WO1999052879A1 - Acylresorcinol derivatives as selective vitronectin receptor inhibitors - Google Patents

Acylresorcinol derivatives as selective vitronectin receptor inhibitors Download PDF

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Publication number
WO1999052879A1
WO1999052879A1 PCT/US1999/008180 US9908180W WO9952879A1 WO 1999052879 A1 WO1999052879 A1 WO 1999052879A1 US 9908180 W US9908180 W US 9908180W WO 9952879 A1 WO9952879 A1 WO 9952879A1
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Prior art keywords
amino
ethoxy
hydroxy
carbonyl
propanoic acid
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PCT/US1999/008180
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French (fr)
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Kenneth Lewis Kees
Lloyd Michael Garrick
Ariamala Gopalsamy
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American Home Products Corporation
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Priority to AU35610/99A priority Critical patent/AU3561099A/en
Publication of WO1999052879A1 publication Critical patent/WO1999052879A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
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    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
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    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
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    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/12—Nitrogen atoms not forming part of a nitro radical
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the integrin v ⁇ 3 has been shown to mediate the invasion of cancerous melanoma cells into healthy tissue (Sefton et al.. Proc. Natl. Acad. Sci, USA. 1992, 89, 1557-1561) and to protect these cells against natural cell death cycle (apoptosis) (Montgomery et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 8856-8860).
  • Vitronectin receptor ( ⁇ v ⁇ 3 ) antagonists have been shown to inhibit the growth of various solid tumors of human origin (Brooks et al.. Cell. 1994, 79, 1 157-1 164). More recently, ⁇ v ⁇ 3 has been shown to be involved in liver metastasis (Yun et al.. Cancer Res., 1996, 56, 3103-3111).
  • ⁇ v ⁇ 3 was shown to be expressed on human wound tissue but not on normal skin (Brooks, et al., Science, 1994, 264, 569-571) and is preferentially expressed on angiogenic blood vessels, such as those feeding a growing/invading tumor. It has also been shown that antagonists of v ⁇ 3 promote tumor regression by inducing apoptosis of the tumor cells (Brooks et al., Cell, 1994, 79, 1157-1164).
  • v ⁇ 3 has been shown to play a pivotal role in the proliferation and migration of- smooth muscle and vascular endothelial cells, a pathological process leading to restenosis after balloon angioplasty (Choi et al., J. Vase. Surgery, 1994, 19, 125-134; Matsumo et al., Circulation, 1994, 90, 2203-2206). At least one type of vims (adeno virus) has been shown to utilize ⁇ v ⁇ 3 for entering host cells (White et al., Current Biology, 1993, 596-599.
  • osteoclasts Various bone diseases involve bone resorption which is mediated by only one known class of cells, the osteoclasts. When activated for resorption, these motile cells initially bind to bone, a process well known to be mediated by ⁇ v ⁇ 3 (Davies et al., J. Cell. Biol, 1989 109, 1817-1826; Helfrich et al., J Bone Mineral Res., 1992, 7, 335- 343). It is also well known that blockade of ⁇ v ⁇ 3 with antibodies or RGD containing peptides block osteoclast cell adhesion and bone resorption in vitro (Horton et al, Exp. Cell Res.
  • ⁇ v ⁇ 3 also plays an important role in autoimmune diseases such as psoriasis and rheumatoid arthritis. Peacock, et al., supra.
  • WO9532710 teaches compounds for inhibiting bone resorption.
  • the preferred compounds are compounds having a 4-alkyloxy substituted benzoic acid core coupled to an ( ⁇ -phenylsulfonylamino-3-amino propanoic acid) terminus. None of the exemplary compounds teach a 2-hydroxy substitution of the benzoyl core.
  • the lead compound of WO9532710 exhibited limited bioavailability in vivo. (VnR symposium Abstracts, 211th ACS National Meeting, New La, LA, March 24-28 (1996).)
  • WO9708145 discloses certain meta-guanidine, urea, thiourea and azacyclic amino substituted benzoic acid derivitaves as integrin antagonists.
  • European patent application number EP0320032 broadly claims certain 2- aminoalkoxy-substituted pyridazine derivatives. The compounds disclosed do not comprise an acid functionality.
  • WO9513262 teaches certain 2-hydroxy-4-heteroarylmethoxy benzamide derivatives are endothelin inhibitors.
  • R 1 and R 2 are independently, hydrogen, alkyl of 1 to 6 carbon atoms, mono or bicyclic aralkyl of 6 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
  • R 3 is hydrogen, mono or bicyclic aryl of 6 to 10 carbon atoms, 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O;
  • R 4 is hydrogen, NHR 9 , OR 9 , NHCO 2 R 9 , NHCONHR 9 , NHCOR 9 or NHSO 2 R 9 ; provided that R 3 and R 4 are not both hydrogen;
  • R 5 is hydrogen or alkyl of 1 to 6 carbon atoms which may optionally be substituted with a teirninal group which serves as a prodrug.
  • the alkyl group may be substituted with an acid, alcohol or amino functionality to form an alkylamino, carboxyalkyl or alkanol group;
  • R 6 and R 7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or aralkoxy of 6 to 10 carbon atoms; -5-
  • R 8 and R 9 are independently hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbons, alkynyl of 2 to 10 carbons, mono or polycycloalkyl of 3-12 carbon atoms, mono or polycycloalkyl-alkyl of 4-12 carbon atoms, mono or bicyclic aryl of 6 to 10- carbon atoms, 6 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O, mono or bicyclic aralkyl of 7 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
  • n is an integer from 1 to 4; and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
  • G is is 6- aminopyridin-2yl, pyridin-2yl, pyrimidyl, tetrahydropyrimidyl. tetrahydropyrimid-4- one. dihydroimidazolyl. amino(irnir ⁇ o)-, pyridyl-urea, benzyl-urea, or imidazolidinyl.
  • G is 6-amino- pyridin-2-yl, pyridin-2yl. dihydroimidazolyl, 5-amino 1 ,2,4-triazol-4yl (and/or all tautomers thereof) or tetrahydropyrimidyl, R 3 is H, and n is 2 or 3.
  • R9 is methyl, ethyl, n-propyl. i- propyl, allyl, homoallyl, propargyl, pentyl, n-hexyl, octyl, neopentyl, trichloroethyl. n- butyl, i-butyl, butynyl, phenyl, methylphenyl, dimethylphenyl, halophenyl.
  • Alkyl whether used alone or as part of a group such as “alkoxy”, means a branched or straight chain having from 1 to 10 carbon atoms.
  • exemplary alkyl groups ' include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • Lower alkyl refers to alkyl having from 1 to 4 carbon atoms.
  • Alkyl groups may be substituted.
  • Cycloalkyl as used herein refers to mono or polycyclic alkyl groups of 3-12 carbon atoms.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclohexyl and adamantyl.
  • Cycloalkyl groups may be substituted.
  • One preferred substitution is phenyl.
  • "Aryl” whether used alone or as part of a group such as “aralkyl”, means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms.
  • Exemplary aryl groups include phenyl and naphthyl.
  • the aryl may be substituted with one or more substituents.
  • Substituents include halogen, lower alkyl, alkoxy. alkykhio, amino. nitro, cyano, carboxy, carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl. hydroxy. oxy and phenyl.
  • One preferred aryl group is phenyl.
  • Heterocycloalkyl whether used alone or as part of a group such as “heterocycloalkyl-alkyl” means a stable, saturated or unsaturated 5 to 10 membered mono or bicyclic ring having from 1 to 3 heteroatoms selected from N, O and S.
  • exemplary heterocycloalkyls include pyrazinyl, pyrazolyl, tetrazolyl. furanyl. thienyl, pyridyl. imidazolyl. pyrimidinyl, tetrahydropyrimidinyl. isoxazolyl, thiazolyl. isothiazolyl, quinolinyl.
  • heteroaryl groups include pyrimidinyl, tetrahydropyrimidinyl, pyridyl. and imidazolyl. Most preferred heteroaryls include pyridin-2yl, and tetrahydropyrimidine.
  • the heteroaryl may also be substituted with one or more substituents. Substituents include halogen, lower alkyl, alkoxy, alkykhio, amino, nitro, cyano, carboxy. carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl, hydroxy, oxy and phenyl. Preferred substituents include amino and oxy.
  • Preferred substituted heterocycloalkyls include 6 aminopyridin-2yl and tetrahydropyrirnid-4-one.
  • Alkyl means an aryl-alkyl group in which the aryl and alkyl are as previously described.
  • exemplary aralkyl groups include benzyl and phenethyl.
  • the alkyl group may include one or more double bonds.
  • Heterocycloalkyl-alkyl means an heterocycloalkyl group in which the heterocycloalkyl and alkyl are as previously described. Use in this context, the alkyl group may include one or more double bonds.
  • Exemplary heterocycloalkyl-alkyls -7- include pyridy nethyl, pyridylethyl, thienylethyl, thienylmethyl. indolvlmethyl, and furylmethyl.
  • Alkoxy means an alkyl-O group in which the alkyl group is as previously, described.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
  • Alkoxy means an aryl-alkoxy group in which aryl and alkoxy are as previously described.
  • Halogen includes fluorine, chlorine, iodine and bromine.
  • Prodrug as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.
  • the 2-hydroxy compounds of the invention are believed to obviate at least two of the three hydrating water molecules which are known to form intermolecular hydrogen bonds with secondary amide functionalities.
  • the energy needed to desolvate water molecules for efficient transport across cell membranes is thus reduced in compounds of the present invention and is believed to contribute to the markedly improved plasma concentrations seen with compounds of the present invention.
  • Preferred compounds include: (2S)-3-( ⁇ 2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl ⁇ amino)-2-[(methoxycarbonyl)amino]propanoic acid,
  • Optically active isomers may be prepared, for example by resolving the racemic mixtures.
  • the resolution can be carried out by methods known to those skilled in the art such as in the presence of resolving agent, by chiral chromatography, or combinations thereof.
  • Compounds of Formula I are useful in methods of selectively inhibiting or antagonizing an integrin receptor such as a v b 3 . More specifically, methods of the present invention include but are not limited to methods of inhibiting cancer (tumor metastasis, tumorgenesis/tumor growth), angiogenesis (as in cancer, diabetic retinopathy, rheumatoid arthritis), restenosis (following balloon angioplasty or stent implantation), inflammation (as in rheumatoid arthritis, psoriasis), bone diseases (osteopenia induced by bone matastases, immobilization and glucocortocoid treatment, periodontal disease, hyperparathyroidism and rheumatoid arthritis), and viral infection by administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
  • cancer tumor metastasis, tumorgenesis/tumor growth
  • angiogenesis as in cancer, diabetic retinopathy, r
  • the compounds of this invention are prepared in accordance with the solid phase combinatorial library synthesis methods or solution phase synthesis methods.
  • the starting acylresorcinol ester is condensed with an alkylene chain bearing a terminal primary amino group which is suitably blocked/protected.
  • Methods for this condensation include, but are not limited to selective alkylation of one (the non-H- bonded hydroxyl group) of the resorcinol hydroxy groups, using standard procedures such as the Gabriel synthesis (Angew Chem Int. Ed. Engl. 7, 1968, 919-930 (1968) or Mitsunobu reaction (Synthesis, 1981,1-28).
  • the amine 2-2 was protected as fluorenylmethyloxy carbamate (Fmoc) 2-6.
  • G pyrimidine 2-3
  • the primary amine 2-2 was activated with trimethylsilyl chloride in the presence of 2-bromopyrimidine in refluxing (anhydrous) 1, 4-dioxane.
  • the carboxylic acid 2-3 was activated as pentafluorophenyl ester 2-5.
  • the carboxylic acid 2-3 was also hydrogenated under catalytic hydrogenation conditions to obtain the tetrahydropyrimidine derivative 2-4.
  • 2,3-diamino propionic acid 1-1 was used for carboxylic acid terminus and was immobilized on polymer support with linkers like but not limited to Wang.
  • the 2-amino group of the 2,3-diaminopropionic acid was Fmoc protected, while the 3- amino group was dde (4,4-dimethyl-2,6-dioxocyclohex-l- ylideneethyl) protected.
  • the 2-amino group was deprotected and further derivatized to 1-4, 1-5, 1-6 and 1-7 using various acylating agents including but not limitted to chloroformates, isocyanates, sulfonyl chlorides, carboxylic acids/chlorides.
  • the 3- amino group was deprotected to give 1-8, 1-9, 1-10 and 1-11 and coupled with the resorcinol acid derivatives 2-4, 2-5 or 2-6.
  • N-terminus derivatives such as dihydroimidazole 5-3, azepine 5-4, guanidine 6- 3, and ureas 6-4 were prepared from common primary amine intermediate 4-2.
  • the resin 1-2 (6.956 g) in DMF was treated with 20% piperidine in DMF (40mL) for 10 min and filtered. Another 40mL portion of 20% piperidine in DMF was added to the resin and shaken at room temperature for 20 min. The resin was filtered and washed with DMF (3 x 40mL), MeOH (3 x 40mL) and DCM (3 x 40mL). The resin (1-3) was dried in vacuo.
  • the resin 1-3 (925 mg; 0.75 mmol) was swollen in dichloromethane and treated with diisopropylethylamine (969 mg; 1.3 mL; 7.5 mmol) followed by neopentyl -33-
  • the resin 1-3 (925 mg; 0.75 mmol) was washed with DMF to swell the resin.
  • a solution of benzoic acid (183 mg; 1.5mmole) in DMF was mixed with diisopropylcarbodiimide (192 mg; 0.25 mmole), hydro xybenzotriazole (228 mg; 1.5 mmole) and dimethylaminopyridine (18 mg; 1.5 mmole) and the mixture was added to the resin.
  • the reaction mixture was shaken at room temperature for I6h.
  • the mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol -34-
  • carboxylic acids were used in the above reaction in the place of benzoic acid.
  • the resin 1-4 was shaken with a solution of 2% hydrazine in dimethylformamide (3mL) for 5 min. at room temperature.
  • the reaction mixture was filtered and an additional 3 mL of a solution of 2% hydrazine in dimethylformamide was added and the reaction mixture was shaken at room temperature for 5 min.
  • the mixture was filtered and the resin was washed with dimethylformamide (4 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL).
  • the resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test for the presence of free amine (resin turns blue).
  • Resin bound compounds 1-5, 1-6 and 1-7 were subjected to similar deprotection condition to afford the free amines 1-9, 1-10 and 1-11 respectively. -35-
  • Ester 2-1 (7.2g) was treated with 5eq. KOH (dissolved in rninimum amount of water and equal volume of 1, 4-dioxane) at room temperature until TLC indicated complete absence of starting material (3-12h).
  • the crude product (5.34g) was recrystallized from ether, then dissolved in 1, 4-dioxane and treated with an excess of anhydrous HCl (4M in dioxane, Aldrich).
  • Compound 2-3 (2g) was combined with 10% Pd/C (0.5g), acetic acid (100 mL) and concentrated hydrochloric acid (0.7 mL). The mixture was stirred at room temperature under an atmosphere of H 2 (balloon) for 2 days. Celite was added and the mixture stirred for 0.5h, then filtered through a pad of celite with the aid of isopropanol. Volatile materials were removed on the rotary evaporator and the residue warmed with heptane ( ⁇ 0.5h, 100°C) followed by concentration in vacuo to give 2-4 as a tan foam.
  • the Amino acid 2-2 (1.864g; 8 mmol) was dissolved in 1: 1 acetone - water (50 mL) containing sodium carbonate (1.696g; 16 mmol). To the solution was added Fmoc- Osu (2.696 g; 8 mmol) in acetone (25 mL) dropwise at room temperature. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was dissolved in water and extracted with ether (2 x 50 mL). The aqueous layer was cooled in an ice bath and acidified with 6N HCl to pH 3. The solid obtained was filtered and washed with water and dried under vacuo (3.22g).
  • the resin 1-8 (lOOmg) was washed with DMF to swell the resin.
  • a solution of 2-hydroxy-4-[2-(3,4,5,6-tetrahydropyrimidh-2-ylamino)ethoxy]-benzoic acid 2-4 (70 mg; 0.25mmole) in DMF was mixed with diisopropylcarbodiimide (32 mg; 0.25 mmole), hydroxybenzotriazole (38mg; 0.25 mmole) and dimethylaminopyridine (3 mg; 0.025 mmole) and the mixture was added to the resin.
  • the reaction mixture was shaken at room temperature for 16h.
  • the resin 1-8 (lOOmg) was washed with DMF to swell the resin and was treated with a solution of 2,3,4,5,6-pentafluorophenyl 2-hydroxy-4-[2-(pyrimidine-2- ylamino)ethoxy]-benzoate 2-5 (110 mg; 0.25mmole) in DMF.
  • the reaction mixture was shaken at room temperature for 16h.
  • the mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane
  • the resin 1-8 was washed with DMF to swell the resin.
  • a solution of 4-[(2- fluorenylmethyloxycarbonylamino)ethoxy]-2-hydroxybenzoic acid (2-6) (628.5 mg; 1.5 mmole) in DMF was mixed with diisopropylcarbodiimide (189 mg; 1.5 mmole), hydroxybenzotriazole (202.5 mg; 1.5 mmole) and dimethylaminopyridine (18.33 mg; 0.15 mmole) and the mixture was added to the resin.
  • the reaction mixture was shaken -56- at room temperature for 16h.
  • the resin 4-1 was shaken with a solution of 20% piperidine in DMF (5mL) for 10 min and filtered. Another 5mL portion of 20% piperidine in DMF was added and shaken at room temperature for 20 min. The resin was filtered and washed with DMF
  • the resin 4.2 (lOOmg; O. lmmole) was swollen in DMF. To the resin was added a solution of 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide (123 mg; 0.5 mmole) in DMF (1.5 mL) followed by d ⁇ opropylamine (0.15 mL; 1 mmole). The reaction vessel was shaken at 60 °C for 18h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated. O 99/52879
  • Example 114 3-( ⁇ 4-[2-(2,5-dihydro-lH-irnidazol-4-ylamino)ethoxy]-2-hydroxyber ⁇ zoyl)amino-N- ( ⁇ ⁇ (lS,2R)-phenylcyclopropyl]amino)carbonyl alanine.
  • the resin 4-2 (100 mg: O.lmmole) was swollen in dioxane and treated with a solution of l-aza-2-methoxy-l-cycloheptene (127 mg; 1 mmole) in dioxane (1.5 mL). The reaction mixture was shaken at room temperature for 18h. The mixture was filtered and the resin was washed with dioxane (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
  • the resin 5-3 was cleaved by tratment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 5-4 was purified via preparative HPLC.
  • the resin 4-2 (100 mg; O.lmmole) was swollen in DMF and treated with a solution of l,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (145 mg; (0.5 mmole) in DMF (1.5 mL) followed by d ⁇ opropylamine (0.15 mL; 1 mmole).
  • the reaction mixture was shaken at room temperature for 18h.
  • the mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL).
  • the resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated. -69-

Abstract

Compounds of formula (I) are useful in the treatment of various disorders including, but not limited to, cancer, angiogenesis, restenosis, inflammation, bone diseases, and as antiviral agents. Novel methods of makings compounds of formula (I) are also provided.

Description

ACYLRESORCINOL DERIVATIVES AS SELECTIVE VITRONECTIN RECEPTOR INHIBITORS
Background of Invention
The integrin vβ3 has been shown to mediate the invasion of cancerous melanoma cells into healthy tissue (Sefton et al.. Proc. Natl. Acad. Sci, USA. 1992, 89, 1557-1561) and to protect these cells against natural cell death cycle (apoptosis) (Montgomery et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 8856-8860). Vitronectin receptor (αvβ3 ) antagonists have been shown to inhibit the growth of various solid tumors of human origin (Brooks et al.. Cell. 1994, 79, 1 157-1 164). More recently, αvβ3 has been shown to be involved in liver metastasis (Yun et al.. Cancer Res., 1996, 56, 3103-3111).
Although angiogenesis is an important and natural process in growth and wound healing, it is now appreciated that a variety of clinically relevant conditions are pathologically related to these processes, and that the integrin αvβ3 is involved. For example, αvβ3 was shown to be expressed on human wound tissue but not on normal skin (Brooks, et al., Science, 1994, 264, 569-571) and is preferentially expressed on angiogenic blood vessels, such as those feeding a growing/invading tumor. It has also been shown that antagonists of vβ3 promote tumor regression by inducing apoptosis of the tumor cells (Brooks et al., Cell, 1994, 79, 1157-1164). This process of neovascularization which is critical for tumor growth and metastasis, is also an important event in ocular tissue, leading to diabetic retinopathy, glaucoma and blindness (Adonis et al., Am. J. OphthaL 1994, 118, 445-450; Hammes et al., Nature Med., 1996, 2,529-533; Friedlander, et al., Natl. Acad. Sci. U.S.A., 1996, 93, 9764- O 99/52879 rL
-2-
9769) and in joints, promoting rheumatoid arthritis (Peacock et al.. J. Exp. Med., 1992, 175, 1135-1138).
vβ3 has been shown to play a pivotal role in the proliferation and migration of- smooth muscle and vascular endothelial cells, a pathological process leading to restenosis after balloon angioplasty (Choi et al., J. Vase. Surgery, 1994, 19, 125-134; Matsumo et al., Circulation, 1994, 90, 2203-2206). At least one type of vims (adeno virus) has been shown to utilize αvβ3 for entering host cells (White et al., Current Biology, 1993, 596-599.
Various bone diseases involve bone resorption which is mediated by only one known class of cells, the osteoclasts. When activated for resorption, these motile cells initially bind to bone, a process well known to be mediated by αvβ3 (Davies et al., J. Cell. Biol, 1989 109, 1817-1826; Helfrich et al., J Bone Mineral Res., 1992, 7, 335- 343). It is also well known that blockade of αvβ3 with antibodies or RGD containing peptides block osteoclast cell adhesion and bone resorption in vitro (Horton et al, Exp. Cell Res. 1991, 195, 368-375) and that echistatin, an RGD containing protein, inhibits bone resorption in vivo (Fisher et al., Endocrinology, 1993, 132, 141 1-1413). More recently, an RGD peptidomimetic has likewise been shown to inhibit osteoclasts in vitro and, by i.v. administration in vivo prevents osteoporosis (Engleman et al., J. Clin. Invest., 1997, 99, 2284-2292).
αvβ3 also plays an important role in autoimmune diseases such as psoriasis and rheumatoid arthritis. Peacock, et al., supra.
Numerous patents/applications have claimed various non-peptide αvβ3 inhibitors for some or all of the above applications (e.g. EP92307157.5A, EP92307156.7A, WO9708145, WO9532710, WO96/00730, WO9637492, WO9626190, WO9606087, WO97/23451, WO9724119, WO9724122, WO9724124, WO96-US20744961220, EP796855, WO9733887, WO97/34865, WO97/35615, WO97/36859, WO97/35615, WO97/08145, US5668159, WO98/08840, WO98/14192). -3-
WO9532710 teaches compounds for inhibiting bone resorption. Among the preferred compounds are compounds having a 4-alkyloxy substituted benzoic acid core coupled to an (α-phenylsulfonylamino-3-amino propanoic acid) terminus. None of the exemplary compounds teach a 2-hydroxy substitution of the benzoyl core. The lead compound of WO9532710 exhibited limited bioavailability in vivo. (VnR symposium Abstracts, 211th ACS National Meeting, New Orleans, LA, March 24-28 (1996).)
WO9708145 discloses certain meta-guanidine, urea, thiourea and azacyclic amino substituted benzoic acid derivitaves as integrin antagonists. European patent application number EP0320032 broadly claims certain 2- aminoalkoxy-substituted pyridazine derivatives. The compounds disclosed do not comprise an acid functionality.
WO9513262 teaches certain 2-hydroxy-4-heteroarylmethoxy benzamide derivatives are endothelin inhibitors.
Detailed Description of the Invention
According to the present invention are provided novel compounds of Formula I:
wherein
OH < ϊ f ϋ i
R1 ΓY
G- φ / \ R2 -o U vr* 1 ι<
Figure imgf000005_0001
-4-
G is
O JJ
O N^R7 o
R8
Figure imgf000006_0001
Figure imgf000006_0002
H2ϊT ' R' N
H H A. '
(rC» N N
-N
H H ^ * H ' N- i
R1 and R2 are independently, hydrogen, alkyl of 1 to 6 carbon atoms, mono or bicyclic aralkyl of 6 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
R3 is hydrogen, mono or bicyclic aryl of 6 to 10 carbon atoms, 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O;
R4 is hydrogen, NHR9, OR9, NHCO2R9, NHCONHR9, NHCOR9or NHSO2R9; provided that R3 and R4 are not both hydrogen;
R5 is hydrogen or alkyl of 1 to 6 carbon atoms which may optionally be substituted with a teirninal group which serves as a prodrug. For example, the alkyl group may be substituted with an acid, alcohol or amino functionality to form an alkylamino, carboxyalkyl or alkanol group;
R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or aralkoxy of 6 to 10 carbon atoms; -5-
R8 and R9 are independently hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbons, alkynyl of 2 to 10 carbons, mono or polycycloalkyl of 3-12 carbon atoms, mono or polycycloalkyl-alkyl of 4-12 carbon atoms, mono or bicyclic aryl of 6 to 10- carbon atoms, 6 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O, mono or bicyclic aralkyl of 7 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
n is an integer from 1 to 4; and m is 0 or 1 ; or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the present invention G is is 6- aminopyridin-2yl, pyridin-2yl, pyrimidyl, tetrahydropyrimidyl. tetrahydropyrimid-4- one. dihydroimidazolyl. amino(irnirιo)-, pyridyl-urea, benzyl-urea, or imidazolidinyl.
In a still more preferred embodiment of the present invention G is 6-amino- pyridin-2-yl, pyridin-2yl. dihydroimidazolyl, 5-amino 1 ,2,4-triazol-4yl (and/or all tautomers thereof) or tetrahydropyrimidyl, R3 is H, and n is 2 or 3.
In some preferred aspects of the invention R9 is methyl, ethyl, n-propyl. i- propyl, allyl, homoallyl, propargyl, pentyl, n-hexyl, octyl, neopentyl, trichloroethyl. n- butyl, i-butyl, butynyl, phenyl, methylphenyl, dimethylphenyl, halophenyl. methoxy- phenyl, acetylphenyl, biphenyl, naphthyl, benzyl, phenethyl, cyclohexyl, cyclohexyl- methyl, trimethylcyclopropyl, phenylcyclopropyl, adamantyl, adamantylmethyl. cinnamic, pyridyl or dimethylfuranyl.
"Alkyl", whether used alone or as part of a group such as "alkoxy", means a branched or straight chain having from 1 to 10 carbon atoms. Exemplary alkyl groups' include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl. Lower alkyl refers to alkyl having from 1 to 4 carbon atoms. Alkyl groups may be substituted. "Cycloalkyl" as used herein refers to mono or polycyclic alkyl groups of 3-12 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclohexyl and adamantyl. Cycloalkyl groups may be substituted. One preferred substitution is phenyl. "Aryl" whether used alone or as part of a group such as "aralkyl", means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl. The aryl may be substituted with one or more substituents. Substituents include halogen, lower alkyl, alkoxy. alkykhio, amino. nitro, cyano, carboxy, carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl. hydroxy. oxy and phenyl. One preferred aryl group is phenyl.
"Heterocycloalkyl" whether used alone or as part of a group such as "heterocycloalkyl-alkyl" means a stable, saturated or unsaturated 5 to 10 membered mono or bicyclic ring having from 1 to 3 heteroatoms selected from N, O and S. Exemplary heterocycloalkyls include pyrazinyl, pyrazolyl, tetrazolyl. furanyl. thienyl, pyridyl. imidazolyl. pyrimidinyl, tetrahydropyrimidinyl. isoxazolyl, thiazolyl. isothiazolyl, quinolinyl. indolyl, isoquinolinyl, oxazolyl and oxadiazolyl. Preferred heteroaryl groups include pyrimidinyl, tetrahydropyrimidinyl, pyridyl. and imidazolyl. Most preferred heteroaryls include pyridin-2yl, and tetrahydropyrimidine. The heteroaryl may also be substituted with one or more substituents. Substituents include halogen, lower alkyl, alkoxy, alkykhio, amino, nitro, cyano, carboxy. carboxyalkyl, alkanoyl, alkylamino, perhaloalkyl, hydroxy, oxy and phenyl. Preferred substituents include amino and oxy. Preferred substituted heterocycloalkyls include 6 aminopyridin-2yl and tetrahydropyrirnid-4-one.
"Aralkyl" means an aryl-alkyl group in which the aryl and alkyl are as previously described. Exemplary aralkyl groups include benzyl and phenethyl. Use in this context, the alkyl group may include one or more double bonds.
"Heterocycloalkyl-alkyl" means an heterocycloalkyl group in which the heterocycloalkyl and alkyl are as previously described. Use in this context, the alkyl group may include one or more double bonds. Exemplary heterocycloalkyl-alkyls -7- include pyridy nethyl, pyridylethyl, thienylethyl, thienylmethyl. indolvlmethyl, and furylmethyl.
"Alkoxy" means an alkyl-O group in which the alkyl group is as previously, described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
"Aralkoxy" means an aryl-alkoxy group in which aryl and alkoxy are as previously described.
"Halogen" includes fluorine, chlorine, iodine and bromine.
"Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I.
NMR and IR spectra indicate the 2-hydroxy substitution of Formula I is strongly H-bonded to the adjacent carbonyl, effectively forming a six-membered ring which conformationally restricts the amide residue bearing the carboxy terminus.
Thus, the 2- hydroxy substitution of the phenyl core of Formula I plays a significant role in integrin receptor selectivity.
In addition, the 2-hydroxy compounds of the invention are believed to obviate at least two of the three hydrating water molecules which are known to form intermolecular hydrogen bonds with secondary amide functionalities. The energy needed to desolvate water molecules for efficient transport across cell membranes is thus reduced in compounds of the present invention and is believed to contribute to the markedly improved plasma concentrations seen with compounds of the present invention.
Preferred compounds include: (2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl} amino)-2-[(methoxycarbonyl)amino]propanoic acid,
(2S)-2-[(ethoxycarbonyl)arnino]-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-( {2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl} amino)-2-[(propoxycarbonyl)arnino]propanoic acid, (2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5)6-tetrahydropyrimidin-2- ylamho)ethoxy]berιzoyl}arnino)-2-[(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2-{ [(aUyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrirnidin- 2-ylarnino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-{ [(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-( 1,4,5,6- tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2- { [(hexyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidh-2-ylammo)ethoxy]berιzoyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2- { [(octyloxy)carbonyl]amino }propanoic acid,
(2S)-3-( {2-hydroxy-4-[2-( 1,4,5.6-tetrahydropyr imidm-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(neopentyloxy)carbonyl]amino} propanoic acid,
(2S)-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidh-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(2,2,2-tricMoroethoxy)carbonyl]amino}propanoic acid,
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyriiriidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(butoxycarbonyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(isobutoxycarbonyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5 ,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - amko)-2-{ [(prop-2-ynyloxy)carbonyl]amino}propanoic acid,
(2S)-2- { [(benzyloxy)carbonyl] amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl } amino)propanoic acid, (2S)-2-{[(butylanτino)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-2-{ [(hexylarnmo)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidm-2-ylarnino)ethoxy]benzoyl}- amino)-2- { [(octylamino)carbonyl] amino } propanoic acid,
(2S)-2- { [(allylamino)carbonyl] amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid, -9-
(2S)-2-{ [(l-adamantylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6- tetrahydropyrinτidin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-[(anilmocarbonyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrirnidin-2- ylarnino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-2- { [(cyclohexylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidm-2-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2- { [(benzylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidm-2-ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - ammo)-2-[(4-toluidinocarbonyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl} - amino)-2-[(2-toluidinocarbonyl)amino]propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrir din-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(2-methoxyanilino)carbonyl] amino} propanoic acid,
(2S)-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr imidh-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(4-methoxyanilino)carbonyl] amino} propanoic acid,
(2S)-2-{ [(2-chloroarιilino)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrirnidm-2-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2-{ [(2-bromoarιilino)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyriιridm-2-ylamino)ethoxy]benzoyl}arnino)propanoic acid,
(2S)-2- { [([1,1 '-biphenyl]-2-ylamino)carbonyl] amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-2-{ [(4-cmoroarιilino)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrirrύdin-2-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- ammo)-2-{ [(l-naphthylamino)carbonyl]amino}propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - amino)-2-({ [(2-phenylethyl)amino]carbonyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2-(isobutyrylamino)propanoic acid, •10-
(2S)-2-(hexanoylamino)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidm-2-ylamino)ethoxy]- benzoyl } amino)-2-(pentanoylamino)propanoic acid,
(2S)-2-[(3,3-dimethylbutanoyl)amino]-3-({2-hydroxy-4-[2-(1.4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid.
