(12) United States Patent (10) Patent No.: US 9,085,606 B2 · (21) Appl. No.: 13/944,599 WO WO...

USOO9085.606B2

(12) United States Patent (10) Patent No.: US 9,085,606 B2 Ruminski et al. (45) Date of Patent: Jul. 21, 2015

(54) BETA AMINO ACID DERIVATIVES AS 6,689,787 B1 2/2004 McKearn et al. INTEGRIN ANTAGONSTS 6,933,304 B2 8/2005 Nagarajan et al.

7,119,098 B2 10/2006 Nagarajan et al.

(71) Applicant: sity Louis University, St. Louis,MO FOREIGN PATENT DOCUMENTS

EP 1667668 T 2008 (72) Inventors: Peter Ruminski, Wildwood, MO (US); WO WO 96/23771 8, 1996

David Griggs, Ballwin, MO (US) WO WO97/08145 3, 1997 WO WO 97.36859 10, 1997

(73) Assignee: Saint Louis University, St. Louis, MO WO WO97,36860 10, 1997 (US) WO WO97,36862 10, 1997

WO WO99.44994 9, 1999 c WO WO99.44996 9, 1999

(*) Notice: Subject to any disclaimer, the term of this WO WO99,52896 10, 1999 patent is extended or adjusted under 35 WO WOOO, 51686 9, 2000 U.S.C. 154(b) by 0 days. WO WO 2004/060376 T 2004

WO WO 2008/O18827 2, 2008 (21) Appl. No.: 13/944,599 WO WO 2010/010184 1, 2010

y x- - - 9

(Continued) (22) Filed: Jul. 17, 2013 OTHER PUBLICATIONS

(65) Prior Publication Data Abdollahi et al., “Inhibition of alpha(v)beta;3 integrin survival sig US 2014/OO3891 O A1 Feb. 6, 2014 naling enhances antiangiogenic and antitumor effects of radio

• as therapy,” Clin. Cancer Res., 11:6270-6279, 2005. Adachi et al., “Significance of integrin alpha5 gene expression as a

Related U.S. Application Data prognostic factor in node-negative non-small cell lung cancer. Clin. Cancer Res., 6(1):96-101, 2000.

(60) Provisional application No. 61/ 673,058, filed on Jul. Asano et al., “Increased expression of integrin alpha(v)betas contrib 18, 2012, provisional application No. 61/764,443, utes to the establishment of autocrine TGF-beta signaling in filed on Feb. 13, 2013. scleroderma fibroblasts.” J. Immunol., 175(11):7708-7718, 2005.

(51) Int. Cl. (Continued) C07K5/06 (2006.01) CO7D 403/2 (2006.01) Primary Examiner — Thomas S Heard CO7D 309/06 (2006.01) (74) Attorney, Agent, or Firm — Parker Highlander PLLC CO7D 309/08 (2006.01) C07C 279/18 (2006.01) (57) ABSTRACT C07D 233/50 (2006.01) Disclosed herein are novel pharmaceutical agents which are CO7D 40/12 (2006.01) useful as integrin receptor antagonists that mediate the patho CO7D 239/6 (2006.01) logic processes of angiogenesis and fibrosis and as Such are CO7D 405/2 (2006.01) useful in pharmaceutical compositions and in methods for C07D 21 1/72 (2006.01) treating conditions mediated by these integrins by inhibiting

(52) U.S. Cl. or antagonizing these integrins. The novel pharmaceutical CPC ................. C07K5/06 (2013.01); C07C 279/18 agents include those of the formula:

(2013.01); C07D 21 1/72 (2013.01); C07D 233/50 (2013.01); C07D 239/16 (2013.01);

C07D 309/06 (2013.01); C07D309/08 O (I) (2013.01); C07D401/12 (2013.01); C07D 403/12 (2013.01); C07D405/12 (2013.01) W.

(58) Field of Classification Search N None See application file for complete search history. a

(56) References Cited

U.S. PATENT DOCUMENTS

5,602,155 A 2f1997 Ruminski 5,639,765 A 6, 1997 Ruminski 5,681,820 A 10, 1997 Ruminski 5,773,646 A 6, 1998 Chandrakumar et al. 5,798,370 A 8, 1998 Ruminski 5,840,961 A 1 1/1998 Behling et al. 5,852,210 A 12/1998 Chen et al. 6,013,651 A 1/2000 Rogers et al. 6,028,223 A 2, 2000 Ruminski et al. 6,372,719 B1 4/2002 Cunningham et al. 6,414, 180 B1 7/2002 Colson et al.

wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufac ture comprising Such pharmaceutical agents. Methods and intermediates useful for making the pharmaceutical agents and methods of using the pharmaceutical agents are also provided.

18 Claims, No Drawings

US 9,085,606 B2 Page 2


FOREIGN PATENT DOCUMENTS

WO WO 2010/104933 9, 2010 WO WO 2011/O25927 3, 2011 WO WO 2012/O27322 3, 2012

OTHER PUBLICATIONS

Avraamides et al., “Integrins in angiogenesis and lymphangiogenesis.” Nat. Rev. Cancer, 8(8):604-617, 2008. Awasthi et al., “Practical enantioselective synthesis of B-substituted f5-amino esters,” J. Org. Chem., 70:5387-5397, 2005. Babadzhanova et al., "Convenient syntheses of 1,1,1,3,3,3- hexafluoro-2-organyl-propan-2-ols and the corresponding trimethylsilyl ethers.” Tetrahedron, 61(7): 1813-1819, 2005. Bax et al., "Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha 5 beta 1 and alpha v beta 3 integrins,” J. Biol. Chem., 278(36):34605-34616, 2003. Becker et al., “An expedient synthesis of 3-amino-5-hydroxy benzoic acid and its n-alkyl analogues.” Tetrahedron, 39:4189-4192, 1983. Bhaskar et al., "A function blocking anti-mouse integrin alpha5betal antibody inhibits angiogenesis and impedes tumor growth in vivo..”.J. Transl. Med., 5:61, 2007. Blase et al., “The capacity of human malignant B-lymphocytes to disseminate in SCID mice is correlated with functional expression of the fibronectin receptor alpha 5 beta 1 (CD49e/CD29).” Int. J. Can cer, 60(6):860-866, 1995. Carron et al., “A peptidomimetic antagonist of the integrin avb3 inhibits Leydig cell tumor growth and the development of hypercalcemia of malignancy.” Cancer Res., 58:1930-1935, 1998. Carron et al., “Peptidomimetic antagonists of avb3 inhibit bone resorption by inhibiting osteoclast bone resorptive activity, not osteoclast adhesion to bone.” J. Endocrinol., 165:587-598, 2000. Chai et al., “OV and fl integrins regulate dynamic compression induced proteoglycan synthesis in 3D gel culture by distinct comple mentary pathways.” Osteoarthritis and Cartilage, 18:249-256, 2009. Clark, et al., “Pilot Plant Preparation of an OVfB3 Integrin Antagonist. Part 1. Process Research and Development of a (S)-B-Amino Acid Ester Intermediate: Synthesis via a Scalable, Diastereoselective Imino-Reformatsky Reaction.” Organic Process Research & Devel opment, 8:51-61, 2004. Clark, et al., “Pilot-Plant Preparation of an OVfB3 Integrin Antagonist. Part 2. Synthesis of N-2-(5-Hydroxy-4,6-tetrahydropyrimidine)-3- amino-5-hydroxybenzoic Acid.” Organic Process Research & Development, 8:571-575, 2004. Collo, "Endothelial cell integrin alpha5betal expression is modu lated by cytokines and during migration in vitro.J. CellSci, 112(Pt 4):569-578, 1999. Cue et al., “A nonpeptide integrin antagonist can inhibit epithelial cell ingestion of Streptococcus pyogenes by blocking formation of integrin alpha 5beta 1-fibronectin-M1 protein complexes.” Proc Natl AcadSci USA,97(6):2858-2863, 2000. Danen et al., “Emergence of alpha 5 beta 1 fibronectin- and alpha v beta 3 vitronectin-receptor expression in melanocytic tumour pro gression.” Histopathology, 24(3):249-256, 1994. Database Registry, Chemical Abstracts Service, Database accession No. 773126-23-1, retrieved from STN, 2004. Database Registry, Chemical Abstracts Service, Database accession No. 682803-43-6, retrieved from STN, 2011. Database Registry, Chemical Abstracts Service, Database accession No. 1270085-65-8, retrieved from STN, 2011. Duggan et al., “Ligands to the integrin receptor alphavbeta3. Expert Opinion on Therapeutic Patents, 10(9): 1367-1383, 2000. Edward, “Integrins and other adhesion molecules involved in melanocytic tumor progression.” Curr: Opin. Oncol., 7(2):185-191, 1995. Engleman et al., “A peptidomimetic antagonist of the avb3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo..”.J. Clin. Invest., 99:2284-2292, 1997.

Faulconbridge et al., “Preparation of enantiomerically enriched aro matic -amino acids via enzymatic resolution.” Tetrahedron Lett.. 41:2679-2681, 2000. Ferrariet al., “VEGF, a proSurvival factor, acts in concert with TGF betal to induce endothelial cell apoptosis.” Proc Natl AcadSci USA, 103(46): 17260-17265, 2006. Gao and Brigstock, "A novel integrin alpha5betal binding domain in module 4 of connective tissue growth factor (CCN2/CTGF) pro motes adhesion and migration of activated pancreatic stellate cells.” Gut, 55:856-862, 2006. Gisch et al., “Enzymatically Activated cycloSal-d4T monophosphates: The Third Generation of cycloSal Pronucleotides. J. Med. Chem., 50:1658-1667, 2007. Gisch et al., “Studies on Enzyme-Cleavable Dialkoxymethyl cycloSaligenyl-2',3'-dideoxy-2',3'-didehydrothymidine Monophosphates.” J. Med. Chem. 51:6752-6760, 2008. Goodman et al., “Nanomolar small molecule inhibitors for alphav(beta)6, alphav(beta)5, and alphav(beta)3 integrins,” J Med Chem., 45(5):1045-1051, 2002. Griggs et al., “Characteristics of cation binding to the I domains of LFA-1 and MAC-1. J. Biol. Chem. 273:221 13-22119, 1998. Griggs et al., “Promoter elements determining weak expression of the GAL4 regulatory gene of Saccharomyces cerevisiae," Mol. Cell. Biol. 13(8):4999-5009, 1993. Griggs et al., “Regulated expression of the GAL.4 activator gene in yeast provides a sensitive genetic Switch for glucose repression.” Proc. Natl. Acad. Sci., 88:8597-8601, 1991. Harms et al., “A Small molecule antagonist of the CVB3 integrin suppresses MDA-MB-435 skeletal metastasis.” Clin. Exp. Metastasis, 21:119-128, 2004. Heckman et al., “Probing integrin selectivity: rational design of highly active and selective ligands for the alpha5beta1 and alphavbeta3 integrin receptor.” Angew Chem Int Ed Engl. 46(19):3571-3574, 2007. Heckman et al., “Rational design of highly active and selective ligands for the alpha5betal integrin receptor.” Chembiochem. 9(9): 1397-1407, 2008. Henderson et al., “Selective Olav integrin deletion identifies a core, targetable molecular pathway that regulates fibrosis across Solid organs.” Nature Medicine, in press, 2013. Herlt et al., “Synthesis of unlabeled and carboxyl-labelled 3-amino 5-hydroxybenzoic acid.” Austr. J. Chem., 34(6): 1319-1324, 1981. Hippenmeyer et al., “Adenovirus inhibition by peptidomimetic integrin antagonists.” Antiviral Res., 55: 169-178, 2002. Horan et al., “Partial inhibition of integrin alpha(v)betao prevents pulmonary fibrosis without exacerbating inflammation.” Am. J. Respir: Crit. Care Med., 177(1):56-65, 2008. Huang, et al., “Direct Trifluoromethylation of Nitriles Promoted by Tetrabutylammonium Bifluoride.” Synlett, 15:2518-2520, 2009. Jorgensen, et al., “Efficient Synthesis of O-Aryl Esters by Room Temperature Palladium-Catalyzed Coupling of Aryl Halides with Ester Enolates.” J. Am. Chem. Soc., 124(42): 12557-12565, 2002. Kapp et al., “Integrin modulators: a patent review.” Institute for Advanced Study and Center for Integrated Protein Science. Oct. 2013: 23(10): 1273-95. Kim et al., “Regulation of angiogenesis in vivo by ligation of integrin alpha5beta1 with the central cell-binding domain offibronectin.” Am. J. Pathol. 156(4): 1345-1362, 2000. Kurahashi et al., “One-Electron Oxidation of Electronically Diverse Manganese(III) and Nickel(II) Salen Complexes: Transition from Localized to Delocalized Mixed-Valence Ligand Radicals.” J. Am. Chem. Soc., 133(21): 8307-8316, 2011. Landis et al., “Kinetic Resolution of B-Amino Esters by Acylation Using Immobilized Penicillin Amidohydrolase.” Organic Process Research & Development, 6:539-546, 2002. Li et al., “Integrin alpha5betal mediates attachment, migration, and proliferation in human retinal pigment epithelium: relevance for pro liferative retinal disease.” Invest. Ophthalmol. Vis. Sci., 50(12):5988 5996, 2009. Livant et al., “The PHSRN sequence induces extracellular matrix invasion and accelerates wound healing in obese diabetic mice.” J. Clin. Invest. 105(11): 1537-1545, 2000.

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OTHER PUBLICATIONS

Lobert et al., “Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin integrin complexes.” Dev. Cell, 19(1): 148-159, 2010. Malfait et al., “Proprotein convertase activation of accrecanases in cartilage in situ.” Arch. Biochem. Biophy's. 478:43-51, 2008. Melton et al., “Expression of ov?58 integrin on dendritic cells regu lates Th17 cell development and experimental autoimmune encephalomyelitis in mice.” J. Clin. Invest., 120(12):4436-4444. 2010. Millard et al., “Integrin targeted therapeutics.” Theranostics, 1:154 88, 2011. Mu et al., “The integrin alpha(v)beta8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF beta1° Cell Biol. 157(3):493-507, 2002. Munger et al., “Interactions between growth factors and integrins: latent forms of transforming growth factor-beta are ligands for the integrin alphavbeta1.” Mol. Biol. Cell, 9:2627-2638, 1998. Munger et al., The integrin alpha v beta 6 binds and activates latent TGFbeta1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell., 96(3):319-328, 1999. Nagarajan et al., “Discovery of diphenylmethanepropionic and dihydrostilbeneacetic acids as antagonists of the integrin OVB3.” Chem. Biol. Drug Des., 67: 177-181, 2006. Nagarajan et al., “R-isomers of Arg-Gly-Asp (RGD) mimics as potent alphavbeta3 inhibitors.” Bioorganic & Medicinal Chemistry, 15(11):3783-3800, 2007. Nandrot et al., “Novel role for alphavbeta5-integrin in retinal adhe sion and its diurnal peak.” Am J Physiol Cell Physiol. 290(4):C1256 C1262, 2006. Nishimura, “Integrin-mediated transforming growth factor-beta acti vation, a potential therapeutic target in fibrogenic disorders.” Am. J. Pathol., 175(4): 1362-1370, 2009. Nomura et al., "Stereoselective Ring-Opening Polymerization of a Racemic Lactide by Using Achiral Salen- and Homosalen-Alumi num Complexes.” Chemistry A Europ.J. 13(16):4433-4451, 2007. PCT International Search Report issued in International Application No. PCT/US2013/050917, mailed Sep. 23, 2013. Perdih, "Small molecule antagonists of integrin receptors.” Curr: Med. Chem., 17(22):2371-2392, 2010. Popov et al., “Integrin alphavbetao is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies.”.J. Hepatol. 48(3):453-464, 2008.

