to all samples at 200 ng/mL (final), as well as 150 uL of acetonitrile. Plasma samples (50 uL total volume) were diluted with control na'1've rat plasma as appropriate to bring the sample ement into the linear dynamic range of the rd curve. The samples were capped and mixed on a multi-plate vortexer for 5 minutes and fuged for 5 minutes at 3200 rmp. The supemant was transferred to 96-well sample plate and capped for LC/MS/MS analysis. Compounds were optimized and monitored for their respective MRM transitions. The mobile phases consisted of 0.1% formic acid us) and 100% itrile (organic) with an Amour C18 reverse phase column (2.1 X 30 mm, 5 ) at a flow rate of 0.35 mL/min. The starting phase was 10% acetonitrile for the 0.9 minutes then increased to 90% acetonitrile over 0.4 minutes, and was ined for an additional 0.2 minutes before returning to 10% itrile over 0.4 minutes. The 10% 2016/069511 acetonitrile was held for an additional 1.6 s. Peak areas were integrated using Analyst 1.5.1 (AB ScieX, Foster City, CA.).

Similar rat PK studies were conducted by PRESCOS, LLC (San Diego, CA) for comparison compounds C19-C28. Female Sprague-Dawley rats with an initial body weight of 195 to 220 g were used. te formulations with 1 mg/kg/compound in 40/60 glycerol formal/saline were administered intravenously to three rats. The dosing volume for each animal was 5 mL/kg body weight. Blood samples were collected via a jugular vein catheter at 0.017, 0.25, 0.5, 1, 2, 4 and 8 hours post-dose into K2EDTA tubes. Animals were euthanized with C02 at the end of the experiment. Sample processing and nd measurement by LC/MS/MS was performed by HT Laboratories (San Diego, CA).

Table 3A - Integrin Assay Results for Comparison Compounds 015131 @8131 owBl och3 ochS owB6 ochS SPRA SPRA SPRA SPRA SPRA SPRA SPRA IC50 1C5.) IC50 1C5.) 1C5.) 1C5.) 1C5.) (11M) (11M) (11M) (11M) (11M) (11M) (11M) Compounds --_ C1 16::9 8::2 17::2 5:2 3:1 C4 7 4 2 C5 24 4 1 C6 7 :: 4 6 1 C7 59 11 25 C11 33 16 4 4 11 Table 3B - Integrin Assay Results for Examples _----____-- —-m--- (x5131 SPRA ICSO Examples 4 0.7 0.4 0.4 \OOO\]O\UI 0.8 0.5 0.5 0.6 O U] 0.2 0.4 0.7 O N II II 0 0 .0 m 0.6 0.1 0.4 0.3 0.5 U) 0.3 0.3 099 WJ>J>UIOJ> : 0.4 1.1 2:II I-I N4; I-I O U) I III O I—* O U) II: 01 11 0.5 0.7 .0 4; 0.3 0.5 .0 ox 12 4; II N 4; 0.4 0.6 13 0.6 0.6 I-I .0 o 0.1 0.4 14 0.6 0.4 O . U) 0.1 0.2 : 0.3 1.2 i0.3 0.6 16 : 0.4 0.5 II .0 U) 0.6 0.5 17 : 0.1 0.7 .N 00 HII I-I I-I 0.6 0.7 Table 4A — Plasma Half Life of Examples Examples plasma t 1/2 after 1 mg/kg IV bolus dose in rat .2 hrs \DOOQQM-bUJN 9.1 hrs 6.1 hrs Not Tested 6.6 hrs 16.7 hrs 4.6 hrs 23.9 hrs .6 hrs I—«I—«I—«I—II—«I—I m-bUJNI—‘O 3.9 hrs 24.0 hrs 13.7 hrs 11.0 hrs 34.2 hrs 23.8 hrs plasma t 1/2 after 1 mg/kg IV bolus dose1n rat Table 4B — Plasma Half Life of Comparison Compounds Comparison nds plasma t 1/2 after 1 mg/kg iv bolus dose in rat C12 0.5 hrs C13 1.1 hrs C14 1.0 hr C15 0.6 hrs C16 1.6 hrs C17 0.8 hrs C18 1.2 hrs C19 0.43 hrs C20 0.38 hrs C21 1.5 hrs C22 0.30 hrs C23 0.21 hrs C24 0.28 hrs C25 0.23 hrs C26 0.25 hrs C27 0.21 hrs C28 0.3 hrs C29 < .08 hrs C30 1.6 hrs Table 5A — AUC Plasma Exposure of Compounds AUC (0-inl) (nthr/mL) after a 2 mg/kg PO dose in rat 25048 19257 4870 11402 Example AUC (0-inl) (nthr/mL) after a 2 mg/kg PO dose in rat 6 34386 7 3887 8 4468 9 4121 12969 11 9136 12 9107 13 13929 14 6502 15610 16 6808 17 13128 Table 5B — AUC Plasma re of Comparison Compounds Comparison Compound AUC ) (nthr/mL) after a 2 mg/kg PO dose in rat C12 205 C14 224 C15 87 C16 62 C29 < 1 C30 <1 The AUC of the es described herein and select comparison compounds was determined after a single 2 mg/kg oral (PO) dose in rat, demonstrating improved plasma exposure of the examples of the present disclosure. * >l< * >l< * >l< * >l< * >l< * All of the compounds, itions, and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure.