(2S)-2-[(cyclohexylcarbonyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(2-phenylacetyl)amino]propanoic acid,
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2-ylarnino)ethoxy]benzoyl}- amino)-2-[(3-phenylpropanoyl)amino]propanoic acid,
(2S)-2-[(2-cyclohexylacetyl)amino]-3-({2-hydroxy-4-[2-( 1,4.5.6-tetrahydropyrimidin- 2-ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - arrιino)-2-{[(E)-3-phenylprop-2-enoyl]amino} propanoic acid,
(2S)-2-[(2-chlorobenzoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(2-methylbenzoyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrirr din-2-ylamino)ethoxy]benzoyl}- aιrιmo)-2-[(2-methoxybenzoyl)amino]propanoic acid,
(2S)-2-[(4-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylambo)ethoxy]beri2oyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidh-2-ylamino)ethoxy]benzoyl}- amino)-2-[(4-methylbenzoyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrirmdh-2-ylamino)ethoxy]benzoyl} - amino)-2-[(4-methoxybenzoyl)amino]propanoic acid,
(2S)-2-[(2,5-dimethyl-3-furoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylaπιino)ethoxy]benzoyl}amino)propanoic acid, ■11-
(2S)-2-[(2-bromobenzoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-2-[(4-bromobenzoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid
(2S)-2-[(2,3-dimethylbenzoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyriiridh-2-ylaniirio)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-[(3-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylammo)ethoxy]benzoyl}amino)-2- [(phenoxycarbonyl)amino]propanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]ammo}-3-({2-hydroxy-4-[2-(pyrinridin-2-ylamino)- ethoxyjbenzoyl} amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimid -2-ylamino)ethoxy]benzoyl}amino)-2- [(isobutoxycarbonyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4- [2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2- { [(4- methoxyphenoxy)carbonyl]amino Jpropanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2- { [(octyloxy)carbonyl]amino Jpropanoic acid,
(2S)-2-[(butoxycarbonyl)aιτιmo]-3-({2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]- benzoyl} amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl} amino)-2- { [(2,2,2- trichloroethoxy)carbonyl] amino Jpropanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-(pyrirddin-2-ylamino)ethoxy]benzoyl} amino)-2- { [(neopentyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-( { 2-hydroxy-4- [2-(pyrimidm-2-ylamino)ethoxy]benzoyl } amino)-2-( { [(4- nitrobenzyl)oxy]carbonyl } amino)propanoic acid,
(2S)-2- { [(hexyloxy)carbonyl] amino } -3-( { 2-hydroxy-4- [2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4- [2-(pyι±rιidin-2-ylamino)ethoxy]benzoyl } amino)-2- { [(prop-2- ynyloxy)carbonyl] amino } propanoic acid, •12-
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2- { [(4- methylphenoxy)carbonyl] amino Jpropanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoylJamino)-2- [(methoxycarbonyl)amino]propanoic acid,
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxy]benzoylJamino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoylJ amino)-2- [(propoxycarbonyl)amino]propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamho)ethoxy]benzoyl}arnino)-2- [(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2- { [(allyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxy] benzoyl }amino)propanoic acid,
(2S)-2-{ [(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-2-[(anilinocarbonyl)amino]-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-{[(tert-butylan ino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl J amino)propanoic acid,
(2S)-2- { [(butylamino)carbonyl]amino } -3-( { 2-hydroxy-4- [2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylaιrιino)ethoxy]berιzoyl}amino)-2-{[(4- methoxyanilino)carbonyl]amino Jpropanoic acid,
(2S)-2-{[(2-ethylanilino)carbonyl]aιrιko}-3-({2-hydroxy-4-[2-(ρyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2- { [(aUylamino)carbonyl] amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2- { [(2,4-dicMoroarιilino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamho)ethoxy]benzoylJamino)-2-[(2- toluidinocarbonyl)amino]propanoic acid, ■13-
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoylJamino)-2-{ [(2- methoxyanilino)carbonyl] amino Jpropanoic acid,
(2S)-2-{ [(2-cUoroanilino)carbonyl]arriino}-3-({2-hydroxy-4-[2-(pyrirriidin-2- ylamino)ethoxy]benzoyl J amino)propanoic acid,
(2S)-2-{ [(2-bromoanilino)carbonyl]arnmo}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-{ [([l, -biphenyl]-2-ylamino)carbonyl]amino }-3-({2-hydroxy-4-[2-(pyrimidin- 2-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyriιrύdin-2-ylambo)ethoxy]benzoyl}amino)-2-[(4- toluidinocarbonyl)amino]propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrirddm-2-ylammo)ethoxy]benzoyl}amino)-2-({ [4- (triiluoromethyl)anilino]carbonyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2-( { [4- (trifluoromethoxy)anilino]carbonyl} amino)propanoic acid,
(2S)-2-{ [(4-cUoroanilmo)carbonyl]arnino}-3-({2-hydroxy-4-[2-(pyrirnidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2- { [(4-fluoroanilino)carbonyl]arnino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2-{ [(4-acetylanilino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-( { [4-(ethoxycarbonyl)anilino]carbonylJamino)-3-( {2-hydroxy-4-[2-(pyrimidin- 2-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2-{ [(eye lohexylamino)carbonyl] amino }-3-({ 2-hydroxy-4- [2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)proρanoic acid,
(2S)-3-( { 2-hydroxy-4- [2-(pyrimidin-2-ylamino)ethoxy]berιzoyl } amino)-2- { [( 1 - naphthylamino)carbonyl] amino Jpropanoic acid,
(2S)-2- { [(berzylamino)carbonyl]amino }-3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy] benzoyl }amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl}amino)-2-({ [(2- phenylethyl)amino]carbonylJamino)propanoic acid, -14-
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylarnino)ethoxy]benzoylJ amino)-2- { [(octylaιrιino)carbonyl]amino Jpropanoic acid,
(2S)-2- { [(benzyloxy)carbonyl]amino }-3-( {4-[2-(4,5-dihydro- lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dmydro-lH-in idazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2-[(methoxycarbonyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- arnino)-2-[(ethoxycarbonyl)arnino]propanoic acid,
(2S)-3-({4-[2-(4,5-di ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- aιτιino)-2-[(propoxycarbonyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2-[(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2-{ [(aUyloxy)carbonyl]aminoJ-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylambo)ethoxy]-2-hydroxyberrzoyl}amino)propanoic acid,
(2S)-2-{ [(but-3-enyloxy)carbonyl]aminoJ-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-irmdazol-2-ylamino)ethoxy]-2- hydroxybenzoylJamino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoylJamino)-2-{ [(hexyloxy)carbonyl]aminoJpropanoic acid,
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-{ [(octyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-{ [(neopentyloxy)carbonyl] amino Jpropanoic acid,
(2S)-2-[(butoxycarbonyl)amino]-3-({4-[2-(4,5-dihydro-lH-irrύdazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dmydro-lH-irrιidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-[(isobutoxycarbonyl)amino]propanoic acid,
(2S)-2- { [(butylamino)carbonyl] amino } -3-( {4-[2-(4,5-dihydro- lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid, •15-
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2-{ [(hexylamino)carbonyl] amino Jpropanoic acid,
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(octylanτino)carbonyl]amino}propanoic acid,
(2S)-2- { [(aUylamino)carbonyl] amino }-3-( {4-[2-(4,5-dihydro- lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid,
(2S)-2-{ [(cyclohexylammo)carbonyl]amino }-3-({4-[2-(4,5-dihydro- lH-imidazol-2- ylamino)ethoxy]-2-hydroxyberιzoyl}amino)propanoic acid,
(2S)-2-{ [(benzylarrιino)carbonyl]aminoJ-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoylJamino)propanoic acid,
3-({4-[2-(2,5-dihydro-lH-irddazol-4-ylamino)ethoxy]-2-hydroxybenzoyl)amino)-N- { [(IS, 2R)-2-phenylcyclopropyl]amino)carbonyl)alanine,
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(2-methoxyanilino)carbonyTJ amino Jpropanoic acid,
(2S)-2- {[([1,1 '-biphenyl]-2-ylamino)carbonyl]amino } -3-( { 4-[2-(4,5-dihydro- 1H- imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl } amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2-({ [(2-phenylethyl)amino]carbonyl}amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dil ydro-lH-iιτιidazol-2-ylarnino)ethoxy]-2-hydroxybenzoyl}- ammo)-2-(isobutyrylamino)propanoic acid,
(2S)-2-(butyιylamino)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl } amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-irmdazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2-(hexanoylamino)propanoic acid,
(2S)-3-( { 4-[2-(4,5-dihydro- lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl} - amino)-2-(pentanoylamino)propanoic acid,
(2S)-3-( { 4-[2-(4,5-dihydro- 1 H-irnidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl } - amino)-2-[(3,3-dimethylbutanoyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2- { [(2,2,3,3-tetramethylcyclopropyl)-carbonyl]amino Jpropanoic acid, -16-
(2S)-2- { [2-( 1 -adamantyl)acetyl]amino } -3-( { 4-[2-(4,5-dihydro- 1 H-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl} amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-(pent-4-ynoylamino)propanoic acid,
(2S)-2-[(cyclohexylcarbonyl)arrώιo]-3-({4-[2-(4,5-dihydro-lH-irnidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid,
(2S)-3-({4-[2-(4,5-di ydro-lH-imidazol-2-ylarnino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(2-phenylacetyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylaιrιino)ethoxy]-2-hydroxybenzoyl}- amino)-2-[(3-phenylpropanoyl)amino]propanoic acid,
(2S)-2-[(2-cyclohexylacetyl)aιnino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylarnino)ethoxy]-2-hydroxybenzoylJ amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-irrύdazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(E)-3-phenylprop-2-enoyl]amino Jpropanoic acid,
(2S)-2-[(2-cMorobenzoyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoylJamino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-iιrύdazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- arrιino)-2-[(2-methylbenzoyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-irnidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(2-methoxyberιzoyl)amino]propanoic acid,
(2S)-2-[(4-chlorotenzoyl)amino]-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino)propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(4-methylbenzoyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-irrύdazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- aιrιino)-2-[(4-methoxybenzoyl)amino]propanoic acid,
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amώo)-2-[(2,5-dimethyl-3-furoyl)amino]propanoic acid,
(2S)-2-[(2-bromoberιzoyl)arnino]-3-({4-[2-(4,5-di ydro-lH-imidazol-2-ylaιrιino)- ethoxy]-2-hydroxybenzoyl}amino)propanoic acid, -17-
(2S)-2-[(4-bromobenzoyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoylJamino)propanoic acid,
(2S)-3-({4-[2-(4,5-dilιydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl}- amino)-2-[(2,3-dimethylbenzoyl)amino]propanoic acid,
(2S)-2-[(3-cMorobenzoyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl} amino)propanoic acid,
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepin-7-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepm-7-ylamino)ethoxy]benzoylJ- ammo)-2-[(methoxycarbonyl)amino]propanoic acid,
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin- 7-ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azeph-7-ylamino)ethoxy]benzoylJ- amino)-2-[(propoxycarbonyl)amino]propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylamino)ethoxy]benzoylJ- amino)-2-[(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2-{ [(aUyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepώ-7-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2-{ [(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro- 2H-azepin-7-ylamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylamino)ethoxy]benzoylJ- amino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid,
(2S)-2-{[(hexyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepin-7-ylamino)ethoxy]benzoylJ amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylamino)ethoxy]benzoylJ- amino)-2-{ [(octyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepij -7-ylaιrιino)ethoxy]benzoyl}- amino)-2-{ [(neopentyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylamino)ethoxy]benzoylJ- amino)-2-{[(2,2,2-trichloroethoxy)carbonyl]amino Jpropanoic acid, -18-
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin- 7-ylamino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylamino)ethoxy]benzoylJ- amino)-2-[(isobutoxycarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [ammo(imino)methyl]amino}ethoxy)-2-hydroxyberιzoyl]aminoJ-2- { [(benzyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3- { [4-(2- { [amko(imho)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- [(methoxycarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amώo(imino)methyl]an±ιo}ethoxy)-2-hydroxybenzoyl]amino}-2- [(ethoxycarbonyl)amino]propanoic acid,
(2S)-3- { [4-(2- { [ammo(iιτιho)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino J-2- [(propoxycarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [arrιώo(iiΩino)methyl]arnbo}ethoxy)-2-hydroxybenzoyl]amino}-2- [(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2- { [(allyloxy)carbonyl] amino }-3-{ [4-(2-{ [amino(imino)methyl]amino }ethoxy)-2- hydroxybenzoyljamino Jpropanoic acid,
(2S)-3- { [4-(2- { [anτino(iιrιino)methyl] amino } ethoxy)-2-hydroxybenzoyl]amino } -2- { [(but-3-enyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]an ino}ethoxy)-2-hydroxyber^oyl]amino}-2- [(butoxycarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [arn o(imino)methyl]arnmo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(2,2,2-trichloroethoxy)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [arnino(irnino)methyl]amho}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(neopentyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [ammo(imino)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(hexyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [ammo(irnino)methyl] amino }ethoxy)-2-hydroxybenzoyl]amino}-2- { [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3- { [4-(2- { [anτko(iιnino)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2- {[([l, -biphenyl]-2-ylmethoxy)carbonyl]amino}propanoic acid, -19-
(2S)-3- { [4-(2- { [ambo(irrιmo)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino } -2- ({ [(4-bromobenzyl)oxy]carbonyl}amino)propanoic acid,
(2S)-3- { [4-(2- { [amino(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino } -2- ({ [(4-fluorobenzyl)oxy]carbonyl}amino)propanoic acid,
(2S)-3- { [4-(2- { [arnino(iιruno)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino J-2- ( { [(2-bromobenzyl)oxy]carbonyl } amino)propanoic acid,
(2S)-3-{ [4-(2-{[amho(imko)methyl]ambo}ethoxy)-2-hydroxybenzoyl]arninoJ-2- [({ [4-(trifluoromethyl)benzyl]oxy}carbonyl)amino]propanoic acid,
(2S)-3-{[4-(2-{[ammo(imino)methyl]amino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- [(2-toluidinocarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(immo)methyl]amino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(2-methoxyanilino)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [ammo(irnino)methyl]amino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- {[(2-chloroanilino)carbonyl] amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [am o(imino)methyl]aminoJethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(2-bromoarιilino)carbonyl] amino Jpropanoic acid,
(2S)-3- { [4-(2- { [amino(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino J -2- { [([1,1 '-biphenyl]-2-ylamino)carbonyl] amino } propanoic acid,
(2S)-3-{ [4-(2-{ [arrιώo(imino)methyl]amino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- [(4-toluidinocarbonyl)amino]propanoic acid,
(2S)-3-{[4-(2-{ [amino(imino)methyl]arrιino}ethoxy)-2-hydroxytenzoyl]aminoJ-2- ({ [4-(trifluoromethoxy)amino]carbonyl}amino)propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imho)methyl]amho}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(4-cMoroanilino)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [ammo(iιτιino)methyl]amij o}ethoxy)-2-hydroxyberιzoyl]amino}-2- { [(4-fluoroanilino)carbonyl] amino Jpropanoic acid,
(2,S)-2-{ [(4-acetylanilino)carbonyl]amino}-3-{ [4-(2-{ [amino(imino)methyl]aminoJ- ethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid,
(2S)-3-{ [4-(2- { [anτmo(inιino)methyl] amino }ethoxy)-2-hydroxybenzoyl] amino J-2- { [(cyclohexylamino)carbonyl] amino } propanoic acid -20-
(2S)-3- { [4-(2- { [amino(iιnώo)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino } -2- { [( l-naphthylamino)carbonyl] amino Jpropanoic acid,
(2S)-3- { [4-(2- { [amino(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino J -2- { [(benzylamino)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl] amino }ethoxy)-2-hydroxybenzoyl]amino J-2- ({ [(2-phenylethyl)amino]carbonyl}amino)propanoic acid,
(2S)-3-{[4-(2-{ [amino(imho)methyl]an ho}ethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(octylarnino)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(4-methoxyanilino)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [arnino(imho)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- [(anilinocarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{[aπιino(inτino)methyl]an±ιo}ethoxy)-2-hydroxybenzoyl]amino}-2- (isobutyrylamino)propanoic acid,
(2S)-3-{[4-(2-{ [amino(imino)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- (butyrylamino)propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]anιino}ethoxy)-2-hydroxybenzoyl]amjrιo J-2- (hexanoylamino)propanoic acid,
(2S)-3-{ [4-(2-{ [amino(immo)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- (pentanoylamino)propanoic acid,
(2S)-3- { [4-(2- { [amiιιo(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2- [(3,3-dimethylbutanoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]ammo}ethoxy)-2-hydroxyber^oyl]amino}-2- { [(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino Jpropanoic acid,
(2S)-2-{ [2-(l-adamantyl)acetyl]amino}-3-{ [4-(2-{ [amino(imino)methyl]- amino }ethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]amho}ethoxy)-2-hydroxyberιzoyl]amino}-2- (pent-4-ynoylamino)propanoic acid,
(2S)-3-{ [4-(2-{ [amino(inτjjιo)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- [(cyclohexylcarbonyl)amino]propanoic acid, -21-
(2S)-3- { [4-(2- { [amino(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2-[(2- phenylacetyl)amino]propanoic acid,
(2S)-3- { [4-(2- { [amino(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino } -2-[(3- " phenylpropanoyl)amino]propanoic acid,
(2S)-3- { [4-(2- { [amino(imino)methyl]amino Jethoxy)-2-hydroxybenzoyl]amino } -2-[(2- cyclohexylacetyl)amino]propanoic acid,
(2S)-3-{[4-(2-{ [amino(immo)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- { [(E)-3-phenylprop-2-enoyl] amino Jpropanoic acid,
(2S)-3-{[4-(2-{ [arnino(imino)methyl]anιmo}ethoxy)-2-hydroxybenzoyl]amino }-2-[(2- chlorobenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [ambo(imino)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2-[(2- methylbenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]anιko}ethoxy)-2-hydroxybenzoyl]amirιo}-2-[(2- methoxybenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]arrιmo }ethoxy)-2-hydroxybenzoyl]amirιo}-2-[(4- chlorobenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{[amino(imino)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- methylbenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino }-2-[(4- methoxybenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [ammo(imino)methyl]ammo}ethoxy)-2-hydroxybenzoyl]aminoJ-2- [(pyridin-3-ylcarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]arrιino}ethoxy)-2-hydroxybenzoyl]aιnino}-2- (isonicotinoylamino)propanoic acid,
(2S)-3- { [4-(2- { [amino(irnino)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- [(2,5-dimethyl-3-mroyl)amino]propanoic acid,
(2S)-3-{[4-(2-{[amino(imino)methyl]amho}ethoxy)-2-hydroxyber^oyl]amino}-2-[(2- bromobenzoyl)amino]propanoic acid,
(2S)-3-{[4-(2-{[amino(iιrιmo)methyl]ammo}ethoxy)-2-hydroxyberιzoyl]aminoJ-2-[(4- bromobenzoyl)amino]propanoic acid, -22-
(2S)-3-{ [4-(2-{ [amino(imino)methyl]ammoJethoxy)-2-hydroxybenzoyl]amino}-2- [(2,3-dimethylbenzoyl)amino]propanoic acid,
(2S)-3- { [4-(2- { [amino(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2- [(3-chlorobenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [amino(imino)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- (benzoylamino)propanoic acid,
(2S)-3-{[4-(2-{[amino(imino)methyl]an ino}ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- ethylbenzoyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [arnmo(imino)methyl]aπιino }ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- butoxybenzoyl) amino] propano ic acid,
(2S)-3- { [4-(2- { [(benzylamino)carbonyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- { [(benzyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [(benzylarnino)carbonyl]amino }ethoxy)-2-hydroxybenzoyl]aminoJ-2- [(methoxycarbonyl)arnino]propanoic acid,
(2S)-3-{ [4-(2-{ [(benzylamino)carbonyl]arnino}ethoxy)-2-hydroxybenzoyl]amino}-2- [(ethoxycarbonyl)amino]propanoic acid,
(2S)-3-{ [4-(2-{ [(berιzylamino)carbonyl]ammo}ethoxy)-2-hydroxyber zoyl]aminoJ-2- [(propoxycarbonyl)amino]propanoic acid,
(2S)-3- { [4-(2- { [(benzylamino)carbonyl]amino }ethoxy)-2-hydroxybenzoyl]amino J -2- [(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2- { [(allyloxy)carbonyl]amino } -3- { [4-(2- { [(benzylanτino)carbonyl]amino } - ethoxy)-2-hydroxybenzoyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [(benzylamino)carbonyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- { [(but-3-enyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3- { [4-(2- { [(benzylamino)carbonyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2- { [(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3-{ [4-(2-{ [(benzylamino)carbonyl] amino }ethoxy)-2-hydroxybenzoyl] amino J -2- { [(hexyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3- { [4-(2- { [(benzylammo)carbonyljamino J ethoxy)-2-hydroxybenzoyl] amino J -2- { [(octyloxy)carbonyl]amino Jpropanoic acid, -23-
(2S)-3- { [4-(2- { [(benzylanτino)carbonyl]arnino }ethoxy)-2-hydroxybenzoyl]amino } -2- { [(neopentyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3- { [4-(2- { [(benzylamino)carbonyl] amino }ethoxy)-2-hydroxybenzoyl]amino J -2- { [(2,2, 2-trichloroethoxy)carbonyl]amino Jpropanoic acid,
(2S)-3-{[4-(2-{ [(benzylarnmo)carbonyl]amko}ethoxy)-2-hydroxyberrzoyl]amino}-2- [(butoxycarbonyl)amino]ρropanoic acid,
(2S)-3-{ [4-(2-{ [(benzylammo)carbonyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- [(isobutoxycarbonyl)aminojpropanoic acid,
(2S)-2- { [(benzyloxy)carbonyl] amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)amino]carbonyl}amino)ethoxy]benzoylJamino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonyl J amino)ethoxy]- benzoylJamino)-2-[(methoxycarbonyl)amino]propanoic acid,
(2S)-2-[(ethoxycarbonyl)amino]-3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)amho]carbonylJamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonylJ amino)- ethoxy]benzoylJamino)-2-[(propoxycarbonyl)arnino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonyl J amino)- ethoxy]benzoylJamino)-2-[(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2- { [(aUyloxy)carbonyljamino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)amho]carbonylJamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-{ [(but-3-enyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-({[(pyridin-3- ylmethyl)aπιino]carbonyl}arrLino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonyl } amino)- ethoxyjbenzoyl J amino)-2- { [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid,
(2S)-2- { [(hexyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)amino]carbonyl}ammo)ethoxy]berιzoyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-({ [(pyridin-3-ylmethyl)amino]carbonyl}amino)- ethoxy]benzoylJamino)-2-{ [(octyloxy)carbonyl]amino Jpropanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonylJ amino)- ethoxy]benzoylJamino)-2-{ [(neopentyloxy)carbonyl] amino Jpropanoic acid, -24-
(2S)-3-({2-hydroxy-4-[2-({ [(pyridin-3-ylmethyl)arnmo]carbonyl}amino)ethoxy]- benzoyl}amino)-2-{ [(2, 2,2-trichloroethoxy)carbonyl]arnino Jpropanoic acid,
(2S)-2-[(butoxycarbonyl)ammo]-3-({2-hydroxy-4-[2-({ [(pyridin-3-ylmethyl)amino]- carbonyl}amino)ethoxy]benzoyljamino)propanoic acid,
(2S)-3-( { 2-hydroxy-4- [2-( { [(pyridin-3-ylmethyl)amino]carbonyl J amino)- ethoxy]benzoyl}arrιino)-2-[(isobutoxycarbonyl)amino]propanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]amino J-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)amino]carbonyl}amino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl)amino]carbonyl } arnino)- ethoxy]benzoylJamino)-2-[(methoxycarbonyl)amino]propanoic acid,
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)amino]carbonyl } amino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl)amino]carbonylJ arnino)- ethoxy]benzoyl}amino)-2-[(propoxycarbonyl)amino]propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl)amino]carbonyl } amino)- ethoxy]benzoyl}amino)-2-[(isopropoxycarbonyl)amino]propanoic acid,
(2S)-2-{ [(aUyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)amino]carbonyl } amino)ethoxy]benzoyl } amino)propanoic acid,
(2S)-2- { [(but-3-enyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)aιrιino]carbonyl}amino)ethoxy]berιzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl)amino]carbonyl J amino)- ethoxy]benzoyl}amino)-2-{[(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid,
(2S)-2- { [(hexyloxy)carbonyl] amino J -3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)amino]carbonylJamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-({ [(pyridm-4-ylmethyl)amino]carbonylJ amino)- ethoxy]benzoylJamino)-2-{ [(octyloxy)carbonyl] amino Jpropanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl) amino] carbonyl} amino)- ethoxy]benzoyl}amino)-2-{ [(neopentyloxy)carbonyl]arnino Jpropanoic acid,
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridm-4-ylmethyl)amino]carbonyl } amino)- ethoxy]benzoyl}amino)-2-{ [(2,2,2-trichloroethoxy)carbonyl] amino Jpropanoic acid, -25-
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)arnmo]carbonylJamino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-3-({2-hydroxy-4-[2-({ [(pyridin-4-ylmethyl)amino]carbonyl}amino)- ethoxy]benzoyl}amino)-2-[(isobutoxycarbonyl)amino]propanoic acid,
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({ [(4-methylbenzyl)- amino]carbonylJammo)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-({[(4-methoxybenzyl)- arnino]carbonylJarrιmo)ethoxy]berιzoyl}amino)propanoic acid,
(2S)-2- { [(benzyloxy)carbonyl] amino } -3-( { 4- [2-( { [(4-chlorobenzyl)amino]carbonyl } - arrιino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]aminoJ-3-[(4-{2-[({ [4-(dimethylarnino)benzyl]aminoJ- carbonyl)amino]ethoxyJ-2-hydroxybenzoyl)amino]propanoic acid,
(2S)-3-[(4- { 2-[( { [4-(arninosulfonyl)benzyl] amino } carbonyl)amino]ethoxy J-2- hydroxybenzoyl)amino]-2-{ [(benzyloxy)carbonyl]amino Jpropanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]amino}-3-[(2-hydroxy-4-{2-[({ [4-(trifluoromethoxy)- benzyl]amino Jcarbonyl)amko]ethoxyJbenzoyl)amino]propanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]amino}-3-({4-[2-({ [(2-chlorobenzyl)amino]carbonylJ- amino)ethoxy]-2-hydroxybenzoylJ amino)propanoic acid,
(2S)-2- { [(benzyloxy)carbonyl] amino }-3-( { 2-hydroxy-4-[2-( { [(2-methylbenzyl)- amino]carbonyl}amino)ethoxy]benzoylJamino)propanoic acid,
(2S)-2-{ [(berιzyloxy)carbonyl]amino}-3-({4-[2-({ [(2-bromobenzyl)amino]- carbonylJamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]amho}-3-({4-[2-({ [(2,4-dichlorobenzyl)amino]- carbonyl }arrιino)ethoxy]-2-hydroxybenzoyl}arnino)propanoic acid,
(2S)-3-({4-[2-({ [(2-aminobenzyl)amho]carbonyl}arnino)ethoxy]-2-hydroxybenzoyl}- amino)-2-{ [(benzyloxy)carbonyl]amino Jpropanoic acid,
(2S)-2-{ [(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({ [(pyridin-2-ylmethyl)- aιmno]carbonyl}amino)ethoxy]benzoyl}amino)propanoic acid,
(2S)-2-Benzenesulfonylamino-3-(2-hydroxy-4-[3-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)-propoxy]-benzoylamino)-propionic acid, -26-
(2S)-2-Benzenesulfonylamino-3- { 2-hydroxy-4-[2-( 1 ,4,5.6-tetrahydro- pyrir din-2-ylamino)-ethoxy]-benzoylamino J-propionic acid tert-butyl ester,
(2S)-2-Benzenesulfonylamino-3-{2-hydroxy-5-[4-(pyrimidin-2-ylamino)- butoxy]-benzoylamino J-propionic acid,
3- { 2-Hydroxy-5-[3-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)-propoxyl- benzoylamino)-3-phenyl-propionic acid ethyl ester,
(2S)-2-Benzenesulfonylamino-3- { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyriιrύdin-2-ylamino)-ethoxy]-benzoylamino J-propionic acid 2-(2-tert-butoxy- carbonylamino-ethoxy)-ethyl ester,
(2S)-2-Benzenesulfonylamino-3- { 2-hydroxy-5-[4-( 1 ,4,5,6- tetrahydropyrintidh-2-ylamino)-butoxy]-benzoylamino J-propionic acid ethyl ester,
(2S)-2-Benzenesulfonylammo-3-{2-hydroxy-4-[3-(pyrimidin-2-ylamino)- propoxy] -benzoylamino } -propionic acid,
3-{2-Hydroxy-5-[3-(pyrimid -2-ylamino)-propoxy]-benzoylamino}-3-phenyl- propionic acid,
(2S)-2-{Adamantan-l-yloxycarbonylamino)-3-{2-hydroxy-4-[2-( 1,4.5,6- tetrahydro-pyrimidin-2-ylamino)-ethoxy]-benzoylamino)-propionic acid,
(2S)-2-Benzenesulfonylamino-3-(2-hydroxy-4-[3-( 1,4,5, 6-tetrahydropyrimidin- 2-ylamino)-propoxy]-benzoylarnino)-propionic acid ethyl ester,
3-{2-Hydroxy-5-[3-(pyrimidin-2-ylambo)-propoxy)-benzoylamino)-3-phenyl- propionic acid ethyl ester,
(2S)-2-(Adamantan- 1 -ylmethoxycarbonylamino)-3- { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydro-pyrimidm-2-ylamino)-ethoxyl]-benzoylamino J-propionic acid,
(2S)-2-Benzenesulfonylamino-3-{2-hydroxy-4-[2-( 1,4,5, 6-tetrahydro- pyrirrύdin-2-ylamino)-ethoxy]-benzoylamino J-propionic acid isopropyl ester,
(2S)-2-tert-Butoxycarbonylamino-3- { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)-ethoxy]-benzoylarnino J-propionic acid,
(2S)-2-Benzenesulfonylamino-3- { 2-hydroxy-5- [4-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylaιrιino)-butoxy]-benzoylamino J-propionic acid, -27-
2(S)-Benzenesulfonylarnko-3-[2-hydroxy-4-(2-pyrimidh-2-ylamino)ethoxy]- benzoylaminojpropionic acid ethyl ester,
2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidm-2-ylamino)ethoxy]- benzoylaminojpropionic acid, 2(S)-Benzenesulfonylamino-3-[2-hydroxy- 4-[2-(3,4,5,6-tetrahydropyrimidin-
2-ylamino)ethoxy]benzoylamino]propionic acid hydrochloride,
2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylamino)ethoxy]- benzoylaminojpropionic acid ethyl ester hydrochloride,
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoylamino]propionic acid ethyl ester hydrochloride,
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoylamino]propionic acid hydrochloride,
3-[4-(2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoic acid ethyl ester hydrochloride, 3-[4-(2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoic acid hydrochloride,
3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoylamino]-3-pyridin-3- yl-propanoic acid ethyl ester,
3-[2-hydroxy-4-[2-(pyrirm^in-2-ylamino)-ethoxy]benzoylamino]-3-pyridin-3- yl:propanoic acid,
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]benzoyl- amino]-3-pyridin-3-yl-propanoic acid ethyl ester dihydro-chloride,
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]benzoyl- amino]-3-pyridin-3-yl-propanoic acid, 3-[4-(2-Guanidino-ethoxy)-2-hydroxybenzoyl-amino]-3- pyridin-3-yl-propanoic acid ethyl ester dihydrochloride, -28-
3-[4-(2-Guanidino-ethoxy)-2-hydroxybenzoyl-amino]-3- pyridin-3-yl-propanoic acid,
3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoyl-amino]-3-phenyl- propanoic acid ethyl ester, 3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoyl-amino]-3-phenyl- propanoic acid hydrochloride,
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]- benzoylamino]-3-phenyl-propanoic acid ethyl ester hydrochloride,
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]- benzoylamino]-3-phenyl-propanoic acid,
3-[2-hydroxy-5-[3-(pyrimidin-2-ylamino)-propoxy]-benzoylamino]-3-phenyl- propanoic acid ethyl ester,
3-[2-hydroxy-5-[3-(pyrimidin-2-ylamino)-propoxy]-benzoylamino]-3-phenyl- propanoic acid,
3-[2-hydroxy-5-[3-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)propoxy]- benzoylamino]-3-phenyl-propanoic acid ethyl ester hydrochloride,
3-[2-hydroxy-5-[3-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)propoxy]- benzoylamino]-3-phenyl-ρropanoic,
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]-benzoylamino]propionic acid ethyl ester hydro-chloride,
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]-benzoylamino]propionic acid methyl ester,
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]-benzoylamino]propionic acid, 2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-methyl-pyrimidin-2-ylamino)- ethoxy]benzoylamino]propionic acid, and -29-
2-Amino-3-[2-hydroxy-4-[2-(3,4,5,6-tetra-hydropyrimidin-2-ylamino)ethoxy]- benzoylamino]propionic acid dihydrochloride, or pharmaceutical salts thereof.
It is understood that the definition of compounds of Formula (I) include racemates, (racemic mixtures) and individual enantiomers or diastereomers. All asymmetric forms, individual isomers and combinations thereof are within the scope of the present invention.
Optically active isomers may be prepared, for example by resolving the racemic mixtures. The resolution can be carried out by methods known to those skilled in the art such as in the presence of resolving agent, by chiral chromatography, or combinations thereof.
Compounds of Formula I are useful in methods of selectively inhibiting or antagonizing an integrin receptor such as avb3. More specifically, methods of the present invention include but are not limited to methods of inhibiting cancer (tumor metastasis, tumorgenesis/tumor growth), angiogenesis (as in cancer, diabetic retinopathy, rheumatoid arthritis), restenosis (following balloon angioplasty or stent implantation), inflammation (as in rheumatoid arthritis, psoriasis), bone diseases (osteopenia induced by bone matastases, immobilization and glucocortocoid treatment, periodontal disease, hyperparathyroidism and rheumatoid arthritis), and viral infection by administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
The compounds of this invention are prepared in accordance with the solid phase combinatorial library synthesis methods or solution phase synthesis methods.
Generally, to prepare the compounds via combinatorial methodology, the starting acylresorcinol ester is condensed with an alkylene chain bearing a terminal primary amino group which is suitably blocked/protected. Methods for this condensation include, but are not limited to selective alkylation of one (the non-H- bonded hydroxyl group) of the resorcinol hydroxy groups, using standard procedures such as the Gabriel synthesis (Angew Chem Int. Ed. Engl. 7, 1968, 919-930 (1968) or Mitsunobu reaction (Synthesis, 1981,1-28). After conventional deprotection of the N- -30-
terminus and the acid, the amine 2-2 was protected as fluorenylmethyloxy carbamate (Fmoc) 2-6. On the other hand, in the case of G = pyrimidine 2-3, the primary amine 2-2 was activated with trimethylsilyl chloride in the presence of 2-bromopyrimidine in refluxing (anhydrous) 1, 4-dioxane. The carboxylic acid 2-3 was activated as pentafluorophenyl ester 2-5. The carboxylic acid 2-3 was also hydrogenated under catalytic hydrogenation conditions to obtain the tetrahydropyrimidine derivative 2-4.
Orthogonally protected 2,3-diamino propionic acid 1-1 was used for carboxylic acid terminus and was immobilized on polymer support with linkers like but not limited to Wang. The 2-amino group of the 2,3-diaminopropionic acid was Fmoc protected, while the 3- amino group was dde (4,4-dimethyl-2,6-dioxocyclohex-l- ylideneethyl) protected. The 2-amino group was deprotected and further derivatized to 1-4, 1-5, 1-6 and 1-7 using various acylating agents including but not limitted to chloroformates, isocyanates, sulfonyl chlorides, carboxylic acids/chlorides. The 3- amino group was deprotected to give 1-8, 1-9, 1-10 and 1-11 and coupled with the resorcinol acid derivatives 2-4, 2-5 or 2-6.
N-terminus derivatives such as dihydroimidazole 5-3, azepine 5-4, guanidine 6- 3, and ureas 6-4 were prepared from common primary amine intermediate 4-2.
Schemes 1-6, below, demonstrate the solid phase synthesis practice of this invention as it relates to the examples specified. Detailed synthetic procedures for representative compounds of this invention follow.
Throughout the Examples data for LC (@254 nM) were obtained under the following conditions. HP 1100, 23oC, lOμL injected; Column: YMC-ODS-A 4.6 x 50 5μ; Gradient A: 0.05% TFA/Water, B: 0.05% TFA/Acetonitrile Time 0 & 1 min: 98%A &2%B; 7 min: 10%A & 90%B; 8 min: 10%A & 90%B; 8.9 min: 98%A & 2%B; Post time 1 min; Flow rate 2.5 mL min.; Detection: 215 and 254 nm, DAD. -31-
Scheme 1 o
OH OH
Figure imgf000033_0001
NHFmoc 1-1
HOBT, HBTU DIEA, DMF
Figure imgf000033_0002
NHFmoc dde
1-2
Figure imgf000033_0003
20% Piperidine DMF
(CH3)3CCH2OCOCI O
P COOH, DIC
Et3N, CH2CI2 dde-
'O' DMAP, DMF
NH,
♦ o T O
1-3 dde- dde
N PhNCO „ H r ^Q « Phso2cι Et3N Et3N HN "y^-
1-4 1-7
O
O O r Ph dde... dde.
O'
2% NH2NH2 DMF HN^O HN„ so2 ^o 2% NH2NH2 DMF
1 -5 NHPh 1-6 Ph
2% NH2NH2 2% NH2NH2 O DMF DMF
H2N' r ^O H,N
O
HNγ HN^O D""0
H,N o Ph
HN^ "O O H,N
H , o^O
1-8 SO, 1-11
NHPh Ph 1-9 1-10 -32-
2(S)-(Fluorenylmethyloxycarbonyl)amino-3-(4,4-dimethyl-2,6dioxocylohex-l- ylideneethvDaminopropionic Acid on Wang Resin (1-2)
Wang resin (Wang, S. J. Am. Chem. Soc. 1973, 95, 1328-1333) (Advanced ChemTech 200-400 mesh, 1% crosslinked; loading: 0.92 mmol/g; 5g, 4.6 mmol) was swollen in N,N-dimethylformamide (DMF) (20 mL). A solution of N-a-fmoc-N-b-1- (4,4-dimethyl-2,6-dioxocyclohex-l-ylidene)ethyl-L-diaminopropionic acid 1-1 (Fmoc- Dpr(Dde)-OH) (Nova Biochem) (4.513g; 9.2 mmol) in DMF (30mL) was treated with N-hydroxybenzotriazole (HOBT) (1.242g; 9.2 mmol), 2-(lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (3.487g; 9.2 mmol) and N,N-diisopropylethylamine (DIEA) (3.2 mL; 18.4 mmol) and added to the resin. The mixture was shaken at room temperature for 8 h. The mixture was filtered and the resin was washed with DMF (3 x 40mL), methanol (MeOH) (3 x 40mL) and dichloromethane (DCM) (3x 40mL). The resin was dried in vacuo to give 6.956g. Resin Loading: 0.8 mmol/g.
2-Amho-3-(4,4-dimethyl-2.6-dioxocylohex-l-ykdeneethyl)aminopropionic Acid on Wang Resin (1-3)
The resin 1-2 (6.956 g) in DMF was treated with 20% piperidine in DMF (40mL) for 10 min and filtered. Another 40mL portion of 20% piperidine in DMF was added to the resin and shaken at room temperature for 20 min. The resin was filtered and washed with DMF (3 x 40mL), MeOH (3 x 40mL) and DCM (3 x 40mL). The resin (1-3) was dried in vacuo.
2(S)-(2,2-Dimethyl-propoxycarbonylarnino)-3-(4,4-dimethyl-2,6-dioxocylohex-l- ylideneethyDamino-propionic acid on Wang Resin (1-4)
The resin 1-3 (925 mg; 0.75 mmol) was swollen in dichloromethane and treated with diisopropylethylamine (969 mg; 1.3 mL; 7.5 mmol) followed by neopentyl -33-
chloroformate (451.8 mg; 3mmol). The reaction mixture was shaken at room temperature using orbital shaker (Thermolyne RotoMix Type 50800) for 18 h. The mixture were filtered and the resin was washed with dichloromethane (4 x 4 mL),_ methanol (4 x mL) and dichloromethane (2 x 4 mL). The resins was dried under vacuum. A sample of the was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
A sample of the resin was removed and subjected to cleavage with dichloromethane (0.5 mL) and trifluro acetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. The product was characterized by HPLC: 4.28 min (82% @ 220 nm); MS: 383 (M+H)+.
The above reaction conditions were applied for synthesis of urea 1-5 and sulfonamide 1-6, using phenyl isocyanate and phenyl sulfonyl chloride, respectively, in the place of neopentyl chloroformate.
A number of chloro formates, isocyanates and sulfonyl chlorides were used in the above reaction.
2(S)-benzoylamino-3-(4,4-dimethyl-2.6-dioxocylohex-l-yhdeneethyl)amino-propionic acid on Wang Resin (1-7)
The resin 1-3 (925 mg; 0.75 mmol) was washed with DMF to swell the resin. A solution of benzoic acid (183 mg; 1.5mmole) in DMF was mixed with diisopropylcarbodiimide (192 mg; 0.25 mmole), hydro xybenzotriazole (228 mg; 1.5 mmole) and dimethylaminopyridine (18 mg; 1.5 mmole) and the mixture was added to the resin. The reaction mixture was shaken at room temperature for I6h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol -34-
(4 x mL) and dichloromethane (4 x 4 mL). The resulting resin 1-7 was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described^ above was repeated.
Alternately, carboxylic acids were used in the above reaction in the place of benzoic acid.
3-Amino-2(S)-(2.2-dimethyl-propoxycarbonylamino)-propionic acid on Wang Resin (1-8)
The resin 1-4 was shaken with a solution of 2% hydrazine in dimethylformamide (3mL) for 5 min. at room temperature. The reaction mixture was filtered and an additional 3 mL of a solution of 2% hydrazine in dimethylformamide was added and the reaction mixture was shaken at room temperature for 5 min. The mixture was filtered and the resin was washed with dimethylformamide (4 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test for the presence of free amine (resin turns blue).
A sample of the resin was removed and subjected to cleavage with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. The product was characterized by HPLC: 4.686 min (78% @ 220 nm); MS m/z 219 (M+H)+.
Resin bound compounds 1-5, 1-6 and 1-7 were subjected to similar deprotection condition to afford the free amines 1-9, 1-10 and 1-11 respectively. -35-
Scheme 2
OH O
BocHN, + OH
Figure imgf000037_0001
Aldrich Aldrich
DEAD Ph3P, THF
OH O
^V "OMe
BocHN.
2-1
1. KOH 2. HCl
OH O
OH
HCl. H2N.
Figure imgf000037_0002
H O' ^ * N^N. ^
Figure imgf000037_0003
N
2-4 2-5
Methyl 4-[2-N-(t-butoxycarbonyl)ethoχy]-2-hvdroxy benzoate (2-1)
Methyl 2, 4-dihydroxy benzoate (14.5g, Aldrich), 2-(N-t-butoxycarbonyl)ethanol
(13.9g, Aldrich) and triphenyl phosphine (22.6g, Aldrich) were combined in 350 mL of THF and cooled in ice under N2 atmosphere. Diethyl diazodicarboxylate (DEAD, -36-
15g, Aldrich) was added, the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 15h. The solvent was removed on a rotary evaporator and the residue chromatographed on silica gel (300g, Merck silica 60), elution with CH2C12 to give 18g of methyl 4-[2-N-(t-butoxycarbonyl)ethoxy]-2-hydroxy benzoate, as a viscous oil. NMR (300 MHz, CDC13) δ 11.0 (s, 1 H), 9.5 (d, J = 8Hz, IH), 6.4 (m, 2H), 5.0 (broad, IH), 4.0 (t, J = 5Hz, 2H), 3.91 (s, 3H), 3.54 (m, 2H), 1.45 (s, 9H), MS (+ESI) m/z 334 (M+Na)+.
4-(2-Aminoethoxy)-2-hydroxybenzoic acid, hydrochloride (2-2)
Ester 2-1 (7.2g) was treated with 5eq. KOH (dissolved in rninimum amount of water and equal volume of 1, 4-dioxane) at room temperature until TLC indicated complete absence of starting material (3-12h). The reaction mixture was acidified (pH = 6) with the addition of IN HCl solution and extracted with ethyl acetate. The extract was washed with saturated aqueous brine solution, dried over MgSO4, filtered and concentrated on the rotary evaporator. The crude product (5.34g) was recrystallized from ether, then dissolved in 1, 4-dioxane and treated with an excess of anhydrous HCl (4M in dioxane, Aldrich). The mixture was allowed to stand at ambient temperature for 24h. Volatile materials were removed in vacuo on the rotary evaporator to give 2-2 as a hydroscopic off-white solid. NMR (400 MHz, DMSO-d6) 6 13.6 (broad, IH), 11.6 (broad, IH), 8.3 (broad, 3H), 7.7 (d, J = 9 Hz, 2H), 6.53 (m, 2H), 4.23 (t, J = 5Hz, 2H), 3.2 (s, broad, 2H).
2-Hvdroxy-4-[2-(pwimidine-2ylamino)ethoxy]benzoic acid (2-3)
A mixture of compound 2-2 (20g), diissopropylethylamine (DIPEA, 74 mL), trimethylsilylchloride (TMSC1, 21.6 mL) and 2-bromopyrimidine (Lancaster, 13.5g) were combined in 350 mL 1, 4-dioxane at room temperature, then brought to reflux under N2 atmosphere. After 2 days, an additional 12 mL trimethylsilyl chloride was added, and the mixture continued at reflux for an additional 2 days (until TLC showed -37-
no stating material remained). The reaction mixture was cooled to ambient temperature, concentrated to dryness in vacuo on a rotary evaporator and the residue suspended in water. The heterogeneous mixture was refluxed briefly, allowed to cool to room temperature, the product collected on a vacuum filter and air dried to give 15.3g of 2-3, as a tan powder. NMR (400 MHz, DMSO-d6) δ 12 (very broad, 2H) 8.3 (d, J = 5 Hz, 2H) 7.7 (d, J = 9Hz, IH), 7.28 (t, J = 6Hz, IH), 6.57 (t, J = 5Hz, IH), 6.49 (m, 2H), 4.13 (t, J = 6Hz, 2H). 3.62 (q, 2H); MS (+ESI) m/z 276 (M+H)+ ; IR (HBr) v (cm"1) 3275, 3000, 1660, 1625.
2-Hvdroxy-4-[2-(3,4,5,6-tetrahvdropyrimidm-2ylamino ethoxyl-benzoic acid (2-4).
Compound 2-3 (2g) was combined with 10% Pd/C (0.5g), acetic acid (100 mL) and concentrated hydrochloric acid (0.7 mL). The mixture was stirred at room temperature under an atmosphere of H2 (balloon) for 2 days. Celite was added and the mixture stirred for 0.5h, then filtered through a pad of celite with the aid of isopropanol. Volatile materials were removed on the rotary evaporator and the residue warmed with heptane (~0.5h, 100°C) followed by concentration in vacuo to give 2-4 as a tan foam. NMR (400 MHz, DMSO-d6) δ 12.9 (broad, 2H), 8.25 (s, broad, 2H), 7.85 (t, J = 6Hz, IH), 7.66 (d, J = 9 Hz, IH), 6.48 - 6.41 (m, 2H), 4.07 (t, J = 5Hz, 2H), 3.56 - 3.50 (m, 2H), 3.22 (m. 2H, overlapping with H2O peak), 1.79 (m, 2H); IR (KBr) n (cm"1) 3450 (broad); MS (+ESI) m/z 280 (M + H)+ .
2,3,4,5.6-Pentafluorophenyl 2-hydroxy-4-[2-(pyrimidine-2-ylamino)ethoxyl-benzoate (2-5)
Acid 2-3 (1.18g; 4.3 mmol) in dioxane (40 mL) was treated with DIEA (1.5 mL; 8.6 mmol) and cooled to 0°C. Pentafluorophenol (3.16g; 17.2 mmol) was added followed by dicyclohexyl carbodϋmide. The reaction mixture was allowed to warm to room temperature and stirred for additional 16 h. The solid precipitated was filtered off and the mother liquor was concentrated to dryness and the residue was purified using silica -38-
column chromatography, eluted with 50% ethyl acetate in hexane to give 1.01 g of 2- 5 as a white solid. NMR (300 MHz, CDC13) δ 10.0 (s, IH), 8.3 (d, J = 5 Hz, 2H) 8.0 (d, J = 9Hz, IH), 6.57 (t, J = 5Hz, IH), 6.49 (m, 2H), 5.5 (t, J = 3Hz, IH), 4.2 (t, J =_ 6Hz, 2H), 3.9 (q, 2H).
4-[(2-fluorenylmethyloxycarbonylamino)ethoxy1-2-hvdroxybenzoic acid (2-6)
The Amino acid 2-2 (1.864g; 8 mmol) was dissolved in 1: 1 acetone - water (50 mL) containing sodium carbonate (1.696g; 16 mmol). To the solution was added Fmoc- Osu (2.696 g; 8 mmol) in acetone (25 mL) dropwise at room temperature. The solution was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was dissolved in water and extracted with ether (2 x 50 mL). The aqueous layer was cooled in an ice bath and acidified with 6N HCl to pH 3. The solid obtained was filtered and washed with water and dried under vacuo (3.22g). NMR (300 MHz, DMSO-d6) δ 7.9 (d, 2H), 7.65-7.75 (m, 2H), 7.55 (t, 2H), 7.4 (t, 2H), 7.3 (t, 2H), 6.5 (m, 2H), 4.35 (d, 2H), 4.25 (t, IH), 4.05 (t, 2H), 3.4 (t, 2H).
-39-
Scheme 3 o
H,N
HN^ JO.
OH O O OH O
Figure imgf000041_0001
OH O
OH O O
H ^NrN.
Figure imgf000041_0002
H
HN ^Q
Figure imgf000041_0003
^Q
HN.
NH 3-1 Ύ°^ H N 3-3 τ oυ>-ττ
TFA-CH2CI2(1:1) TFA-CH2CI2(1:1)
OH O
OH O o
OH
^N^N. H Ό
Figure imgf000041_0004
H ^O. NγN.
Figure imgf000041_0005
HN
O ^NH 3-2 YU^ ^Ov
N 3-4 O T
-40-
Example l (2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl}amino)-2-{[(neopentyloxy)carbonyl]amino}propanoic acid (3-2)
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2-ylamino ethoxylbenzoyl }- amino)-2-([(neopentyloxy)carbonyll amino Jpropanoic acid on Wang Resin (3-1)
The resin 1-8 (lOOmg) was washed with DMF to swell the resin. A solution of 2-hydroxy-4-[2-(3,4,5,6-tetrahydropyrimidh-2-ylamino)ethoxy]-benzoic acid 2-4 (70 mg; 0.25mmole) in DMF was mixed with diisopropylcarbodiimide (32 mg; 0.25 mmole), hydroxybenzotriazole (38mg; 0.25 mmole) and dimethylaminopyridine (3 mg; 0.025 mmole) and the mixture was added to the resin. The reaction mixture was shaken at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resulting resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
The resin 3-1 was treated with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 3-2 was purified via preparative HPLC. NMR (400MHz, MeOH-d4) δ 7.7 (d, J = 7 Hz, IH), 6.5 (m, 2H), 4.45 (q, IH), 4.1 (t, 2H), 3.8 - 3.65 (m, 4H), 3.55 (t, 2H), 3.35 (t, 4H), 2.0 (m, 2H), 0.9 (s, 9H).
HR-MS FAB m/z for C22H33N5O7 calcd. 480.2458 (M++l), obsd. 480.2431. -41-
The following compounds were synthesized as described in the above Scheme 3 (Path A), using various resin bound carbamates in the place of (1-8). These compounds were characterized using LC and MS as shown in Table 1.
Example 2
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyriιnidh-2-ylamino)ethoxy]benzoyl}- aιτιino)-2-[(methoxycarbonyl)amino]propanoic acid.
Example 3
(2S)-2-[(ethoxycarbonyl)amino]-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid.
Example 4
(2S)-3-( { 2-hydroxy-4- [2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - amino)-2-[(propoxycarbonyl)amino]propanoic acid.
Example 5
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(isopropoxycarbonyl)amino]propanoic acid.
Example 6
(2S)-2- { [(allyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin- 2-ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 7
(2S)-2-{ [(but-3-enyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid.
Example 8
(2S)-2- { [(hexyloxy)carbonyl] amino } -3-( {2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylanτino)ethoxy]benzoyl} amino)propanoic acid.
Example 9
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidm-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(octyloxy)carbonyl] amino Jpropanoic acid. -42-
Example 10
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyriιmdin-2-ylamino)ethoxy]- benzoyl}arnino)-2-{[(2,2,2-tricMoroethoxy)carbonyl]amino Jpropanoic acid.
Example 11
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidk-2-ylamino)ethoxy]- benzoyl}ammo)-2-[(butoxycarbonyl)amino]propanoic acid.
Example 12
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidk-2-ylamino)ethoxy]benzoyl } • amino)-2-[(isobutoxycarbonyl)amino]propanoic acid.
Example 13
(2S)-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyriιmdm-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid.
Example 14
(2S)-2- { [(benzyloxy)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydropyriiradin-2-ylamu o)ethoxy]benzoylJamino)propanoic acid.
-43-
Table 1
OH 0
H OH Nγ .
Figure imgf000045_0001
HNYa"9
NH O
Ex. R9 LC @ 254 (M+H) + Ex. R9 LC @ 254 (M+H)+ nm nm
2 Methyl 2.92 min 424 8 n-Hexyl 4.12 min 494
3 Ethyl 3.09 min 438 9 n-Octyl 4.62 min 522
4 n-Propyl 3.30 min 452 1 (CH3)3CCH2 3.77 min 480
5 i-Propyl 3.28 min 452 10 (CC13)3CCH2 3.81 min 542
6 Allyl 3.21 min 450 1 1 n-Butyl 3.60 min 466
7 Homoallyl 3.46 min 463 12 i-Butyl 3.58 min 466
13 Propargyl 3.18 min 448 14 Benzyl 3.74 min 500
Figure imgf000045_0002
The following compounds were synthesized as described in the above Scheme 3, (Path A) using various resin linked ureas 1-9 in the place of carbamate (1-8). These compounds were characterized using LC and MS as shown in Table 2.
Example 15
(2S)-2-{ [(butylanώιo)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 16
(2S)-2- { [(hexylamώo)carbonyl]arnino J -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrirr dm-2-ylamino)ethoxy]benzoyl}amino)propanoic acid.
Example 17
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrirmdm-2-ylamino)ethoxy]benzoylJ- amino)-2- { [(octylaιrιino)carbonyl]amino Jpropanoic acid.
Example 18
(2S)-2- { [(allylamino)carbonyl] amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidm-2-ylamino)ethoxy]benzoylJamino)propanoic acid. -44-
Example 19
(2S)-2-{ [(l-adamantylammo)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6- tetrahydropyrirmdin-2-ylarnmo)ethoxy]benzoylJamino)propanoic acid.
Example 20
(2S)-2-[(arιilmocarbonyl)arnino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy] benzoyl Jamino)propanoic acid.
Example 21 (2S)-2- { [(cyclohexylamino)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoylJ amino)propanoic acid.
Example 22
(2S)-2- { [(benzylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5.6-tetrahydro- pyriιrύdin-2-ylamino)ethoxy]benzoylJamino)propanoic acid.
Example 23
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrirmdin-2-ylamino)ethoxy]benzoylJ- amino)-2-[(4-toluidinocarbonyl)amino]propanoic acid.
Example 24
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidm-2-ylamino)ethoxy]benzoylJ- arnino)-2-[(2-toluidinocarbonyl)amino]propanoic acid.
Example 25
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl }- amino)-2-{ [(2-methoxyanilino)carbonyl]amino Jpropanoic acid.
Example 26 (2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyriιnidin-2-ylamino)etho xy]benzoyl J- arruno)-2-{ [(4-methoxyariilino)carbonyl]amino Jpropanoic acid.
Example 27
(2S)-2- { [(2-chloroanilino)carbonyl] amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydropyrimidh-2-ylammo)ethoxy]benzoyl}amino)ρropanoic acid.
Example 28
(2S)-2- { [(2-bromoanilino)carbonyl] amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydropyrimidh-2-ylamino)ethoxy]benzoyl J amino)propanoic acid.
Example 29
(2S)-2-{ [([1,1 '-biphenyl]-2-ylamino)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydro pyrirnidin-2-ylamino)etho xy]benzoyl} amino)propanoic acid. -45-
Example 30
(2S)-2-{ [(4-cMoroaru ho)carbonyl]arnino}-3-({2-hydroxy-4-[2-(l, 4,5,6- tetrahydropyrirrύdin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid.
Example 31
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - am o)-2-{[(l-naphthylamino)carbonyl]amino Jpropanoic acid.
Example 32 (2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidh-2-ylamino)ethoxy]benzoylJ- amino)-2-({ [(2-phenylethyl)amino]carbonyl}amino)propanoic acid.
Table 2
OH O
Figure imgf000047_0001
M
H N^9 /NH 0
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 (M+Hf nm
15 H3C^ -'^ 3.30 min 465 24 cς 3.45 min 499
16 3.77 min 493 25 cc 3.50 min 515
17 -°^o 4.31 min 521 26 3.39 min 515
C»^3 ^
18 * ^ 3.02 min 449 27 cς 3.60 min 521
19 4.00 min 543 28 60 min 565
&- σ. 3.
20 σ 3.42 min 485 29 σ. 3.95 min 561
21 σ 3.45 min 491 30 3.79 min 521 X
22 c^ 3.43 min 499 31 cό 3.67 min 535
Figure imgf000047_0002
-46-
23 3.62 min 499 32 w^ ^^
Figure imgf000048_0001
cr 3.56 min 513
The following compounds were synthesized as described in the above Scheme 3, (Path A) using various resin linked amides 1-11 in the place of carbamate (1-8). These compounds were characterized using LC and MS as shown in Table 3. Example 33
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoylJ- arnώo)-2-(isobutyrylamino)propanoic acid.
Example 34 (2S)-2-(hexanoylamino)-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoylJ amino)propanoic acid.
Example 35
(2S)-3-({2-hydroxy-4-[2-( 1,4.5, 6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoylJ- amino)-2-(pentanoylamino)propanoic acid.
Example 36
(2S)-2-[(3,3-dimethylbutanoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidώ-2-ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 37
(2S)-2-[(cyclohexylcarbonyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-
2-ylamino)ethoxy]benzoyl}amino)propanoic acid.
Example 38
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidh-2-ylamino)ethoxy]benzoyl J - amino)-2-[(2-phenylacetyl)amino]propanoic acid.
Example 39 (2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidm-2-ylamino)ethoxy]benzoylJ- amino)-2-[(3-phenylpropanoyl)amino]propanoic acid.
Example 40
(2S)-2-[(2-cyclohexylacetyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin- 2-ylamino)ethoxy]benzoylJ amino )propanoic acid.
Example 41
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidh-2-ylamino)ethoxy]benzoylJ- amino)-2-{ [(E)-3-phenylprop-2-enoyl]arnino Jpropanoic acid. -47-
Example 42
(2S)-2-[(2-cWorobenzoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylarrιino)ethoxy]berιzoyl}amino)propanoic acid.
Example 43
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamho)ethoxy]benzoyl}ammo)-2-[(2-methylbenzoyl)amino]propanoic acid.
Example 44
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidk-2-ylamino)ethoxy]benzoylJ- amino)-2-[(2-methoxyberrzoyl)amino]propanoic acid.
Example 45 (2S)-2-[(4-cMorobenzoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 46
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrin idin-2-ylamino)ethoxy]benzoylJ- amino)-2-[(4-methylbenzoyl)amino]propanoic acid.
Example 47
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoylJ- amho)-2-[(4-methoxybenzoyl)amino]propanoic acid.
Example 48
(2S)-2-[(2,5-dimethyl-3-mroyl)amino]-3-({2-hydroxy-4-[2-(l,4,5.6-tetrahydro- pyrimidh-2-ylaιrιino)ethoxy]benzoyl } amino)propanoic acid.
Example 49
(2S)-2-[(2-bromobenzoyl)ammo]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl J amino)propanoic acid.
Example 50 (2S)-2-[(4-bromobenzoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 51
(2S)-2-[(2,3-dimethylbenzoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylaιτιho)ethoxy]benzoyl}amino)propanoic acid.
Example 52
(2S)-2-[(3-cWorobenzoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl J amino)propanoic acid. -48-
Table 3
OH 0
H NγN. H T OH
NH Υ 0
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
33 3.03 min 436 43 3.42 min 484
H3C ^CH3
34 H3C^^-^^~ 3.46 min 464 44 3.48 min 500
CC
35 HaC^-^^ 3.24 min 450 45 3.70 min 504
36 3.37 min 464 46 3.57 min 484
HaA^
37 σ 3.49 min 476 47 3.44 min 500
Hjpcr ^
38 c 3.35 min 484 48 H3C^C -CH3 3.59 min 488
39 3.54 min 498 49 cς 3.39 min 548
40 cr 3.62 min 490 50 3.76 min 548
&X-^
41 cr 3.66 min 496 51 3.58 min 498 cC
42 cς 3.36 min 504 52 3.70 min 504
Figure imgf000050_0001
. -49-
Example 53 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl}- amino)-2-{[(neopentyloxy)carbonyI]amino}propanoic acid (3-4)
(2S)-3-(f 2-hvdroxy-4-[2-(p irnidin-2-ylammo)ethoxylbenzoyl}amino)-2-
{ f (neopentyloxy)carbonyll amino jpropanoic acid on Wang Resin (3-3)
The resin 1-8 (lOOmg) was washed with DMF to swell the resin and was treated with a solution of 2,3,4,5,6-pentafluorophenyl 2-hydroxy-4-[2-(pyrimidine-2- ylamino)ethoxy]-benzoate 2-5 (110 mg; 0.25mmole) in DMF. The reaction mixture was shaken at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane
(4 x 4 mL). The resulting resin 3-3 was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
The resin 3-3 was treated with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 3-4 was purified via preparative
HPLC. 3.907 min (78% @ 220 nm); MS m/z 476 (M+H)+.
The following compounds were synthesized as described in the above Scheme 3 (Path
B), using various resin bound carbamates in the place of (1-8). These compounds were characterized using LC and MS as shown in Table 4.
Example 54 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylarnino)ethoxy]berιzoyl}aιnino)-2- [(phenoxycarbonyl)amino]propanoic acid.
Example 55
(2S)-2- { [(benzyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylarnmo)ethoxy]terizoyl}amino)propanoic acid.
Example 56
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2-
[(isobutoxycarbonyl)amino]propanoic acid. -50-
Example 57
(2S)-3-({2-hydroxy-4-[2-(pyriιr din-2-ylamino)ethoxy]benzoyl}amino)-2-{ [(4- methoxyphenoxy)carbonyl] amino Jpropanoic acid.
Example 58
(2S)-3-( { 2-hydroxy-4- [2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2- { [(octyloxy)carbonyl] amino Jpropanoic acid.
Example 59 (2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 60
(2S)-3-({2-hydroxy-4-[2-(pyrimidh-2-ylamino)ethoxy]benzoylJamino)-2-{ [(2.2,2- trichloroethoxy)carbonyl] amino Jpropanoic acid.
Example 61
(2S)-3-({2-hydroxy-4-[2-(pyriπύdώ-2-ylamino)ethoxy]benzoyl}amino)-2-({ [(4- nitrobenzyl)oxy]carbonylJamino)propanoic acid.
Example 62
(2S)-2-{ [(hexyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-(pyrimidώ-2-ylamino)- ethoxyjbenzoylj amino)propanoic acid.
Example 63
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]benzoyl J amino)-2- { [(prop-2- ynyloxy)carbonyl]amino Jpropanoic acid.
Example 64 (2S)-3-({2-hydroxy-4-[2-(pyrimidh-2-ylammo)ethoxy]benzoyl}amino)-2-{ [(4- methylphenoxy)carbonyl] amino Jpropanoic acid.
Example 65
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]benzoyl}amino)-2- [(methoxycarbonyl)amino]propanoic acid.
Example 66
(2S)-2-[(ethoxycarbonyl)amino]-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxy]benzoylJamino)propanoic acid.
Example 67
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylamho)ethoxy]benzoyl}amino)-2- [(propoxycarbonyl)amino]propanoic acid. O 99/52879
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Example 68
(2S)-3-({2-hydroxy-4-[2-(pyrimidk-2-ylarrLino)ethoxy]benzoylJamino)-2- [(isopropoxycarbonyl)amino]propanoic acid.
Example 69
(2S)-2- { [(allyloxy)carbonyl] amino J -3-( { 2-hydroxy-4- [2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid.
Example 70
(2S)-2- { [(but-3-enyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid.
Table 4
OH 0
H OH
Figure imgf000053_0001
HN αB N 0
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 n (M+H)+
54 Phenyl 3.77 min 481 62 n-Hexyl 4.26 min 490
55 Benzyl 3.88 min 495 63 Propargyl 3.30 min 444
56 i-Butyl 3.73 min 461 64 p-Me-Phenyl 3.94 v 496
57 p-OMe-phenyl 3.75 min 511 65 Methyl 3.06 v 420
58 Octyl 4.79 min 517 66 Ethyl 3.26 min 434
59 n-Butyl 3.77 min 462 67 n-Propyl 3.48 v 448
60 CC13CH2 3.94 min 538 68 i-Propyl 3.46 v 448
53 neopentyl 3.90 min 476 69 Allyl 3.40 min 446
61 p-N02-Benzyl 3.80 min 541 70 Homoallyl 3.58 min 460
Figure imgf000053_0002
The following compounds were synthesized as described in the above Scheme 3 (Path B), using various resin bound ureas 1-9 in the place of (1-8). These compounds were characterized using LC and MS as shown in Table 5. -52-
Example 71
(2S)-2-[(anilmocarbonyl)ammo]-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]- benzoyl}amino)propanoic acid
Example 72
(2S)-2- { [(tert-butylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 73 (2S)-2- { [(butylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} arnino)propanoic acid.
Example 74
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]benzoyl}amino)-2-{[(4- methoxyanilino)carbonyl] amino Jpropanoic acid
Example 75
(2S)-2- { [(2-ethylarιilmo)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 76
(2S)-2-{ [(aUylamino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxyjbenzoyl J amino)propanoic acid
Example 77
(2S)-2-{ [(2,4-dicmoroanilho)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid.
Example 78 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylambo)ethoxy]benzoylJarnino)-2-[(2- toluidinocarbonyl)amino]propanoic acid.
Example 79
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylarrιino)ethoxy]benzoyl}amino)-2-{ [(2- methoxyanilino)carbonyl] amino Jpropanoic acid.
Example 80
(2S)-2- { [(2-cUoroanilino)carbonyl]amino }-3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoylJ amino)propanoic acid.
Example 81
(2S)-2- { [(2-bromoarιilino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid. 99/52879
-53-
Example 82
(2S)-2-{ [([1, 1 '-biphenyl]-2-ylamino)carbonyl] amino }-3-({2-hydroxy-4-[2-(pyrimidin-
2-ylamino)ethoxy]benzoylJamino)propanoic acid.
Example 83
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl}amino)-2-[(4- toluidinocarbonyl)amino]propanoic acid.
Example 84 (2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylammo)ethoxy]benzoyl}amino)-2-({[4- (trifluoromethyl)anilino]carbonyl J amino )propanoic acid.
Example 85
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2-( { [4- (trifluoromethoxy)anilino]carbonyl}amino)propanoic acid.
Example 86
(2S)-2-{[(4-chloroanilino)carbonyl]amώoJ-3-({2-hydroxy-4-[2-(pyrirnidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 87
(2S)-2-{[(4-fluoroanilmo)carbonyl]arninoJ-3-({2-hydroxy-4-[2-(pyrirnidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid.
Example 88
(2S)-2-{ [(4-acetylanilino)carbonyl]amkoJ-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoylJ amino)propanoic acid.
Example 89 (2S)-2-({[4-(ethoxycarbonyl)anilmo]carbonylJan ino)-3-({2-hydroxy-4-[2-(pyrimidin- 2-ylamino)ethoxy]benzoyl}amino)propanoic acid.
Example 90
(2S)-2- { [(cyclohexylarnino)carbonyl amino } -3-( { 2-hydroxy-4- [2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid.
Example 91
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl J amino)-2- { [( 1 - naphthylamino)carbonyl] amino Jpropanoic acid.
Example 92
(2S)-2- { [(benzylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid. O 99/52879
-54-
Example 93
(2S)-3-({2-hydroxy-4-[2-(pyrimidώ-2-ylamho)ethoxy]benzoyl}amino)-2-({ [(2- phenylethyl)amino]carbonyl} amino)ρropanoic acid
Example 94
(2S)-3-( { 2-hydroxy-4- [2-(pyrinιidm-2-ylamino)ethoxy]benzoyl } amino)-2-
{ [(octylamino)carbonyl]arnino Jpropanoic acid
Table 5
OH 0
H H
Figure imgf000056_0001
HNγ N 0
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
71 σ 3.70 min 480 83 xy 3.79 min 495
72 3.45 min 460 84 r 4.22 min 549
73 3.50 min 460 85 4.27 min 565
F3CC3 ^
74 3.56 min 510 86 3.96 min 515
^0 cr-σ
75 CC 3.81 min 508 87 3.68 min 499
76 3.13 min 444 88 3.50 min 523
-yCT
0
77 4.19 min 549 89 3.92 min 553 cr ^ ei
0
78 3.63 min 495 90 min 487
& σ 3.66
79 cς 3.68 min 51 1 91 3.86 min 487
Figure imgf000056_0002
cό O 99/52879
-55-
80 cς 3.78 min 515 92 c^ 3.55 min 495
81 cς 3.80 min 559 93 cr 3.70 min 509
82
Figure imgf000057_0003
cς 4.13 min 557 94 4.56 min 517
Scheme 4 o
H,N
HN ,0^. o
T O
1-8 OH O
OH
FmocHN a
2-6
DIC, D AP, DMF
OH O
Figure imgf000057_0001
4-1 O
20% Piperidine DMF
OH O O
H,
Figure imgf000057_0002
HN ,0.
4-2 O
2(S)-(2,2-dimethyl-propoxycarbonylamino)-3- ( [2-Hydroxy-4-(2- fluorenylmethyloxy- carbonylamino)ethoxy]benzoylamino J-propionic acid on Wang Resin (4-1)
The resin 1-8 was washed with DMF to swell the resin. A solution of 4-[(2- fluorenylmethyloxycarbonylamino)ethoxy]-2-hydroxybenzoic acid (2-6) (628.5 mg; 1.5 mmole) in DMF was mixed with diisopropylcarbodiimide (189 mg; 1.5 mmole), hydroxybenzotriazole (202.5 mg; 1.5 mmole) and dimethylaminopyridine (18.33 mg; 0.15 mmole) and the mixture was added to the resin. The reaction mixture was shaken -56- at room temperature for 16h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
2(S)-(2.2-dimethyl-propoxycarbonylammo)-3-f2-Hydroxy-4-(2-aminoethoxy benzoyl- aminol-propionic acid on Wang Resin (4-2)
The resin 4-1 was shaken with a solution of 20% piperidine in DMF (5mL) for 10 min and filtered. Another 5mL portion of 20% piperidine in DMF was added and shaken at room temperature for 20 min. The resin was filtered and washed with DMF
(3 x 40mL), MeOH (3 x 40mL) and DCM (3 x 40mL). The resin were dried under vacuum.
A sample of the resin was removed and subjected to cleavage with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. The product was characterized by HPLC: 3.35 min (70% @ 220 nm); MS m/z 398 (M+H)+.
-57- Scheme 5
OH O O
H?NN 3Λ^ HN^O^-
4-2
M-N
DIEA, DMF, N HN .
N / Path A
Figure imgf000059_0002
OH O OH O
H H
X H H -^O^^
IT 5-1 γu^ τ
-N
TFA-CH2Cl2 (1 :1) α TFA-CH2Cl2 (1 :1)
OH O OH O O
OH OH
H fc!
Figure imgf000059_0001
HN
Figure imgf000059_0003
if -r -N O o
5-2 f HN γ .0u.
5-4
Example 95 (2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-{[(neopentyloxy)carbonyl]amino}propanoic acid (5-2)
(2S)-3-((4-r2-(4.5-dihvdro-lH-imidazol-2-ylamino)ethoxy1-2-hvdroxybenzoyl)- amino)-2-([(neopentyloxy)carbonvnamino Jpropanoic acid on Wang Resin (5-1)
The resin 4.2 (lOOmg; O. lmmole) was swollen in DMF. To the resin was added a solution of 2-(3,5-dimethylpyrazolyl)-4,5-dihydroimidazole hydrobromide (123 mg; 0.5 mmole) in DMF (1.5 mL) followed by dώopropylamine (0.15 mL; 1 mmole). The reaction vessel was shaken at 60 °C for 18h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated. O 99/52879
-58-
The resin 5-1 was cleaved by treatment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 5-2 was purified via preparative HPLC. NMR (300MHz, MeOH-d4) δ 7.7 (d, J = 7 Hz, IH), 6.5 (m, 2H), 4.5 (q, IH), 4.2 (t, 2H), 3.85 (m, IH), 3.75-3.8 (m, 7H), 3.5 (t, 2H), 0.9 (s, 9H).
HR-MS FAB m/z for C21H31N5O7 calcd. 466.2302 (M++l), obsd. 466.2289.
The following compounds were synthesized as described in the above Scheme 5 (Path A), using various resin bound carbamates in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 6.
Example 96
(2S)-2-{ [(benzyloxy)carbonyl]ammoJ-3-({4-[2-(4,5-d ydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoylJamino)propanoic acid.
Example 97
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(methoxycarbonyl)amino]propanoic acid.
Example 98
(2S)-3-( {4-[2-(4,5-dihydro- lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl } - amino)-2-[(ethoxycarbonyl)amino]propanoic acid.
Example 99 (2S)-3-({4-[2-(4,5-dmydro-lH-irru^azol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(propoxycarbonyl)amino]propanoic acid.
Example 100
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- arnino)-2-[(isopropoxycarbonyl)amino]propanoic acid.
Example 101
(2S)-2-{[(aUyloxy)carbonyl]ammoJ-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl } amino)propanoic acid.
Example 102
(2S)-2- { [(but-3-enyloxy)carbonyl]amino } -3-( { 4-[2-(4,5-dihydro- lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl J amino)proρanoic acid. -59-
Example 103
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2- { [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid.
Example 104
(2S)-3-({4-[2-(4,5-dmydro-lH-irmdazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(hexyloxy)carbonyl] amino Jpropanoic acid.
Example 105 (2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(octyloxy)carbonyl] amino Jpropanoic acid.
Example 106
(2S)-2-[(butoxycarbonyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl J amino)propanoic acid.
Example 107
(2S)-3-({4-[2-(4,5-dihydro-lH-iιru^azol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(isobutoxycarbonyl)amino]propanoic acid.
Table 6
OH O O
OH
H H
Figure imgf000061_0001
ΪΓ HNY°- 9
-N O
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
97 Methyl 2.82 min 410 104 n-Hexyl 3.97 min 480
98 Ethyl 2.99 min 424 105 n-Octyl 4.49 min 508
99 n-Propyl 3.21 min 438 95 (CH3)3CCH2 3.63 min 466
100 i-Propyl 3.17 min 438 106 n-Butyl 3.46 min 452
101 Allyl 3.13 min 436 107 i-Butyl 3.44 min 452
102 Homoallyl 3.31 min 450 96 Benzyl 3.60 min 486
103 Propargyl 3.01 min 434
Figure imgf000061_0002
The following compounds were synthesized as described in the above Scheme 5 (Path A), using various resin bound ureas in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 7. -60-
Example 108
(2S)-2-{ [(butylan mo)carbonyl]ammoJ-3-({4-[2-(4,5-d ydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoylJ amino)propanoic acid.
Example 109
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(hexylamino)carbonyl]amino}propanoic acid.
Example 110 (2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(octylamino)carbonyl]amino Jpropanoic acid.
Example 111
(2S)-2-{ [(aUylamώo)carbonyl]ammo }-3-({4-[2-(4,5-d ydro-lH-irnidazol-2- ylammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid.
Example 1 12
(2S)-2-{ [(cyclohexylanιmo)carbonyl]ammo}-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylammo)ethoxy]-2-hydroxybenzoylJamino)propanoic acid. Example 113
(2S)-2-{ [(benzylan ino)carbonyl]ammo}-3-({4-[2-(4,5-dmydro-lH-irnidazol-2- ylanτmo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid.
Example 114 3-({4-[2-(2,5-dihydro-lH-irnidazol-4-ylamino)ethoxy]-2-hydroxyberιzoyl)amino-N- ({ {(lS,2R)-phenylcyclopropyl]amino)carbonyl alanine.
Example 115
(2S)-3-({4-[2-(4,5-dihydro-lH-irmdazol-2-ylaιrιino)ethoxy]-2-hydroxybenzoyl}- amino)-2- { [(2-methoxyanilino)carbonyl]amino Jpropanoic acid.
Example 116
(2S)-2-{ [([l,l'-biphenyl]-2-ylammo)carbonyl]amino}-3-({4-[2-(4,5-dihydro-lH- m idazol-2-ylanιmo)ethoxy]-2-hydroxybenzoyl}arnino)propanoic acid.
Example 117
(2S)-3-( { 4- [2-(4,5-dihydro- 1 H-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoyl J - amino)-2-({ [(2-phenylethyl)anτino]carbonyl}amino)propanoic acid. -61-
Table 7
OH 0
H flH
Figure imgf000063_0001
HNY%
0
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 (M+H)* nm
108 H3C'" ' — ~ 3.20 min 451 113 0 3.26 min 485
109 H3C^^^^^ 3.69 min 479 1 14 G 3, 3.57 min 51 1
1 10 ""CO 4.24 min 507 1 15 σoc„, 3.42 min 501
11 1 ^^ 2.84 min 435 1 16 α„ 3.89 min 547
1 12
Figure imgf000063_0002
σ 3.37 min 477 1 17 cr 3.47 min 499
The following compounds were synthesized as described in the above Scheme 5 (Path A), using various resin bound amides in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 8.
Example 118
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- ammo)-2-(isobutyrylamino)propanoic acid.
Example 119
(2S)-2-(butyιylammo)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylarnino)ethoxy]-2- hydroxybenzoyl}amino)propanoic acid.
Example 120
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- ammo)-2-(hexanoylamino)propanoic acid.
Example 121
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-(pentanoylamino)propanoic acid. -62-
Example 122
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- aιτιino)-2-[(3,3-dimethylbutanoyl)amino]propanoic acid.
Example 123
(2S)-3-({4-[2-(4,5-dihydro-lH-iιrύdazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2- { [(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino Jpropanoic acid.
Example 124 (2S)-2-{ [2-(l-adamantyl)acetyl]amώo}-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid.
Example 125
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- arnino)-2-(pent-4-ynoylamino)propanoic acid.
Example 126
(2S)-2-[(cyclohexylcarbonyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl } amino)propanoic acid.
Example 127
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amjLno)-2-[(2-phenylacetyl)amino]propanoic acid.
Example 128
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(3-phenylpropanoyl)amino]propanoic acid.
Example 129 (2S)-2-[(2-cyclohexylacetyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl J amino)propanoic acid.
Example 130
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{[(E)-3-phenylprop-2-enoyl]amino Jpropanoic acid.
Example 131
(2S)-2-[(2-cMorobenzoyl)arrώιo]-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylammo)ethoxy]-2-hydroxybenzoylJamino)propanoic acid.
Example 132
(2S)-3-( {4-[2-(4,5-dihydro- lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-[(2-methylbenzoyl)amino]propanoic acid. -63-
Example 133
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(2-methoxybenzoyl)amino]propanoic acid.
Example 134
(2S)-2-[(4-cUorobenzoyl)ar no]-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)- ethoxy]-2-hydroxybenzoyl} amino)propanoic acid.
Example 135 (2S)-3-({4-[2-(4,5-d ydro-lH-inιidazol-2-ylarnino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(4-methylbenzoyl)amino]propanoic acid.
Example 136
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(4-methoxybenzoyl)amino]propanoic acid.
Example 137
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(2,5-dimethyl-3-foroyl)amino]propanoic acid.
Example 138
(2S)-2-[(2-bromobenzoyl)aπιho]-3-({4-[2-(4,5-dmydro-lH-irnidazol-2-ylaιrιino)- ethoxy]-2-hydroxybenzoylJamino)propanoic acid.
Example 139
(2S)-2-[(4-bromobenzoyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylammo)ethoxy]-2-hydroxybenzoyl}arnino)propanoic acid.
Example 140 (2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- ammo)-2-[(2,3-dimethylbenzoyl)amino]ρropanoic acid.
Example 141
(2S)-2-[(3-cmoroberrzoyl)arnino]-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)- ethoxy] -2-hydroxybenzoyl}amino)propanoic acid. -64-
Table 8
OH O
OH
T
Figure imgf000066_0001
-N Ύ
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
118 2.90 min 422 130
H3C (M+H) cr 3.57 min 482 (M+H)
119 H3C- _^\. 2.90 min 422 131 3.24 min 490 (M+H) cς (M+H)
120 H3C ^^^^,^^ 3.34 min 450 132 3.30 min 470 (M+H) ^CH3 (M+H)
121 H3C^^^ 3.10 min 436 133 3.38 min 486 (M+H) αoc„, (M+H)
122 3.26 min 450 134 (M+H) X 3.59 min 490 (M+H)
123 H3Q 3.71 min 476 135 3.46 min 470 (M+H) (M+H) H3C
124 ι&- 3.90 min 528 136 3.34 min 486 (M+H) H3CcA^ (M+H)
125 ^. 2.86 min 432 137 H3C^,CH3 3.45 min 474 (M+H) (M+H)
126 σ 3.36 min 462 138 (M+H) αBr 3.16 min 534 (M+H)
127 cr 3.22 min 470 139 3.28 min 534 (M+H) (M+H)
128 cr- 3.42 min 484 140 3.65 min 484 (M+H) άr; (M+H)
129 cr 3.50 min 476 141 3.56 min 490 (M+H) ώ. (M+H)
Figure imgf000066_0002
-65-
Example l42 (2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylamino)ethoxy]benzoyI}amino)-2-{[(neopentyIoxy)carbonyl]amino}propanoic acid (5-4)
(2S)-3-((2-hydroxy-4-[2-(3.4.5,6-tetrahvdro-2H-azepin-7-ylamino)ethoxylbenzoyl }- amino)-2-( [(neopentyloxy)carbonyllamino jpropanoic acid on Wang Resin (5-3)
The resin 4-2 (100 mg: O.lmmole) was swollen in dioxane and treated with a solution of l-aza-2-methoxy-l-cycloheptene (127 mg; 1 mmole) in dioxane (1.5 mL). The reaction mixture was shaken at room temperature for 18h. The mixture was filtered and the resin was washed with dioxane (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated.
The resin 5-3 was cleaved by tratment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 5-4 was purified via preparative HPLC. NMR (300MHz, DMSO-d6) δ 12.8 (s, IH), 9.55 (t, IH), 9.25 (t,'lH), 8.8 (t, IH), 7.8 (d, J = 9 Hz, IH), 7.7 (d, J = 8 Hz, IH), 7.3 (m, 5H), 6.5 (m, 2H), 5.0 (s, 2H), 4.3 (q, IH), 4.2 (t, 2H), 3.8 (m, 3H), 3.6 (m, IH), 3.5 (m, 2H), 2.7 (m, 2H), 1.7 (m, 2H), 1.6 (m, 4H).
The following compounds were synthesized as described in the above Scheme 5 (Path B), using various resin bound carbamates in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 9. -66-
Example 143
(2S)-2-{[(benzyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepin-7-ylamino)ethoxy]benzoyl } amino)propanoic acid. Example 144
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7-ylamino)ethoxy]benzoylJ- amino)-2-[(methoxycarbonyl)amino]propanoic acid.
Example 145 (2S)-2-[(ethoxycarbonyl)arrώ o]-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylammo)ethoxy]berιzoyl}amino)propanoic acid.
Example 146
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azeph-7-ylamino)ethoxy]benzoylJ- aιrmo)-2-[(propoxycarbonyl)arnino]propanoic acid.
Example 147
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azeph-7-ylamino)ethoxy]benzoylJ- amino)-2-[(isopropoxycarbonyl)amino]propanoic acid.
Example 148
(2S)-2-{[(aUyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepin-7-ylamino)ethoxy]benzoyl J amino)propanoic acid.
Example 149
(2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro- 2H-azepm-7-ylamino)ethoxy]benzoyl } amino)propanoic acid.
Example 150 (2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepm-7-ylamino)ethoxy]benzoylJ- amino)-2-{ [(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid.
Example 151
(2S)-2- { [(hexyloxy)carbonyl] amino } -3-( { 2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepm-7-ylarnino)ethoxy]benzoylJamino)propanoic acid.
Example 152
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepώ-7-ylamino)ethoxy]benzoylJ- amino)-2- { [(octyloxy)carbonyl] amino Jpropanoic acid.
Example 153
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azep -7-ylamino)ethoxy]benzoylJ- amino)-2-{ [(2,2,2-trichloroethoxy)carbonyl] amino Jpropanoic acid. -67-
E Exxaammppllee 1544
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahyd l;ro-2H-azepin-7- ylamino)ethoxy] benzoyl }amino)propanoic acid.
Example 155
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepm-7-ylamino)ethoxy]- benzoylJammo)-2-[(isobutoxycarbonyl)amino]propanoic acid.
Table 9
OH 0
OH
Figure imgf000069_0001
" HN_.0.
Y R9 o
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
144 Methyl 3.08 min 437 151 n-Hexyl 3.19 min 507
145 Ethyl 3.25 min 451 152 n-Octyl 4.67 min 535
146 n-Propyl 3.46 min 465 142 (CH3)3CCH2 3.85 min 493
147 i-Propyl 3.38 min 465 153 (CC13)3CCH2 3.89 min 553
148 Allyl 3.37 min 463 154 n-Butyl 3.70 min 479
149 Homoallyl 3.55 min 477 155 i-Butyl 3.67 min 479
150 Propargyl 3.27 min 461 143 Benzyl 3.83 min 513
Figure imgf000069_0002
-68-
Scheme 6
OH O
O'
H,N.
Figure imgf000070_0001
HN
4-2 o
BocN -^S 1. p-N02PhOCOCI DIEA, THF, CH2CI2
NHBoc 2. PhCH2NH2 DIEA, DMF Path A Path B \ Et3N, DMF
OH O OH O
H N- Y O H H BocHN .N^
Figure imgf000070_0002
υ. Ph. ,N, -N.
Figure imgf000070_0004
HN^O^O
T 6-1 Y ^" 6-3 γu^rτ
NBoc o Y O o
TFA-CH2CI2 (1 :1) TFA-CH2CI2 (1 :1)
OH O OH O
N Υ OH 'OH H H
Figure imgf000070_0003
H HN_0.^- Ph^NγN.
Figure imgf000070_0005
HN^ λ,
NH o o o
6-2 6-4
Example 156 (2S)-3-{[4-(2-{[amino(imino)methyI]amino}ethoxy)-2-hydroxy- benzoyI]amino}-2-{[(neopentyloxy)carbonyl]amino}propanoic acid (6-2)
(2S)-3-( f4-(2-f [amino(ir ^o)methyπamino]ethoxy)-2-hvdroxybenzoyl1amino}-2- { [(neopentyloxy)carbonyl] amino Jpropanoic acid on Wang Resin (6-1)
The resin 4-2 (100 mg; O.lmmole) was swollen in DMF and treated with a solution of l,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (145 mg; (0.5 mmole) in DMF (1.5 mL) followed by dώopropylamine (0.15 mL; 1 mmole). The reaction mixture was shaken at room temperature for 18h. The mixture was filtered and the resin was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum. A sample of the resin was removed and subjected to Kaiser Ninhydrin test. If the test showed the presence of free amine (resin turned blue) the coupling described above was repeated. -69-
The resin 6-1 was cleaved by tratment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 6-2 was purified via preparative HPLC. NMR (300MHz, MeOH-d4) δ 7.7 (d, J = 7 Hz, IH), 6.5 (m, 2H), 4.5 (q, IH), 4.2 (m, 2H), 3.85 (m, IH), 3.8 (m, 2H), 3.75 (m, IH), 3.7 (m, 2H), 0.9 (s, 9H).
HR-MS FAB m/z for C^H^NsOγ calcd. 440.2145 (M++l), obsd. 440.2154.
The following compounds were synthesized as described in the above Scheme 6 (Path A), using various resin bound carbamates in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 10.
Example 157
(2S)-3- { [4-(2- { [ammo(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino } -2- { [(benzyloxy)carbonyl] amino Jpropanoic acid.
Example 158 (2S)-3-{ [4-(2-{[amdno(imino)methyl]aπιmoJethoxy)-2-hydroxyberi2oyl]amino}-2- [(methoxycarbonyl)amino]propanoic acid.
Example 159
(2S)-3- { [4-(2- { [arrώιo(iιrmo)methyl] amino }ethoxy)-2-hydroxybenzoyl]amino J-2- [(ethoxycarbonyl)amino]propanoic acid.
Example 160
(2S)-3- { [4-(2- { [ammo(iιrιino)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino } -2- [(propoxycarbonyl)amino]propanoic acid.
Example 161
(2S)-3-{ [4-(2-{ [amko(mτino)methyl]ammo}ethoxy)-2-hydroxyb€rιzoyl]amino}-2- [(isopropoxycarbonyl)amino]propanoic acid.
Example 162
(2S)-2-{ [(allyloxy)carbonyl]amino}-3-{ [4-(2-{ [amino(imino)methyl] amino } ethoxy)-2- hydroxybenzoyl] amino Jpropanoic acid. O 99/52879
-70-
Example 163
(2S)-3- { [4-(2- { [amino(immo)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2-
{ [(but-3-enyloxy)carbonyl]amino Jpropanoic acid.
Example 164
(2S)-3- { [4-(2- { [ammo(immo)methyl]amino Jethoxy)-2-hydroxybenzoyl]amino J-2- [(butoxycarbonyl)amino]propanoic acid.
Example 165 (2S)-3-{[4-(2-{[ammo(immo)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- { [(2.2, 2-tricWoroethoxy)carbonyl]amino Jpropanoic acid.
Example 166
(2S)-3-{[4-(2-{[ammo(imko)methyl]ammoJethoxy)-2-hydroxybenzoyl]aminoJ-2- {[(hexyloxy)carbonyl] mino Jpropanoic acid.
Example 167
(2S)-3-{[4-(2-{[amino(irn o)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- { [(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid.
Example 168
(2S)-3- { [4-(2- { [aπι o(iιrπno)methyl]amino J ethoxy)-2-hydroxybenzoyl]amino } -2-
{[([1,1 '-biphenyl]-2-ylmethoxy)carbonyl]amino Jpropanoic acid.
Example 169
(2S)-3- { [4-(2- { [amώo(imώo)methyl]amino Jethoxy)-2-hydroxybenzoyl] amino J-2- ({ [(4-bromobenzyl)oxy]carbonyl}amino)propanoic acid.
Example 170 (2S)-3-{[4-(2-{[amino(imko)methyl]ammoJethoxy)-2-hydroxybenzoyl]aminoJ-2- ({ [(4-fluorobenzyl)oxy]carbonyl}amino)propanoic acid.
Example 171
(2S)-3- { [4-(2- { [amino(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- ({[(2-bromobenzyl)oxy]carbonyl}amino)propanoic acid.
Example 172
(2S)-3- { [4-(2- { [amino(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2-
[({ [4-(trifiuoromethyl)benzyl]oxyJcarbonyl)amino]propanoic acid. -71-
Table 10
OH 0
H Λ^N ^OH H2Nγ H HN^O.D
Y *
NH 0
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
158 Methyl 2.75 min 384 165 (CC13)3CCH2 3.60 min 502
159 Ethyl 2.93 min 397 164 n-Butyl 3.39 min 426
160 n-Propyl 3.15 min 412 157 Benzyl 3.53 min 460
161 i-Propyl 3.1 1 min 412 168 <x 4.20 min 536
162 Allyl 3.05 min 410 169 3.85 min 539
XX
163 Ho oallyl 3.25 min 424 170 tr 3.60 min 478
167 Propargyl 2.95 min 408 171 3.81 min 539
(X
166 n-Hexyl 3.91 min 4454 172 3.97 min 528
FjC^^
156 (CH3)3CCH2 3.57 min 440
Figure imgf000073_0001
The following compounds were synthesized as described in the above Scheme 6 (Path A), using various resin bound ureas in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 11.
Example 173 (2S)-3-{[4-(2-{ [amώo(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]arruno}-2-[(2- toluidinocarbonyl)amino]propanoic acid.
Example 174
(2S)-3- { [4-(2- { [amino(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2-
{ [(2-methoxyanilino)carbonyl] amino Jpropanoic acid. -72-
Example 175
(2S)-3-{[4-(2-{[am o(immo)methyl]ammoJethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(2-chloroarιilino)carbonyl]amino Jpropanoic acid.
Example 176
(2S)-3- { [4-(2- { [am o(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2-
{ [(2-bromoanilino)carbonyl] amino Jpropanoic acid.
Example 177
(2S)-3- { [4-(2- { [ammo(imino)methyl] amino J ethoxy)-2-hydroxybenzoyl] amino } -2-
{[([1,1 '-biphenyl]-2-ylamino)carbonyl]amino Jpropanoic acid.
Example 178
(2S)-3-{[4-(2-{ [arn o(imino)methyl]am oJethoxy)-2-hydroxybenzoyl]amino}-2-[(4- toluidinocarbonyl)arnino]propanoic acid.
Example 179 (2S)-3- { [4-(2- { [amώo(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2- ( { [4-(trifluoromethoxy)anilino]carbonyl } amino)propanoic acid.
Example 180
(2S)-3- { [4-(2- { [ammo(imino)methyl] amino J ethoxy)-2-hydroxybenzoyl]amino J -2- { [(4-cUoroanilino)carbonyl]amino Jpropanoic acid.
Example 181
(2S)-3-{ [4-(2-{ [ammo(jm o)methyl]ammoJethoxy)-2-hydroxybenzoyl]arnino}-2- { [(4-fluoroanilino)carbonyl]amino Jpropanoic acid
Example 182
(2S)-2- { [(4-acetylanilώo)carbonyl]amino } -3- { [4-(2- { [ammo(imino)methyl]- amino }ethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid.
Example 183
(2S)-3- { [4-(2- { [ammo(imino)methyl] amino }ethoxy)-2-hydroxybenzoyl] amino } -2- { [(cyclohexylamino)carbonyl] amino Jpropanoic acid.
Example 184 (2S)-3-{ [4-(2-{ [ammo(imino)methyl] amino }ethoxy)-2-hydroxybenzoyl] amino} -2- {[(l-naphthylamino)carbonyl]arnino}propanoic acid.
Example 185
(2S)-3- { [4-(2- { [ammo(mιino)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2- {[(benzylamino)carbonyl] amino Jpropanoic acid. -73-
Example 186
(2S)-3- { [4-(2- { [ammo(imho)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino } -2- ({ [(2-phenylethyl)amino]carbonyl}amino)propanoic acid.
Example 187 (2S)-3-{[4-(2-{[ammo(im o)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(octylamino)carbonyl]amino Jpropanoic acid.
Example 188
(2S)-3-{ [4-(2-{ [aιrjino(imώo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(4-methoxyanilino)carbonyl]amino Jpropanoic acid.
Example 189
(2S)-3- { [4-(2- { [amko(imino)methyl] amino }ethoxy)-2-hydroxybenzoyl] amino } -2- [(anilinocarbonyl)amino]propanoic acid.
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Table 11
OH 0
H H2 ^ .N Ψ
T
Figure imgf000076_0001
NH 0
Ex. Rl LC @ 254 nm (M+H)+ Ex. Rl LC @ 254 nm (M+H)+
187 H,CX) 4.18 min 481 182 3.26 min 487
0
189 σ 3.29 min 445 175 Cζ 3.46 min 481
183 σ 3.32 min 451 176 (X 3.48 min 525
185 cr 3.20 min 459 177 σP 3.81 min 521
173 σCHl 3.32 min 459 181 xx 3.39 min 463
178 X 3.50 min 459 180 XX 3.68 min 481
188 J X 3.27 min 475 184 3.57 min 495
K^X
174 cc 3.36 min 475 186 Or 3.37 min 473
179 3.92 min 529
CF3cr ^
Figure imgf000076_0002
The following compounds were synthesized as described in the above Scheme 6 (Path A), using various resin bound amides in the place of 4-2. These compounds were characterized using LC and MS as shown in Table 12.
Example 190
(2S)-3- { [4-(2- { [amino(imώo)methyl]amino } ethoxy)-2-hydroxyberrzoyl]amino J -2-
(isobutyrylamino)propanoic acid. -75-
Example 191
(2S)-3-{[4-(2-{[amino(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- (butyrylamino)propanoic acid.
Example 192
(2S)-3- { [4-(2- { [ammo(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino J -2-
(hexanoylamino)propanoic acid.
Example 193
(2S)-3- { [4-(2- { [amino(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl]amino } -2- (pentanoylamino)propanoic acid.
Example 194 (2S)-3-{[4-(2-{ [arnho(irnino)methyl]aπιmo Jethoxy)-2-hydroxybenzoyl]aminoJ-2- [(3,3-dimethylbutanoyl)amino]propanoic acid.
Example 195
(2S)-3- { [4-(2- { [amino(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2- { [(2,2, 3, 3-tetramethylcyclopropyl)carbonyl]amino Jpropanoic acid.
Example 196
(2S)-2-{[2-(l-adamantyl)acetyl]ammoJ-3-{[4-(2-{[an mo(inτmo)methyl]amino}- ethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid.
Example 197
(2S)-3-{[4-(2-{ [amho(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]aminoJ-2- (pent-4-ynoylamino)propanoic acid.
Example 198
(2S)-3- { [4-(2- { [ammo(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino } -2- [(cyclohexylcarbonyl)amino]propanoic acid.
Example 199 (2S)-3-{ [4-(2-{ [amino(immo)methyl]amino}ethoxy)-2-hydroxyberιzoyl]amino}-2-[(2- phenylacetyl)amino]propanoic acid.
Example 200
(2S)-3- { [4-(2- { [ammo(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2-[(3- phenylpropanoyl)amino]propanoic acid.
Example 201
(2S)-3- { [4-(2- { [amino(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl] amino J -2-[(2- cyclohexylacetyl)amino]propanoic acid. -76-
Example 202
(2S)-3- { [4-(2- { [amώo(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2- { [(E)-3-phenylprop-2-enoyl]amino Jpropanoic acid.
Example 203
(2S)-3-{[4-(2-{[ammo(iιrιmo)methyl]arrιinoJethoxy)-2-hydroxybenzoyl]aminoJ-2-[(2- chlorobenzoyl)amino]propanoic acid.
Example 204
(2S)-3- { [4-(2- { [ammo(irnmo)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino } -2-[(2- methylbenzoyl)amino]propanoic acid.
Example 205 (2S)-3-{[4-(2-{[amώo(imino)methyl]aπιmo}ethoxy)-2-hydroxybenzoyl]amino}-2-[(2- methoxybenzoyl)amino]propanoic acid.
Example 206
(2S)-3- { [4-(2- { [amho(irnino)methyl]amino Jethoxy)-2-hydroxybenzoyl]amino } -2-[(4- chlorobenzoyl)amino]propanoic acid.
Example 207
(2S)-3- { [4-(2- { [amino(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino }-2-[(4- methylbenzoyl)amino]propanoic acid.
Example 208
(2S)-3-{[4-(2-{[amώo(imho)methyl]anιino}ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- methoxybenzoyl)amino]propanoic acid.
Example 209
(2S)-3- { [4-(2- { [amino(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2- [(pyridin-3-ylcarbonyl)amino]propanoic acid.
Example 210 (2S)-3-{ [4-(2-{ [aιrιko(immo)methyl]aιrιino}ethoxy)-2-hydroxybenzoyl]amino}-2- (isonicotinoylamino)propanoic acid.
Example 211
(2S)-3-{[4-(2-{[am o(immo)methyl]aminoJethoxy)-2-hydroxybenzoyl]amino}-2- [(2,5-dimethyl-3-furoyl)amino]propanoic acid.
Example 212
(2S)-3-{[4-(2-{[ammo(imino)methyl]aminoJethoxy)-2-hydroxytenzoyl]amino}-2-[(2- bromobenzoyl)amino]propanoic acid. -77-
Example 213 (2S)-3-{[4-(2-{[amώo(immo)methyl]ammoJethoxy)-2-hydroxybenzoyl]aminoJ-2-[(4- bromobenzoyl)amino]propanoic acid.
Example 214
(2S)-3- { [4-(2- { [anιmo(imino)methyl]amino Jethoxy)-2-hydroxybenzoyl]amino J -2- [(2,3-dimethylbenzoyl)amino]propanoic acid.
Example 215
(2S)-3-{[4-(2-{ [amώo(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]aminoJ-2-[(3- chlorobenzoyl)amino]propanoic acid.
Example 216
(2S)-3- { [4-(2- { [ammo(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl]amino J -2-
(benzoylamino)propanoic acid.
Example 217
(2S)-3-{ [4-(2-{ [ammo(iιrώιo)methyl]ammoJethoxy)-2-hydroxybenzoyl]amino}-2-[(4- ethylbenzoyl)amino]propanoic acid.
Example 218 (2S)-3-{ [4-(2-{ [amho(imώo)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- butoxybenzoyl)amino]propanoic acid.
-78-
Table 12
OH O
Ύ O Y
NH O
Ex. R9 LC @ 254 nm (M+H)+ Ex. R9 LC @ 254 nm (M+H)+
190 H3C^ 2.88 min 396 (M+H) 205 H3C cc 3.38 min 460 (M+H)
191 H3C - 2.88 min 396 (M+H) 206 3.58 min 464 (M+H)
XX
192 H3C ^^^ 3.34 min 424 (M+H) 207 3.45 min 444 (M+H) 3cX
193 H3C^^^^ 3.09 min 410 (M+H) 208 3.33 min 460 (M+H)
H-sCcr ^^
194 3.24 min 424 (M+H) 209 σ 2.61 min 431 (M+H)
195 H3C 3.70 min 450 (M+H) 210 H3C σ 2.58 min 431 (M+H)
196 X- 3.85 min 502 (M+H) 211 H.O^ H, 3.45 min 448 (M+H)
197 V^ 2.84 min 406 (M+H) 212 cc 3.27 min 509 (M+H)
198 σ 3.35 min 436 (M+H) 213 3.65 min 509 (M+H) aJ*X
199 cr 3.21 min 444 (M+H) 214 3.65 min 458 (M+H) άl;
200 CT" 3.42 min 458 (M+H) 215 3.46 min 464 (M+H) άc,
201 cr 3.50 min 450 (M+H) 216 σ 3.19 min 430 (M+H)
202 c 3.55 min 456 (M+H) 217 JX 3.66 min 458 (M+H)
Figure imgf000080_0001
O 99/52879
-79-
203 cς 3.25 min 464 (M+H) 218 X 4.08 min 502 (M+H)
204 3.29 min 444 (M+H)
^ H3 -
Figure imgf000081_0001
Example 219 (2S)-3-{[4-(2-{[(benzylamino)carbonyI]amino}ethoxy)-2-hydroxy- benzoyl]amino}-2-{[(neopentyloxy)carbonyl]amino}propanoic acid (6-4)
(2S)-3-{ [4-(2-{ [(benzylammo carbonyllarrιmo}ethoxy)-2-hydroxybenzoyllamino )-2- {[(neopentyloxy)carbonyl]amino Jpropanoic acid on Wang Resin (6-3)
The resin 4-2 (100 mg; O.lmmole) was swollen in 1: 1 tetrahydrofuran and dichloromethane. To it was added a solution of 4-nitrophenylchloroformate (50 mg; 0.25 mmole) in 1:1 THF: DCM (1.5 mL) followed by dϋsopropylamine (0.075 mL; 0.5 mmole). The reaction mixture was shaken at room temperature for 30 min. The mixture was filtered and the resin was washed with THF (4 x 4 mL) and dichloromethane (4 x 4 mL) and dried. The resin was suspended in DMF (1.5 mL) and benzyl amine (54 mg; 0.5 mmole) was added followed by triethylamine (101 mg; 1 mmole). The reaction mixture was shaken at room temperature for 2 h. The mixture were filtered and the resin in each vessel was washed with dimethylformamide (4 x 4 mL), methanol (4 x mL) and dichloromethane (4 x 4 mL). The resin was dried under vacuum.
The resin 6-3 was cleaved by treatment with dichloromethane (0.5 mL) and trifluroacetic acid (0.5 mL) for 30 min at room temperature. The reaction mixture was filtered and the resin was washed with dichloromethane. The filtrate was concentrated and dried in vacuo on a Savant Speed Vac Plus. This crude product 6-4 was purified via preparative HPLC. NMR (300MHz, MeOH-d4) δ 7.65 (d, J = 7 Hz, IH), 7.25 (m, 5H), 6.5 (m, 2H), 4.4 (q, IH), 4.3 (s, 2H), 4.15 (t, 2H), 3.85 (m, IH), 3.75 (m, 3H), 3.5 (t, 2H). 0.9 (s, 9H). -80- HR-MS FAB m/z for C26H34N4O8 calcd. 531.2455 (Ivf+1), obsd. 531.2459.
The following compounds were synthesized as described in the above Scheme 6 (Path B), using various amines in the place of benzyl amine. These compounds were characterized using LC and MS as shown in Table 13. _
Example 220
(2S)-3- { [4-(2- { [(benzylammo)carbonyl]amino } ethoxy)-2-hydroxybenzoyl]amino J -2-
{ [(benzyloxy)carbonyl]amino Jpropanoic acid.
Example 221
(2S)-3-{ [4-(2-{ [(benzylambo)carbonyl] amino }ethoxy)-2-hydroxybenzoyl]amino}-2- [(methoxycarbonyl)amino]propanoic acid.
Example 222 (2S)-3-{ [4-(2-{ [(benzylammo)carbonyl]ammoJethoxy)-2-hydroxybenzoyl]amino}-2- [(ethoxycarbonyl)amino]propanoic acid.
Example 223
(2S)-3-{ [4-(2-{ [(benzylamino)carbonyl]arr no}ethoxy)-2-hydroxybenzoyl]amino}-2- [(propoxycarbonyl)amino]propanoic acid.
Example 224
(2S)-3-{ [4-(2-{ [(benzylamino)carbonyl] amino }ethoxy)-2-hydroxybenzoyl] amino} -2- [(isopropoxycarbonyl)amino]propanoic acid.
Example 225
(2S)-2-{ [(aUyloxy)carbonyl]ammoJ-3-{ [4-(2-{ [(benzylammo)carbonyl]aminoJ- ethoxy)-2-hydroxybenzoyl]amino Jpropanoic acid.
Example 226
(2S)-3- { [4-(2- { [(berιzylamino)carbonyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2- { ['(but-3-enyloxy)carbonyl] amino Jpropanoic acid.
Example 227 (2S)-3-{ [4-(2-{ [(berιzylammo)carbonyl] ammo} ethoxy)-2-hydroxybenzoyl] amino} -2- { [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid.
Example 228
(2S)-3-{ [4-(2-{ [(beιιzylaπιino)carbonyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(hexyloxy)carbonyl] amino } propanoic acid.
Example 229
(2S)-3-{ [4-(2-{ [(b«rιzylammo)carbonyl]amώo}ethoxy)-2-hydroxyberizoyl]amino}-2- { [(octyloxy)carbonyl] amino Jpropanoic acid. -81-
Example 230
(2S)-3-{ [4-(2-{ [(benzylamino)carbonyl]amino }ethoxy)-2-hydroxybenzoyl] amino} -2-
{ [(2, 2,2-trichloroethoxy)carbonyl]amino Jpropanoic acid.
Example 231
(2S)-3- { [4-(2- { [(benzylammo)carbonyl] amino }ethoxy)-2-hydroxybenzoyl]amino } -2-
[(butoxycarbonyl)amino]propanoic acid.
Example 232
(2S)-3-{ [4-(2-{ [(benzylammo)carbonyl]arnώo}ethoxy)-2-hydroxybenzoyl]amino}-2- [(isobutoxycarbonyl)amino]propanoic acid.
Example 233
(2S)-2- { [(be nzyloxy)carbonyl] amino }-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylrnethyl)- ammo]carbonylJamino)ethoxy]benzoyl}amino)propanoic acid.
Example 234
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-3-ylmethyl)ammo]carbonyl}-amino)ethoxy]- benzoyl}ammo)-2-[(methoxycarbonyl)amino]propanoic acid.
Example 235
(2S)-2-[(ethoxycarbonyl)ammo]-3-({2-hydroxy-4-[2-({ [(pyrid -3-ylmethyl)arrιino] carbonyl } amino)ethoxy]benzoyl } amino)propanoic acid.
Example 236
(2S)-3-({2-hydroxy-4-[l-({(pyridm-3-ylmethyl)amino]carbonyl}amino)ethoxy]- benzoyl}amino)-2-[(propoxycarbonyl)amino]propanoic acid.
Example 237 (2S)-3-({2-hydroxy-4-[2-({ [(pyridh-3-ylmethyl)amino]carbonyl}-amino)ethoxy]- benzoyl}arnino)-2-[(isopropoxycarbonyl)amino]propanoic acid.
Example 238
(2S)-2- { [(aUyloxy)carbonyl]amino } -3-( { 2-hydroxy-4- [2-( { [(pyridin-3- ylmethyl)ammo]carbonyl}amho)ethoxy]benzoyl}amino)proρanoic acid.
Example 239
(2S)-2- { [(but-3-enyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)amino]carbonyl} amino)ethoxy]benzoyl} amino)proρanoic acid
Example 240
(2S)-3-( { 2-hydroxy-4- [2-( { [(pyridin-3-ylmethyl)amino]carbonyl } -amino)ethoxy]- benzoyl}amino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid. -82-
Example 241
(2S)-2- { [(hexyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)- ammo]carbonyl}ammo)ethoxy]berιzoyl}arnino)propanoic acid.
Example 242
(2S)-3-({2-hydroxy-4-[2-({ [(pyridώ-3-ylmethyl)aιruιio]carbonyl}-amino)ethoxy]- benzoyl}amino)-2-{[(octyloxy)carbonyl]amino Jpropanoic acid.
Example 243 (2S)-3-({2-hydroxy-4-[2-({ [(pyridm-3-ylmethyl)ammo]carbonyl}-amino)ethoxy]- benzoylJamino)-2-{ [(neopentyloxy)carbonyl] amino Jpropanoic acid.
Example 244
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonyl } amino)- ethoxy]benzoyl}amino)-2-{ [(2,2,2-trichloroethoxy)carbonyl]amino}propanoic acid.
Example 245
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({[(pyridin-3- ylmethyl)ammo]carbonyl}amώo)ethoxy]benzoyl}amino)propanoic acid.
Example 246
(2S)-3-({2-hydroxy-4-[2-({ [(pyridh-3-ylmethyl)ammo]carbonyl}-amino)ethoxy]- benzoyl}ammo)-2-[(isobutoxycarbonyl)amino]propanoic acid.
Example 247
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)an mo]carbonyl}arrmo)ethoxy]benzoyl}arnino)propanoic acid.
Example 248 (2S)-3-( { 2-hydroxy-4-[2-( { [(pyridm-4-ylmethyl)amino]carbonyl J -amino)- ethoxy]benzoylJammo)-2-[(methoxycarbonyl)arnino]propanoic acid.
Example 249
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({[(pyridin-4-ylmethyl)- am o]carbonyl}amino)ethoxy]benzoyl}amino)propanoic acid.
Example 250
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-4-ylmethyl)amino]carbonyl}- ammo)ethoxy]berιzoyl}amώo)-2-[(propoxycarbonyl)amino]propanoic acid.
Example 251
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridh-4-ylmethyl)amino]carbonyl } - ammo)ethoxy]benzoyl}ammo)-2-[(isopropoxycarbonyl)amino]propanoic acid. -83-
Example 252
(2S)-2- { [(allyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)amko]carbonyl}ammo)ethoxy]benzoyl}arnino)propanoic acid.
Example 253
(2S)-2- { [(but-3-enyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)ammo]carbonyl}am o)ethoxy]benzoyl}amino)propanoic acid.
Example 254 (2S)-3-({2-hydroxy-4-[2-({ [(pyridm-4-ylmethyl)amko]carbonyl}-amino)ethoxy]- benzoyl}amino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid.
Example 255
(2S)-2- { [(hexyloxy)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)arnho]carbonylJamho)ethoxy]tenzoyl}amino)propanoic acid.
Example 256
(2S)-3-({2-hydroxy-4-[2-({ [(pyrid -4-ylmethyl)anιmo]carbonyl}-amino)ethoxy]- benzoylJamino)-2-{ [(octyloxy)carbonyl]amino Jpropanoic acid.
Example 257
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-4-ylmethyl)anώ o]carbonyl}-amino)ethoxy]- benzoyl}amino)-2-{ [(neopentyloxy)carbonyl]amino Jpropanoic acid.
Example 258
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridm-4-ylmethyl)amino]carbonylJ amino)-ethoxy]- benzoyl}ammo)-2-{ [(2,2.2-tricUoroethoxy)carbonyl]amino Jpropanoic acid.
Example 259 (2S)-2-[(butoxycarbonyl)amino]-3-( {2-hydroxy-4-[2-( { [(pyridm-4-ylmethyl)amino]- carbonyl } amino)ethoxy]benzoyl J amino)proρanoic acid.
Example 260
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-4-ylmethyl)ammo]carbonyl}-amino)ethoxy]- benzoyl}amino)-2-[(isobutoxycarbonyl)amino]propanoic acid.
Example 261
(2S)-2-{ [(benzyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(4-methylbenzyl)- amino]carbonyl}amino)ethoxy]benzoyl}amino)propanoic acid. LC 4.75 min., M+H 565.
Example 262
(2S)-2-{ [(benzyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( { [(4-methoxybenzyl)- ammo]carbonyl}amino)ethoxy]benzoylJamino)propanoic acid. LC 3.75 min., M+H 581. -84-
Example 263
(2S)-2-{ [(benzyloxy)carbonyl]arrnnoJ-3-({4-[2-({ [(4-cmorobenzyl)amino]-carbonylJ- amino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid. LC 4.83 min., M+H 5.86.
Example 264
(2S)-2- { [(benzyloxy)carbonyl] amino } -3-[(4- { 2-[( { [4-(djmethylamino)benzyl]- ammo}carbonyl)ammo]ethoxy}-2-hydroxybenzoyl)amino]propanoic acid. LC 3.7 min., M+H 594.
Example 265
(2S)-3-[(4- { 2-[( { [4-(ammosulfonyl)berιzyl]amino }carbonyl)amino]ethoxy J-2- hydroxybenzoyl)amino]-2- { [(benzyloxy)carbonyl]amino Jpropanoic acid. LC 4.08 min., M+H 630.
Example 266
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(2-hydroxy-4-{2-[({ [4-(trifluoromethoxy)- benzyl]arrnnoJcarbonyl)am o]ethoxy}benzoyl)amino]propanoic acid. LC 5.06 min., M+H 635.
Example 267
(2S)-2-{ [(benzyloxy)carbonyl]amho}-3-({4-[2-({ [(2-cMorobenzyl)amino]carbonylJ- amino)ethoxy]-2-hydroxybenzoylJamino)propanoic acid. LC 4.8 min., M+H 586.
Example 268 (2S)-2-{[(benzyloxy)carbonyl]arnmo J-3-({2-hydroxy-4-[2-({ [(2-methylbenzyl)amino]- carbonylJamho)ethoxy]benzoyl}amino)propanoic acid. LC 4.74 min., M+H 565.
Example 269
(2S)-2-{[(benzyloxy)carbonyl]amko}-3-({4-[2-({ [(2-bromobenzyl)amino]-carbonylJ- arnino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid. LC 4.85 min., M+H 630.
Example 270
(2S)-2-{[(benzyloxy)carbonyl]ammoJ-3-({4-[2-({ [(2,4-dichlorobenzyl)amino]- carbonyl}arrιmo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid. LC 5.08 min., M+H 620.
Example 271
(2S)-3-({4-[2-({ [(2-ammobenzyl)ammo]carbonyl}amino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{[(benzyloxy)carbonyl] amino Jpropanoic acid. LC 3.81 min., M+H 566.
Example 272
(2S)-2- { [(benzyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-2-ylmethyl)- ammo]carbonyl}ammo)ethoxy]b€rιzoyl}amino)propanoic acid. LC 3.58 min., M+H
552. -85-
Table 13
OH O
H H OH
Figure imgf000087_0001
HN^.0.
Y R« o 0
Ex. 221-227 248-254 234-240 219-220 247 & 233 &
228-232 255-260 241-246
R8 — R8 -—
R9 CT N^ R9 \ 0^ ^ r
219-220 & 228-232 methyl 475 M+H 476 M+H 476 M+H hexyl 545 M+H 546 M+H 546 M+H
3.84min 2.84min 2.84min 4.90min 3.90min 3.90min
228 255 241
221 248 234 ethyl 489 M+H 490 M+H 490 M+H octyl 573 M+H 574 M+H 574 M+H
4.00min 3.01min 2.99min 5.37min 4.38min 4.37min
229 256 242
222 249 235 n-propyl 503 M+H 504 M+H 504 M+H (CH3)3CCH2- 531 M+H 532 M+H 532 M+H
4.21min 3.20min 3.19min 4.58min 3.57min 3.58min
219 257 243
223 250 236 i-propyl 503 M+H 504 M+H 504 M+H (CC13)3CCH2- 593 M+H 594 M+H 594 M+H
4.19min 3.17min 3.17min 4.62min 3.62min 3.62min
224 251 237 230 258 244 allyl 501 M+H 502 M+H 502 M+H n-butyl 517 M+H 518 M+H 518 M+H
4.14min 3.12min 3.12min 4.43min 3.43min 3.43min
225 252 238 231 259 245 homo 515 M+H 516 M+H 516 M+H i-butyl 517 M+H 518 M+H 518 M+H allyl 4.31min 3.28min 3.29min 4.41min 3.40min 3.40min
226 253 239 232 260 246 propargyl 499 M+H 500 M+H 500 M+H benzyl 551 M+H 552 M+H 552 M+H
4.06min 3.01min 3.02min 4.59min 3.52min 3.55min
227 254 240 220 247 233
Figure imgf000087_0002
Alternatively, Schemes 7-12 demonstrate the solution phase synthesis practice of this invention with detailed synthetic procedures for representative compounds. -86-
Scheme 7.
)H
OMe +
Figure imgf000088_0001
HC
DEAD, (Ph^P / THF
)H
Figure imgf000088_0002
7-1
1.KOH 2. HCl
)H
HCl •l-feN^
7-2
TMSCI
Figure imgf000088_0003
DIPEA/1, 4-dioxane Br
Figure imgf000088_0004
H -^cft
7-3 -87-
Example 273 2(S)-Benzenesulfonylanι o-3-[2-hydroxy-4-(2-pyrimidm-2-ylamino)- ethoxy]benzoylamino]propionic acid ethyl ester (8-1)
Methyl 4-[2-N-(t-butoxycarbonyl)ethoxy]-2-hvdroxy benzoate (7-1)
Methyl 2, 4-dihydroxy benzoate (14.5g, Aldrich), 2-(N-t-butoxycarbonyl)ethanol (13.9g, Aldrich) and triphenyl phosphine (22.6g, Aldrich) were combined in 350 mL of THF and cooled in ice under N2 atmosphere. Diethyl diazodicarboxylate (DEAD, 15g, Aldrich) was added, the ice bath removed and the reaction mixture allowed to stir at ambient temperature for 15h. The solvent was removed on a rotary evaporator and the residue chromatographed on silica gel (300g, Merck silica 60), elution with CH2C12 to give 18g of methyl 4-[2-N-(t-butoxycarbonyl)ethoxy]-2-hydroxy benzoate, as a viscous oil. NMR (300 MHz, CDC13) δ 11.0 (s, 1 H), 9.5 (d, J = 8Hz, IH), 6.4 (m, 2H), 5.0 (broad, IH), 4.0 (t, J = 5Hz, 2H), 3.91 (s, 3H), 3.54 (m, 2H), 1.45 (s, 9H), MS (+ESI) m/z 334 (M+Na)+.
4-(2-Aminoethoxy)-2-hvdroxybenzoic acid, hydrochloride (7-2)
Ester 7-1 (7.2g) was treated with 5eq. KOH (dissolved in minimum amount of water and equal volume of 1 , 4-dioxane) at room temperature until TLC indicated complete absence of starting material (3-12h). The reaction mixture was acidified (pH = 6) with the addition of IN HCl solution and extracted with ethyl acetate. The extract was washed with saturated aqueous brine solution, dried over MgSO , filtered and concentrated on the rotary evaporator. The crude product (5.34g) was recrystallized from ether, then dissolved in 1, 4-dioxane and treated with an excess of anhydrous
HCl (4M in dioxane, Aldrich). The mixture was allowed to stand at ambient temperature for 24h. Volatile materials were removed in vacuo on the rotary evaporator to give 7-2 as a hydroscopic off-white solid. NMR (400 MHz, DMSO-d6)
6 13.6 (broad, IH), 11.6 (broad, IH), 8.3 (broad, 3H), 7.7 (d, J = 9 Hz, 2H), 6.53 ( , 2H), 4.23 (t, J = 5Hz, 2H), 3.2 (s, broad, 2H). -88-
2-Hydroxy-4-r2-(p ir dme-2ylamino)ethoxylbenzoic acid (7-3)
A mixture of compound 7-2 (20g), dώsopropylethylamine (DIPEA, 74 mL),- trimethylsilylchloride (TMSC1, 21.6 mL) and 2-bromopyrimidine (Lancaster, 13.5g) were combined in 350 mL 1, 4-dioxane at room temperature, then brought to reflux under N atmosphere. After 2 days, an additional 12 mL trimethylsilyl chloride was added, and the mixture continued at reflux for an additional 2 days (until TLC showed no stating material remained). The reaction mixture was cooled to ambient temperature, concentrated to dryness in vacuo on a rotary evaporator and the residue suspended in water. The heterogeneous mixture was refluxed briefly, allowed to cool to room temperature, the product collected on a vacuum filter and air dried to give 15.3g of 7-3, as a tan powder. NMR (400 MHz, DMSO-d6) δ 12 (very broad, 2H) 8.3 (d, J = 5 Hz, 2H) 7.7 (d, J = 9Hz, IH), 7.28 (t, J = 6Hz, IH), 6.57 (t, J = 5Hz, IH), 6.49 (m, 2H), 4.13 (t, J = 6Hz, 2H), 3.62 (q, 2H); MS (+ESI) m/z 276 (M+H)+ ; IR (KBr) v (cm-1) 3275, 3000, 1660, 1625.
A mixture of compound 7-3 (5.5 lg), N-hydroxybenzotriazole hydrate(HOBt»H20, 4.6g, Aldrich), N-methyl morpholine (NMM,8.8 mL) and l-[3-(dimethylamino)- propyl]-3-ethyl carbodimide hydrochloride (DEC, 7.6g, Aldrich) were stirred at room temperature in 60 mL DMF for ~ 0.3 h, followed by the addition of 2(S)- berizenelsulfonylamino-β-alanine ethyl ester (WO9532710, Scheme 2). The mixture was allowed to stir at room temperature for 2 days under N2 atmosphere. Volatile materials were removed in vacuo on a rotary evaporator, and the residue dissolved in ethanol. Twenty grams of silica gel (silica 60, Merck) were added and the solvent removed. Chromatography on 300g of silica gel (ethyl acetate elution, gave 8.1g of the title compound as a pale yellow glass, which upon hardening and pulverizing produced an off-white powder. NMR (400 MHz, DMSO-d6) δ 12.5 (s, IH), 8.68 (t, J = 6Hz, IH), 8.48 (d, J = 9Hz, IH), 8.27 (d, J = 5Hz, IH), 7.73 (m, 2H), 7.64 (d, J = 9Hz, IH), 7.55-7.5 ( , IH), 7.48-7.44 (m, 2H), 7.27 (t, J = 6Hz, IH), 6.58 (t, J = -89-
5Hz, IH), 6.47 (dd, J = 6Hz, 3Hz, IH), 6.42 (d, J = 2Hz, IH), 4.1 (t, J = 6Hz, 2H), 4.05 (q, J = 7Hz, IH), 3.79 (q, J = 7Hz), 3.62 (q, 2H), 3.54 (m, IH), 3.34 (m, IH overlapping with H20 peak), 0.94 (t, J = 7Hz); MS (+ESI) m/z 530 (M + H)+; IR (KBr) v (cm"1) 3400, 1740, 1650, 1580.
-90-
Scheme 8
^%> 0H
H ^—^ OH
7-3
DEC, HOBt, NMM / HCl
HN
S02P
OH o
Figure imgf000092_0001
H ^
"S02Ph
8-1
NaOH /20- 1,4-
OH
OH
Figure imgf000092_0003
HN
"•S02-Ph
N H
Figure imgf000092_0002
HN^ -2
^N H ^SO^h 8
HCl. 8-4
ht/Pd/ HCI-
HCI-
OH
Figure imgf000092_0004
HCl . Cλ N HNA.
S02P»h H
8-3 -91-
Example 274 2(S)-Benzenesulfonylammo-3-[2-hydroxy-4-(2-pyrimidm-2-ylamino)- ethoxy]benzoylamino]propionic acid (8-2).
To a solution of compound 8-1 (8.1g), dissolved in 75 mL 1, 4-dioxane, was added a solution of NaOH (4g) in 75 mL H2O and the reaction mixture was stirred at room temperature for 15h. The mixture was concentrated in vacuo and the residue partitioned between water and dichloromethane. The aqueous phase was acidified with IN aqueous HCl solution to pH 7, which produced a gum precipitate. This material (7g) was absorbed onto 15g of silica gel as in example 1, followed by chromatography on 200g silica gel. Elution with chloroform (90)-methanol (lθ)-acetic acid (0.1) gave the title compound as an amber syrup. MS (-ESI) m/z 500 (M-H)"; [α]D 25 = 6.84 (c. 9.497, methanol). Analysis for: C22H2 NsO7S: Calculated: C, 52.69; H, 4.62; N, 13.96. Found: C, 52.65; H, 4.43; N, 13.6.
Example 275 2(S)-Benzenesuifonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro- pyrimidM-2-ylamino)ethoxy]benzoylamino]propionic acid hydrochloride ( 8-3).
A mixture of compound 8-2 (8g) and 10% Pd/C (lg) was stirred at room temperature in 1, 4-dioxane (125 mL), acetic acid (125 mL), water (50 mL) and concentrated HCl (2 mL) under H2 atmosphere (balloon) for 2 days. Celite was added to the mixture with stirring for 0.25h, and the mixture was filtered through a pad of celite with the aid of isopropanol. The filtrate was concentrated on the rotary evaporator and the residue treated sequentially with (l)warm heptane, then concentrated; (2) 1:1 water -1, 4- dioxane, then filtered and concentrated, followed by vacuum drying in an abderhalden apparatus (isopropanol, reflux) to give the title compound 8-3 (4.7g) as a hygroscopic white powder. NMR (400 MHz, DMSO-d6) δ 12.6 (broad, 2H) 8.77 (broad, IH), 8.2 (broad, IH), 8.1 (broad, 2H), 7.72 (m, 3H), 7.47-7.37 (m, 3H), 6.46 (m, IH), 6.44 (s, broad, IH), 4.07 (t, J = 5Hz, 2H), 3.93 (broad, IH), 3.63 - 3.43 (m, IH), 3.4 - 3.25 O 99/52879
-92-
(m, 2H), 1.9 - 1.77 (m, 2H); IR (KBr) v (cm'1) 3360, 1720, 1580; MS (+ESI) m/z 506 (M+H)+.
Example 276 2(S)-Benzenesulfonylamώo-3-[2-hydroxy-4-(2-pyriιτύdm-2-ylamino)- ethoxy]benzoylamino]propionic acid ethyl ester hydrochloride ( 8-4)
The above acid (8-3) was dissolved in ethanol (25 mL) and concentrated HCl (1 mL).
The mixture was heated to reflux for 15h, concentrated on a rotary evaporator and filtered through a short plug of silica gel with the aid of ethanol to give the title compound as a hygroscopic tan powder. IR(KBr) v (cm'1) 1745, 1690; MS (+ESI) m/z 534 (M+H)+.
Analysis for C24H3ιN5O7S.HCl.
Calculated: C, 50.57; H, 5.66; N, 12.29.
Found: C, 50.71; H, 5.66; N, 12.53
-93-
Scheme 9
Figure imgf000095_0001
7-3
H2 / Pd /C HCl - AcOH
r^NH /=<
HCl . I I / \ //
N ¥ * // OH
9-1
BOP /DMF
Figure imgf000095_0002
σ^ . HCl
Figure imgf000095_0003
O
HCl
Figure imgf000095_0004
H ,- H
9-2 H
Figure imgf000095_0005
HCl / H20
HCl
Figure imgf000095_0006
H ,- 9-3 ft
Figure imgf000095_0007
-94-
Example 277 2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetra- hydropyrirnidm-2-ylamino)ethoxy]benzoylamino]propionic acid ethyl ester hydrochloride (9-2).
2-Hydroxy-4-[2-(3.4.5.6-tetrahydropyriιrύdm-2ylamino) ethoxyl-benzoic acid (9-1).
Compound 7-3 (2g) was combined with 10% Pd/C (0.5g), acetic acid (100 mL) and concentrated hydrochloric acid (0.7 mL). The mixture was stirred at room temperature under an atmosphere of H2 (balloon) for 2 days. Celite was added and the mixture stirred for 0.5h, then filtered through a pad of celite with the aid of isopropanol. Volatile materials were removed on the rotary evaporator and the residue warmed with heptane (~0.5h, 100°C) followed by concentration in vacuo to give 9-1 as a tan foam. NMR (400 MHz, DMSO-d6) δ 12.9 (broad, 2H), 8.25 (s, broad, 2H), 7.85 (t, J = 6Hz, IH), 7.66 (d, J = 9 Hz, IH), 6.48 - 6.41 (m, 2H). 4.07 (t, J = 5Hz, 2H), 3.56 - 3.50 (m, 2H), 3.22 (m, 2H, overlapping with H2O peak), 1.79 (m , 2H); IR (KBr) v (cm 1) 3450 (broad); MS (+ESI) m/z 280 (M + H)+ .
Compound 9-1 (1.58g), 3-arnmo-2(S)-benzyloxycarbonylaminopropionic acid, ethyl ester hydrochloride (1.51g; from the amino acid (Fluka) esterified with HCl in ethanol), N-methyl morpholine (NMM, 1.52g) and benzotriazol-1- yloxytris(dimethylamino) phosphoniumhexafluorophosphate (BOP, 2.2 lg) were combined in 40 mL anhydrous DMF. The mixture was stirred for 48h at room temperature, additional BOP reagent (lg) was added and the reaction stirred for 15h. Volatile materials were removed on the rotary evaporator, the residue dissolved in ethanol and absorbed onto 20g silica gel, and this added to the top of a 200g silica gel column. Flash chromatography, elution with chloroform-methanol-acetic acid
(90:10:1) followed by treatment with an equivalent concentrated aqueous HCl in ethanol and concentration provided the title compound as a hygroscopic tan powder. NMR (400 MHz, DMSO-ds) δ 12.7 (s, IH), 8.85 (t, J = 6 Hz, IH), 8.00 (s, broad, -95-
2H), 7.84 (d, J = 7.5Hz, IH), 7.80 (d, J = 9 Hz, IH), 7.60 (t, J = 6 Hz, IH), 7.32 (m, 5H), 6.49-6.45 (m, 2H), 5.02 (s, 2H), 4.27 (q, IH), 4.06 (m, 4H). 3.66 - 3.55 (m. 2H), 3.49 (m, 2H), 3.23 (m, 4H), 1.79 (m, 2H), 1.10 (t, J = 7 Hz, 3H); IR (KBr) v (cm'1) 3300, 1730, 1650; MS (+ESI) m/z 528 (M+H)+.
Example 278 2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro- pyriirudin-2-ylainmo)ethoxy]berizoylarnino]propionic acid hydrochloride (9-3).
The above ester 9-2 was hydro lyzed to the title compound 9-3 by refluxing (15-24h) IN aqueous HCl solution. When TLC indicated no starting ester remained, the solution was concentrated on the rotary evaporator and the residue treated with warm isopropanol, filtered and concentrated to give 9-3 as a hygroscopic tan powder. MS
(+FAB) m z 500 (M+H)+; [α]D 25 = -7.83 (c. 5.36, MeOH).
Analysis for C24H29N5O7«HCl. H2O; Calculated: C, 52.03; H, 5.82; N, 12.64.
Found: C, 52.02, H, 5.53; N, 12.00.
-96-
Scheme 10
χH OH o
Figure imgf000098_0001
10-1
^
1. LΕC, HOBt, NVM DMF o m H^J- O'
^
-^
H O O OH O
AA 2.FO o^\
Y
Figure imgf000098_0002
3.KDH H^J
Figure imgf000098_0004
Figure imgf000098_0003
o 10-3
10-2 NH
4. HND3- H^J NaHCO I Hp-l,4dioxane
5. HO-EOH
Figure imgf000098_0005
m
Figure imgf000098_0006
-97-
Example 279 3-[4-(2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3- phenylpropanoic acid ethyl ester hydrochloride. (10-4)
Compound 10-1 (1.33g, scheme 7) and β-phenylalanine ethyl ester hydrochloride (1.03g; from ethanol - HCl treatment of β-phenylalanine (Aldrich)) were combined in dichloromethane (20 mL) with DEC coupling agent (0.94g), HOBt (0.75g) and NMM (0.99g). The mixture was stirred at room temperature for 15h. Volatile materials were removed in vacuo on a rotary evaporator and the residue partitioned between ethyl ether and IN aqueous HCl solution. The organic phase was washed with saturated aqueous brine solution, dried over MgSO , filtered and concentrated to give 2.8g of crude coupling product 10-2 (Scheme 10). The N-terrninal Boc group was removed by dissolving the product in a minimum amount of absolute ethanol and adding an equal volume of anhydrous HCl in 1, 4-dioxane (4M, Aldrich). This mixture was allowed to stand at room temperature for 15h, concentrated in vacuo on a rotary evaporator, and treated with an excess of 5 eq. of the theoretical amount of KOH (~1.7g, -85%, Baker) in water (20 mL) at reflux for 24h. The mixture was cooled to room temperature and acidified with IN HCl solution to pH 6. 3,5-Dimethylpyrazol- 1-carboxamidine nitrate (lg, Aldrich) and 0.75g of NaHCO were added and the mixture refluxed for 15h. An additional 0.2g carboxamidine were added, and reflux continued for 3h, when TLC (MeOH:CHCl3:NH4OH (2:8:0.1) indicated complete conversion of 10-3 (lower spot) to product 10-4 (upper spot). The reaction mixture was concentrated on the rotary evaporator, and the residue slurried in a mixture of MeOH-CHCij-NFLiOH (3:7:0.1). Anhydrous Na2SO4 was added and the mixture was stirred at room temperature for 12h, filtered and concentrated to give 3.4g of crude guanidino acid 10-5. This material was chromatographed on silica gel (50g), elution with MeOH-CHCl3-NH4OH (2:8:0.1) to give 0.65g of 10-5, contaminated with inorganic matter (inferred from C,H,N analysis). This material was treated with concentrated HCl ( 0.5 mL) in absolute ethanol (10 mL) at reflux for 15h, cooled to room temperature, concentrated, dissolved in EtOH (95:5), dried (MgSO ), filtered and concentrated to give 0.34g of the title compound as a hygroscopic tan powder. -98-
NMR (400 MHz, DMSO-d6) δ 12.78 (s, IH), 9.15 (d, J = 8Hz, IH), 7.93 (d, J = 9 Hz, IH), 7.84 (t, J = 6 Hz, IH), 7.37 (d, J = 7 Hz, 2H), 7.32 (t, J = 7Hz, 2H), 7.25 (m, IH), 7.1 - 7.6 (broad, 3H), 7.11 (s, broad IH), 6.5 (dd, J = 6 Hz, 2.6 Hz, IH), 6.44 (d, J = 2.6 Hz, IH), 5.48 (q, A portion of an AMX, JAM = 4Hz, IH), 4.07 (t, J = 5Hz, 2H), 4.0 (m, 2H), 3.53 (m, 2H), 3.03 (q, M portion of an AMX, JMχ = 16 Hz, 2H), 2.89(q, X portion of an AMX, JA = 6 Hz, 2H), 1.08 (t, J = 7 Hz, 3H); (KBr) v (cm"1) 3350, 3180, 1745, 1690; MS(+FAB) m/z 415 (M+H)+. Analysis for C21H26N4O5.HC1.0.5H2O Calculated: C, 54.85; H, 6.14; N, 12.18. Found: C, 54.54; H, 6.04; N, 12.58.
Example 280 3-[4-Guanidmoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoic acid, hydrochloride (10-5)
Ester 10-4 was refluxed in IN HCl for 15h. The reaction was cooled and concentrated in vacuo to provide the title compound as a hygroscopic tan powder. MS (-FAB) m z 385 (M-H)'; IR (KBr) v (cm'1) 3350, 3180, 1720, 1590. Analysis for CI9H22N4O5.HCl.H2O Calculated: C, 51.76; H, 5.72; N, 12.71 Found: C, 51.76; H, 5.74; N, 12.77.
-99-
Scheme 11
10-1 + .2 HCl
Figure imgf000101_0001
(J. Org. Chem. 1990,58,7948)
1. DEC, HOBt, NMM / DMF 2. HCL /dioxane
OH O
Figure imgf000101_0003
2 HCl
N" •0' H
H^,
Figure imgf000101_0002
11-1
TMSCI, EtN(i-Pr) 2 /dioxane
OH o
Figure imgf000101_0005
N' H
Y
Figure imgf000101_0004
^ 11-2
Figure imgf000101_0006
HCI-EtOH
OH O
2 HCl
Figure imgf000101_0009
H
Figure imgf000101_0008
Figure imgf000101_0007
11-4 -100-
Example 281 3-[2-Hydroxy-4-[2-(pyrimidώ-2ylamino)ethoxy]-benzoylamino]- 3- pyridine- 3-ylpropionic acid ethyl ester (11-2).
3- [4-(2-ammoethoxy)-2-hydroxy-benzoylamino1-3-pyridine-3-yl-propionic acid ethyl ester dihydrochloride (11-1).
Compound 10-1 (2.05g; see Scheme 1), 3-amino-3-(pyridine-3yl, propionic acid ethyl ester dihydrocloride (1.84g; see J. Org. Chem. 1993, 58, 7948), NMM (2.58g). HOBt (1.16g), and DEC (1.45g) were combined in dichloromethane (50 mL) and stirred at room temperature for 60 h. Volatile materials were removed on the rotary evaporator, the residue partitioned between ether and H2O, the organic phase washed with saturated aqueous brine solution, dried over MgS0 , filtered and concentrated to give 3.52g of crude coupled product, which was dissolved in a minimum amount of ethanol and treated with an excess of 4M HCl in anhydrous dioxane (Aldrich). After standing overnight (-15 h), volatile materials were removed on the rotary evaporator to give 3.3 lg of 11-1. NMR (400 MHz, DMSO-d6) was consistent with the structure of 11- 1; MS (+ FAB) m/z 374 (M + H)+.
Compound 11-1 (3.31g), 2-bromopyrimidine (1.1 lg, Lancaster) and DIPEA (7.5 mL) were combined in dioxane (50 mL) at room temperature under N2. Chlorotri- methylsilane (1.89 mL) was added and the mixture was brought to reflux. Stirring continued at this temperature for 4 days. The mixture was concentrated on the rotary evaporator, and the residue partitioned between aqueous HCl solution and chloroform. The aqueous phase was concentrated to a dark oil and the pH adjusted to 7 with aqueous ammonia. Volatile materials were removed in vacuo and the residue chromatographed on 200g of silica gel, elution with ethyl acetate to give 1.37g of the title compound, as an off-white powder. NMR (400 MHz, DMSO-dή) was consistent with the structure of 11-2; (KBr) v (cm'1) 1720; MS (+FAB) m/z 452 (M+H)+. Analysis for C23H25N5O5.O.5H2O Calculated: C, 59.99; H, 5.69; N, 15.21 Found: C, 60.45; H, 5.61; N, 14.79. -101-
Example 282 3-[2-Hydroxy-4-[2-(3, 4, 5, 6 - tetrahydropyrir dme-2ylamino)- ethoxy]benzoylamino]-3-pyridin-3-ylpropionic acid (5-3).
A mixture of compound 11-2 (0.9g) and KOH (0.34g) were stirred in water-dioxane mixture (1: 1) at room temperature. When TLC (EtOAc) showed complete absence of starting ester, solvents were removed on the rotary evaporator, 10% Pd/C (0.2g, Aldrich) was added and the mixture suspended in acetic acid (20 mL), dioxane (10 ml), water (5 ml) and concentrated HCl (0.6 mL). The mixture was stirred at ambient temperature under H atmosphere (balloon) for 2 days. Celite was added, and the mixture stirred 0.25h, filtered through a pad of celite with the aid of dioxane-water (1:1), and concentrated. The residue was chromotographed on silica gel (25g). elution with chloroform-methanol-ammonium hydroxide (7:3:0.1) to give the title compound 11-3 as an off-white hygroscopic powder. NMR (400 MHz, DMSO-d6 + D2O) was consistent with the structure 11-3; IR (KBr) v (cm"1) 3400, 1650 (broad), 1580; MS (+FAB) m/z 428 (M+H)+.
Example 283 3-[2-Hydroxy-4-[2-(3, 4, 5, 6 -tetrahydropyrimidin - 2-ylamino)ethoxy] benzoylamino]-3-pyridin-3-ylpropionic acid ethyl ester dihydrochloride (11-4).
A sample of the above zwitterion 11-3 (0.285g) was esterified with absolute ethanol- HC1 mixture at reflux. Concentration on the rotary evaporator gave the title compound 11-4. NMR (400 MHz, DMSO-d6) δ 12.55 (s, broad, IH), 9.5 (d, J = 8Hz, IH), 8.94 (d, J = 2Hz, IH), 8.73 (m, IH), 8.48 (d, J = 2 Hz, IH), 8.73 (m, IH), 8.48 (d, J = 8 Hz, IH), 8.1 (s, broad, 2H), 7.99 (d, J = 9 Hz, IH), 7.86 (m, IH), 7.68 (t, J = 6Hz, IH), 6.5 (d, J = 2 Hz, IH), 6.47 (m, IH), 5.58 (q, A portion of an AMX, JAM = 14 Hz, IH), 4.08 - 4.0 (overlapping m, 4H), 3.5 (m, 2H), 3.25 - 3.19 (overlapping m, 3H), 3.09 (q, X portion of an AMX, JMX = 16 Hz, JAX = 6 Hz, IH), 1.79 (m, 2H), 1.08(t, J = 7 Hz, 3H). Analysis for C23H29N5O5«2HC1.0.7 H2O. Calculated: C, 51.39; H, 6.00; N, 13.03. Found: C, 51.40; H, 6.01; N, 12.56. ■102-
Scheme 12
OB rV
Figure imgf000104_0001
N
12-1
1. NaOH, H2O,
2. EtOH,
rV
Figure imgf000104_0002
N
12-2 a or
^
Figure imgf000104_0003
H^O
12-3 α,
H>, Pd/C,
Figure imgf000104_0004
a) KOH, 2O, then 2O; ιoHι5(CH2nO(CO) όH4NQ, 3CN, then
HR-MS FAB m/z for C26H34N4O8 calcd.531.2455 (M++1), obsd.531.2459. O 99/52879
-103-
Example 284 2(S)-2-tert-Butoxycarbonylamino-3-{2-hydroxy-4-[2-( 1,4,5,6- tetrahydroρyrinιidm-2-ylam o)ethoxy]-benzoylamino}propionic acid, (12-4) acetic acid salt.
Compound 12-1 (2.43g, scheme 12; obtained as for compound 8-1, Scheme 8, by substituting 2(S)-2-benzyloxycarbonylamino-3-amino propionic acid ethyl ester (from esterification of the acid (Fluka) using EtOH-HCl) for 2(S)-2-phenylsulfonylamino-3- amino propionic acid) and NaOH (4g) in 1 ,4-dioxane-water (-1: 1) were refluxed for 1.5h. The mixture was cooled and volatile materials removed on the rotary evaporator. The residue was neutralized with aqueous IN HCl and stirred overnight at room temperature. The precipitate was collected by vacuum filtration, re-esterified (EtOH-HCl, reflux), and chromatographed on silica gel, elution with CHCl3,/MeOH/HOAc (90: 10: 1→80:20:2) to give 850 mg of 12-2, as a tan powder.
The ester 12-2 (0.5g) was hydro lyzed with excess KOH in dioxane-H2O at room temperature. When TLC analysis indicated an absence of starting material, an excess of di-tert-butyl dicarbonate was added and the mixture stirred at room temperature until complete by TLC. The mixture was concentrated on the rotary evaporator and the residue chromatographed on silica gel, elution with CHCl3/MeOH/NH OH
(90:1:1→80:20:2) to give 200 mg of 12-3. This material was dissolved in a minimum amount of acetic acid, then diluted with an ~ volume of dioxane-H2O (2:1). Hydrogenation (5% Pd C (catalytic), H2, balloon, it,) was complete within 2 days. The catalyst was filtered, and the filtrate concentrated on the rotary evaporator. The residue was stirred/concentrated sequentially with heptane and isopropanol, dissolved in CHC1 and treated with a mixture of activated charcoal and celite, filtered and concentrated to give the title compound 12-4 (0.18g) as a fine buff powder. NMR (400 MHz, DMSO-de) δ 8.85 (broad, IH), 8.6 (broad, IH), 8.4 (broad, IH), 7.68 (d, J = 8.8 Hz, IH), 6.47(overlapping peaks, 2H), 6.4 (d, J = 8.8Hz, IH) 4.02 (t, broad, 2H), 3.88 (m, IH), 3.45 (m, overlapping, 4H), 3.23 (m, broad, 4H), 1.9 (s, 3H), 1.8 -104-
(m, broad, 2H), 1.35 (s, 9H); IR (KBr) v (cm"1) 3400 (broad), 1710, 1640; MS (ESI-) m/z 464 (M-l)+. Analysis for C2ιH31N5O7»HOAc»H2O Calculated: C, 50.82; H, 6.86; N, 12.88 Found: C, 50.96; H, 6.56; N, 12.11 HPLC analysis of purity: 96.8%
In like manner, examples 284-315 (Table 14) were prepared, using the synthetic methods outlined above, as indicated by scheme numbers in the table. All final products were characterized as in Examples 1-283, and had spectra consistent with the assigned structures.
Am = Amidino
Pyr = pyriιτιidin-2-yl
Table 14. Examples 284-315 Thp = letrahydropyrimidinc δi
Ph = phenyl 00
G Py = 3-pyridin-3-yl -α Cbz = bcnzyloxycarbonyl
Figure imgf000107_0001
Example Synth. No. # G R1 R2 R1 R4 R5 Method Description
284 4 Am J H H Py II Et 10 brown powder
285 4 Am 1 H H Py H H 10 buff powder
286 4 Pyr 1 H H Py H H 11 yellow powder
287 4 Pyr 1 H H Ph H H 8 yellow powder σ
288 4 Pyr 1 H H Ph H Et 8 white wax cn i
289 5 Pyr 1 H H Ph II H 8 tan powder
290 5 Pyr 1 H H Ph H Et 8 gold powder
291 4 Thp 1 H H Ph H H 8 buff powder
292 4 Thp 1 H H Ph H Et 8 buff powder
293 5 Thp H H Ph H H 8 buff powder
293 5 Thp H H Ph H Et 8 tan powder
295 4 Thp II H II NH2 H 8 off-white powder
296 4 Pyr 1 H H H NHCbz Me 8 white powder O
297 4 Pyr 1 II H 11 NHCbz II 8 crystalline white powder »5
298 4 Pyr 1 Me H H NHSO2Ph H 8 yellow powder © — . 00
Figure imgf000107_0002
299 4 Pyr 1 H H H NHCbz Et 8 white solid mpl 24- 125°C 00
©
Table 14 (Continued) O
300 5 Thp 3 H H Ph II II 12 bu f powder
301 5 Pyr 3 H I I Ph H Et 8 fused golden powder
302 5 Pyr 3 II II Ph H H 8 fine tan powder
303 5 Pyr 4 H H II NHSO2Ph H 8 fine off-white powder
304 5 Thp 4 11 H II NHSO2Ph Et 8 fused tan solid
305 5 Thp 4 H H H NHSO-Ph H 8 fine buff powder
306 4 Pyr 3 H H H NHSO2Ph H 8 fine white powder
307 4 Thp 3 II H H NHSO2Ph Et 8 fused tan solid
308 4 Thp 3 II H H NHSO2Ph H 8 white powder
309 5 Thp 3 H H Ph H Et 8 off-white powder σ
310 4 Thp 2 H H H NHSO2Ph i-Pr 8a fine white powder
31 1 4 Thp 2 II H H NHSO2Ph t-Bu 8b fine off-white powder
312 4 Thp 2 H H II NHSO2Ph (CH2)20 8C tan wax
(CH2)2NH-
BOC
313 4 Thp 2 II H II NHCO H 12 fine tan powder CH2CH2CUIH,5
*ϋ
314 4 Thp 2 11 I I 11 NHCO2C,„Π,, I I 12 fin tan powder
315 4 Thp 2 11 I I I I NHSO2Ph H2N-C 8d Ian powder CΛ (CH2OH)3 .
Figure imgf000108_0001
1 o
•107-
Vitronectin Receptor αvβ3 Binding Assay
The purpose of this assay is to measure the effect of various compounds on the αvβ3 - ligand interaction.
Reagents
Plasma Membrane Isolation: 15 confluent T150 flasks of 512P5 cells (αvβ - overexpressing cell line) are washed 2X with Dulbecco's phosphate buffered saline (D-PBS) without calcium or magnesium, pH 7.1. Cells are harvested with 10 mL of trypsin/EDTA and collected by centrifugation. The cell pellet is washed 2X with 0.5 mg/mL of soybean trypsin inhibitor, and resuspended at 10% weight/volume in homogenization buffer (25 mM Tris-HCl, pH=7.4; 250 mM sucrose). The cell suspension is homogenized with 2x30 seconds bursts of a Polytron homogenizer. The homogenate is centrifuged at 3000g for 10 minutes at 4 C. The supernatant is collected, measured, and made 100 mM in NaCl and 0.2 mM in MgSOφ The supernatant is centrifuged at 22,000g for 20 minutes at 4
C, the pellet is resuspended in 7 mL of membrane buffer (25 mM Tris- HCl, pH=7.4; 100 mM NaCl; 2 mM MgCl2) by 5 strokes of a Dounce homogenizer (tight pestle) and recentrifuged at 22,000g for 20 minutes at '4 C. The pellet is resuspended in 0.5 mL/flask of membrane buffer (stock membranes) and frozen at -80C. Prior to use, stock membranes are Dounce homogenized and diluted 2 μL to 1000 μL in membrane buffer.
Compound Dilution: The stock compounds are dissolved in an appropriate vehicle (typically DMSO) and subsequently diluted in assay buffer composed as follows: 25 mM Tris-HCl ( pH=7.4), 100 mM NaCl, 2 mM MgCl2, 0.1 % BS A.
Plate Preparation
Wells of Multiscreen-FB assay plates (Millipore MAFB NOB
50) are blocked with 150 mL of 0.1% polyethyleruiriine for 2 hours at -108-
4° C. Following incubation the wells are aspirated and washed with isotonic saline solution.
Binding Assay
125 μL of assay buffer is added to each well. Next, 25 μL of labeled ligand is added to each well. 25 μL of unlabeled ligand is added to non-specific binding wells (NSB). 25 μL of assay buffer is added to all other wells. 2 μL of compound is added to appropriate sample wells, and 2 μL of DMSO is added to NSB and total binding (TB) wells. Finally, 25 μL of membrane is added to each well.
The plates are covered and incubated at 37° C for 2 hours in a humidified incubator. Wells are aspirated on a Miϋipore vacuum manifold, and the wells are washed with 150 μL isotonic saline solution. Wells are again aspirated. The plates are then dried for 1 hour in an 80° C vacuum drying oven. Plates are placed on a MiHipore filter punch apparatus, and filters are placed in 12 x 75 mm polypropylene culture tubes. The samples are counted on a Packard gamma counter.
Example
Using 125I- Echistatin (specific activity = 2000 Ci/mmol) supplied by Amersham at a final concentration of 50pM, the following parameters are routinely observed:
Input 80000 cpm
Total Counts 8000 cpm
Non-specific binding 200 cpm
Analysis of Results:
The individual well activity is expressed as a percentage of the specific binding; % Max, and reported as the mean + standard deviation. Dose-inhibition relationships are generated for dose (X-axis) vs. % Max (Y-axis) for active compounds using a non-linear regression -109-
computer program (PS-NONLIN), and IC50 values with corresponding 95% confidence intervals are estimated from 50% of maximal attachment. Results are shown in Table 15 (VnR).
Reference Compounds:
Various Arginine-Glycine-Aspartic Acid (RGD)-containing peptides were assessed for the ability to inhibit avb binding and the corresponding IC50 values with 95% confidence intervals were generated; peptide structures are given by the standard single letter designation for amino acids. Values obtained compared favorably with adhesion assay results.
Peptid IC50 (μM) 95% Confidence Interval
GPenGRGDSPCA 0.064 0.038 to 0.102
GRGDSP 1.493 1.058 to 2.025
GRGDTP 0.490 0.432 to 0.556
GRGDS 0.751 0.690 to 0.817
RGDS 1.840 1.465 to 2.262
GRGDNP 0.237 0.144 to 0.353
GdRGDSP 0.692 0.507 to 0.942
GRGESP inactive at 100 μM
Figure imgf000111_0001
References
1. Nesbitt, S. A. And M. A. Horton, (1992), A nonradioactive biochemical characterization of membrane proteins using enhanced chemiluminescence, Anal. Biochem., 206 (2), 267-72.
Osteopontin- αvβ3 Cell Attachment Assay
The purpose of this assay is to measure the effect of various compounds on the RGD-dependent attachment of cells to osteopontin mediated by the αvβ3 integrin. O 99/52879
-110-
Reagents
Cell Suspension Media: The cells are suspended for assay in the tissue culture media used for normal culture maintenance buffered . with 25 mM HEPES (pH 7.4) without serum supplementation.
Compound Dilution Media: The stock compounds are dissolved in an appropriate vehicle (typically DMSO) and subsequently diluted in the tissue culture media used for normal culture maintenance buffered with 25 mM HEPES (pH 7.4) supplemented with 0.2% BSA (no serum); final vehicle concentration is < 0.5%.
Plate Preparation
Human recombinant osteopontin (prepared such as described in Stubbs, J. Ill, Connective Tissue Research. 1996, 35 (1-4), 393-399 is diluted to an appropriate concentration in Dulbecco's phosphate buffered saline (D-PBS) without calcium or magnesium, pH 7.1. 100 mL of this solution is incubated in the wells of PRO-BIND assay plates (Falcon 3915) for 2 hours at 37° C. Following incubation the wells are aspirated and washed once with D-PBS; plates can either be used immediately or stored for up to 1 week at 4° C. Prior to assay, the wells are blocked with 1% bovine serum albumin (BSA) in cell suspension media for 1 hour at 37° C. Following the blocking period, wells are aspirated and washed once with D-PBS.
Cell Suspension
αvβ3-expressing cell lines are maintained by standard tissue culture techniques. For assay, the cell monolayer is washed three times with D-PBS, and the cells are harvested with 0.05% trypsin/0.53 mM EDTA (GIBCO). The cells are pelleted by low-speed centrifugation and washed three times with 0.5 mg/mL trypsin inhibitor in D-PBS (Sigma). The final cell pellet is resuspended in cell suspension media at a concentration of 10° cells/mL. -111- Attachment Assay
Incubation: 100 mL of diluted test compound is added to osteopontin-coated wells (in triplicate) followed by 100 mL of celL. suspension; background cell attachment is determined in uncoated wells. The plate is incubated at 25° C in a humidified a atmosphere for 1.5 hours. Following the incubation period, the wells are gently aspirated and washed once with D-PBS.
Cell Number Detection: The number of cells attached is determined by an MTT dye conversion assay (Promega) according to the manufacturer's instructions. Briefly, MTT dye is diluted in cell suspension media (15:85) and 100 mL is added to each well. The assay plates are incubated for 4 hours at 37° C in a humidified 5% CO2/95% air atmosphere, followed by the addition of 100 mL stopping/solubilization solution. The assay plates are covered and incubated at 37° C in a humidified air atmosphere overnight. After the solubilization period, the optical density of the wells is measured at a test wavelength of 570 nM with a reference measurement taken simultaneously at 630 nM.
Analysis of Results: The individual well optical density is expressed as a percentage of the maximal attachment (% Max) wells minus background attachment, and reported as the mean + standard deviation. Dose- inhibition relationships are generated for dose (X-axis) vs. % Max (Y- axis) for active compounds using a non-linear regression computer program (PS-NONLIN), and IC50 values with corresponding 95% confidence intervals are estimated from 50% of maximal attachment. Results are shown in Table 16 ("cell").
Reference .Compounds:
Various Arginine-Glycine-Aspartic Acid (RGD)-containing peptides, and monoclonal antibodies (Chemicon, Temecula, CA) were assessed for the ability to inhibit osteopontin-avb3 attachment and the corresponding IC50 values with 95% confidence intervals were generated in the SK-MEL-24 human malignant melanoma cell line; -112-
peptide structures are given by the standard single letter designation for amino acids:
Peptide IC50 (95% Confidence Interval)
GPenGRGDSPCA 0.58 mM (0.51 TO 0.67) n-Me-GRGDSP 4.0 mM (3.4 TO 4.7)
GRGDSP 4.1 mM (3.4 TO 4.9)
GRGDTP 5.2 mM (3.4 TO 4.9)
Antibody Dilution % Maximal Attachment
(mean + SD) vβ5 (P1F6) 1:1000 11 1 ± 3.3
1:100 112 ± 2.6
1:10 111 ± 3.3
vβ3 (LM609) 1: 1000 0
Figure imgf000114_0001
1: 100 5.1 + 1.7
Literature References:
Ruoslahti, R. Fibronectin and its receptors. Ann. Rev. Biochem. 57:375-413, 1988.
Hynes, R.O. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell. 69: 11-25, 1992. ■113-
Osteoclast Pitting Assay
The assay is conducted as described in Murrills and Dempster (1990). Briefly ,- 4 x 4 x 0.2mm skces of devitalized bovine cortical bone are numbered, placed in the wells of 96- well culture plates and wetted with lOOul of Medium 199 containing Hanks salts, lOmM HEPES, pH 7.0 (Medium 199/Hanks). Bone cell suspensions containing osteoclasts are prepared by mincing the long bones of neonatal rats (Sprague-Dawley , 4-6 days old) in Medium 199 Hanks. IOOUL of the suspension is then plated onto each slice and incubated 30 minutes to allow osteoclasts to adhere. The slices are rinsed to remove non-adherent cells and incubated 24h in Medium 199 containing Earle's salts, lOmM HEPES and 0.7g/L NaHCO3, which equilibrates at pH 6.9 in a 5% CO2 atmosphere. At this pH the adherent osteoclasts excavate an adequate number of resorption pits for assay purposes. Skces are fixed in 2.5% glutaraldehyde and osteoclasts counted following tartrate-resistant acid phosphatase staining. In experiments in which osteoclast numbers are significantly reduced in a particular treatment, a check is made for non-specific cytotoxicity by counting the number of contaminant fibroblast-like cells following toluidine staining. All cells are stripped from the skce by sonication on 0.25M NH4OH and the resorption pits formed by the osteoclasts during the experiment stained with toluidine blue. Resorption pits are quantified by manually counting.
Statistics
The experiments are conducted according to a block design with osteoclasts from each animal exposed to each treatment. Three repkcate slices are used per treatment per animal, such that a total of 96 slices are examined for an experiment involving four animals and eight treatments (including control). Several parameters are recorded on a "per slice" basis: number of pits, number of osteoclasts, number of pits per osteoclast, number of fibroblast-like bone cells. SAS or JMP statistical software is used for statistical analysis. If analysis of variance reveals significant effects in the 99/52879
-114- experiment, those treatments differing significantly from control are identified using Dunnett's test. IC50S are calculated for active compounds using dose-response curves. Results are shown in Table 16 ("Bone Pitting"). _
Reference Compound: Rat calcitonin. Clinical Relevance:
Osteoclasts are responsible for the bone loss that occurs in the onset of osteoporosis and anti-resorptive drugs d ected against the osteoclast are a requ ement for patients losing bone. Calcitonin and bisphosphonates, both used as anti-resorptives in the clinic, show significant osteoclast inhibitory activity in this assay. Hence it is a reasonable assay in which to identify novel anti-resorptives.
Reference: Murrills and Dempster (1990) Bone 11:333-344.
Effects of test compounds on PTH-induced hypercalcemia of thyro- parathyroidectomized male rats.
Male thyro-parathyroidectomized (TPTX) rats (Charles River) were randomly assigned to groups of 7 rats/group. Following a baseline serum calcium determination an Alzet 1003D minipump (Alza Corporation, Palo Alto, CA) loaded with 0.3 mg/ml PTH (Bachem, Philadelphia, PA) was implanted subcutaneously in each rat. For evaluation of prophylactic effects of a test drug, another minipump with appropriate concentration of the test drug solution was implanted subcutaneously at a site away from PTH minipump. Alternatively, test drugs were administered by oral gavage as a solution or uniform suspension in an appropriate medium depending on the physical properties of the test compound. A group of 7 unimplanted TPTX rats was set aside as a normal control group. Twenty hours after minipump implantation blood was collected from each rat to confirm the presence of hypercalcemia (judged by elevation of serum calcium levels, 2 SD > normal non-implanted level). At various intervals between 0.5 and 24 hours after dosing (usually one to three time points), blood was collected from each rat and the serum evaluated for total calcium. Serum calcium levels were measured using the Nova 7 + 7 calcium auto analyzer spectrophotometrically using the Sigma test kit (#587 A). Test results were -115- determined by the difference in serum calcium between vehicle and treatment group following PTH administration, using a one-way analysis of variance with Dunnett's test or other multiple comparison methods. Results are shown in Table 17.
References:
1. Takeuchi M, Sakamoto S, Kawamuki K, Kudo M, Abe T, Fujita S, Murase K, and Isomura Y, (1990). Synthesis and structure activity relationship of new bisphosphonate derivative. Abstract #53, 199th American Chemical Society Meeting, Boston, MA.
2. Fisher J, Caulfield M, Sato M, Quartuccio H, Gould R, Garsky V, Rodan G. Rosenblatt M, (1993). Inhibition of osteoclastic bone resorption in vivo by echistatin, an "arginyl-glycyl-aspartyl" (RGD) -containing protein . Endocrinology, Vol. 132 (3) 141 1-1413.
Table 15 Representative Biological Data
Example VnR (IC50μM) Example VnR(IC50μM)
1 0.0241 137 >luM
2 0.187 138 0.361
3 0.123 139 >luM
4 0.095 140 0.0978
5 0.061 141 >luM
6 0.108 142 1.6
7 0.092 143 4.79
8 >luM 144
9 0.11 145
10 0.061 149
1 1 0.0696 150
12 0.0661 151
13 0.1828 152
14 0.0445 153 2.4
Figure imgf000117_0001
879
-116-
Example VnR (ICsoμM) Example VnR(IC50μM)
15 154
16 155
17 156 0.25
18 157
19 158 4.6
20 1.437 159 2
21 1.516 160 0.97
22 161 0.9
23 1.0216 162 1.1
24 1.48 163 1.1
25 0.6743 164 0.61
26 165 0.39
27 0.3308 166 0.8
28 0.159 167 2.6
29 0.405 168
30 1.27 169
31 0.261 170
32 171
33 172
34 173 4.28
35 174 3.89
36 175 3.8
37 176 2.14
38 177 4.87
39 178 3.13
40 179 >luM
41 180 19.46
42 181 19.72
43 182 40.88
44 183 4.98
45 184 17.88
46 185 4.57
47 186 6.99
Figure imgf000118_0001
879
-117-
Example VnR (ICsoμM) Example VnR(ICsoμM)
48 187 19.46
49 188 12.14
50 189 6.87
51 190 >luM
52 191 >luM
53 34 192 >luM
54 34 193 >luM
55 100.6 194 >luM
56 85.8 195 >luM
57 196 5.7127
58 100 197 >luM
59 100 198 >luM
60 199 14.694
61 200 >luM
62 100 201 13.215
63 202 >luM
64 203 14.136
65 100 204 7.4788
66 100 205 >luM
67 100 206 >luM
68 100 207 >luM
69 100 208 >luM
70 100 209 >luM
71 >luM 210 >luM
72 >luM 211 >luM
73 >luM 212 13.066
74 >luM 213 >luM
75 214 2.3125
76 215 >luM
77 216
78 >luM 217
79 >luM 218
80 >luM 219 1.8
Figure imgf000119_0001
•118-
Example VnR (IC50μM) Example VnR(IC5flμM)
81 >luM 220 8.8
82 >luM 221 22.8
83 >luM 222 20.8
84 223 5.5
85 >luM 224 4.1
86 >luM 225 5
87 >luM 226 5.2
88 >luM 227 5.1
89 228 10.2
90 >luM 229 17.1
91 >luM 230 4
92 >luM 231 6.7
93 >luM 232 3.7
94 >luM 233 3.3
95 0.105 234 8.7
96 0.1 19 235 3
97 0.77 236 1.9
98 0.15 237 2.7
99 0.088 238
100 0.079 239 2.1
101 0.094 240
102 0.069 241 4.1
103 0.21 242 7.9
104 0.086 243 0.69
105 0.135 244 1.6
106 0.114 245
107 0.13 246 1.6
108 1.105 247 5.5
109 0.251 248
110 0.544 249
11 1 0.856 250
112 1.092 251
113 3.026 252
Figure imgf000120_0001
-119-
Example VnR (IC50μM) Example VnR(ICsoμM)
1 14 3.139 253
115 0.258 254
116 2.761 255 5.31
1 17 1.518 256 9.08
118 >luM 257 1.26
119 >luM 258 4.31
120 >luM 259
121 >luM 260
122 >luM 261 20.18
123 >luM 262 12.64
124 0.734 263 29.03
125 >luM 264 59.27
126 >luM 265 12.88
127 0.9546 266 29.57
128 >l uM 267 10.16
129 0.6349 268 33.44
130 >luM 269 21.23
131 0.4055 270 21.66
132 0.9625 271 13.7
133 >luM 272 10.63
134 >luM 273
135 >luM 274
136 >luM 275
276
277
278
279 0.013
280 12.3
281 inactive
282 -42% @ 100
283 123
284 inactive
285 5
Figure imgf000121_0001
-120-
Example VnR (ICsoμM) Example VnR(IC50μM)
286 2.8
287 0.26
288 0.003 bone pining IC 0=0.44 μM
289 inactive
290 0.334
291 0.44
292 0.115
293 0.006
294 0.0035
295 0.0018
Figure imgf000122_0001
Table 16. In Vitro Biological Data
Example IC50 (μM) No. Cell A Bone Pitting B
280 78 inactive @200
297 50 25
277 0.05 0.4
278 0.02 0.5
274 18 0.9
293 48
276 0.12 0.15
291 28
275 0.002 0.43
299 inactive @ 100 1.9
298
285 56
286 86
282 33
Figure imgf000122_0002
289 34
A Osteopontin - θvβ3 Cell Attachment Assay B Osteoclast Pitting Assay -121-
Table 17. In Vivo Biological Data
Example TPTX dose (mg/kg, No. (% inhibition) route)
292 111 * 100. s.c.
279 59 100. s.c.
273 57 100. s.c.
277 86* 100. s.c.
79* 100, p.o.
276 170* 100, s.c.
274 54* 100. s.c.
275 1 12* 100. s.c.
(64) 30, s.c.
105* 75. s.c.
39 100, p.o.
291 41 100. s.c.
Figure imgf000123_0001
299 102* 100, p.o.
* p< 0.05 when compared to vehicle control
The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and salts with organic acids such as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium calcium or magnesium. The compounds of the present invention can also be used in the form of esters at the C-terminus; carbamates, amides and the like at the N-terminus or other conventional "pro-drug" forms which, when administered, convert to the active moiety in vivo.
Compounds of the present invention may be administered in combination with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene -122- glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils. Adjuvents customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. These compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. When administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions, formulations may contain, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, or elixirs containing, for example, from about 20 to 50% ethanol, and the like. When administration is parenterally, formulation may be, for example, sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% by weight of active ingredient in combination with a carrier, and more preferably between about 5% and 60% by weight of active ingredient.
The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are sokd compositions, particularly tablets and hard- filled or Uquid-filled capsules. Oral administration of the compounds is preferred.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release release form. Preferably, the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response as would be -123-
appreciated by one skilled in the art. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

Claims

-124-CLAIMSWhat is claimed is:
1. Compounds of the formula
Figure imgf000126_0001
wherein:
G is
O
A l\ i x?R7 ^ Cl
Figure imgf000126_0002
Hi
Figure imgf000126_0003
╬┤ lf i ff H ^N w /Γûá
^ r H r H ' ^ H ^rf ^l
R and R" are independently, hydrogen, alkyl of 1 to 6 carbon atoms, mono or bicyckc aralkyl of 6 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
R3 is hydrogen, mono or bicyclic aryl of 6 to 10 carbon atoms, 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O;
R4 is hydrogen, NHR9, OR9, NHCO2R9, NHCONHR9, NHCOR9or NHSO2R9; provided that R3 and R4 are not both hydrogen; -125-
R5 is hydrogen, or alkyl of 1 to 6 carbon atoms, optionally substituted with a terminal group forming a prodrug;
R6 and R7 are independently hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or aralkoxy of 6 to 10 carbon atoms;
R8 and R9 are independently hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to
10 carbons, alkynyl of 2 to 10 carbons, mono or polycycloalkyl of 3-12 carbon atoms, mono or polycycloalkyl-alkyl of 4-12 carbon atoms, mono or bicyclic aryl of 6 to 10 carbon atoms, 6 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O, mono or bicycuc aralkyl of 7 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyckc heterocycloalkyl having 1 to 3 heteroatoms selected from S. N and O and an alkyl of 1 to 6 carbon atoms;
n is an integer from 1 to 4; and m is 0 or 1; or a pharmaceutically acceptable salt thereof.
2. Compounds of Claim 1 wherein G is 6-aminopyridin-2yl. pyridin-2yl, pyrimidin-2yl. tetrahydropyrimidin-2yl, tetrahydropyrimid-4-one-2yl, imidazol-2yl, 5- amino l,2,4-triazol-4-yl , dihydroimidazol-2yl, airimo(imino). pyridyl-urea or benzyl- urea.
3. Compounds of Claim 2 wherein G is pyridin-2yl, imidzazolyl-2yl, 5-amino l,2,4-triazol-4-yl, or tetrahydropyrimidinyl.
4. Compounds of Claim 1 wherein Ri and R2 are hydrogen.
5. Compounds of Claim 1 wherein R is hydrogen, phenyl, or pyridyl.
6. Compounds of Claim 1 wherein Rj is hydrogen or HNSO2phenyl, HNSO alkyl or NHCO benzyl or NHCO2neopentyl, NHCO2adamantyl, NHCO2CH2adamantyl, NHCONHphenyl, NHCONHbenzyl, NHCONHalkyl, NHCOphenyl, NHCObenzyl, NHCOalkyl, NHCOadamantyl. -126-
7. Compounds of Claim 1 wherein G is pyridin-2yl, 6-aminopyridin-2yl, 5-amino l,2,4-triazol-4-yl or imidazol-2yl or dihydroimidazol-2yl or tetrahydropyrimidin-2yl, Ri, R2 and R are hydrogen, j is NHSO phenyl, NHCO2benzyl, NHCO neopentyl and R5 is hydrogen or alkyl of 1 to 3 carbon atoms.
8. Compounds of Claim 1 wherein G is pyridin-2yl, 6-aminopyridin-2yl 5-amino l,2,4-triazol-4yl, irnidazol-2yl, dihydroimidazol-2yl, or tetrahydropyrimidin-2yl, R R and R are hydrogen, R3 is phenyl or pyridyl and R5 is hydrogen or alkyl of 1 to 4 carbon atoms.
9. Compounds of Claim 1 wherein n is 2 or 3.
10. A compound of Claim 1 where G is 1,4,5,6-tetrahydropyrimidyl and P is NHCO2R9.
1 1. A compound of Claim 1 , which is:
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl}- am o)-2-[(methoxycarbonyl)amino]propanoic acid;
(2S)-2-[(ethoxycarbonyl)amino]-3-( {2-hydroxy-4-[2-( 1,4.5, 6-tetrahydropyr imidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr irnidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(propoxycarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrirnidin-2-ylamino)ethoxy]benzoyl}- amino)-2-[(isopropoxycarbonyl)amino]propanoic acid;
(2S)-2- { [(allyloxy)carbonyl] amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin- 2-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-{ [(but-3-enyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidm-2-ylammo)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2- { [(hexyloxy)carbonyl] amino }-3-({ 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrirrύdm-2-ylamino)ethoxy]benzoyl}- amino)-2- { [(octyloxy)carbonyl]amino Jpropanoic acid; -127-
(2S)-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidm-2-ylamino)ethoxy]benzoyl}- amino)-2-{ [(neopentyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyri╬╣rkdm-2-ylamino)ethoxy]benzoylJ- amino)-2-{ [(2, 2,2-trichloroethoxy)carbonyl]amino Jpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr imidm-2-ylamino)ethoxy]benzoylJ- amino)-2-[(butoxycarbonyl)amino]propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5.6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl J - amino)-2-[(isobutoxycarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1.4,5, 6-tetrahydropyrimidin-2-ylamino)ethoxy]be nzoylj - amino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid; or
(2S)-2- { [(benzyloxy)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl}amino)propanoic acid, or pharmaceutical salts thereof.
12. A compound of Claim 1 wherein G is 1,4,5,6-tetrahydropyrimidyl and ; is NHCONHR9.
13. A compound of Claim 1 which is: (2S)-2- { [(butylamino)carbonyl]amino J-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidin-2-ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-2-{ [(hexylarnino)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4.5,6-tetrahydro- pyrimidm-2-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-( {2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr imidin-2-ylamino)ethoxy]be nzoylj - amino)-2-{ [(octylamino)carbonyl] amino Jpropanoic acid;
(2S)-2- { [(aUylamino)carbonyl]amino }-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydro- pyrimidm-2-ylammo)ethoxy]benzoylJamino)propanoic acid;
(2S)-2- {[(1 -adamantylamho)carbonyl]aminoJ-3-({2-hydroxy-4-[2-( 1,4,5,6- tetrahydropyrimidώ-2-ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-2-[(anilmocarbonyl)ammo]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-2-{ [(cyclohexylammo)carbonyl]amino}-3-({2-hydroxy-4-[2-(l,4,5,6- tetrahydropyri╬╣mdm-2-ylamino)ethoxy]benzoyl}amino)propanoic acid; -128-
(2S)-2- { [(benzylarruno)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( 1 ,4,5,6- tetrahydropyrirrkdώ-2-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]- benzoyl }an╬╣mo)-2-[(4-toluidmocarbonyl)amino]propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]- benzoyl } ammo)-2-[(2-toluidinocarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrirnidin-2-ylamino)ethoxy]- benzoyl } amino)-2- { [(2-methoxyanilino)carbonyl] amino } propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrirnidin-2-ylamino)ethoxy]benzoylJ- amino)-2-{ [(4-methoxyanilino)carbonyl]arnino Jpropanoic acid;
(2S)-2-{ [(2-chloroanilino)carbonyl]amino J-3-({2-hydroxy-4-[2-(1.4,5,6- tetrahydropyriirkd -2-ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-2- { [(2-bromoanilino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( 1.4.5,6- tetrahydropyriπkd -2-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-{ [([l, l'-biphenyl]-2-ylammo)carbonyl]amino}-3-( {2-hydroxy-4-[2-(l,4,5,6- tetrahydropyrirnidin-2-ylammo)ethoxy]benzoyl}amino)propanoic acid
(2S)-2- { [(4-cMoroanilino)carbonyl] amino J-3-( { 2-hydroxy-4-[2-( 1.4,5,6- tetrahydropyriιτύdm-2-ylammo)ethoxy]benzoyl}amino)propanoic acid; or
(2S)-3-( { 2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoylJ- amko)-2-{ [( l-naphthylan╬╣ko)carbonyl]amino Jpropanoic acid or pharmaceutical salts thereof.
14. A compound of Claim 1 wherein G is 1,4,5,6-tetrahydropyrimidyl and R4 is NHCOR9.
15. A compound of Claim 1 which is:
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidm-2-ylamino)ethoxy]benzoyl }- amino)-2-({ [(2-phenylethyl)ammo]carbonyl}amino)propanoic acid; (2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrin idh-2-ylamino)ethoxy]benzoyl}- ammo)-2-(isobuty╬╣ylamino)propanoic acid;
(2S)-2-(hexanoylamino)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid; -129-
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr imidin-2-ylamino)ethoxy] benzoyl }- arnino)-2-(pentanoylamino)propanoic acid;
(2S)-2-[(3.3-dimethylbutanoyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrimidm-2-ylarrύno)ethoxy]benzoylJamino)propanoic acid;
(2S)-2-[(cyclohexylcarbonyl)amino]-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydro- pyrimidh-2-ylamino)ethoxy]benzoylJ amino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2-ylamino)ethoxy]benzoyl } - ammo)-2-[(2-phenylacetyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr imidin-2-ylamino)ethoxy]benzoylJ- amino)-2-[(3-phenylpropanoyl)amino]propanoic acid;
(2S)-2-[(2-cyclohexylacetyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin- 2-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4, 5.6-tetrahydropyr irnidin-2-ylarnino)ethoxy]- benzoyl }amino)-2-{ [(E)-3-phenylprop-2-enoyl]amino Jpropanoic acid;
(2S)-2-[(2-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoylJamino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidm-2-ylamino)ethoxy]benzoylJ- amino)-2-[(2-methylbenzoyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4.5, 6-tetrahydropyr imidm-2-ylamino)ethoxy]benzoylJ- amino)-2-[(2-methoxybenzoyl)amino]propanoic acid;
(2S)-2-[(4-chlorobenzoyl)amino]-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyr imidin-2-ylamino)ethoxy]benzoylJ- ammo)-2-[(4-methylbenzoyl)arnino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(l,4,5,6-tetrahydropyrir d -2-ylamino)ethoxy]benzoylJ- amino)-2-[(4-methoxybenzoyl)amino]propanoic acid;
(2S)-2-[(2,5-dimethyl-3-mroyl)amino]-3-( {2-hydroxy-4-[2-( 1,4,5,6- tetrahydropyrimid -2-ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-2-[(2-bromobenzoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid; -130-
(2S)-2-[(4-bromobenzoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5.6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-[(2,3-dimethylbenzoyl)amino]-3-({2-hydroxy-4-[2-( l,4,5,6-tetrahydro- pyrirrύdm-2-ylamino)ethoxy]benzoyl}amino)propanoic acid; or
(2S)-2-[(3-crdorobenzoyl)amino]-3-( { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid or pharmaceutical salts thereof.
16. A compound of Claim 1 wherein G is pyrimidin-2-yl and Rj is NHCO R9.
17. A compound of Claim 1 which is:
(2S)-3-({2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl}amino)-2- [(phenoxycarbonyl)amino]propanoic acid;
(2S)-2- { [(benzyloxy)carbonyl]amino }-3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]benzoyl}amino)-2- [(isobutoxycarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrin╬╣idm-2-ylan╬╣mo)ethoxy]benzoylJamino)-2-{ [(4- methoxyphenoxy)carbonyl]amino Jpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrimidb-2-ylam o)ethoxy]benzoylJamino)-2- { [(octyloxy)carbonyljamino Jpropanoic acid;
(2S)-2-[(butoxycarbonyl)amino]-3-( { 2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]- benzoylJamino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(ρyrimidώ-2-ylamino)ethoxy]benzoyl } amino)-2- { [(2,2,2- trichloroethoxy)carbonyl]amino Jpropanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(pyrirmdh-2-ylamino)ethoxy]benzoylJ amino)-2- { [(neopentyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrimidώ-2-ylammo)ethoxy]benzoyl}amino)-2-({ [(4- nitroberizyl)oxy]carbonylJamino)propanoic acid;
(2S)-2- { [(hexyloxy)carbonyl] amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid; -131-
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-yla╬╣nino)ethoxy]benzoyl}amino)-2-{[(prop-2- ynyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylammo)ethoxy]benzoylJamino)-2-{ [(4- methylphenoxy)carbonyl]amino Jpropanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]benzoyl } amino)-2- [(methoxycarbonyl)amino]propanoic acid;
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(pyrirnidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidm-2-ylamino)ethoxy]benzoyl J amino)-2- [(propoxycarbonyl)aminojpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyriιrύdin-2-ylamino)ethoxy]be nzoylj amino)-2- [(isopropoxycarbonyl)amino]propanoic acid;
(2S)-2-{ [(aUyloxy)carbonyl]am o J-3-({2-hydroxy-4-[2-(pyrirnidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid; or
(2S)-2-{ [(but-3-enyloxy)carbonyl]arnmo}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoylJambo)propanoic acid or pharmaceutical salts thereof.
18. A compound of Claim 1 wherein G is pyrimidin-2-yl and R╬▒ is NHCONH9.
19. A compound of Claim 1 which is:
(2S)-2-[(anilinocarbonyl)anιώo]-3-( {2-hydroxy-4-[2-(pyrirnidm-2-ylamino)ethoxy]- benzoyl }amino)propanoic acid;
(2S)-2- { [(tert-butylammo)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-2-{ [(butylammo)carbonyl]ammoJ-3-({2-hydroxy-4-[2-(pyrimidm-2-yla╬╣r╬╣ino)- ethoxy]benzoylJamino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoyl } amino)-2- { [(4- methoxyanilino)carbonyl] amino Jpropanoic acid;
(2S)-2- { [(2-ethylanilino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-2- { [(aUylamino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid; ΓÇó132-
(2S)-2-{ [(2,4-dichloroanUmo)carbonyl]an╬╣mo}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrinιidώ-2-ylammo)ethoxy]benzoyl}amino)-2-[(2- toluidinocarbonyl)amino]propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]benzoylJ amino)-2- { [(2- methoxyanilino)carbonyl]amino Jpropanoic acid;
(2S)-2-{ [(2-cUoroanilmo)carbonyl]aminoJ-3-({2-hydroxy-4-[2-(pyrin╬╣idin-2- ylamino)ethoxy]benzoylJamino)propanoic acid;
(2S)-2- { [(2-bromoanilino)carbonyl]amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-{ [([l, l'-biphenyl]-2-ylan ino)carbonyl]amino}-3-({2-hydroxy-4-[2-(pyrirnidin- 2-ylamιώo)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylammo)ethoxy]benzoylJamino)-2-[(4- toluidmocarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrirrύdin-2-ylan mo)ethoxy]benzoyl}amino)-2-({ [4- (trifluoromethyl)anilino]carbonyl}amino)propanoic acid;
(2S)-3-( {2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]be nzoylj amino)-2-({ [4- (trifluoromethoxy)anilmo]carbonyl}amino)propanoic acid;
(2S)-2-{ [(4-cUoroanilmo)carbonyl]ammoJ-3-({2-hydroxy-4-[2-(pyrimidin-2- ylam o)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2- { [(4-fluoroanilino)carbonyl] amino } -3-( { 2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-2-{ [(4-acetylanilmo)carbonyl]amώo}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-( { [4-(ethoxycarbonyl)anilino]carbonyl } amino)-3-( { 2-hydroxy-4- [2-(pyrimidin- 2-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2- { [(cyclohexylamino)carbonyl]amino } -3-( { 2-hydroxy-4- [2-(pyrimidin-2- ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrirddm-2-yla╬╣runo)ethoxy]benzoylJamino)-2-{ [(l- naphthylamino)carbonyl] amino } propanoic acid; -133-
(2S)-2-{ [(benzylammo)carbonyl]arrnno}-3-({2-hydroxy-4-[2-(pyrimidin-2- ylamino)ethoxy]benzoyl} amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylarnino)ethoxy]benzoyl}amino)-2-({ [(2- phenylethyl)ammo]carbonyl}amino)propanoic acid; or
(2S)-3-({2-hydroxy-4-[2-(pyrimidm-2-ylarnmo)ethoxy]benzoyl}amino)-2- { [(octylamino)carbonyl]amino Jpropanoic acid or pharmaceutical salts thereof.
20. A compound of Claim 1 wherein G is 4,5-dihydro-lH-imidazolyl and R 4 is NHCO2R9.
21. A compound of Claim 1 which is:
(2S)-2-{ [(benzyloxy)carbonyl]aminoJ-3-({4-[2-(4,5-dihydro-lH-irnidazol-2- ylammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid; (2S)-3-({4-[2-(4,5-dmydro-lH-in╬╣idazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- arr╬╣mo)-2-[(methoxycarbonyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(ethoxycarbonyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(propoxycarbonyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- arruno)-2-[(isopropoxycarbonyl)arnino]propanoic acid;
(2S)-2-{ [(aUyloxy)carbonyl]amho}-3-({4-[2-(4,5-d ydro-lH-imidazol-2- ylammo)ethoxy]-2-hydroxybenzoylJamino)propanoic acid;
(2S)-2-{ [(but-3-enyloxy)carbonyl]ammo}-3-({4-[2-(4,5-d ydro-lH-imidazol-2- ylammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-irrkdazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-irddazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(hexyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{[(octyloxy)carbonyl] amino Jpropanoic acid; -134-
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylarnino)ethoxy]-2-hydroxybenzoylJ- ammo)-2-{ [(neopentyloxy)carbonyl]amino Jpropanoic acid;
(2S)-2-[(butoxycarbonyl)aιrύno]-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylam o)ethoxy]-2-hydroxybenzoylJamino)propanoic acid;
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-[(isobutoxycarbonyl)amino]propanoic acid;
22. A compound of Claim 1 wherein G is 4,5-dihydro- lH-imidazolyl and R is NHCONHR?.
23. A compound of Claim 1 which is:
(2S)-2-{ [(butylammo)carbonyl]ammo }-3-({4-[2-(4,5-dmydro-lH-irnidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-{ [(hexylamino)carbonyl] amino Jpropanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(octylan mo)carbonyl]amino Jpropanoic acid;
(2S)-2-{ [(aUylammo)carbonyl]ammo}-3-({4-[2-(4,5-d ydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl } amino)propanoic acid;
(2S)-2-{ [(cyclohexylammo)carbonyl]amho }-3-({4-[2-(4,5-dmydro-lH-irnidazol-2- ylammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-2-{ [(benzylammo)carbonyl]arnmoJ-3-({4-[2-(4,5-d ydro-lH-imidazol-2- ylarnino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
3-({4-{2-(2,5-dmydro-lH-mτidazol-4-ylaπιmo)ethoxy]-2-hydroxybenzoyl)anιino)-N- ({ [(IS, 2R)-2-phenylcyclopropyl]amino)carbonyl)alanine;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(2-methoxyanilino)carbonyl] amino Jpropanoic acid;
(2S)-2-{ [([l,l'-biphenyl]-2-ylammo)carbonyl]amino}-3-({4-[2-(4,5-dihydro-lH- imidazol-2-ylammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid; or -135-
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-({ [(2-phenylethyl)arn o]carbonylJamino)propanoic acid or pharmaceutical salts thereof.
24. A compound of Claim 1 wherein G is 4,5-dihydro-lH-imidazolyl and Ri is NHCOR9.
25. A compound of Claim 1 which is:
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- aιτώo)-2-(isobutyrylamino)propanoic acid;
(2S)-2-(butyrylammo)-3-( {4-[2-(4,5-d ydro-lH-i╬╣nidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)propanoic acid;
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-(hexanoylamino)propanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-(pentanoylamino)propanoic acid;
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(3,3-dimethylbutanoyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-d ydro-lH-in╬╣idazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(2,2, 3, 3-tetramethylcyclopropyl)carbonyl]amino Jpropanoic acid;
(2S)-2-{ [2-(l-adamantyl)acetyl]aπιmo}-3-({4-[2-(4,5-dώydro-lH-imidazol-2- ylarn o)ethoxy]-2-hydroxybenzoylJamino)propanoic acid;
(2S)-3-({4-[2-(4,5-dώydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-(pent-4-ynoylamino)propanoic acid;
(2S)-2-[(cyclohexylcarbonyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl } amino)propanoic acid;
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-[(2-phenylacetyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-d ydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- ammo)-2-[(3-phenylpropanoyl)amino]propanoic acid;
(2S)-2-[(2-cyclohexylacetyl)amino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid; Γûá136-
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(E)-3-phenylprop-2-enoyl] amino Jpropanoic acid;
(2S)-2-[(2-chlorobenzoyl)ammo]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-3-({4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoylj amino)-2-[(2-methylbenzoyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-[(2-methoxybenzoyl)amino]propanoic acid;
(2S)-2-[(4-cWorobenzoyl)an ino]-3-({4-[2-(4,5-dihydro-lH-irnidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-3-( {4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}amino)-2-[(4-methylbenzoyl)aminoJpropanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-imidazol-2-ylamino)ethoxy]-2- hydroxybenzoyl}ammo)-2-[(4-methoxybenzoyl)amino]propanoic acid;
(2S)-3-({4-[2-(4,5-dihydro-lH-iιrύdazol-2-ylamino)ethoxy]-2- hydroxybenzoylJammo)-2-[(2,5-dimethyl-3-mroyl)aminoJpropanoic acid;
(2S)-2-[(2-bromobenzoyl)a╬╣nino]-3-({4-[2-(4,5-dihydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl } amino)propanoic acid;
(2S)-2-[(4-bromobenzoyl)ammo]-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylamino)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-3-({4-[2-(4,5-dmydro-lH-irddazol-2-ylamino)ethoxy]-2-hydroxybenzoylJ- arnino)-2-[(2,3-dimethylbenzoyl)amino]propanoic acid; or
(2S)-2-[(3-cmorobenzoyl)ammo]-3-({4-[2-(4,5-dmydro-lH-imidazol-2- ylarrnno)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid or pharmaceutical salts thereof.
26. A compound of Claim 1 wherein G is 3,4,5,6-tetrahydro-2H-azepinyl and is NHCO2R9.
27. A compound of Claim 1 which is:
(2S)-2-{ [(be╬╣╬╣zyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepm-7-ylammo)ethoxy]benzoyl}amino)propanoic acid; ΓÇó137-
(2S)-3-( { 2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylamino)ethoxy]benzoyl } aιrώιo)-2-[(methoxycarbonyl)amino]propanoic acid;
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin- 7-ylamko)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylammo)ethoxy]benzoylJamino)-2-[(propoxycarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylammo)ethoxy]benzoyl}am o)-2-[(isopropoxycarbonyl)amino]propanoic acid;
(2S)-2-{ [(allyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepώ-7-ylamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-{ [(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro- 2H-azepin-7-ylamino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(3,4,5.6-tetrahydro-2H-azepin-7- ylamino)ethoxy]benzoylJamino)-2-{ [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid;
(2S)-2-{ [(hexyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H- azepm-7-ylam o)ethoxy]benzoylJamino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylamino)ethoxy]benzoylJamino)-2-{ [(octyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylammo)ethoxy]benzoyl}amino)-2-{ [(neopentyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azeph-7-ylamino)ethoxy]benzoylJ- amino)-2-{ [(2,2, 2-trichloroethoxy)carbonyl]amino Jpropanoic acid;
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin- 7-ylamώo)ethoxy]benzoylJamino)propanoic acid; or
(2S)-3-({2-hydroxy-4-[2-(3,4,5,6-tetrahydro-2H-azepin-7- ylamino)ethoxy]benzoylJ amino)-2-[(isobutoxycarbonyl)amino]propanoic acid or pharmaceutical salts thereof.
28. A compound of Claim 1 wherein G is NH2C(NH)- and R4 is NHCO^R,. -138-
29. A compound of Claim 1 which is:
(2S)-3-{ [4-(2-{ [am o(immo)methyl]arnmo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(benzyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3- { [4-(2- { [ammo(imino)methyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2- - [(methoxycarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- [(ethoxycarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(i╬╣runo)methyl]am oJethoxy)-2-hydroxybenzoyl]amino }-2- [(propoxycarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(imino)methyl]amώo}ethoxy)-2-hydroxybenzoyl]amino }-2- [(isopropoxycarbonyl)amino]propanoic acid;
(2S)-2- { [(allyloxy)carbonyl] amino J -3- { [4-(2- { [ammo(immo)methyl]amino } ethoxy)- 2-hydroxybenzoyl] amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [an o(immo)methyl]an╬╣mo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(but-3-enyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3- { [4-(2- { [ammo(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2- [(butoxycarbonyl)aminojpropanoic acid;
(2S)-3-{ [4-(2-{ [an mo(immo)methyl]am o}ethoxy)-2-hydroxybenzoyl]arnino}-2- {[(2,2,2-trichloroethoxy)carbonyl] amino Jpropanoic acid;
(2S)-3- { [4-(2- { [an o(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino } -2- { [(neopentyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [a╬╣n o(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(hexyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3- { [4-(2-{ [ammo(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino J-2- { [(prop-2-ynyloxy)carbonyl] amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [aπιmo(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino}-2- { [([l,l'-biphenyl]-2-ylmethoxy)carbonyl] amino Jpropanoic acid;
(2S)-3-{[4-(2-{[ammo(immo)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- ({ [(4-bromobenzyl)oxy]carbonylJamino)propanoic acid; -139-
(2S)-3-{ [4-(2-{[ammo(im o)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- ({ [(4-fluorobenzyl)oxy]carbonyl}amino)propanoic acid;
(2S)-3-{ [4-(2-{ [amino(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]aminoJ-2- ({ [(2-bromobenzyl)oxy]carbonyl}amino)propanoic acid; or
(2S)-3-{ [4-(2-{ [am o(immo)methyl]a╬╣rnno}ethoxy)-2-hydroxybenzoyl]aminoJ-2- [({ [4-(trifluoromethyl)benzyl]oxy}carbonyl)amino]propanoic acid or pharmaceutical salts thereof.
30. A compound of Claim 1 wherein G is NH2(NH)- and R4 is NHCONHR9.
31. A compound of Claim 1 which is:
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]ammoJethoxy)-2-hydroxybenzoyl]amino}-2-[(2- toluidmocarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(in╬╣mo)methyl]ammo }ethoxy)-2-hydroxybenzoyl]amino}-2- { [(2-methoxyanilino)carbonyl]amino Jpropanoic acid;
(2S)-3- { [4-(2- { [amho(immo)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2- { [(2-cUoroanilώo)carbonyl] amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [am o(i╬╣nmo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(2-bromoanilmo)carbonyl] amino Jpropanoic acid;
(2S )-3-{ [4-(2-{ [ammo(imino)methyl] amino} ethoxy)-2-hydroxybenzoyl] amino J -2- { [([l,r-biphenyl]-2-ylamino)carbonyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [am o(imino)methyl] amino Jethoxy)-2-hydroxybenzoyl]amino}-2-[(4- toluidmocarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(in╬╣ o)methyl]ammo}ethoxy)-2-hydroxybenzoyl]aminoJ-2- ({ [4-(trifluoromethoxy)anilino]carbonylJamino)propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(in╬╣mo)methyl]ammo}ethoxy)-2-hydroxyrjenzoyl]am o}-2 { [(4-chloroanilino)carbonyl] amino Jpropanoic acid;
(2S)-3-{[4-(2-{[ammo(immo)methyl]ammoJethoxy)-2-hydroxybenzoyl]aniino}-2- { [(4-fluoroanilino)carbonyl]amino Jpropanoic acid;
(2S)-2- { [(4-acetylanilino)carbonyl]amino } -3- { [4-(2- { [ammo(imino)methyl]- amino}ethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid; -140-
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]a╬╣nmo }ethoxy)-2-hydroxybenzoyl]amino}-2- { [(cyclohexylarnino)carbonyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [arnmo(immo)methyl]ammo Jethoxy)-2-hydroxybenzoyl]amino}-2- { [( 1 -naphthylamino)carbonyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(benzylamino)carbonyl] amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2- ({ [(2-phenylethyl)amino]carbonylJamino)propanoic acid;
(2S)-3-{ [4-(2-{ [an mo(immo)methyl]aπτhoJethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(octylamino)carbonyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [arnmo(in^o)methyl]amho}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(4-methoxyanilino)carbonyl] amino Jpropanoic acid; or
(2S)-3-{ [4-(2-{ [arn o(immo)methyl]amino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- [(anilkocarbonyl)aminojpropanoic acid or pharmaceutical salts thereof.
32. A compound of Claim 1 wherein G is NH:(NH)- and R; is NHCOR9.
33. A compound of Claim 1 which is:
(2S)-3-{ [4-(2-{ [ammo(m╬╣ o)methyl]amino }ethoxy)-2-hydroxybenzoyl]-amino}-2- (isobutyrylamino)propanoic acid:
(2S)-3-{ [4-(2-{ [ammo(imino)methyl] amino }ethoxy)-2-hydroxybenzoyl] amino J-2- (butyrylamino)propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]an ino}ethoxy)-2-hydroxybenzoyl]amino}-2- (hexanoylamino)propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]arnho}ethoxy)-2-hydroxybenzoyl]aminoJ-2- (pentanoylamino)propanoic acid;
(2S)-3- { [4-(2- { [ammo(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino } -2- [(3,3-dimethylbutanoyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [arrιώo(imino)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino J-2- { [(2,2,3,3-tetramethylcyclopropyl)carbonyl]amino Jpropanoic acid;
(2S)-2-{ [2-( l-adamantyl)acetyl]an mo}-3-{ [4-(2-{ [ammo(in╬╣mo)methyl]amino}- ethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid; Γûá141-
(2S)-3-{ [4-(2-{ [a╬╣n o(immo)methyl]ammoJethoxy)-2-hydroxybenzoyl]amino}-2- (pent-4-ynoylamino)propanoic acid;
(2S)-3-{ [4-(2-{ [amko(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- [(cyclohexylcarbonyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [arn o(im o)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino }-2-[(2- phenylacetyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [ammo(immo)methyl]a╬╣nino }ethoxy)-2-hydroxybenzoyl]amino }-2-[(3- phenylpropanoyl)amino]propanoic acid:
(2S)-3-{ [4-(2-{ [ambo(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2-[(2- cyclohexylacetyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [arr no(immo)methyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- { [(E)-3-phenylprop-2-enoyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]amino}ethoxy)-2-hydroxybenzoyl]amino}-2-[(2- chlorobenzoyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [an mo(immo)methyl]am o}ethoxy)-2-hydroxybenzoyl]amino }-2-[(2- methylbenzoyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [arnmo(irnmo)methyl]amino } ethoxy)-2-hydroxybenzoyl]amino } -2-[(2- methoxybenzoyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [arnmo(imino)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino J-2-[(4- chlorobenzoyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [an ko(irruno)methyl]amino }ethoxy)-2-hydroxybenzoyl] amino J-2-[(4- methylbenzoyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{[arruno(immo)methyl]an mo}ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- methoxybenzoyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(imino)methyl] amino} ethoxy)-2-hydroxybenzoyl] amino J -2- [(pyridin-3-ylcarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(irr╬╣ino)methyl] amino Jethoxy)-2-hydroxyberrzoyl]amino}-2- (isom^otmoylamino)propanoic acid;
(2S)-3-{ [4-(2-{ [arrιώo(immo)methyl]aιrιώo}ethoxy)-2-hydroxybenzoyl]amino}-2- [(2,5-dimethyl-3-furoyl)amino]propanoic acid; -142-
(2S)-3- { [4-(2- { [arnho(immo)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino J-2-[(2- bromobenzoyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [amώo(iιnino)methyl]arnino } ethoxy)-2-hydroxybenzoyl] amino } -2-[(4- bromobenzoyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [ ammo (immo) methyl] amino }ethoxy)-2-hydroxybenzoyl] amino J-2- [(2,3-dimethylbenzoyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino J-2-[(3- cbJorobenzoyl)amino]propanoic acid;
(2S)-3- { [4-(2- { [amino(imino)methyl] amino } ethoxy)-2-hydroxybenzoyl] amino J -2- (benzoylamino)propanoic acid:
(2S)-3-{ [4-(2-{ [aπιmo(immo)methyl]ammo }ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- ethylbenzoyl)amino]propanoic acid; or
(2S)-3-{ [4-(2-{ [ammo(immo)methyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2-[(4- butoxybenzoyl)amino]propanoic acid or pharmaceutical salts thereof.
34. A compound of Claim 1 wherein G is R8NHCO-, R8 is benzyl and R4 is NHCO2R9.
35. A compound of Claim 1 which is:
(2S)-3-{ [4-(2-{ [(benzylarnmo)carbonyl]arnino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- { [(benzyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3- { [4-(2- { [(benzylamino)carbonyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2- [(methoxycarbonyl)aminojpropanoic acid;
(2S)-3-{ [4-(2-{ [(benzylam o)carbonyl]ammo }ethoxy)-2-hydroxybenzoyl]amino}-2- [(ethoxycarbonyl)aminojpropanoic acid;
(2S)-3-{ [4-(2-{ [(benzyla╬╣r╬╣mo)carbonyl] ammo} ethoxy)-2-hydroxybenzoyl] amino} -2- [(propoxycarbonyl)amino]propanoic acid;
(2S)-3-{ [4-(2-{ [(benzylammo)carbonyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- [(isopropoxycarbonyl)amino]propanoic acid;
(2S)-2-{ [(allyloxy)carbonyl] amino J-3-{ [4-(2-{ [(benzylamino)carbonyl]- amino Jethoxy)-2-hydroxybenzoyl] amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [(ber╬╣zylammo)carbonyl]ammo}ethoxy)-2-hydroxyber╬╣zoyl]amino}-2- {[(but-3-enyloxy)carbonyl]amino Jpropanoic acid; Γûá143-
(2S)-3-{ [4-(2-{[(benzylan mo)carbonyl]ammo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3- { [4-(2- { [(benzylamino)carbonyl] amino } ethoxy)-2-hydroxybenzoyl]amino } -2- { [(hexyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3-{[4-(2-{[(benzylammo)carbonyl]arnmo}ethoxy)-2-hydroxybenzoyl]amino}-2- { [(octyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3- { [4-(2- { [(benzylamino)carbonyl]amino } ethoxy)-2-hydroxybenzoyl] amino } -2- { [(neopentyloxy)carbonyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2-{ [(benzylammo)carbonyl]ammoJethoxy)-2-hydroxybenzoyl]amino}-2- { [(2, 2, 2-trichloroethoxy)carbonyl]amino Jpropanoic acid;
(2S)-3-{ [4-(2- { [(benzylamino)carbonyl]amino }ethoxy)-2-hydroxybenzoyl]amino J-2- [(butoxycarbonyl)amino]propanoic acid: or
(2S)-3-{[4-(2-{ [(benzylarnmo)carbonyl]amino}ethoxy)-2-hydroxybenzoyl]aminoJ-2- [(isobutoxycarbonyl)amino]propanoic acid or pharmaceutical salts thereof.
36. A compound of Claim 1 wherein G is RgNHCO. R8 is pyridin-3yl methyl, and i is NHCO2R9.
37. A compound of Claim 1 which is:
(2S)-2- { [(benzyloxy)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)ammo]carbonyljamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyridm-3-ylmethyl)amino]carbonyl}amino)- ethoxy]benzoyl}amino)-2-[(methoxycarbonyl)amino]propanoic acid;
(2S)-2-[(ethoxycarbonyl)amino]-3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)an╬╣mo]carbonylJammo)ethoxy]ber╬╣zoyl}arnino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridm-3-ylmethyl)amino]carbonyl J amino)- ethoxy]benzoyl}amino)-2-[(propoxycarbonyl)amino]propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-3-ylmethyl)arnmo]carbonyl}a╬╣r╬╣ino)ethoxy]- benzoyl}an o)-2-[(isopropoxycarbonyl)amino]propanoic acid;
(2S)-2- { [(allyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(ρyridin-3- ylmethyl)ammo]carbonyl}ammo)ethoxy]benzoyl}arnino)propanoic acid; -144-
(2S)-2-{ [(but-3-enyloxy)carbonyl]aminoJ-3-({2-hydroxy-4-[2-({[(pyridin-3- ylmethyDaminojcarbonyl } amino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-3-ylmethyl)ammo]carbonyl}amino)- ethoxy]benzoyl}amino)-2-{ [(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid;
(2S)-2- { [(hexyloxy)carbonyl] amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-3- ylmethyl)ammo]carbonyljarnmo)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyridm-3-y]methyl)ammo]carbonyl}amino)ethoxy]- benzoyl}amino)-2-{ [(octyloxy)carbonyl]amino}propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyrid -3-ylmethyl)an╬╣mo]carbonyl}arnino)ethoxy]- benzoyl } amino)-2- { [(neopentyloxy)carbonyl] amino } propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-3-ylmethyl)amino]carbonyl}amino)ethoxy]- benzoyl } amino)-2- { [(2,2,2-trichloroethoxy)carbonyl]amino } propanoic acid;
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({ [(pyridin-3- ylmethyl)ammo]carbonyl}amώo)ethoxy]benzoyl}amirιo)propanoic acid; or
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-3-ylmethyl)amino]carbonyl } amino)ethoxy]- benzoylJamino)-2-[(isobutoxycarbonyl)amino]propanoic acid or pharmaceutical saks thereof.
38. A compound of Claim 1 wherein G is R8NHCO and R8 is pyridin-4yl and t is NHCO2R9.
39. A compound of Claim 1 which is:
(2S)-2- { [(benzyloxy)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)arnmo]carbonyljamino)ethoxy]benzoyljamino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyrid -4-ylmethyl)ammo]carbonyl}amino)ethoxy]- benzoyl }amino)-2-[(methoxycarbonyl)amino]propanoic acid;
(2S)-2-[(ethoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)a╬╣r╬╣mo]carbonyl}ammo)ethoxy]berizoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyridm-4-ylmethyl)a╬╣r╬╣ o]carbonyl}an╬╣ino)ethoxy]- benzoyl}ambo)-2-[(propoxycarbonyl)amino]propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridin-4-ylmethyl)amino]carbonyl } amino)ethoxy]- benzoyl} amino)-2-[(isopropoxycarbonyl)amino]propanoic acid; -145-
(2S)-2- { [(allyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)amino]carbonyl } amino)ethoxy]benzoyl } amino)propanoic acid;
(2S)-2-{[(but-3-enyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(pyridin-4- ylmethyl)arr╬╣mo]carbonyl}ammo)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-( { 2-hydroxy-4-[2-( { [(pyridm-4-ylmethyl)amino]carbonyl } amino)ethoxy]- benzoyl}amino)-2-{[(prop-2-ynyloxy)carbonyl]amino Jpropanoic acid;
(2S)-2- { [(hexyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-4- ylmethyl)am o]carbonyljammo)ethoxy]benzoyl}amino)propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyridm-4-ylmethyl)aπιmo]carbonyl}amino)ethoxy]- benzoyl } amino)-2- { [(octyloxy)carbonyl] amino } propanoic acid ;
(2S)-3-({2-hydroxy-4-[2-({ [(pyridm-4-ylmethyl)ammo]carbonylJanτino)ethoxy]- benzoyl } amino)-2- { [(neopentyloxy)carbonyl] amino } propanoic acid;
(2S)-3-({2-hydroxy-4-[2-({[(pyrid -4-ylmethyl)amino]carbonyl}amino)ethoxyj- benzoyl }an╬╣mo)-2-{[(2,2,2-tricMoroethoxy carbonyl]amino Jpropanoic acid;
(2S)-2-[(butoxycarbonyl)amino]-3-({2-hydroxy-4-[2-({ [(pyridin-4- ylmethyl)aπτ o]carbonyl}ammo)ethoxy]benzoyl}amino)propanoic acid; or
(2S)-3-({2-hydroxy-4-[2-({[(pyrid -4-ylmethyl)amino]carbonylJamino)ethoxy]- benzoyl}amho)-2-[(isobutoxycarbonyl)amino]propanoic acid or pharmaceutical salts thereof.
40. A compound of Claim 1 which is:
(2S)-2- { [(benzyloxy)carbonyl]amino J -3-( { 2-hydroxy-4-[2-( { [(4-methylbenzyl)- arninojcarbonyl } amino)ethoxy]benzoyl J amino)propanoic acid;
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({[(4-methoxybenzyl)- arnmo]carbonylJamino)ethoxy]benzoylJamino)propanoic acid;
(2S)-2- { [(benzyloxy)carbonyl]amino } -3-( {4-[2-( { [(4-chlorobenzyl)amino]carbonyl J - amino)ethoxy]-2-hydroxybenzoylJamino)propanoic acid;
(2S)-2- { [(benzyloxy)carbonyljamino } -3-[(4- { 2-[( { [4-(dimethylamino)benzyl]amino } - carbonyl)amino]ethoxy } -2-hydroxytenzoyl)amino]propanoic acid;
(2S)-3-[(4-{2-[({[4-(arnmosulfonyl)benzyl]ammo}carbonyl)amino]ethoxy}-2- hydroxybenzoyl)amino]-2-{ [(benzyloxy)carbonyl]amino Jpropanoic acid; -146-
(2S)-2- { [(benzyloxy)carbonyl] amino } -3-[(2-hydroxy-4- { 2-[( { [4-(trifluoromethoxy)- benzyljamino Jcarbonyl)amino]ethoxyJbenzoyl)amino]propanoic acid;
(2S)-2-{[(benzyloxy)carbonyl]ammoJ-3-({4-[2-({ [(2-chlorobenzyl)amino]carbonylJ- amho)ethoxy]-2-hydroxybenzoylJarnino)propanoic acid;
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-({2-hydroxy-4-[2-({ [(2-methylbenzyl)- ammo]carbonyljamino)ethoxy]benzoyl}amino)propanoic acid;
(2S)-2-{[(benzyloxy)carbonyl]amino}-3-({4-[2-({[(2-bromobenzyl)- ammo]carbonylJammo)ethoxy]-2-hydroxybenzoyl}amino)propanoic acid;
(2S)-2-{[(benzyloxy)carbonyl]animo}-3-({4-[2-({[(2,4-dicUorobenzyl)arnino]- carbonyl } amino)ethoxy]-2-hydroxybenzoyl } amino)propanoic acid;
(2S)-3-({4-[2-({ [(2-ammobenzyl)ammo]carbonyl}amino)ethoxy]-2-hydroxybenzoylJ- amino)-2-{ [(benzyloxy)carbonyl]amino Jpropanoic acid; or
(2S)-2- { [(benzyloxy)carbonyl]amino } -3-( { 2-hydroxy-4-[2-( { [(pyridin-2- ylmethyl)ammo]carbonyl}am o)ethoxy]benzoyl}amino)propanoic acid or pharmaceutical salts thereof.
41. A compound of Claim 1 which is:
(2S)-2-Benzenesulfonylamino-3-(2-hydroxy-4-[3-( 1,4,5.6-tetrahydropyrimidin-2- yla╬╣nmo)-propoxy]-benzoylamino)-propionic acid;
(2S)-2-Benzenesulfonylamino-3-{2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)-ethoxy]-benzoylamino } -propionic acid tert-butyl ester;
(2S)-2-Benzenesulfonylam o-3-{2-hydroxy-5-[4-(pyrin idm-2-ylamino)-butoxy]- benzoylamino } -propionic acid;
3- { 2-Hydroxy-5-[3-( 1 ,4,5,6-tetrahydropyrimidm-2-ylammo)-propoxyl-berrzoylamino)- 3-phenyl-propionic acid ethyl ester;
(2S)-2-Benzenesulfonylarnino-3- { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylan mo)-ethoxy]-benzoylamino } -propionic acid 2-(2-tert-butoxycarbonylamino- ethoxy)-ethyl ester;
(2S)-2-Benzenesulfonylamino-3- { 2-hydroxy-5-[4-( 1 ,4,5,6-tetrahydropyrimidin-2- ylammo)-butoxy]-benzoylamino J-propionic acid ethyl ester;
(2S)-2-Berrzenesulfonylammo-3-{2-hydroxy-4-[3-(pyrimidm-2-ylamino)-propoxy]- benzoylamino J-propionic acid; ΓÇó147-
3-{2-Hydroxy-5-[3-(pyriιτύd -2-ylan ώo)-propoxy]-benzoylamino}-3-phenyl- propionic acid;
(2S)-2- { Adamantan- 1 -yloxycarbonylamino)-3- { 2-hydroxy-4- [2-( 1 ,4,5,6-tetrahydro- pyriιrύdm-2-ylamώo)-ethoxy]-benzoylamino)-propionic acid;
(2S)-2-Benzenesulfonylamino-3-(2-hydroxy-4-[3-( 1,4, 5, 6-tetrahydropyr imidin-2- ylamώo)-propoxy]-benzoylamino)-propionic acid ethyl ester;
3-{2-Hydroxy-5-[3-(pyrimidm-2-ylammo)-propoxy)-benzoylamino)-3-phenyl- propionic acid ethyl ester;
(2S)-2-(Adamantan- 1 -ylmethoxycarbonylamino)-3- { 2-hydroxy-4-[2-( 1 ,4,5.6- tetrahydro-pyrimidm-2-ylamino)-ethoxyl]-benzoylamino} -propionic acid:
(2S)-2-Benzenesulfonylamino-3- { 2-hydroxy-4-[2-( 1 ,4,5,6-tetrahydropyrimidin-2- ylamho)-ethoxy]-benzoylamino J-propionic acid isopropyl ester:
(2S)-2-tert-Butoxycarbonylamino-3-{2-hydroxy-4-[2-( 1,4,5, 6-tetrahydropyrimidin-2- ylamino)-ethoxy]-benzoylamino} -propionic acid; or
(2S)-2-Benzenesulfonylamino-3-{2-hydroxy-5-[4-( 1,4,5.6-tetrahydropyrimidin-2- ylamino)-butoxy]-benzoylamino J-propionic acid or pharmaceutical salts thereof.
42. A compound of Claim 1, which is:
2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylamino)ethoxy]- benzoylaminojpropionic acid ethyl ester;
2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylamino)ethoxy]- benzoylaminojpropionic acid;
2(S)-Benzenesulfonylamino-3-[2-hydroxy- 4-[2-(3,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoylamino]propionic acid hydrochloride;
2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-pyrimidin-2-ylamino)ethoxy]- benzoylamino]propionic acid ethyl ester hydrochloride; 2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoylamino]propionic acid ethyl ester hydrochloride; -148-
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydropyrimidin-2- ylamino)ethoxy]benzoylamino]propionic acid hydrochloride;
3-[4-(2-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoic acid ethyl ester hydrochloride; 3-[4-Guanidinoethoxy)-2-hydroxy-benzoylamino]-3-phenylpropanoic acid hydrochloride;
3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoylamino]-3-pyridin-3-yl- propanoic acid ethyl ester;
3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoylamino]-3-pyridin-3-yl- propanoic acid ;
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]benzoylamino]- 3-pyridin-3-yl-propanoic acid ethyl ester dihydro-chloride;
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]benzoylamino]- 3-pyridin-3-yl-propanoic acid; 3-[4-(2-Guanidino-ethoxy)-2-hydroxybenzoyl-amino]-3- pyridin-3-yl-propanoic acid ethyl ester dihydrochloride;
3-[4-(2-Guanidino-ethoxy)-2-hydroxybenzoyl-amino]-3- pyridin-3-yl-propanoic acid;
3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoylamino]-3-phenyl-propanoic acid ethyl ester;
3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)-ethoxy]benzoylamino]-3-phenyl-propanoic acid hydrochloride;
3-[2-hydroxy-4-[2-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)ethoxy]benzoylamino]- 3-phenyl-propanoic acid ethyl ester hydrochloride; 3- [2-hydroxy-4- [2-(3 ,4,5, 6-tetrahydro-pyrimidin-2-ylamino)ethoxy]benzoylamino] - 3-phenyl-propanoic acid; -149-
3-[2-hydroxy-5-[3-(pyrimidin-2-ylamino)-propoxy]benzoylamino]-3-phenyl- propanoic acid ethyl ester;
3-[2-hydroxy-5-[3-(pyrimidin-2-ylamino)-propoxy]benzoylamino]-3-phenyl- propanoic acid;
3-[2-hydroxy-5-[3-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)propoxy]benzoylamino]- 3-phenyl-propanoic acid ethyl ester hydrochloride;
3-[2-hydroxy-5-[3-(3,4,5,6-tetrahydro-pyrimidin-2-ylamino)propoxy]benzoylamino]- 3-phenyl-propanoic;
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]- benzoylaminojpropionic acid ethyl ester hydrochloride;
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)- ethoxyjbenzoylaminojpropionic acid methyl ester;
2(S)-Benzyloxycarbonylamino-3-[2-hydroxy-4-[2-(pyrimidin-2-ylamino)ethoxy]- benzoylamino]propionic acid ;
2(S)-Benzenesulfonylamino-3-[2-hydroxy-4-(2-methyl-pyrimidin-2- ylamino)ethoxy]benzoylamino]propionic acid; or
2-Amino-3-[2-hydroxy-4-[2-(3,4,5,6-tetra-hydropyrimidin-2-ylamino)ethoxyj- benzoylamino] propionic acid dihydrochloride or pharmaceutical salts thereof.
43. A pharmaceutical composition comprising a compound of Claim 1 and at least one pharmaceutically acceptable carrier or excipient.
44. A method of treating a mammal afflicted with a condition that is mediated by an integrin receptor which comprises administration to the mammal a compound of the formula: -150-
Figure imgf000152_0001
G- C wherein:
G is
ϋ y. x£ R<
^ -
Figure imgf000152_0002
Figure imgf000152_0003
r xS Hl r C Hl '
R1 and R2 are independently, hydrogen, alkyl of 1 to 6 carbon atoms, mono or bicyclic aralkyl of 6 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyckc heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
R is hydrogen, mono or bicyclic aryl of 6 to 10 carbon atoms. 5 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O;
R4 is hydrogen, NHR9, OR9, NHCO2R9, NHCONHR9, NHCOR9or NHSO2R9; provided that R3 and R4 are not both hydrogen;
R5 is hydrogen, or alkyl of 1 to 6 carbon atoms, optionally substituted with a terminal group forming a prodrug;
R and R are hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, or aralkoxy of 6 to 10 carbon atoms; 99/52879
-151-
R8 and R9 are independently hydrogen, alkyl of 1 to 10 carbon atoms, alkenyl of 2 to 10 carbons, alkynyl of 2 to 10 carbons, mono or polycycloalkyl of 3-10 carbon atoms, mono or bicyckc aryl of 6 to 10 carbon atoms, 6 to 10 membered mono or bicyclic heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O, mono or bicyckc aralkyl of 7 to 10 carbon atoms, or heterocycloalkyl-alkyl comprised of a 5 to 10 membered mono or bicyckc heterocycloalkyl having 1 to 3 heteroatoms selected from S, N and O and an alkyl of 1 to 6 carbon atoms;
45. The method of Claim 44 wherein the integrin receptor is avb3.
46. The method of Claim 44 wherein the condition is cancer.
47. The method of Claim 46 wherein the cancer is associated with at least one of metastasis, angiogenesis, neovascularization and tumor growth.
48. The method of Claim 44 wherein the condition is benign tumor growth.
49. The method of Claim 44 wherein the condition is neovascularization.
50. The method of Claim 49 wherein neovascularization is associated with diabetic retinopathy, glaucoma, macular degeneration or blindness.
51. The method of Claim 49 wherein neovascularization is associated with rheumatoid arthritis.
52. The method of Claim 44 wherein the condition is inflammation.
53. The method of Claim 52 wherein the inflammation is associated with rheumatoid arthritis or psoriasis.
54. The method of Claim 44 wherein the condition is restenosis.
55. The method of Claim 54 wherein restenosis is associated with at lease one of smooth muscle cell migration, smooth muscle cell proliferation, vascular endothelial cell migration and vascular endothekal cell proliferation.
56. The method of Claim 44 wherein the condition is viral infection. -152-
57. The method of Claim 56 wherein the viral infection is caused by an adenovirus.
58. The method of Claim 44 wherein the condition is characterized by bone resorption.
59. The method of Claim 58 wherein bone resorption is associated with osteoporosis, Paget's disease, hypercalcemia, osteopenia, hyperparathyroidism, periarticular erosions, and periodontal disease.
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