Rico, “Synthesis of novel f-amino acid precursors: f-amino hydrocoumarins as unusual aspartic acid mimetics used in fibrinogen receptor antagonists.” Tett. Let., 35:6599-6602, 1994. Schmidt et al., "Characterization of spontaneous metastasis in an aggressive breast carcinoma model using flow cytometry.” Clin. Exp. Metastasis, 17:537-544, 1999. Scotton et al., “Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury.” J Clin Invest., 119(9): 2550-2563, 2009. Shannon et al., “Anti-metastatic properties of RGD-peptidomimetic agents S137 and S247.” Clin. Exp. Metastasis, 21:129-138, 2004. Song et al., "Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5.” Arthri tis Rheum., 56:575-585, 2007. Stragies et al., “Design and synthesis of a new class of selective integrin alpha5beta1 antagonists.” J Med Chem., 50(16):3786-3794. 2007. Suehiro et al., “Fibrinogen binds to integrin alpha(5)beta(1) via the carboxyl terminal RGD site of the Aalpha-chain' J. Biochem. 128(4):705-710, 2000. Tanaka and Shishido, “Synthesis of aromatic compounds containing a 1,1-dialkyl-2-trifluoromethyl group, a bioisostere of the tert-alkyl moiety.” Bioorg Med. Chem. Lett., 17(22):6079-6085, 2007. Wan, et al., “Synthesis of Potent and Orally Efficacious 11 f Hydroxysteroid Dehydrogenase Type 1 Inhibitor HSD-016.” J. Org. Chem.76(17):7048-7055, 2011. Wipffet al., “Myofibroblast contraction activates latent TGF-betal from the extracellular matrix.”.J. Cell Biol., 179(6): 1311-1323, 2007. Wong et al., "o, Integrins mediate adhesion and migration of breast carcinoma cell lines.” Clin. Exp. Metastasis, 16:50-61, 1998. Wu, et al., “Mild Palladium-Catalyzed Selective Monoarylation of Nitriles,” J. Am. Chem. Soc., 127(45): 15824-15832, 2005. Yang et al., “Embryonic mesodermal defects in alpha 5 integrin deficient mice.” Development, 119(4): 1093-1105, 1993. Yoshimura and Muto, "TGF-B function in immune suppression.” Curr Top Microbiol Immunol. 350: 127-147, 2011. Zack et al., “ADAM-8 isolated from human osteoarthritic chondrocytes is capable of cleaving fibronectin at Ala271.” Arthritis Rheum. 60:2704-2713, 2009. Zahn et al., “Assessment of the integrin alpha5betal antagonist JSM6427 in proliferative vitreoretinopathy using in vitro assays and a rabbit model of retinal detachment.” Invest. Ophthalmol. Vis. Sci., 51(2):1028-1035, 2010. Zahn et al., “Preclinical evaluation of the novel small-molecule integrin alpha5beta1 inhibitor JSM6427 in monkey and rabbit mod els of choroidal neovascularization.” Arch. Ophthalmol., 127(10): 1329-1335, 2009.

US 9,085,606 B2 1.

BETAAMNO ACID DERVATIVES AS INTEGRIN ANTAGONSTS

PRIORITY CLAIM

This application claims the benefit of U.S. Provisional Applications Nos. 61/673,058 filed Jul.18, 2012 and 61/764, 443 filed Feb. 13, 2013, both of which are incorporated herein by reference in their entirely.

BACKGROUND OF THE INVENTION

I. Field of the Invention The present invention relates to the fields of pharmaceuti

cals, medicine and cell biology. More specifically, it relates to pharmaceutical agents (compounds) which are useful as inte grin receptor antagonists, with particularly exceptional bio logical activity as antagonists of a group of integrins that mediate the pathologic processes of angiogenesis and fibro sis. As such, these compounds are useful in pharmaceutical compositions and in methods for treating conditions medi ated by Such integrins by inhibiting or antagonizing these integrins.

II. 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-asparate (RGD), that is contained within the sequence of their cognate protein ligands. It has been established in the art that peptides con taining 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 physi ologic ligands (Millard et al., 2011.). The biological effects of treatment with Such agents is dependent on intrinsic molecu lar properties, reflected in the structure, that determine to what degree a particular integrin, or combination of integrins, 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: angio genesis and fibrosis. Different subsets of the RGD-binding integrins have predominant roles in driving these dual pro cesses, so that simultaneous antagonism of angiogenesis and fibrosis requires agents capable of binding potently to several target integrins. This contrasts with agents designed specifi cally for binding to a single integrin which may be less effec tive in Some applications due to their more restricted mecha nism of action.

Integrins which have been shown to have a role in promot ing angiogenesis include, CVB3, CVB5, and C.531. CVB3 and CVB5 were initially described as mediators of bFGF- and VEGF-induced angiogenesis, respectively, in corneal orcho riallantoic models. More recently, data from studies using mice lacking these integrins also support an important func tional role for C.5B1. The integrin C.5 B1 (also known as VLA 5) is often referred to as the classic fibronectin receptor reflecting its well characterized interaction with this extracel lular matrix protein. Cells expressing C.5 B1 bind to fibronec tin 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 fibronectin, C.5B1 has been reported to interact with other RGD-contain ing extracellular matrix proteins including fibrinogen, dena tured collagen, and fibrillin-1 (Bax et al., 2003; Perdih, 2010; Suchiro et al., 2000). These ligands are components of the

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2 provisional matrix that is laid down by cells as part of the wound healing response in tissues. Key components 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 con teXtS.

Antagonists of RGD-binding integrins should be useful for treatment of human diseases having angiogenesis or fibrosis as a principal part of their pathology. In particular, the impor tant role of C5B1 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 embryonic and extraembryonic vasculature (Yang et al., 1993). Angiogenic cytokines such as bFGF, IL-8, TGFB, and TNFC. upregulate C.5 B1 expression on endothelial cells in vitro and in Vivo, and immunohistochem istry shows coordinated increases in both C.5 B1 and fibronec tin 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 C.5 B1, and compounds that have been described as C.5 B1 inhibitors, significantly reduce angiogenesis in a num ber of experimental models (Kim et al., 2000; Bhaskar et al., 2007: Livant et al., 2000; Zahn et al., 2009).

Because C.5B1 expression is not confined to the endothe lium, 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 al., 2000; Blasé et al., 1995; Danen et al., 1994: Edward, 1995). In human fibroblasts, C.5 B1 pro motes motility and survival (Lobert et al., 2010). In pancreatic stellate cells, it interacts with connective tissue growth factor to stimulate adhesion, migration, and fibrogenesis (Gao and Brigstock, 2006). It has been shown that pharmacologic antagonism of C.531 inhibits the attachment migration, and proliferation of human retinal epithelial cells in vitro, and reduces retinal cell proliferation and Scarring when adminis tered intravitreally to rabbits with retinal detachment (Liet al., 2009; Zahn et al., 2010).

Multiple RGD-binding integrins of the alpha v family have been implicated in promoting the biological activation of the latent pro-fibrotic cytokine TGFB. This is mediated by bind ing to the latency associated peptide (LAP), particularly by CVB6 and CVB8, but also by CVB1, CVB3, and CVB5. These integrin interactions 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 are incapable of cytokine activation and phenocopy TGFB-null mice. It is anticipated that simultaneous inhibition of multiple integrins with the potential to activate TGFB may have par ticular utility to prevent or treat a range of fibrotic conditions. In addition, such broad spectrum integrin antagonists may be particularly useful for simultaneous modulation of both angiogenesis and fibrosis.

SUMMARY OF THE INVENTION

The present disclosure provides novel integrin receptor antagonists, pharmaceutical compositions, and methods for their manufacture, and methods for their use.

In some aspects, the present invention provides a com pound of the formula:

US 9,085,606 B2

(I)

wherein: W is

wherein: R is —H or F, F: R is —CN, oralkoxys wherein if R is —F, then R is - Hor —F. and m is 0-3: A is C R" or N, wherein: R" is -H, —OH, -COR, —C(=O)R, or —N(R)(C=O)R, or

H, -OH, -NH.

alkoxyces acyloxyces, alkylaminoes, dialkyl aminos, or a substituted version of any of the groups, wherein: R is -H, alkylcs) or substituted alkylcs: R2 is alkylaminocs dialkylaminocs heterocycloalkylos), heteroaryles, or a substituted version of any of the groups: Rs is alkylcs) arylcs) aralkylc's heteroarylc's het erocycloalkyls, or a substituted version of any of the groups; R is -H, alkylcs) or substituted alkylcs: X is: hydrogen, halo, alkylc-12), alkoxyc-12). arylc-12), aralkylc-12 heteroarylcs, heterocyclo alkylc-12 aryloxyc-12 acyloxyc-12 or a substituted Ver sion of any of the groups: -(CH2), CO-alkyl wherein, n' is 0-3:

or cyano;

R6,

Rs

wherein Ra and Rs are each independently alkyls. Substi tuted alkyls, or —CH2O-alkyls: R is -OH, -CN. NH, CF, CFH, —CHF, —COH, -CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkylos, or alkoxys provided that where Ra and Rs are each —CFs, then R is -OH, alkoxys or -NH2:

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cut-Co. wherein n is 1 or 2 and X is —H or alkyls; or

A.

wherein: A' is a covalent bond, thereby forming a cyclopro pane ring, —CF, , -O-, alkanediyl or alkoxy diyles; and R, is -OH, -CN, -NH2, —CO.H. —CO alkyls, —C(=O)NH2. —CFs. -CF.H. —CH2F, —CH2OH, -CHO-alkylcs, alkylcs) or alkoxycs:Y is: t-butyl, neopentyl, norbornyl, or adamantyl:

wherein Rs and Rs are each independently alkyls substi tuted alkyls, or—CH2O-alkyls: Rio is -OH, -CN. NH, —CF, CFH, —CFH, —COH, -CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkyles, or alkoxys provided that where Rs and Rs are each —CF, then Rio is -OH, alkoxys or -NH2:

cir-(or, wherein n" is 1 or 2 and Y is -H or alkyls; or

wherein: A" is a covalent bond, thereby forming a cyclopro pane ring, —O , —CF , alkanediyl or alkoxy diyles; and R is -OH, -CN, -NH2. —CO.H. —CO alkyls, —C(=O)NH2. —CF, -CFF, —CH2OH. —CH2O-alkylcs, alkylcs) or alkoxycs: L is hydrogen, hydroxy or alkoxys; and Z is hydrogen, fluorine, or hydroxy and is attached to either carbonatom 2 or 6: provided that if W is

US 9,085,606 B2 5

OH F

C. O C. HN HN

then X and Y are not both each t-butyl; and further provided that if W is

OH

Nan -NH

r X A is C—OH, Z is hydrogen, and X is bromo or iodo, then Y is not t-butyl, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is further defined as:

(LA) O

W. N

2 A.

wherein: W is

X N- N- 2N "N."

HN HN HN HN

s s , or s

wherein: R is —H or —F: R is —H. —OH, -NH2, —F. —CN, or alkoxys, wherein if R is —F, then R is -H or —F. and m is 0-3: A is C R" or N, wherein: R" is -H, —OH, -COR, —C(=O)R, or —N(R)(C=O)R. or alkoxyces, acyloxyces, alkylaminocs, dialkyl aminos, or a substituted version of any of the groups, wherein: R is -H, alkylcs) or substituted alkylcs: R2 is alkylaminocs dialkylaminocs heterocycloalkylos),

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6 heteroaryles, or a substituted version of any of the groups: Rs is alkylcs: arylcs) aralkylc's heteroarylc's het erocycloalkyls, or a substituted version of any of the groups; R is -H, alkyls or substituted alkyls: X is: hydrogen, halo, alkylc-12), alkoxyc-12). arylc-12), aralkylc-12 heteroarylcs, heterocyclo alkylc-12), aryloxyc-12 acyloxyc-12 or a Substituted Ver sion of any of the groups: -(CH2), CO-alkyl wherein, n' is 0-3:

or cyano;

wherein R and Rs are each independently alkyls, or sub stituted alkyls: R is -OH, -CN, -NH2, —CF, —CF2H, -CO.H. —CO-alkyls —C(=O)NH2. —CH2OH, oralkoxys provided that where Ra and Rs are each CF, then R is OH:

CH3

o cis-(-oil, CH

wherein n is 1 or 2; or

A.

wherein: A' is a covalent bond, thereby forming a cyclopro panering, alkanediylco oralkoxydiyles; and R7 is -OH, —CN, -NH2, -COH, -CO-alkyls, —C(=O)NH2. —CF, -CFH, oralkoxys;Y is: t-butyl, neopentyl, nor bornyl, or adamantyl:

wherein Rs and Rs are each independently alkyls, or sub stituted alkyls: Rio is -OH, -CN, -NH2, —CF, —CF2H, -CO.H. —CO-alkyls —C(=O)NH2. —CH2OH, oralkoxys provided that where Rs and Rs are each CF, then Rio is OH:

CH

-cis-(-oil. CH3

US 9,085,606 B2

whereinn" is 1 or 2; or

it A",

wherein: A" is a covalent bond, thereby forming a cyclopro pane ring, alkanediylco) or alkoxydiylos); and R is —OH, -CN, -NH2. —CO.H. —CO-alkylos, —C(=O)NH2. —CF, -CF.H, or alkoxys; L is hydro gen, hydroxy or alkoxys and Z is hydrogen or hydroxy and is attached to either carbonatom 2 or 6: provided that if W 1S

N- O N- s HN HN

then X and Y are not both each t-butyl; and further provided that if W is

OH

Nan -NH

r X A is C—OH, Z is hydrogen, and X is bromo or iodo, then Y is not t-butyl, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound is further defined as:

(II)

10

15

25

30

35

40

45

50

55

60

65

wherein: W is

wherein: R is —H or —F: R is —H. —OH, -NH2, —F. —CN, or alkoxys wherein if R is —F, then Reis-H or —F. and m is 0-3: A is C R" or N, wherein: R" is -H, —OH, -COR, —C(=O)R, or —N(R)(C=O)R. or alkoxyces, acyloxyces, alkylaminocs, dialkyl aminos, or a substituted version of any of the groups, wherein: R is -H, alkylcs) or substituted alkylcs: R2 is alkylaminocs, dialkylaminocs heterocycloalkylos), heteroaryles, or a substituted version of any of the groups: Rs is alkylcs: arylcs) aralkylc's heteroarylc's het erocycloalkyls, or a substituted version of any of the groups: X is: hydrogen, halo, or cyano; alkyl-2, alkoxyc-12 arylc-12 aralkylc-12 heteroarylc's het erocycloalkylc-12 aryloxyc-12), acyloxyc-12), or a substi tuted version of any of the groups: —(CH), CO alkylco, wherein, n' is 0-3:

wherein Ra and Rs are each independently alkyls substi tuted alkyls, or -CHO-alkyls: R is -OH, -CN. NH = CF, —CFH, —CHF. COH, CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkyles, or alkoxys provided that where Ra and Rs are each —CFs, then R is -OH, alkoxys or -NH2:

----(os. wherein n is 1 or 2 and X is —H or alkyls; or

A.

wherein: A' is a covalent bond, thereby forming a cyclopro pane ring, —CF, , —O , alkanediyl or alkoxy diyles; and R, is -OH, -CN, -NH2, —CO.H. —CO alkyls, —C(=O)NH2. —CF, -CF.H. —CHF, —CH2OH, -CHO-alkylcs, alkylcs) or alkoxycs:Y is: t-butyl:

US 9,085,606 B2

wherein Rs and Rs are each independently alkyls, or sub stituted alkyls: Rio is -OH, -CN, -NH2, —CFs, —CF2H, -COH, -CO-alkyls, —C(=O)NH2. —CH2OH, oralkoxycs, provided that where Rs and Rs are each CF, then Rio is OH:

CH3

-cis-(-oil. CH3

whereinn" is 1 or 2; or

it A",

R11

wherein: A" is a covalent bond, thereby forming a cyclopro pane ring, alkanediylco or alkoxydiylcs; and R is —OH, -CN, -NH2. —CO.H. —CO-alkylos, —C(=O)NH2. —CF, -CFH, or alkoxys; and Z is hydrogen or hydroxy and is attached to either carbon atom 2 or 6: provided that if W is

N& NH NS NH

x - "y then X and Y are not both each t-butyl; and further provided that if W is

OH

Nan -NH

r X. A is C—OH, Z is hydrogen, and X is bromo or iodo, then Y is not t-butyl, or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the carbonatom labeled B is in the R configuration. In other embodiments, the carbon atom labeled B is in the S configuration. In some embodiments, Y 1S

10

15

25

30

35

40

45

50

55

60

65

wherein: Rs and Rs are each independently alkyls, substi tuted alkyls, or -CHO-alkyls and Rio is -OH, —CFs. -CF.H. —CFH, -CO-alkyls, —CH2OH. —CH2O-alkylcs, or alkoxycs, provided that where Rs and Rs are each -CF, then Rio is -OH, alkoxys, or —NH.

In some embodiments, W is

OH

Nn-NH

In some embodiments, A is C—OH. In other embodiments, A is N. In some embodiments, X is halo. In some embodiments, X is bromo. In other embodiments, X is chloro. In other embodiments, X is alkyls, or substituted alkyls. In some embodiments, X is t-butyl. In other embodiments, X is 2-hydroxy-isopropyl. In other embodiments, X is —CF. In other embodiments, X is cyano. In other embodiments, X is heteroaryl. In some embodiments, X is pyrimidyl. In other embodiments, X is pyridyl. In some embodiments, L is hydrogen. In some embodiments, Y is t-butyl. In other embodiments, Y is 2-hydroxy-isopropyl. In other embodi ments, Y is

wherein Rs and Rs are each independently alkyls substi tuted alkyls, or -CHO-alkyls: Rio is -OH, -CN. NH, —CF, CFH, —CFH, —COH, -CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkyles, or alkoxys provided that where Rs and Rs are each —CFs, then Rio is -OH, alkoxys or -NH2. In some embodiments, Rs and Rs are alkyls. In some embodi ments. Rs and R are methyl. In some embodiments, Ro is —CN, —CH2OH, -CH2O-alkyls, or -CFs. In other embodiments, wherein Rio is —CHO CH. In other embodiments, Y is

US 9,085,606 B2 13

In other embodiments, Y is


vko In other embodiments, Y is

wk, In other embodiments, Rs is alkyls. In other embodi ments. Rs is methyl. In other embodiments, R is substituted alkyls. In other embodiments, R. is —CFs. In other embodiments, Ro is —OH. In other embodiments, Y is

FC


wherein: A" is a covalent bond, thereby form a cyclopropane ring, -O-, -CF, , alkanediylco or alkoxydiyles: and R is -OH,-CN, -NH2, -COH,-CO-alkylos, —C(=O)NH2, CF, CFH, CHF, CHOH, —CH2O-alkylcs, alkylcs) or alkoxyces. In some embodiments, A" is a covalent bond. In other embodiments, A" is alkoxydiyls. In some embodiments, A" is —CHOCH2 . In other embodiments. A" is alkanediyl.co. In some embodiments, A" is —CH2—. In other embodi ments, R is —CN, —CH2OH, -CH2O-alkylos, —CFH, or —CFH. In some embodiments, R is —CHOCH. In other embodiments, Y is

HFC

10

15

25

30

35

40

45

50

55

60

65

14 In other embodiments, Y is

4. O


4. O


6. In other embodiments, Y is

S. O


/S, In some embodiments, Z is hydrogen. In other embodiments, Z is hydroxy and attached to carbon atom 2. In other embodi ments, Z is hydroxy and attached to carbon atom 6. In other embodiments, Z is fluoride and attached to carbonatom 2. In other embodiments, Z is fluoride and attached to carbonatom 6. In some embodiments, R is hydrogen.

In other embodiments, W is

C.

NH

/ HN

US 9,085,606 B2 15 16

In some embodiments, A is C—OH. In other embodiments, A -continued is C—H. In other embodiments, A is N. In some embodi ments, R is hydrogen. In some embodiments, L is hydrogen.

O

H H HN N N

In some embodiments, Z is hydrogen. In some embodiments, N N ~ COOH, Y is alkyl . In some embodiments, Y is t-butyl. In some 5 sy (C-8) NH O embodiments, X is halo. In some embodiments, X is bromo. 2

O

In other embodiments, X is alkyls. In other embodiments, X is t-butyl.

B In some embodiments, W is 10 r

HN H N N N COOH,

H

\ 15 NH2 2 O N N

In some embodiments, A is C—OH. In other embodiments, A Br is C-H. In some embodiments, R is hydrogen. In some

O embodiments, L is hydrogen. In some embodiments, Z is hydrogen. In some embodiments, Y is alkylos. In some H embodiments, Y is t-butyl. In some embodiments, X is halo. s 1. COOH, In some embodiments, X is bromo. C H

In some embodiments, the compound is further defined as: 25

Br O

H H N N N 30 O n N COOH, H H

H N N N

NH O OH s N 1. COOH, H HO NH 2 O

OH HO N Br 35

Br

O O

H H H H H N N N 40 N N N n N COOH, N COOH,

NH O OH HO N O

OH Br OH

45 Br

O O

H H H H HN N N

N-N N 50 N N COOH, N N COOH H NH O NH 2 O

HO N

OH Br

OH, 55

O H H

H O H N-N N N- N N-N-N-rr-Yon. N N1) COOH 60 NH O

NH O HO

HO OH

OH Br C

OH, 65

N

N

OH

s

s

N

2

OH

21 -continued

N ~ NC

gr

NC

C

ir C

US 9,085,606 B2

COH, 10

15

COH, 25

35

40

COH,

45

50

55

COH, 60

65

22 -continued

N NH O

HN

N ir COH, H

2 O N

NC

F

N NH

Y O HN

N N COH, H

2 O N

NC

OH

N NH

Y O HN

N ir CO2H H

2 O N

C OH,

N NH

Y O H HN N

ir CO2H H

O

C OH,

US 9,085,606 B2 31 32

-continued In other embodiments, the compound is further defined as: F

O 5 H H

N N N Nn-NH N ^Yoon, Y NH O OH HO

N

O

HN N N CO2H, 10 OH

H Br

2 O N O

CN H N N

Br 15 s ~ COOH, NH O OH

HO

Br

2O

s N. O

H HN N 25 NH O

ir COH, HO H OH

O Br OH,

CN OH O

Br 30 H N N

N ~ COOH

35 OH

N COOH N

N

C

n-NH O Y H H N N

O

H 40 HN HN N N N COOH,

N CO2H, and H NH2

2 O N

CN

C

OH, N

45 Br

O

HN N F 50 N N N COOH, H

NH2 2 O N

N- O Br H 55 HN N

1 CO2H H O

O H H N N

CN 60 Sir 1. COOH, OH C N O

65 Br

or a pharmaceutically acceptable salt or tautomer thereof.

US 9,085,606 B2 35

-continued O

H H H N N N COH,

N r N1 N O

HO

OH CF C

OH

3

O H H H N N N

N CO2H H

N O HO

OH C

CF3, O

H H H N N N

N COH, H

N O HO

CN OH

C

O H H H N N N

N1 CO2H H N O

HO CN

OH C

O, and O

H H H N N N

N CO2H H

N O HO

OH FC

OH, CF

or a pharmaceutically acceptable salt or tautomer thereof. In some embodiments, the compound of claim 1 of the

formula shown in Table A or a pharmaceutically acceptable salt or tautomer thereof.

In another aspect, the present invention provides a phar maceutical composition comprising: a) the compound of the present invention; and b) an excipient.

In yet another aspect, the present invention provides a method of treating and/or preventing a disease or a disorder in a patient in need thereof, comprising administering to the patient a compound of the present invention 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 disease or disorder is associated with fibrosis. In other embodiments, the disease or disorder is associated with fibrosis and/orangiogenesis. In other embodiments, the disease or disorder is pulmonary, liver, renal, cardiac, and pancreatic fibrosis, Scleroderma, scarring, retinopathy of prematurity, familial exudative Vit reoretinopathy, proliferative vitreoretinopathies, macular degeneration, diabetic retinopathy, cancer, osteoporosis, autoimmune diseases, humoral hypercalcemia of malig nancy, Paget’s disease, periodontal disease, psoriasis, arthri tis, restenosis, and infection. In other embodiments, the dis

10

15

25

30

35

40

45

50

55

60

65

36 ease or disorder is pulmonary fibrosis. In other embodiments, the disease or disorder is liver fibrosis. In other embodiments, the disease or disorder is cardiac fibrosis. In other embodi 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 disease or disorder is scarring. In Some embodiments, the Scarring is dermal scarring. In other embodiments, the scarring is retinal Scarring. In other embodiments, wherein the Scarring is corneal scarring. In other embodiments, the disease or disorder is retinopathy of prematurity. In other embodiments, the disease or disorder is familial exudative vitreoretinopathy. In other embodiments, the disease or disorder is proliferative vitreoretinopathies. In other embodiments, the disease or disorder is macular degen eration. 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 other 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, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, Small intestine, large intes tine, Stomach, testicle, or thyroid. In other embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, mela noma, mesothelioma, multiple myeloma, or seminoma. In other embodiments, the disease or disorder is osteoporosis. In other embodiments, the disease or disorder is an autoimmune disease. In some embodiments, the autoimmune disorder is multiple sclerosis. In other embodiments, the disease or dis order is humoral hypercalcemia of malignancy. In other embodiments, the disease or disorder is Paget’s disease. In other embodiments, the disease or disorder is periodontal disease. 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 disorder 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 other embodiments, the patient is a monkey, cow, horse, sheep,goat, dog, cat, mouse, rat, or guinea pig. In other embodiments, the patient is a human. In another aspect, the present invention provides a compound of the formula:

wherein: R is -H, alkylos Substituted alkylcs alkylaryla and silyl; R" and R" are each independently —H, alkylcs substituted alkylcs, alkylarylc-12 substi tuted alkylaryl-2, acyl, tert-butyloxycarbonyl, 9-fluore nylmethyloxycarbonyl, carbamate, carbobenzyloxy, or ben Zoyl: X is: hydrogen, halo, or cyano; alkyl.c.12.

US 9,085,606 B2 37

alkoxyc-12 arylc-12), aralkylc-12 heteroarylcs het erocycloalkylc-12 aryloxycia, acyloxycl2 or a substi tuted version of any of the groups; —(CH), CO alkylco, wherein, n' is 0-3:

R4

R6,

Rs

wherein R and Rs are each independently alkyls substi tuted alkyls, or —CH2O-alkyls: R is -OH, -CN. NH, CF, CFH, —CHF, —COH, -CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkylos, or alkoxys provided that where Ra and Rs are each —CFs, then R is -OH, alkoxys or -NH2:

--e (s. wherein n is 1 or 2 and X is —H or alkyls; or

A.

R

wherein: A' is a covalent bond, thereby forming a cyclopro pane ring, —CF, , -O-, alkanediyl or alkoxy diyles; and R, is -OH, -CN, -NH2, -CO2H. —CO alkyls, —C(=O)NH2. —CF, -CF.H. —CHF, —CH2OH, -CHO-alkylcs, alkylcs) or alkoxycs:Y is: t-butyl, neopentyl, norbornyl, or adamantyl:

wherein Rs and Rs are each independently alkyls substi tuted alkyls, or—CHO-alkyls: Rio is -OH, -CN. NH = CF, CF.H. —CFH, —COH, -CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkylos, or alkoxys provided that where Rs and Rs are each —CFs, then Rio is -OH, alkoxys or -NH2:

--e. (or wherein n" is 1 or 2 and Y is -H or alkyls; or

10

15

25

30

35

40

45

50

55

60

65

38 wherein: A" is a covalent bond, thereby forming a cyclopro pane ring, -O-, -CF, , alkanediyl or alkoxy diyles; and R is -OH, -CN, -NH2. —CO.H. —CO alkyls, —C(=O)NH2. —CFs. -CF.H. —CH2F, —CH2OH. —CH2O-alkylcs, alkylcs) or alkoxycs: L is hydrogen, hydroxy or alkoxycs; and Z is hydrogen, fluorine, or hydroxy and is attached to either carbonatom 2 or 6; or a salt or tautomer thereof. In other embodiments, the present invention provides a compound of the formula:

wherein: R is -H, alkyls substituted alkyls, alkyl aryl-2, and silyl; R" and R" are each independently —H, alkylcs substituted alkylcs, alkylarylc-12 substituted alkylaryl-2, acyl, tert-butyloxycarbonyl, 9-fluorenylm ethyloxycarbonyl, carbamate, carbobenzyloxy, or benzoyl: X is: hydrogen, halo, or cyano; alkylc-12 alkoxyc12. arylc-12), aralkylc-12 heteroarylcs, heterocyclo alkylc-12), aryloxyc-12 acyloxyc-12 or a Substituted Ver sion of any of the groups: -(CH2), CO-alkyl wherein, n' is 0-3:

wherein Ra and Rs are each independently alkyls substi tuted alkyls, or —CH2O-alkyls: R is -OH, -CN. NH = CF, CFH, —CHF. COH, CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkyles, or alkoxys provided that where Ra and Rs are each —CF, then R is -OH, alkoxys or -NH2:

--in-(s. wherein n is 1 or 2 and X is -H or alkyls, or

A.

wherein: A' is a covalent bond, thereby forming a cyclopro pane ring, —CF, , -O-, alkanediyl or alkoxy diyles; and R, is -OH, -CN, -NH2, —CO.H. —CO alkyls, —C(=O)NH2. —CFs. -CF.H. —CH2F, —CH2OH, -CHO-alkylcs, alkylcs) or alkoxycs:Y is: t-butyl, neopentyl, norbornyl, or adamantyl:

US 9,085,606 B2

wherein Rs and Rs are each independently alkyls. Substi tuted alkyls, or -CHO-alkyls: Rio is -OH, -CN. NH = CF, —CFH, —CFH, —CO.H. —CO

alkyls, —C(=O)NH2. —CH2OH. —CH2O-alkylos, or alkoxys provided that where Rs and Rs are each —CFs, then Rio is -OH, alkoxys or -NH2:

----(o. whereinn" is 1 or 2 and Y is -H or alkyls; or

it A",

R11

wherein: A" is a covalent bond, thereby forming a cyclopro pane ring, —O , —CF , alkanediyl or alkoxy diyles; and R is -OH, -CN, -NH2. —CO.H. —CO alkyls, —C(=O)NH, -CF, -CF.H. —CH.F, —CH2OH. —CH2O-alkylcs, alkylcs) or alkoxycs: L is hydrogen, hydroxy or alkoxycs; and Z is hydrogen, fluorine, or hydroxy and is attached to either carbonatom 2 or 6; or a salt or tautomer thereof. In some embodiments, the compound is limited by the proviso that X and Y are not both each t-butyl; and further provided that Z is hydrogen, and X is bromo or iodo, then Y is not t-butyl. In some embodiments, the carbon atom labeled B is in the R configuration. In other embodiments, the carbon atom labeled B is in the S configu ration. In some embodiments, R is —H. In other embodi ments, R is alkyls. In some embodiments, R is ethyl. In some embodiments, R" is —H. In some embodiments, R" is —H. In other embodiments, R" and R" are both—H. In some embodiments, L is hydrogen. In some embodiments, Z is hydrogen. In other embodiments, Z is hydroxy. In other embodiments, Z is hydroxyl and attached to the carbon labeled 2. In other embodiments, Z is hydroxyl and attached to the carbon labeled 6. In some embodiments, X is halo. In some embodiments, X is chloro. In other embodiments, X is bromo. In other embodiments, X is alkyl-2 or substituted alkyl-2. In some embodiments, X is alkyl-2. In some embodiments, X is t-butyl. In other embodiments, X is sub stituted alkyl-2. In some embodiments, X is trifluorom ethyl. In other embodiments, X is heteroaryles. In some embodiments, X is 3-pyridinyl. In other embodiments, X is 3-pyrimidyl. In other embodiments, X is cyano. In some embodiments, Y is t-butyl. In other embodiments, Y is

10

15

25

30

35

40

45

50

55

60

65

40 wherein Rs and Rs are each independently alkyls substi tuted alkylos, or -CH2O-alkylcs) and Rio is -OH, CN, -NH = CF, —CFH, —CFH, —CO.H. —CO

alkyls, —C(=O)NH2. —CH-OH, -CHO-alkyls, or alkoxys provided that where Rs and Rs are each —CFs, then Rio is -OH, alkoxyces or -NH2. In other embodiments, Rs is alkyls. In some embodiments, Rs is methyl. In some embodiments, R. is alkyls, or substituted alkyls. In some embodiments, R. is alkyls. In some embodiments, Ro is methyl. In other embodiments, Ro is substituted alkyls. In some embodiments, R. is trifluo romethyl. In some embodiments, Rois —OH, -CN. —CF, —CH2OH, or —CH-O-alkyls. In some embodiments, Ro is —OH. In other embodiments, Ro is —CN. In other embodiments, Rois —CH2OH. In otherembodiments, Rois —CFs. In other embodiments, Rio is —CHO-alkyls. In other embodiments, Ro is —CHO CH. In other embodi ments, Y is 2-hydroxy-isopropyl. In other embodiments, Y is



vko In other embodiments, Y is

wk, In other embodiments, Y is

FC

US 9,085,606 B2 41


R11

wherein: A" is a covalent bond, thereby forming a cyclopro pane ring. -O-, -CF, alkanediyl or alkoxydiyles: and R is -OH,-CN, -NH2, -COH,-CO-alkylos, —C(=O)NH2, CF, CFH, CHF, CHOH, —CH2O-alkylcs, alkylcs) or alkoxyces. In some embodiments, A" is a covalent bond, thereby forming a cyclo propane ring. In other embodiments, A" is alkanediyl.co. In some embodiments, A" is —CH2—. In other embodiments, A" is alkoxydiyles. In some embodiments, A" is —CH2— O—CH2—. In some embodiments, R is —CN. In other embodiments, R is —CHF. In other embodiments, R is —CHF. In other embodiments, R is —CH2OH. In other embodiments, R is —CH2O-alkyls. In other embodi ments, R is —CHO CH. In other embodiments, Y is

HFC


A. O


AS O


6.

10

15

25

30

35

40

45

50

55

60

65

42 In other embodiments, Y is

NC


In some embodiments, the compound is further defined as:

O OH, O OH is

H HN

OH O

Br Br

OH, HN

O O

C OH H

O OH ,

5. HN OH,

O

Šs

H

N

H

HN OH,

Br O

O OH, H

HN

Br

HN OH,

O

Br

N

N

US 9,085,606 B2 45 46

-continued -continued HN OH

O 5 H

CN

Br

O 10 Cl OH,

2

or a salt or tautomer thereof. In other embodiments, the com pound is further defined as:

15

HN HN OH

2O O

C

25

N

H,

Br H

O OH ,

HN

OH s

r Br

HN OH,

O 30

H

C OH

35 H, O OH ,

SN, c. HN

2

HN OH,

O

S N

O OH,

HN

C OMe,

s

N

2

H

H

O

HN OH

O

O OH

N

O O

OH

HN O

O OH

B

O HN

O OH O

N

O O

HN

N

O OH

45 HN HN HN

O

50 C

Br s

HFC OH

N

O OH,

N

40 O

O OH Br

OH,

Br 5. CF, 55 O OH

O OH

H HN HN

60

C

FC OH CF3, C s s 65 NC

US 9,085,606 B2

-continued O OH

HN

CN

C

O, and

O OH

HN

FC OH

CF

or a salt or tautomer thereof. In other embodiments, the com

H

pound is further defined as:

O OEt, O OEt ,

HN HN

O OH

Br Br

HN OEt, HN OEt,

O O

Br C OH OH

O OEt, O OEt ,

HN HN

Br

HN O N O

O O

Šs

N

Br

Et, H Et,

IS

10

15

25

30

35

40

45

50

55

60

65

-continued O OEt

O OEt

HN HN

FC OH, Cl OMe,

O OEt

HN

C

O OEt

HN HN OEt

O F

SN, c. e

N O

O OEt

O OEt

HN HN

C Br s CF,

HFC OH

US 9,085,606 B2 49 50

-continued -continued O OEt HN OEt

O OEt

HN 5 O

HN CN

Br

O C 10

CF3, C s

NC or a salt or tautomer thereof. In other embodiments, the com O OEt

O OEt pound is further defined as: 15

HN HN

O OEt, O OEt ,

HN HN CN 2O 2 2

C FC OH OH

s OH, CF

O OEt Br

HN HN HN HN OEt,

30 O O

C C Br C FHC OH

O OEt O OEt 35 O OEt, O OEt ,

HN HN HN HN

40

Br Br B CF3, CF3, r

OH 45

HN HN OEt,

O O

S n N

N

O OE O OEt

N HN

C OMe,

O OEt 25 B

E

O

r

OEt,

OH

O OEt Et, O OEt

HN HN

50

Br

2 2 OH, Br s 55

NC t

O OEt O OEt

H

HN HN 60

FC C * Br and 65 H,

O

O

51 -continued

C

5.

C

O OEt

HN

C OH,

HN OEt

O OH

O

O OEt

HN

N

O OEt

HN

Br HFC

O OEt

HN

C CF, C

HN

OMe,

HN

HN

SN. c. 2

HN

10

15

25

30

35

40

45

50

55

60

65

US 9,085,606 B2

-continued O OEt

HN

CN

C

O, and

O OEt

HN

FC OH

CF

or a salt or tautomer thereof. 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 towards the backbone and the Y is oriented away form the backbone as well as the manner drawn in most commonly in the specification show ing the X group on the oriented towards the backbone and the Yoriented away from the backbone as shown in the structures below. The structure:

given the free rotation of the bond joining the carbon label B in the backbone and the carbon labeled 1 in the aromatic ring.

Other objects, features and advantages of the present dis closure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicat ing specific embodiments of the invention, are given by way

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of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed descrip tion. 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.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Disclosed herein are new compounds and compositions with integrin receptor antagonists properties, methods for their manufacture, and methods for their use, including for the treatment and/or prevention of disease.

I. Definitions

When used in the context of a chemical group, “hydrogen means —H; “hydroxy' means —OH: “oxo” means —O; “halo' means independently —F. —Cl, Bror —I: "amino” means —NH; “hydroxyamino” means —NHOH: “nitro means —NO; imino means —NH; “cyano” means —CN: "isocyanate” means —N=C=O; “azido” means —N; in a monovalent context “phosphate” means —OP(O)(OH) or a deprotonated form thereof; in a divalent context “phosphate' means —OP(O)(OH)O— or a deprotonated form thereof; “mercapto' means —SH: “thio’ means —S; “sulfonyl means —S(O) ; and "Sulfinyl' means —S(O)—.

In the context of chemical formulas, the symbol “ means a single bond, “—” means a double bond; and “=” 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 structure

99

includes the structures

OOOO-O As will be understood by a person of skill in the art, no one such ring atom forms part of more than one double bond. The symbol “Vvv^*, when drawn perpendicularly across a bond 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 rapidly and unambiguously identifying a point of attachment. The sym bol “” means a single bond where the group attached to the thick end of the wedge is “out of the page.” The symbol “"Ill” means a single bond where the group attached to the thick end of the wedge is “into the page'. The symbol “M” means a single bond where the conformation (e.g., either R or S) or the geometry is undefined (e.g., either E or Z). Any undefined Valency on an atom of a structure shown in

this application implicitly represents a hydrogen atom bonded to the atom. When a group “R” is depicted as a “floating group' on a ring system, for example, in the for mula:

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then R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a group “R” is depicted as a “floating group' on a fused ring system, as for example in the formula:

(R), g N 7

N 2X H

then R may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals —CH ), so long as a stable struc ture is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter “y” immediately following the group “R” enclosed in parenthe ses, represents a numeric variable. Unless specified other wise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydro gen atoms of the ring or ring system.

For the groups and classes below, the following parentheti cal subscripts further define the group/class 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 mini mum number as Small as possible for the group in question, e.g., it is understood that the minimum number of carbon atoms in the group "alkenyls,” or the class "alkenesis two. For example, "alkoxyclo" designates those alkoxy groups having from 1 to 10 carbonatoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or any range derivable therein (e.g., 3 to 10 carbon atoms). (Cn-n') defines both the minimum (n) and maximum number (n') of carbon atoms in the group. Simi larly, "alkylcao designates those alkyl groups having from 2 to 10 carbon atoms (e.g., 2, 3, 4, 5, 6,7,8,9, or 10, or any range derivable therein (e.g., 3 to 10 carbon atoms)). The term “saturated as used herein means the compound

or group so modified has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. The term does not preclude carbon-heteroatom multiple bonds, for example a carbon oxygen double bond or a carbon nitrogen double bond. Moreover, it does not preclude a carbon-carbon double bond that may occur as part of keto-enol tautomerism or iminefenamine tautomerism. The term “aliphatic' when used without the “substituted

modifier signifies that the compound/group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group. In aliphatic compounds/groups, the carbon atoms

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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 bonds (alkanes/ alkyl), or unsaturated, with one or more double bonds (alk enes/alkenyl) or with one or more triple bonds (alkynes/alky nyl). When the term “aliphatic' is used without the “substituted modifier only carbon and hydrogen atoms are present. When the term is used with the “substituted” modi fier one or more hydrogen atom has been independently replaced by —OH, - F. —Cl, —Br. —I, NH, NO, —COH,-COCH, —CN, -SH, OCH —OCHCH —C(O)CH, N(CH), C(O)NH, OC(O)CH, or —S(O)NH2.

The term “alkyl” when used without the “substituted” modifier refers to a monovalent Saturated aliphatic group with a carbonatom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, and no atoms other than carbon and hydrogen. Thus, as used herein cycloalkyl is a subset of alkyl. The groups —CH(Me), —CHCH (Et), —CHCHCH (n-Pr), —CH(CH), (iso-Pr), —CH(CH), (cyclopropyl), —CH2CHCH-CH (n-Bu), —CH(CH) CHCH (sec-butyl), —CH2CH(CH) (iso-butyl), —C(CH) (tert-butyl), —CHC(CH) (neo-pentyl). cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexylmethyl are non-limiting examples of alkyl groups. 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, cyclo, cyclic or acyclic structure, no car bon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH2— (Methylene), —CH2CH2—, —CHC(CH3)2CH2—, —CH2CH2CH2—, and

are non-limiting examples of alkanediyl groups. The term “alkylidene' when used without the “substituted” modifier refers to the divalent group —CRR' in which R and R' are independently hydrogen, alkyl, or RandR' are taken together to represent an alkanediyl having at least two carbon atoms. Non-limiting examples of alkylidene groups include:=CH, —CH(CHCH), and—C(CH). 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, NH, NO. —CO.H. —COCH, —CN, —SH, —OCH —OCHCH. —C(O)CH —N(CH), —C(O)NH, OC(O)CH, or—S(O)NH2. The following groups are non-limiting examples of substituted alkyl groups: —CH-OH, -CHCl, CF, -CHCN, -CHC(O)OH, —CHC(O)OCH, -CHC(O)NH, -CHC(O)CH, —CHOCH, -CHOC(O)CH, CHNH, -CHN (CH), and —CH2CH2C1. The term “haloalkyl is a subset of substituted alkyl, in which one or more hydrogenatoms has been Substituted with a halo group and no other atoms aside from carbon, hydrogen and halogen are present. The group, —CH2Cl is a non-limiting examples of a haloalkyl. An “alkane' refers to the compound H R, wherein R is alkyl. The term “fluoroalkyl is a subset of substituted alkyl, in which one or more hydrogen has been substituted with a fluoro group and no other atoms aside from carbon, hydrogen and fluorine are present. The groups, —CHF. —CF, and

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56 —CHCF are non-limiting examples of fluoroalkyl groups. An “alkane' refers to the compound H-R, wherein R is alkyl. The term “alkenyl' when used without the “substituted

modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one non aromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH=CH (vinyl), -CH=CHCH-CH=CHCHCH —CH-CH=CH (allyl), —CH-CH=CHCH, and —CH=CH-CHs. The term “alkenediyl when used with out the “substituted” modifier refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attach ment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no car bon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups, —CH=CH , —CH=C(CH) CH , —CH=CHCH , and

y As7. are non-limiting examples of alkenediyl groups. When these terms are used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH,

F. —Cl, —Br. —I, NH, NO. —COH, -COCH, - CN, -SH, OCH, OCHCH - C(O)CH, - N(CH), C(O)NH, OC(O)CH, or -S(O)NH. The groups, -CH=CHF, -CH=CHCland-CH=CHBr, are non-limiting examples of Substituted alkenyl groups. An “alkene' refers to the compound H-R, wherein R is alkenyl. The term “alkynyl' when used without the “substituted

modifier refers to an monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one car bon-carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups, —C=CH, -C=CCH, and —CH2C=CCH are non-limiting examples of alkynyl groups. When alkynyl is used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH, - F. —Cl, —Br. —I, NH, NO. —COH, - COCH –CN, -SH, OCH —OCHCH, C(O) CH, N(CH), —C(O)NH2. —OC(O)CH, or —S(O) NH. An “alkyne” refers to the compound H R, wherein R is alkynyl. The term “aryl' when used without the “substituted modi

fier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not pre clude the presence of one or more alkyl group (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl) phenyl, —CHCH-CH (ethylphenyl), naphthyl, and the monovalent group derived from biphenyl. The term “arene diyl when used without the “substituted modifier refers to a

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divalent aromatic group, with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. As used herein, the term does not preclude the presence of one or more alkyl group (carbon numberlimitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Non-limiting examples of arenediyl groups include:

C. s /cox and H3C

When these terms are used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH, - F. —Cl, —Br. —I, NH, NO. —COH, —COCH, CN, -SH, OCH —OCHCH, C(O) CH, N(CH), —C(O)NH2. —OC(O)CH, or —S(O) NH. An “arene' refers to the compound H-R, wherein R is aryl. The term “aralkyl when used without the “substituted

modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples of aralkyls are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term is used with the “substituted modifier one or more hydrogen atom from the alkanediyl and/or the aryl has been independently replaced by —OH,

F. —Cl, —Br. —I, NH, NO, COH, -COCH, —CN, -SH, OCH, OCHCH - C(O)CH, - N(CH), C(O)NH, OC(O)CH, or - S(O)NH. Non-limiting examples of substituted aralkyls are: (3-chlo rophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The term "heteroaryl' when used without the “substituted

modifier refers to a monovalent aromatic group with an aro matic carbon atom or nitrogen atom as the point of attach ment, said carbon atom or nitrogenatom forming part of one or more aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or Sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic Sulfur. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon numberlimitation permitting) attached to the aromatic ring or aromatic ring system. If more than one ring is present, the rings may be fused or unfused. Non-limiting examples of heteroaryl groups include furanyl, imidazolyl, indolyl, inda Zolyl (Im), isoxazolyl, methylpyridinyl, oxazolyl, phenylpy ridinyl, pyridinyl, pyrrolyl pyrimidinyl, pyrazinyl, quinolyl,

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58 quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thie nyl, and triazolyl. The term "heteroarenediyl when used without the “substituted” modifier refers to an divalent aro matic group, with two aromatic carbon atoms, two aromatic nitrogen atoms, or one aromatic carbon atom and one aro matic nitrogen atom as the two points of attachment, said atoms forming part of one or more aromatic ring structure(s) wherein at least one of the ring atoms is nitrogen, oxygen or Sulfur, and wherein the divalent group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic Sulfur. As used herein, the term does not preclude the presence of one or more alkyl, aryl, and/or aralkyl groups (carbon number limitation permitting) attached to the aromatic ring or aromatic ring system. If more than one ring is present, the rings may be fused or unfused. Non-limiting examples of heteroarenediyl groups include:

N

and

7 N

x-y When these terms are used with the “substituted” modifier one or more hydrogen atom has been independently replaced by —OH, - F. —Cl, —Br. —I, NH, NO. —COH, - COCH –CN, -SH, OCH –OCHCH, C(O) CH, N(CH), —C(O)NH2. —OC(O)CH, or —S(O) NH. The term "heterocycloalkyl when used without the “sub

stituted” modifier refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attach ment, said carbon atom or nitrogenatom forming part of one or more non-aromatic ring structures wherein at least one of the ring atoms is nitrogen, oxygen or Sulfur, and wherein the heterocycloalkyl group consists of no atoms other than car bon, hydrogen, nitrogen, oxygen and Sulfur. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the ring or ring system. If more than one ring is present, the rings may be fused or unfused. Non-limiting examples of hetero cycloalkyl groups include aziridinyl, aZetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tet rahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. When the term "heterocycloalkyl used with the “substituted modifier one or more hydrogen atom has been independently replaced by —OH, - F. —Cl, —Br. —I, —NH, NO. —COH, -COCH, —CN, —SH, —OCH, OCHCH. —C(O)CH, N(CH), —C(O) NH, OC(O)CH, or—S(O)NH2. The term “acyl when used without the “substituted

modifier refers to the group—C(O)R, in which R is a hydro gen, alkyl, aryl, aralkyl or heteroaryl, as those terms are defined above. The groups, —CHO,-COO)CH (acetyl. Ac), - C(O)CHCH - C(O)CHCHCH –C(O)CH(CH), —C(O)CH(CH), —C(O)CHs —C(O)CHCH. —C(O) CHCH-C(O)(imidazolyl) are non-limiting examples of

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acyl groups. A “thioacyl is defined in an analogous manner, except that the oxygenatom of the group —C(O)R has been replaced with a sulfur atom, —C(S)R. When either of these terms are used with the “substituted” modifier one or more hydrogen atom (including the hydrogen atom directly attached the carbonyl or thiocarbonyl group) has been inde pendently replaced by —OH, - F. —Cl, —Br. —I, NH, —NO. —COH, -COCH, —CN, -SH, —OCH, –OCHCH, C(O)CH, N(CH), C(O)NH, OC (O)CH, or —S(O)NH2. The groups, —C(O)CHCF, —COH (carboxyl), —COCH (Methylcarboxyl), —COCHCH. —C(O)NH2. (carbamoyl), and —CON (CH), are non-limiting examples of substituted acyl 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 of alkoxy groups include: —OCH (Methoxy), —OCHCH. (ethoxy), —OCH2CHCH —OCH(CH) (isopropoxy), —OCH (CH2), —O-cyclopentyl, and —O-cyclohexyl. The terms “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “het eroaryloxy’, and “acyloxy’, when used without the “substi tuted modifier, refers to groups, defined as —OR, in which R is alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and acyl, respec tively. The term “alkoxydiyl refers to the divalent group —O-alkanediyl-, -O-alkanediyl-O-, or -alkanediyl-O-al kanediyl-. 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. 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, NH, NO, COH,

—COCH, CN, -SH, OCH —OCHCH, C(O) CH, N(CH), —C(O)NH2. —OC(O)CH, or —S(O) NH. The term “alcohol corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “alkylamino' when used without the “substi

tuted modifier refers to the group - NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkylamino groups include: —NHCH and —NHCHCH. The term “dialkylamino” when used without the “substi tuted modifier refers to the group —NRR", in which Rand R' can be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl. Non-limiting examples of dialkylamino groups include: —N(CH), —N(CH)(CHCH), and N-pyrrolidinyl. The terms “alkoxyamino”, “alkenylamino”, “alkynylamino”, “ary lamino”, “aralkylamino”, “heteroarylamino', and “alkylsul fonylamino” when used without the “substituted” modifier, refers to groups, defined as —NHR, in which R is alkoxy, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is NHCHs. The term "amido” (acylamino), when used without the “substituted modifier, refers to the group —NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is —NHC(O)CH. The term “alkylimino” when used without the “substituted modifier refers to the divalent group —NR, in which R is an alkyl, as that term is defined above. The term “alkylamin odiyl refers to the divalent group —NH-alkanediyl-, - NH alkanediyl-NH , or -alkanediyl-NH-alkanediyl-. 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, NH, NO, COH,

—COCH, CN, -SH, OCH –OCHCH, C(O) CH, N(CH), —C(O)NH2. —OC(O)CH, or —S(O)

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60 NH. The groups - NHC(O)OCH and - NHC(O)NHCH are non-limiting examples of Substituted amido groups. The terms “alkylsulfonyl and “alkylsulfinyl when used

without the “substituted” modifier refers to the groups —S(O)R and —S(O)R, respectively, in which R is an alkyl, as that term is defined above. The terms “alkenylsulfonyl', “alkynylsulfonyl', 'arylsulfonyl', “aralkylsulfonyl', and "heteroarylsulfonyl', are defined in an analogous manner. When any of these terms is used with the “substituted modi fier one or more hydrogen atom has been independently replaced by —OH, - F. —Cl, —Br. —I, NH, NO, —COH, -COCH, —CN, —SH, —OCH —OCHCH - C(O)CH, N(CH), C(O)NH, OC(O)CH, or —S(O)NH2. As used herein, a "chiral auxiliary” refers to a removable

chiral group that is capable of influencing the Stereoselectiv ity of a reaction. Persons of skill in the art are familiar with Such compounds, and many are commercially available. The use of the word “a” or “an when used in conjunction

with the term “comprising in the claims and/or the specifi cation may mean "one.” but it is also consistent with the meaning of “one or more.” “at least one and “one or more than one.”

Throughout this application, the term “about is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. The terms “comprise.” “have” and “include” are open

ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises.” “comprising.” “has.” “hav ing,” “includes” and “including are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. The term “effective,” as that term is used in the specifica

tion and/or claims, means adequate to accomplish a desired, expected, or intended result. The term “hydrate' when used as a modifier to a compound

means that the compound has less than one (e.g., hemihy drate), one (e.g., monohydrate), or more than one (e.g., dihy drate) water molecules associated with each compound mol ecule. Such as in Solid forms of the compound. As used herein, the term “ICso refers to an inhibitory dose

which is 50% of the maximum response obtained. This quan titative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given bio logical, 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 separate 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 mammalian organism, such as a human, monkey, cow, horse, sheep, goat, pig, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In some embodiments, the patient may also comprise avian, reptilian, amphibian, fish, and insect animals. In other embodiments, the patient may also comprise a Zoo animal or an animal raised as a pet such as a dog, cat, mouse, rat, guinea pig, lizard, Snake, bird, turtle, frog, or fish. Non-limiting examples of avian Subjects include chickens, turkeys, ducks, geese, game birds such as quail and pheasants, and pet birds, such as parakeets, cockatiel, love birds, parrots, and macaws. Turtles, terrapins, tortoises, Snakes and lizards represent non-limiting examples of reptil ian Subjects or patients. Frogs, toads, newts and salamanders

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represent non-limiting examples of amphibian Subjects In certain embodiments, the fish subject is represented by the following non-limiting examples: freshwater fish Such as tila pia, salmon, catfish, carp, eel, and trout, marine fish Such as tuna, cod, herring, sardine, anchovy, flounder, Sole, and shark, as well as mollusk and crustacean Such as shrimp, prawn, octopus, squid, lobsters, crabs, oysters, hill, and mussels. In certain embodiments, the patient is an insect including the non-limiting examples of honey bees. In certain embodi ments, the patient or Subject is a primate. Non-limiting examples of human Subjects are adults, juveniles, infants and fetuses. As generally used herein “pharmaceutically acceptable'

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 prob lems or complications commensurate with a reasonable ben efit/risk ratio.

“Pharmaceutically acceptable salts' means salts of com pounds of the present invention which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include 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 1.2-ethanedisul fonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalene Sulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3- hydroxy-2-ene-1-carboxylic acid), 4-methylbicyclo[2.2.2 oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopen tanepropionic acid, ethanesulfonic acid, fumaric acid, gluco heptonic acid, gluconic acid, glutamic 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, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chloroben Zenesulfonic acid, phenyl-substituted alkanoic acids, propi onic 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, diethanola mine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically accept able salts and their methods of preparation and use are pre sented in Handbook of Pharmaceutical Salts Properties, and Use (2002). The term “pharmaceutically acceptable carrier, as used

herein means a pharmaceutically-acceptable material, com position or vehicle. Such as a liquid or Solid filler, diluent, excipient, solvent or encapsulating material, involved in car rying or transporting a chemical agent.

“Prevention' or “preventing includes: (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

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62 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 symp tomatology of the disease.

“Prodrug' means a compound that is convertible in vivo metabolically into an inhibitor according to the present inven tion. The prodrug itselfmay or may not also have activity with respect to a given target protein. For example, a compound comprising a hydroxy group may be administered as an ester that is converted by hydrolysis in vivo to the hydroxy com pound. Suitable esters that may be converted in vivo into hydroxy compounds include acetates, citrates, lactates, phos phates, tartrates, malonates, oxalates, salicylates, propi onates. Succinates, fumarates, maleates, methylenebis-B-hy droxynaphthoate, gentisates, isethionates, di-p- toluoyltartrates, methane-Sulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, cyclohexyl-Sulfa mates, 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 compound. The term “saturated when referring to an atom means that

the atom is connected to other atoms only by means of single bonds. 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 configuration 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 molecules 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 inter changing of any two groups leads to a stereoisomer. In organic 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 com pounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral car bon), the total number of hypothetically possible stereoiso mers will not exceed 2n, where n is the number of tetrahedral 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 enan tiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or dias teromers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereo center 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 mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoiso mers' means that the composition contains s15%, more pref erably s10%, even more preferably s5%, or most preferably s1% of another stereoisomer(s).

“Effective amount.” “Therapeutically effective amount’ or “pharmaceutically effective amount’ means that amount which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease.

“Treatment' or “treating includes (1) inhibiting a disease in a Subject or patient experiencing or displaying the pathol ogy or symptomatology of the disease (e.g., arresting further

US 9,085,606 B2 63

development of the pathology and/or symptomatology), (2) ameliorating a disease in a subject or patient that is experi encing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and/or symptomatol ogy), and/or (3) effecting any measurable decrease in a dis ease in a Subject or patient that is experiencing or displaying the pathology or symptomatology of the disease. In some embodiments, treatment of a patient afflicted with one of the pathological conditions described herein comprises adminis tering to such a patient an amount of compound described herein which is therapeutically effective in controlling the condition or in prolonging the Survivability of the patient beyond that expected in the absence of such treatment. As used herein, the term “inhibition of the condition also refers to slowing, interrupting, arresting or stopping the condition and does not necessarily indicate a total elimination of the condition. It is believed that prolonging the survivability of a patient, beyond being a significant advantageous effect in and of itself, also indicates that the condition is beneficially con trolled to some extent.

Other abbreviations used herein areas follows: "H-NMR is proton nuclear magnetic resonance, AcOH is acetic acid, Aris argon, ACN or CHCN is acetonitrile, CHN analysis is car bon/hydrogen/nitrogen elemental analysis, CHNCl analysis is carbon/hydrogen/nitrogen/chlorine elemental analysis, CHNS analysis is carbon/hydrogen/nitrogen/sulfur elemen tal analysis, DI water is deionized water, DIC is diisopropyl carbodiimide, DMA is N,N-dimethylacetamide, DMAP is 4-(N,N-dimethylamino)pyridine, DMF is N,N-dimethylfor mamide, EDC1 is 1-(3-dimethylaminopropyl)-3-ethylcarbo diimide hydrochloride, EtOAc is ethyl acetate, EtOH is etha

HN

nol, FABMS is fast atom bombardment mass spectroscopy, g is gram(s), HOBT is 1-hydroxybenzotriazole hydrate, HPLC is high performance liquid chromatography, IBCF is isobu tylchloroformate, KSCN is potassium thiocyanate, L is liter, LiOH is lithium hydroxide, MEM is methoxyethoxymethyl, MEMC is methoxyethoxymethyl chloride, MeOH is metha nol, mg is milligram, MgSO is magnesium sulfate, ml is milliliter, mL is milliliter, MS is mass spectroscopy, MTBE is methyl tert-butyl ether, N is nitrogen, NaHCO, is sodium bicarbonate, NaOH is sodium hydroxide, NaSO is sodium sulfate, NMM is N-methylmorpholine, NMP is N-methylpyr rolidinone, NMR is nuclear magnetic resonance, POs is phosphorous pentoxide, PTSA is para-toluenesulfonic acid,

10

15

25

30

CO2H

55

60

65

64 RPHPLC is reverse phase high performance liquid chroma tography, RT is room temperature, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TMS is trimethylsilyl, and A is heat ing the reaction mixture. The above definitions 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 invention in terms such that one of ordinary skill can appreciate the scope and practice the present invention.

II. Compounds and Synthetic Methods

The compounds provided by the present disclosure may be made using the methods outlined below and further described in the Examples section. General synthetic sequences for preparing the compounds useful in the present invention are outlined in Schemes I-XIV. Both an explanation of, and the actual procedures for, the various aspects of the present inven tion are described where appropriate. The following Schemes and Examples are intended to be merely illustrative of the present invention, 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 invention. Starting materials and equipment employed were either commercially available pre pared by methods previously reported and readily duplicated by those skilled in the art.

HN COH 2 N 2

S 2 A.

Mi

HN N COH

2 NY N 2 SMe 2

A.

Scheme I

NHSCN, HCI, HO

1. DMA or DMF

A 2. dilute HCI

Scheme I illustrates general methodology useful for pre paring the cyclic guanidine Substituted left hand side aro matic acid portion of Formula I of the present invention which can then be coupled to a gly-f-amino acid ester, or to gly ester first, followed by (after ester hydrolysis) coupling to the appropriate B-amino acid ester. Briefly, in Scheme I, the appropriate amino benzoic (or pyridine) acid is reacted with ammonium thiocyanate 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 corre sponding nitro benzoic (or pyridine) acid, which can be

US 9,085,606 B2 65

obtained commercially or synthesized by nitration of the appropriate benzoic (or pyridine) acid, followed by reduction to the desired amino benzoic (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-diamino-2-substituted propane, or ethyl ene diamine, 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. Alternatively, the product may be isolated 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 iso lated 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 LA

HN CO2H N --

2 A.

HN NH2. (HNO3)

1) DIEA N dioxane, H2O

---

\ 2) HCI

H

"N." N CO2H NH *HC

A.

Scheme IA is illustrative of methodology useful for pre paring the simple guanidine Substituted left hand side aro matic acid portion of Formula I, which can then be coupled to a gly-f-amino acid ester, or to gly ester first, followed by

HO CO2H

1. NH4OH, NH4C1, 180 deg. C.

10

15

25

30

35

40

2.37% HCl, reflux

OH

66 (after ester hydrolysis) coupling to the appropriate B-amino acid ester. This can also be accomplished using other appro priate guanidating reagents known to those skilled in the art, for example using pyrazole-carboxamidine. HC1. The meth odology of Scheme IA can be modified using conventional techniques and methods to prepare alternate compounds use ful for coupling to the B-amino acids.

Briefly, in Scheme IA, to 3,5-dimethylpyrazole-1-carboxa midine nitrate in dioxane?water and DIEA, is added the appropriate 3-aminobenzoic (or pyridine) acid. The mixture is stirred at reflux, the precipitate filtered, washed and dried. The precipitate-is then further slurried in water, acidified with HCl and concentrated. The solvent is removed and the residue slurried in ether and dried to yield the appropriate 3-guanidi nobenzoic (or pyridine) acid hydrochloride.

Scheme IB

HN CO2H N N N1), -14 PO 2

A. OMe

N N ) n = 1-4

HN CO2H N

2 A.

Scheme IB is illustrative of methodology useful for pre paring a cyclic amidine Substituted left hand side aromatic acid portion of Formula I, which can then be coupled to a gly-f-amino acid ester, or to gly ester first, followed by (after ester hydrolysis) coupling to the appropriate B-amino acid ester.

Together, Schemes I, IA and IB illustrate general method ologies for the synthesis of left hand side benzoic and pyri dine acids consisting of the varied substituents defined for W and Z in Formula I and II.

Scheme II

HN CO2H

MeNCS, DMF, 25 deg. C. He

OH

H MeHN N

S

CO2H

OH

el

US 9,085,606 B2 67

-continued

OH

s CO2H

3. HO 4. HC

OH

Scheme II illustrates methodology useful for preparing a preferred tetrahydropyrimidinobenzoic acid portion of For mula I or II of the present invention which can then be coupled to a gly-f-amino acid ester, or to gly ester first, followed by (after ester hydrolysis) coupling to the appropriate B-amino acid ester. Briefly, in Scheme II,3,5-dihydroxybenzoic acid is converted to 3-amino-5-hydroxy-benzoic acid using the pro cedure described in Austr. J. Chem. (1981) or Becker et al., (1983), which are incorporated herein by reference. The prod uct is reacted with methyl isothiocyanate in DMF at room temperature taught by Organic Process Research & Devel opment, 2004, which is incorporated herein by reference, to give 3-N'-methyl thiourea-5-hydroxybenzoic acid after nor mal work-up. This thiourea intermediate is converted to the S-methyl derivative by reaction with methyl iodide neat at below 40°C. 1,3-diamino-2-hydroxypropane 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 lyo philizing from dilute hydrochloric acid. Alternatively, the product may be isolated 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 obtained as previously stated or by simply dissolving in dilute hydrochloric acid and concentrat ing to a solid and drying.

Scheme III

CHO

1) malonic acid, ammonium acetate isopropyl alcohol

A 2) EtOH/HCI

Y

a

2.90 deg. C.

25

30

35

40

45

50

55

60

65

68

MeHN N

Y SMe

CO2H

* HI

OH

-continued COEt

HN

resolve

COEt COEt

Scheme III illustrates a general methodology for the syn thesis of the beta amino acid ester portion of Formula I or II of the present invention when Z-H, starting from an appropriate benzaldehyde. This beta amino acid ester can then be coupled to Boc-glycine followed by (after removal of the Boc protect ing group) coupling to the appropriate benzoic acid described in Schemes I and II, or to the benzoic acid that has been coupled to glycine. 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 preferred (S) enantiomers via chiral chromatographic separation, or via enzymatic resolution as described in Faul conbridge et al. (2000) or Landis et al. (2002), which are incorporated herein by reference.

US 9,085,606 B2

Scheme IW

CHO

OH Ac2O/EtN 5

A X Y

O O 10

O O TMSNLi/

Y THF Y -e- HN

15

X X

2O

| EtOH, HCI COEt

25 HN W

OH COEt

HN 30 X Y resolve

OH COEt * HC

HN

OH

X 3. X Y 3 5

Y

40

Scheme IV illustrates a general methodology for the syn thesis of the beta amino acid ester portion of Formula I or II of the present invention, wherein Z-OH, starting from an appro priate benzaldehyde. This beta amino acid ester can then be coupled to Boc-glycine followed by (after removal of the Boc protecting group) coupling to the appropriate benzoic acid described in Schemes I and II (preferred method), or to the benzoic acid that has been coupled to glycine. Briefly, cou marins are readily prepared from Salicylaldehydes using a so modified Perkin reaction taught for example by Vogel's Text book of Practical Organic Chemistry, 1989, which is incor porated herein by reference. The appropriately substituted coumarins are converted to 3-aminohydrocoumarins simi larly to Rico (1994) which is incorporated herein by refer- 55 ence, which are readily opened in acidic alcohol to give 3-amino-3-(3,5-substituted-2-hydroxy)phenyl propanoic acid esters. These racemic beta amino acid esters can be resolved into the (R) and the preferred (S) enantiomers via chiral chromatographic separation (for example, via the CBZ derivative of the racemic ester, which is separated on a reverse phase chiral column, providing, after deprotection with, for example, TMSI, the pure (S) and (R) beta amino acid ester enantiomers) or via enzymatic resolution as described in 65 Faulconbridge et al. (2000) or Landis et al. (2002), which are incorporated herein by reference.

45

60

Scheme V

CHO

C. PhP=CHCOtBu He

X Y

COtBu COtBu

21 HOHN

Z NHOH Z --

X Y X Y

1. ZnHOAc 2. EtOHAHCL

COEt

HN w

Z COEt

HN X Y resolve

Z COEt

HN X Y

Z

X Y

Scheme Villustrates an alternate general methodology for the synthesis of the beta amino acid ester portion of Formula I or II of the present invention, starting from an appropriate benzaldehyde. This beta amino acid ester can then be coupled to Boc-glycine followed by (after removal of the Boc protect ing group) coupling to the appropriate benzoic acid described in Schemes I and II, or to the benzoic acid that has been coupled to glycine. Briefly, the appropriate benzaldehyde is converted to the corresponding cinnamate via the Wittig reac tion. Michael addition of hydroxylamine to the resulting cin namate affords the N-hydroxylated beta-amino acid ester. Reduction of the N-hydroxy-beta-amino acid ester with Zn/acetic acid gives, after conversion to the corresponding ethyl ester in EtOH/HCl, the desired beta amino acid ester as a racemate. As in Scheme IV, these racemic beta amino acid esters can be resolved into the (R) and the preferred (S) enantiomers via chiral chromatographic separation (for example, via the CBZ derivative of the racemic ester, which is separated on a reverse phase chiral column, providing, after deprotection with, for example, TMSI, the pure (S) and (R) beta amino acid ester enantiomers) or via enzymatic resolu tion as described in Faulconbridge et al. (2000) or Landis et al. (2002), which are incorporated herein by reference.

US 9,085,606 B2 71

Scheme VI

CHO

OH MEM-CI, KCO -e-

72

CHO

O O C. N-N-1 no-1 DMF

X Y

(a) S-(+)-phenylglycinol/MgSO4: THF (b) BrznCHCOOtBu; NMP (c) aq. NHCl, HCl; EtOAc

1. Pb(OAc)4; or (NaIO4); MeOH

2. NaOH

3. PTSA, EtOH: reflux -e-

*p-TsOH HN COEt

OH

Scheme VI illustrates an alternate general methodology for the chiral synthesis of the beta amino acid ester portion of Formula I or II of the present invention, wherein Z is OH, starting from an appropriate benzaldehyde, and using a chiral auxiliary. This beta amino acid ester can then be coupled to Boc-glycine followed by (after removal of the Boc protecting group) coupling to the appropriate benzoic acid described in Schemes I and II (particular method), or to the benzoic acid that has been coupled to glycine. As described, Scheme VI illustrates the chiral synthesis of the preferred (S) enantiomer of the desired beta amino acid ester using S-phenylglycinolas the chiral auxiliary (synthesis of the (R) isomer is afforded by utilizing R-phenylglycinol instead). Literature references describing Such reactions include: Organic Process Research & Development (2004); Awasthi et al. (2005); U.S. Pat. No. 6,414, 180; U.S. Pat. No. 5,840,961, which are incorporated herein by reference. Briefly, the appropriate salicylaldehyde is first treated with MEM chloride and potassium carbonate to afford the MEM protected salicylaldehyde. The MEM ether protected salicylaldehyde is then reacted with S-phenylgly cinol in the presence of magnesium sulfate in THF to afford the imine. The Reformatsky reagent, tert-butyl zinc bromoac etate, is then added to the imine in N-methylpyrrolidine. The chiral auxiliary of the resulting beta amino acid ester is cleaved off by treatment with lead tetraacetate. Basic workup of the reaction mixture followed by heating at reflux with p-toluenesulfonic acid in ethanol affords the desired PTSA salt of the (S)-beta amino acid ester.

30

35

40

45

50

55

60

65

OH

HN COtBu

O O 1. n1n 1\O

X Y

Scheme VII

O

s O COEt ls O O 1 NN HN H

O O e

Z NMM

X Y O COEt

ls H N No N ~ H

O Z

X Y

HCIFEtOH dioxane

COEt H N

in O Z

* HC

Scheme VII illustrates a general methodology for prepar ing the ethyl-N-gly-beta amino acid portion of Formula I of the present invention, which can be coupled to the benzoic

US 9,085,606 B2 73

acid portion of Formula I or II described in Schemes I and II). This method describes coupling a beta amino acid ester to glycine. Briefly, the desired beta amino acid ester (example methodologies described in Schemes III-VI above) is treated with activated Boc glycine. Removal of the Boc protective group (by treatment with ethanol/HCl, for example) affords the glycine amide of the corresponding beta amino acid ester (the preferred (S) enantiomer is afforded by utilizing the (S)-beta amino acid ester, described in the above schemes).

Scheme VIII

O

s O COEt ls O O N ~ NN

HN H O

O e

OH NMM

X Y

O COEt

l H N N O N

H

O OH

X Y

HCIFEtOH dioxane

COEt H N

ir O OH

* HC

X Y

Scheme VIII illustrates a general methodology for prepar ing the ethyl-N-gly-beta amino acid portion of Formula I or II of the present invention when Z=OH, which can be coupled to the benzoic acid portion of Formula I described in Schemes I and II). This method describes coupling a beta amino acid ester (where Z-OH) to glycine. Briefly, the desired beta amino acid ester (example methodologies described in Schemes III-VI above) is treated with activated Boc glycine. Removal of the Boc protective group (by treatment with ethanol/HCl, for example) affords the glycine amide of the corresponding beta amino acid ester (the preferred (S) enan tiomer is afforded by utilizing the (S)-beta amino acid ester, described in the above schemes). Scheme VIII is a preferred method for the synthesis of compounds of formula I when Z=OH.

10

15

25

35

40

45

50

55

60

65

Scheme IX

W. N CO2H 1. IBCF, NMM, DMA; (or DIC, HOBt, DMF/DCM) -e-

a 2. NMM, COEt

H N

in O Z

* HC

X Y

O COEt

W. N N

H

21 O Z A.

X Y

1. LiOH (or NaOH), H2O 2. H', HO

O CO2H

W. N N

H

2 O Z A.

X Y

Scheme IX illustrates a general methodology useful for preparing various compounds of the present invention. Briefly, the appropriate left hand side aromatic acid (de scribed for example in Schemes I, IA, IB, 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 tempera tures and IBCF added. To the mixed anhydride intermediate is added the gly-f-amino acid ester and NMM. Upon comple tion 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 solvent (dioxane/water or acetonitrile/ water). Alternatively, a suitable acid, such as TFA can be used. The product is isolated by prep HPLC or by isolating the Zwitterion at pH 5-7 and converting to the desired salt by standard procedures. (The preferred (S) enantiomer is afforded by utilizing the (S)-beta amino acid ester, described in the above schemes).

US 9,085,606 B2 75

Scheme X

OH

N 1. IBCF, NMM, DMA; (or DIC, HOBt, DMF/DCM) -> s

HN COH '' 2. NMM, 10 COEt

H N

HN ~ OH O Z 15

*HC

X Y OH

2O

N NH O COEt

H 25 HN N

N H

O Z

OH 30 X Y

1. LiOH (or NaOH), H2O 2. H', HO 35

OH

40

N NH

s O COEt H

HN N N H 45

O Z

OH X Y

50

Scheme X illustrates a general methodology useful for preparing various compounds of the present invention. Briefly, 3-Hydroxy-5-(1,4,5,6-tetrahydro-5-hydroxy-2-py rimidinyl)aminobenzoic acid (described for example in 55 Scheme 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 anhy dride intermediate is added the gly-f-amino acid ester and 60 NMM. Upon completion of the reaction the product is puri fied by prep 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 suit able acid, such as TFA can be used. The product is isolated by prep HPLC or by isolating the Zwitterion at pH 5-7 and converting to the desired salt by standard procedures. (The

65

76 preferred (S) enantiomer is afforded by utilizing the (S)-beta amino acid ester, described in the above schemes).

Scheme XI

W. CO2H 1. IBCF, NMM, DMA; O s t, s A N DIC HOBt., NMMDM Hoss

2 ethylglycinate HCl, A. 2. NaOH, H2O

3. H+, HO O

W. OH

N 1 H

2 O A.

COEt

HN

1. IBCF, NMM, DMA; Z (or DIC, HOBt, NMM, DMA) ^Sy * HC

SS

X 4S. O COEt

W.

N N ~ H Z

a O SA

X 2 Y

1. LiOH (or NaOH), H2O 2. H', HO

O CO2H

W.

N 1. H O Z

a S4

X 2 Y

Scheme XI illustrates a general methodology useful for preparing various compounds of the present invention. Briefly, the appropriate left hand side aromatic acid (de scribed for example in Schemes I, IA, IB 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 tempera tures 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 prep HPLC and the ester hydrolyzed to the acid by treating with a base. Such as NaOH in a suitable solvent (water, dioxane?water or acetoni trile/water), followed by acidification. This gly adduct is then activated for coupling using known methods. Thus, after dis Solving 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 inter mediate is added the appropriate beta amino acid ester salt (described, for example, in Schemes III-VI above) and

US 9,085,606 B2 77

NMM. Upon completion of the reaction the product is puri fied by prep 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 suit able acid, such as TFA can be used. The product is isolated by prep HPLC or by isolating the Zwitterion at pH 5-7 and converting to the desired salt by Standard procedures (the particular (S) enantiomer is afforded by utilizing the (S)-beta amino acid ester, described in the above schemes).

Scheme XII

Br (I) CHO BuLi ether -e-

DMF

X Y X Y

CHO OH

EtMgBr OH Her

(HCHO) X Y

X Y

CHO CHO

OH Br2 OH ->

HOAc

X X Br

CHO CHO

OH Br2 OH Hip

HOAc

Y Br Y

Scheme XII illustrates general synthetic methodologies for benzaldehyde starting materials that may not be readily avail able from commercial sources and that are useful for prepar ing various compounds of the present invention as described in the previous schemes. In the bottom two examples above, known methods of aromatic chlorination can be substituted

for the bromination reactions depicted, thus yielding the cor responding chlorine substituted benzaldehydes. Such meth ods are well known in the art. See Kurahashi et al. (2011) in the supporting information section; Nomura et al. (2007); and March's Advanced Organic Chemistry. Reactions, Mecha nisms, and Structure (2007), which are all incorporated by reference herein.

Scheme XIII

CHO

X Br (I)

5

10

15

25

30

35

40

45

50

55

60

65

78 -continued

O O

C Z X Br (I)

O O CHO

Z Z

X Y X Y

CHO

cross couplings He

other derivatizations

(I) Br Y

O O

C Z (I) Br Y

O O CHO

Z Z

X Y X Y

Scheme XIII illustrates general synthetic methodologies for benzaldehyde starting materials that may not be readily available from commercial sources and that are useful for preparing various compounds of the present invention as described in the previous schemes. In particular, it illustrates general methodologies for benzaldehyde analogues that ulti lize an appropriate aldehyde protected aromatic Br or I reagent, whereas the Br or I can be displaced using cross coupling or other aromatic Br or I facilitated derivatizations widely known to those skilled in the art and that yield ben Zaldehyde starting materials useful for preparing various compounds of the present invention as described in previous schemes. When Z is OH, the hydroxyl group can be protected with various protecting groups known to those skilled in the art as needed to efficiently execute the synthetic procedures depicted. The protecting group can Subsequently be removed with known de-protecting reagents. These are meant to be general synthetic methods that are readily known and prac ticed by those skilled in the art, and are not meant to be limiting in scope.

cross couplings -e- other derivatizations

US 9,085,606 B2 80 79

Scheme XIIIA

acetOne

Li R Z

Br

O H

O H

Br

acetOne

Li R

Br HO

OH OH

Br Br

HO

Li

Br Br

(CI) Br

(CI) Br

C

Br

Br

(CI) Br

Br

US 9,085,606 B2

-continued

O H f V O O

s

CF Br CF

OH Br CF OH

CF

Br Br

BuLi, DMA TMS-CF THF, -78 deg JOC, 2011,

C. 76,7048-55 CF Br (CI) Br (CI) Br

OH O

BuLi, DMF ether,

-78 deg C.

CHO

CF (CI) Br

OH

Br

NaH, MsC1, THF -e-

Bioorganic Med Chem Lett CF 17 (2007) 6079-85 CF

(CI) Br OH OMS

AlMe, DCM, 0 deg C. Bioorganic Med Chem Lett

17 (2007) 6079-85

CHO Br

BuLi, DMF -e-

ether, -78 deg C. CF CF

(CI) Br

Br Br Tetrahedron 61

SOCl. (2005) 1813-19 He- Her

OH C CF C C

OH O CF

BuLi, DMF ether, -78 deg C.

US 9,085,606 B2 91 92

-continued

O O e.g., JACS, 2002, 124, 12557-65

Hoss -> MeOC

Br COMe CI) Br (CI) Br Br O (CI)

/ O O O O O O

MeI

OMe OMe OH CHO (CI) Br (CI) Br (CI) Br

O O O

CHO

C. (CI) Br

(CI) Br C. CHO d. b O. O.

F

(CI) Br F CF2H (CI) Br (CI) Br

O O

O / O. O.

CFH (CI) Br 2

O

CHO O O e.g., JACS, 2002,

124, 12557-65 -e- He

MeOC

(CI) Br Br COMe (CI) Br

(CI) Br Br

US 9,085,606 B2

-continued O-PG OH

CHO

He- He

CN CN CN

(CI) Br (CI) Br (CI) Br

F F F F F F Br Br Br

Br KCN p1N1

50% NaOH OH C CN TEBACDCE

X X X Br

CN

X

DIBAL-H DCM

Br Br CHO

BuLi DAST DMF DCM re- --

CF2H CF2H CHO

X X

X = Br, Cl, CF, other defined X

X

CHO 7 \ F O O F BuLi, DMA -e- --

PCT

C B 2011025927 F C Br

C Br

TMs1NcN JACS, 2005, 127, 15824-32

CHO O O O O

F MeI, base

F F

CN

C CN CN C C

All references listed in Scheme XIIIA are incorporated described in the previous schemes. When Z is OH, the herein by reference. hydroxyl group can be protected with various protecting

Scheme XIIIA further illustrates general synthetic meth- groups known to those skilled in the art as needed to effi odologies for benzaldehyde starting materials that may not be 65 ciently execute the synthetic procedures depicted. The pro readily available from commercial sources and that are useful tecting group can Subsequently be removed with known de for preparing various compounds of the present invention as protecting reagents. See, for example, Greene & Wuts (1999),

US 9,085,606 B2 97

which is incorporated herein by reference. Furthermore, a trifluoromethyl or other amenable group as defined for X in the general formula can be substituted for the substituent depicted as (Cl)Br— in the above schemes. These schemes are meant to illustrate methods for generating targeted ben Zaldehydes that can be used to synthesize compounds claimed herein, but that are not commercially available. They are not intended to be limiting in nature and can be further adapted and modified in ways that are known to those skilled in the art.

Scheme XIV

N Ph OH Bzl Br, EtOH/H2O, N1

2 h, 60 deg. C. --

HO

NH2 NH r’s Ph Ph

DAST, DCM, -60 deg. C., rt, 16 "

Ph

N Ph F Pd(OH)2 EtOH, EtOAc, N1

50 psi, 48 h. a

F

NH2 NH N

Ph Ph O

F MeOHANH3 OEt --

F

OEt O

O F F

F BH3THF. EtOHHC, 2 -e- F * 2 HC

NH2 NH2 NH2 O

Scheme XIV illustrates general synthetic methodologies for the synthesis of diamine intermediates useful for prepar ing the tetrahydropyrimidinobenzoic acid portion of Formula I of the present invention as described in Scheme I and where A=H and B=F, or when A and B both=F.

Scheme XV

HN COEt

10

15

25

30

35

40

45

50

55

60

65

-continued

s Boc HN COEt HN COEt

Zn (CN)2 -e-

Po cross-coupling

reagents

X Y NC Y

HN COEt

NC Y

X = Br, Cl,

Scheme XV illustrates a convenient synthetic method for the introduction of a cyano substituent in the synthesis of beta amino ester reagents wherein X is cyano as defined in the general formula and Y can be multiple amenable substituents as defined in the general formula and characterized in the above schemes and Subsequent examples. This scheme illus trates one method for synthesizing compounds where X is cyano and is not intended to be limiting in nature and can be further adapted and modified in ways that are known to those skilled in the art.

All these methods described above can be further modified and optimized using the principles and techniques taught in U.S. Pat. Nos. 6,013,651 and 6,028,223, which are incorpo rated herein by reference, as well as the principles and tech niques 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 Chemistry. Reac tions, Mechanisms, and Structure (2007), which is incorpo rated by reference herein.

Non-limiting examples of compounds which may be made by and used in the methods described herein are listed in Table A (below):

TABLE A

Examples of Beta Amino Acid Derivatives

W A.

O

W. CO2H N N

H

2 O A.

C

TABLE A-continued

US 9,085,606 B2


W

OH

N

S HN

OH

N

s HN

OH

N

S HN

C OH

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65

100 TABLE A-continued


W

N

s HN

Nin-NH

r

O

N

a N

Br

C OH

US 9,085,606 B2 101

TABLE A-continued


W A.

OH N

N

S HN

OH C- H

N

s HN

C OH

10

15

25

30

35

40

45

50

55

60

65



W

C OH

CO2H

C OH

US 9,085,606 B2 103

TABLE A-continued


W A.

OH N

N

S HN

OH C- H

N

s HN

C OH

10

15

25

30

35

40

45

50

55

60

65



W

OH

N

NC

C OH

CO2H

C OH


US 9,085,606 B2


W

OH

N

s HN

OH

N

s HN

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65



W

OH

N

C OH


US 9,085,606 B2


W

OH

Nan-NH

y HN

, HN/

N S.

HN 7 N N

HN 7

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65



OH

N

C

C OH

CO2H

OH

C OH


US 9,085,606 B2


W

OH

Nan-NH

y HN

, HN/

N S.

HN 7 N N

HN 7

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65



OH

C OH

CO2H

OH

C OH


US 9,085,606 B2


W

OH

Nan-NH

y HN

, HN/

N S.

HN 7 N N

HN 7

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65



OH

N

NC

C OH

CO2H

OH

C OH


US 9,085,606 B2


W

OH

Nan-NH

y HN

, HN/

N S.

HN 7 N N

HN 7

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

114


N

OH

C OH

CO2H

OH

C OH


US 9,085,606 B2


W

OH

Nan-NH

y HN

, HN/

N S.

HN 7 N N

HN 7

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65



N

OH

N

N H

Br

C OH

CO2H

OH

C OH

US 9,085,606 B2 117 118

TABLE A-continued TABLE A-continued

Examples of Beta Amino Acid Derivatives Examples of Beta Amino Acid Derivatives

W A.

C- H N

N NH2 N HN 10 HN

HN NH2 C- H O

H COH n 15 W. N 2

2 O A.

F C OH 2O

C CN

Nin-NH OH C OH

Y 25 HN

N F N 30 HN

OH N N NH 35

HN

Nan-NH 40

F C- H HN

OH C- H

N- 45 HN

Nan-NH 50

HN

C OH y NN-NH Y HN NH2 C OH HN 55 N

HN HNy 65

US 9,085,606 B2 119

TABLE A-continued


W A.

HN NH2 C- H

y F C OH

N

s HN

N

s HN

C OH

10

15

25

30

35

40

45

50

55

60

65



CO2H H N

N 1 O

Br CN

C OH

NH2 C OH

US 9,085,606 B2 121 122



W A.

W

O

F C OH W. CO2H

N N ~ 10 H

2 O A.

N HO HN 15 OH

OH C OH

F N 2O r Nn-NH

HN Nan -NH Y 25 HN

OH N

30

F C- H Nan -NH

HN

35

N HN OH C- H

40

N NH C OH Sa

N- y 45

HN

HN NH2 C OH

50 N

HN

HN 55 n

HN HNy 65

US 9,085,606 B2 123 124


Examples of Beta Amino Acid Derivatives Examples of Beta Amino Acid Derivatives 5 W A.

W A. O

F C OH W. CO2H

N N ~ 10 H

2 O A.

N HN 15 OH

OH C OH

F N 2O

N

s HN Nan -NH

Y 25 HN

OH N

30

F C- H N HN

35

N HN OH C- H

40

Nin-NH C OH Y

Nin-NH HN Y 45

NH2 C OH

50 N

HN

HN 55 n

HN HNy 65

US 9,085,606 B2 125 126



W A. O

F C OH W. CO2H

N N ~ 10 H

2 O A.

N NH HN 15 CN

OH C OH

F N 2O

N

s HN Nan -NH

Y 25 HN

OH N

30

F C- H N HN

35

N HN OH C- H

40

Nin-NH C OH Y

Nin-NH HN Y 45

NH2 C OH

50 N

HN

HN 55 n

HN HNy 65

US 9,085,606 B2 127 128



W A.

W

O

F C OH W. CO2H

N N ~ 10 H

2 O OH A.

N Br HN 15 OH

OH C OH

N& NH

HN NS NH

Y 25 HN

OH N

30

F C- H Nin NH

HN

N- 35 H HN O C- H

40

N NH C OH Sa

Nin-NH HN Y 45 HN

HN NH2 C OH

50 N

N NH2 N HN

HN 55 n

HN HNy 65

US 9,085,606 B2 129 130



W A.

W

O

F C OH W. CO2H

N N ~ 10 H

2 O OH A.

N C HN 15 OH

OH C OH

F N 2O r Nn-NH

HN Nan -NH Y 25 HN

OH N

30

F C- H Nan -NH

HN

N- 35 H HN O C- H

40

N NH C OH Sa

Nin-NH HN Y 45 HN

HN NH2 C OH

50 N

N NH2 N HN

HN 55 n

HN HNy 65

US 9,085,606 B2 131

TABLE A-continued


W A.

N

s HN

N

s HN

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

132


N H

O

C

H N

CO2H

OH

C OH

C OH

US 9,085,606 B2 133 134



W A. O

F C OH W. CO2H

N 1 10 H

2 O OH A.

NS NH

C HN 15

OH C OH

s HN Nan -NH

Y 25 HN

OH N

30

F C- H N HN

35

N HN OH C- H

40

Nin-NH C OH Y

Nin-NH HN Y 45

NH2 C OH

50 N

HN

HN 55 n

HN HNy 65

US 9,085,606 B2 135 136



W A.

W

O

F C OH W. CO2H

N 1 10 H

2 O OH A.

N HO C HN 15

OH C OH

F N 2O r Nn-NH

HN Nan -NH Y 25 HN

OH N

30

F C- H Nan -NH

HN

N- 35 H HN O C- H

40

N NH C OH Sa

Nin-NH HN Y 45 HN

HN NH2 C OH

50 N

N NH2 N HN

HN 55 n

HN HNy 65

US 9,085,606 B2 137 138



W A.

W

O

F C OH W. CO2H

N 1 10 H

2 O OH A.

N NH HO Br

HN 15

OH C OH

F N 2O r Nn-NH

HN Nan -NH Y 25 HN

OH N

30

F C- H Nan -NH

HN

N- 35 H HN O C- H

40

N NH C OH Sa

Nin-NH HN Y 45 HN

HN NH2 C OH

50 N

N NH2 N HN

HN 55 n

HN HNy 65

US 9,085,606 B2 139

TABLE A-continued


W A.

N

s HN

N

s HN

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued


N N N H

N H

140

~ O

Br

H N

CO2H

OH

C OH

C OH

US 9,085,606 B2 141 142



5 W A. W A.

OH N

10 N

N

N NH

N NH Y HN

HN 15

OH C- H

2O

N S. NH

NS NH HN

25

30 HN

C OH

HN 35

C OH

45

N-NH 50 N NH Y N

y 55

CO2H W.

N 1 H

2 O OH 60 N NH

HN Br y 65

US 9,085,606 B2 143 144



5 W A. W A.

OH N F C- H

10

Nan-NH N n -NH Y Y HN HN

15

OH C- H

C OH

2O NH

s N HN HN

25

N HN NH2 C OH

N NH N s 30 HN HN

HN NH2 N

35 N HN

C- H

N HN 40 N- C- H

y O 45

COH 2 F C OH

N N H

2 O A.

50 OH Nan -NH

Br

y 55

OH C OH F N

N 60

s NS

US 9,085,606 B2 145 146



5 W A. W A.

OH N F C- H

10


15

OH C- H

C OH

2O NH

s N HN HN

25

N HN NH2 C OH

N NH N s 30 HN HN

HN NH2 N

35 N HN

C- H

N HN 40 N- C- H

y O 45

COH 2 F C OH

N N H

2 O A.

50 OH Nan -NH

Br HN

O

55

OH C OH F N

N 60

s NS

US 9,085,606 B2 147 148



5 W A. W A.

OH N F C- H

10


15

OH C- H

C OH

2O NH

s N HN HN

25

N HN NH2 C OH

N NH N s 30 HN HN

HN NH2 N

35 N HN

C- H

N HN 40 N- C- H

y O 45

COH 2 F C OH

N N H

2 O A.

50 OH Nan -NH

C HN

O

55

OH C OH F N

N 60

s NS

US 9,085,606 B2 149 150



5 W A. W A.

OH N

10 N N NH

N NH Y HN

15

OH C- H

C OH 2O

s N HN HN

25

HN NH2 C OH

N N N- 30 y

HN

HN N NH2

35 N

N NH

Y 40 N NH2 C- H

45 O

CO2H F C OH

N N H

2 O 50 A. Nan -NH

OH

C y 55

OH C OH F N

60 NH NH

65

US 9,085,606 B2 151 152



5 W A. W A.

OH N F C- H

10


15

OH C- H

C OH

2O NH

s N HN HN

25

N HN NH2 C OH

N NH N s 30 HN HN

HN NH2 N

35 N HN

C- H

N HN 40 N- C- H

y O 45

COH 2 F C OH

N N H

2 O A.

50 OH Nan -NH

C

y 55

OH C OH F N

N 60

s NS

US 9,085,606 B2 153 154



5 W A. W A.

OH N

10 N N NH

N NH Y HN

15

OH C- H

C OH 2O

s N HN HN

25

HN NH2 C OH

N N N- 30 y

HN

HN N NH2

35 N

N NH

Y 40 N NH2 C- H

45 O

CO2H F C OH

N N H

O

A. 50 Nan -NH OH

C HN

O

55

OH C OH F N

60 NS NS NH NH

65

US 9,085,606 B2 155 156



5 W A. W A.

OH N

10 N N NH

N NH Y HN

15

OH C- H

C OH 2O

s N HN HN

25

HN NH2 C OH

N N N- 30 y

HN

HN N NH2

35 N

N NH

Y 40 N NH2 C- H

45 O

CO2H F C OH

N N H

O

A. 50 Nan -NH OH

Br HN

O

55

OH C OH F N

60 NS NS NH NH

65

US 9,085,606 B2 157 158



5 W A. W A.

OH N

10 N N NH

N NH Y HN

15

OH C- H

C OH 2O

s N HN HN

25

HN NH2 C OH

N N N- 30 y

HN

HN N NH2

35 N

N NH

Y 40 N NH2 C- H

45 O

CO2H F C OH

N N H

2 O 50 A. Nan -NH

OH

Br y 55

OH C OH F N

60 NH NH

65

US 9,085,606 B2 159 160



5 W A. W A.

OH N

F C- H

10

Nan-NH NS-NH Y

HN

HN 15

OH C- H

C OH 2O

s N HN HN

25

HN NH2 C OH

N N s NH 30 HNy HN

HN NH2 N

35 N HN

C- H

Nan-NH 40 HN NH2 C- H

HN n

y O 45

H CO2H F C OH N

N N H

A.2 O 50 OH Nan -NH

Br CF HN

CF y 55

OH C OH F N

N 60 NH NS

US 9,085,606 B2 161 162



5 W A. W A.

OH N

F C- H

10

Nan-NH NS-NH Y

HN

HN 15

OH C- H

C OH 2O

s N HN HN

25

HN NH2 C OH

N N s NH 30 HNy HN

HN NH2 N

35 N HN

C- H

Nan-NH 40 HN NH2 C- H

HN n

y O 45

H CO2H F C OH N

N N H

A.2 O 50 OH Nan -NH

C CF HN

CF y 55

OH C OH F N

N 60 NH NS

US 9,085,606 B2 163 164



5 W A.

W A. OH N

10 N N NH

n-NH Y Y HN HN 15

OH C- H

C OH 2O

NH

s N HN HN

25 y

N-NH

Y 30 HNy HN NH2 N

35 N C- H HN

N HN

40 N NH2 C- H HN

O

CO2H 45

N 1 F C OH H

2 O A.

OH 50 N NH

C N

y 55

OH C OH F N

N NH 60

NS-NH

y 65

US 9,085,606 B2 165 166



5 W A.

W A. OH N

10 N N NH

n-NH Y Y HN HN 15

OH C- H

C OH 2O

NH

s N HN HN

25 y

N-NH

Y 30 HNy HN NH2 N

35 N C- H HN

s NH HN

40 N NH2 C- H HN

O

CO2H 45

N 1 F C OH H

2 O A.

OH 50 N NH

Br N

y 55

OH C OH F N

N NH 60

NS-NH

y 65

US 9,085,606 B2 167 168



5 W A.

W A. OH N

10 N N NH

n-NH Y Y HN HN 15

OH C- H

C OH 2O

NH

s N HN HN

25 y

N-NH

Y 30 HNy HN NH2 N

35 N C- H HN

s NH HN

40 N NH2 C- H HN

O

CO2H 45

N 1 F C OH H

2 O A.

OH 50 N NH

Br N

y 55

OH C OH F N

N NH 60

NS-NH

y 65

US 9,085,606 B2 169 170



5 W A.

W A. OH N

10 N N NH

n-NH Y Y HN HN 15

OH C- H

C OH 2O

NH

s N HN HN

25 y

N-NH

Y 30 HNy HN NH2 N

35 N C- H HN

N HN

40 N NH2 C- H HN

O

CO2H 45

N 1 F C OH H

2 O A.

OH 50 N NH

C N

y 55

OH C OH F N

N NH 60

NS-NH

y 65

TABLE A-continued

171 US 9,085,606 B2


N

W

OH

s

N

C

C OH

CO2H

CF

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

172


W

OH

Nin-NH Y y

Nin-NH Y y

Br

C OH

CO2H

US 9,085,606 B2 173

TABLE A-continued


N

N

N

W

OH

s y OH

s y OH

r y

C OH

C OH



W A. 5 -

O

W. CO2H

N 1 H

10 2 O A.

CF C

OH 15

OH C OH

s HN

25

OH N

30 N

s HN

35

OH C- H

40 N

s HN

45

50

55

60

65

US 9,085,606 B2 175

TABLE A-continued


W

F

N

S HN

O

W. CO2H N N

H

2 O A.

OH

N

s HN

OH

N

s HN

OH

CF Br

OH

C OH

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

176


N

N

W

OH

s OH

s OH

C CF

C OH

TABLE A-continued

177 US 9,085,606 B2


W

OH

OH

Br

C OH

CF

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

178


W

OH

Nan-NH

r y

Nan -NH

r y

N

C

C OH

CO2H

CN

C OH

US 9,085,606 B2 179 180



W A 5 W A

OH N OH C OH

10 N NH Nn-NH

r r y y 15

OH C-H N

2O

s NH s NH

y y 25

F C OH OH C–H

N NH 30 N NH

y y 35

F N F C OH

40

Nn-NH s NH

y HN 45

F C-H F N

NH 50

Nin N NH

y HN 55

O F C-H

H COH N

60 2 O N

A. n-NH

CN

65

Br

US 9,085,606 B2 181

TABLE A-continued


W A.

O

H CO2H N

N N H

A.2 O CN

C F

F

OH C OH

N HN

OH N

N HN

OH C- H

N HN

F C OH

N HN

F N

N

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

182


N

P

N

N

N

W

s HN y

N

OH

NH

OH

NH

OH

s

~ Br

CO2H

CN

C OH

TABLE A-continued

183 US 9,085,606 B2


N

N

N

W

F

r y

N

OH

s OH

s

C

C OH

CO2H

CN

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

184


N

N

N

N

P

W

OH

HN

HN

HN

HN

s

s

s

s

N H

Br

C OH

CO2H

CN

US 9,085,606 B2 185 186



W

O

W. CO2H N N

H

10 2 O A.


W A.

OH C OH

N N NH

Y OMe HN

Cl

15 O

OH N OH C OH

N rs N NH

Y Nn-NH HN

HN

25

30 N-NH Y Nan -NH HN

HN

35

40

NH

HN HN

45

F C OH

OH C-H

N

F C OH

50

NH

HN HN

55

60

NH

HN HN

65

TABLE A-continued

187 US 9,085,606 B2


W

Br

CO2H

OMe

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

188


N

N

N

W

F

r y

N

OH

s OH

s

C

C OH

CO2H

OH

C OH

TABLE A-continued

189


N

N

N

N

P

W

OH

HN

HN

HN

HN

s

s

s

s

N H

Br

US 9,085,606 B2

C OH

CO2H

OH

10

15

25

30

35

40

45

50

55

60

65



N

N

N

W

OH

NH

y OH

NH

y OH

r y

C OH

C OH

US 9,085,606 B2 191

TABLE A-continued


W. cW N N

HN 7 N S.

HN 7 N N

HN 7 N N

HN 7 N N

HN 7

N H

A.

H CO2H

~ N O

F

C

O

C OH

N

C- H

C OH

N

10

15

25

30

35

40

45

50

55

60

65



W

OH

Br

CO2H

C OH

TABLE A-continued

193 US 9,085,606 B2


N

N

N

W

F

r y

N

OH

s OH

s

C

C OH

CO2H

C OH

10

15

25

30

35

40

45

50

55

60

65

TABLE A-continued

194


N

N

N

N

P

W

OH

HN

HN

HN

HN

s

s

s

s

N H

Br

C OH

CO2H

Date post:	27-Jan-2019
Category:	Documents
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