While the compounds, compositions, and methods of this disclosure have been described in terms of preferred embodiments, it will be nt to those of skill in the art that variations may be applied to the compositions and methods, and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both ally and logically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

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Claims (73)

WHAT IS CLAIMED IS:

1. A compound of the formula: (I), wherein: A is C−OH or N; R′ is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8); and X and Y are each independently cyano, halo, fluoroalkoxy(C1-2), alkyl(C1-2), or fluoroalkyl(C1-2), with the proviso that X and Y are not both cyano or alkyl(C1-2); or a pharmaceutically able salt or tautomer of the above formula.

2. The compound of claim 1, wherein A is N.

3. The compound of claim 1, wherein A is C−OH.

4. The compound according to any one of claims 1-3, wherein Rʹ is hydrogen.

5. The compound according to any one of claims 1-4, wherein X is halo.

6. The compound of claim 5, wherein X is −F, −Cl, or −Br.

7. The nd of claim 6, wherein X is −F.

8. The compound of claim 6, wherein X is −Cl.

9. The compound of claim 6, wherein X is −Br.

10. The compound according to any one of claims 1-4, wherein X is fluoroalkoxy(C1-2).

11. The compound of claim 10, wherein X is −OCF3.

12. The compound according to any one of claims 1-4, wherein X is fluoroalkyl(C1-2).

13. The compound of claim 12, n X is −CHF2.

14. The compound of claim 12, wherein X is −CF3.

15. The compound according to any one of claims 1-4, wherein X is alkyl(C1-2).

16. The nd of claim 15, wherein X is −CH3.

17. The compound according to any one of claims 1-16, wherein Y is halo.

18. The compound of claim 17, wherein Y is −F, −Cl, or −Br.

19. The compound of claim 17, wherein Y is −F.

20. The nd of claim 17, wherein Y is −Cl.

21. The compound of claim 17, wherein Y is −Br.

22. The nd according to any one of claims 1-16, wherein Y is fluoroalkoxy(C1-2).

23. The compound of claim 22, wherein Y is −OCF3.

24. The compound according to any one of claims 1-16, wherein Y is fluoroalkyl(C1-2).

25. The compound of claim 24, wherein Y is −CHF2.

26. The compound of claim 24, wherein Y is −CF3.

27. The compound according to any one of claims 1-14, wherein Y is alkyl(C1-2).

28. The compound of claim 27, wherein Y is −CH3.

29. The compound ing to any one of claims 1-4, wherein X and Y are each independently selected from the groups consisting of −F, −Cl, −Br, −OCF3, −CH3, −CHF2, and −CF3, with the proviso that X and Y are not both −CH3.

30. The compound ing to any one of claims 1-29, wherein the carbon atom labeled β is in the S configuration.

31. The compound of claim 1, further defined as: , , , , , , , , , , , , , , , , or or a pharmaceutically acceptable salt or tautomer of any of the above formulas.

32. The compound according to any one of claims 1-31, wherein the compound is ive for inhibiting three or more RGD integrins selected from the group consisting of α5β1, αvβ1, α8β1, αvβ3, αvβ5, αvβ6, and αvβ8, n the iveness of the compound corresponds to an IC50 value of less than 10 nM for each of the three or more RGD integrins as measured using a solid phase receptor assay (SPRA) for function of the tive integrin.

33. The compound according to any one of claims 1-31, wherein the compound has a sustained plasma half life of at least 2 hours as measured in a rat using an iv bolus comprising 1 mg of compound per kg of rat.

34. A pharmaceutical composition comprising: a) the compound according to any one of claims 1-33; and b) an excipient.

35. Use of a compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disease or a disorder.

36. Use according to claim 35, wherein the disease or disorder is associated with angiogenesis.

37. Use according to claim 35, wherein the disease or disorder is associated with fibrosis.

38. Use according to claim 35, wherein the e or disorder is associated with fibrosis and/or angiogenesis.

39. Use ing to any one of claims 35-38, wherein the disease or disorder is pulmonary, liver, renal, cardiac, and pancreatic fibrosis, scleroderma, scarring, retinopathy of prematurity, familial exudative vitreoretinopathy, proliferative vitreoretinopathies, macular degeneration, diabetic retinopathy, cancer, orosis, autoimmune diseases, humoral hypercalcemia of malignancy, Paget’s disease, periodontal e, psoriasis, arthritis, restenosis, and infection.

40. Use according to claim 39, wherein the disease or disorder is pulmonary fibrosis.

41. Use ing to claim 39, n the disease or disorder is liver fibrosis.

42. Use according to claim 39, wherein the disease or disorder is cardiac fibrosis.

43. Use according to claim 39, wherein the disease or er is renal fibrosis.

44. Use according to claim 39, wherein the disease or disorder is atic fibrosis.

45. Use according to claim 39, wherein the disease or disorder is scleroderma.

46. Use according to claim 39, wherein the disease or disorder is scarring.

47. Use ing to claim 46, wherein the scarring is dermal scarring.

48. Use according to claim 46, wherein the scarring is retinal scarring.

49. Use according to claim 46, wherein the scarring is corneal ng.

50. Use according to claim 39, wherein the disease or disorder is retinopathy of prematurity.

51. Use according to claim 39, wherein the disease or disorder is familial exudative retinopathy.

52. Use according to claim 39, wherein the disease or disorder is proliferative vitreoretinopathies.

53. Use according to claim 39, wherein the disease or disorder is macular degeneration.

54. Use according to claim 39, wherein the disease or disorder is diabetic retinopathy.

55. Use according to claim 39, wherein the disease or disorder is cancer.

56. Use according to claim 55, wherein the cancer includes solid tumor growth or neoplasia.

57. Use according to claim 55, wherein the cancer includes tumor metathesis.

58. Use according to claim 55, wherein the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, trium, esophagus, gall bladder, lia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, te, skin, spleen, small intestine, large ine, stomach, testicle, or thyroid.

59. Use according to claim 55, wherein the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple a, or seminoma.

60. Use according to claim 39, wherein the disease or disorder is osteoporosis.

61. Use according to claim 39, wherein the disease or disorder is an autoimmune disease.

62. Use according to claim 61, wherein the autoimmune disorder is multiple sclerosis.

63. Use according to claim 39, n the disease or disorder is humoral alcemia of malignancy.

64. Use according to claim 39, wherein the disease or disorder is Paget’s disease.

65. Use according to claim 39, wherein the disease or er is periodontal disease.

66. Use according to claim 39, wherein the disease or disorder is psoriasis.

67. Use according to claim 39, wherein the disease or disorder is arthritis.

68. Use according to claim 67, wherein the arthritis is toid arthritis.

69. Use ing to claim 39, wherein the disease or disorder is restenosis.

70. Use according to claim 39, n the disease or disorder is an infection.

71. Use ing to any of claims 35-70, wherein the patient is a human, monkey, cow, horse, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof.

72. Use according to claim 71, wherein the patient is a monkey, cow, horse, sheep, goat, dog, cat, mouse, rat, or guinea pig.

73. Use according to claim 71, wherein the patient is a human. {my}: