WO1999057098A2 - Substituted beta-amino acid inhibitors of methionine aminopeptidase-2 - Google Patents

Substituted beta-amino acid inhibitors of methionine aminopeptidase-2 Download PDF

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Publication number
WO1999057098A2
WO1999057098A2 PCT/US1999/009641 US9909641W WO9957098A2 WO 1999057098 A2 WO1999057098 A2 WO 1999057098A2 US 9909641 W US9909641 W US 9909641W WO 9957098 A2 WO9957098 A2 WO 9957098A2
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WO
WIPO (PCT)
Prior art keywords
amino
cyclohexyl
hydroxy
butanamide
hydroxybutanamide
Prior art date
Application number
PCT/US1999/009641
Other languages
French (fr)
Other versions
WO1999057098A3 (en
Inventor
Richard A. Craig
Jack Henkin
Megumi Kawai
Linda Lijewski Lynch
Jyoti Patel
George S. Sheppard
Jieyi Wang
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU38778/99A priority Critical patent/AU3877899A/en
Priority to SK1628-2000A priority patent/SK16282000A3/en
Priority to EP99921611A priority patent/EP1073633A2/en
Priority to JP2000547068A priority patent/JP2002513781A/en
Priority to PL99346444A priority patent/PL346444A1/en
Priority to IL13913999A priority patent/IL139139A0/en
Priority to BR9910092-4A priority patent/BR9910092A/en
Priority to KR1020007012124A priority patent/KR20010043198A/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to CA002329704A priority patent/CA2329704A1/en
Priority claimed from US09/303,807 external-priority patent/US6242494B1/en
Publication of WO1999057098A2 publication Critical patent/WO1999057098A2/en
Publication of WO1999057098A3 publication Critical patent/WO1999057098A3/en
Priority to NO20005506A priority patent/NO20005506L/en
Priority to BG104981A priority patent/BG104981A/en

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D207/26—2-Pyrrolidones
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to organic compounds having biological activity, to compositions containing the compounds, and to medical methods of treatment. More particularly, the present invention concerns a class of substituted beta-amino acids and their pharmaceutically acceptable salts, pharmaceutical compositions containing the compounds, and methods of treating pathological conditions arising from or dependent upon angiogenesis.
  • Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period. (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267: 10931-10934 (1987), and Folkman, J. and Klagsbrun, M., Science, 235: 442-447 (1987)).
  • angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as “angiogenic diseases") are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness.
  • the present invention provides a compound having activity for inhibiting methionine aminopeptidase type 2 (MetAP2 or MetAP2-2) having the structural, formula I
  • n 1-3;
  • R 1 is selected from the group consisting of (1) hydrogen
  • alkanoyl where the alkanoyl can be optionally substituted with hydroxyl, and (5) -(CH 2 ) n CO 2 R , where n is 0-6, and R 4 is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • R ⁇ is selected from the group consisting of
  • R 3 is selected from the group consisting of (1) an aminoacyl group optionally capped with a carboxyl protecting group,
  • R 6 is defined above, and R 7 is selected from the group consisting of
  • alkyl where the alkyl can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
  • aryl where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
  • R 6 is defined above, and R ⁇ is selected from the group consisting of (i) hydrogen ( ⁇ ) alkyl, (iii) aryl, and
  • heterocycle (g) heterocycle, where the heterocycle can be optionally substituted with one, two, or three groups independently selected from the group consisting of
  • R 2 ⁇ and R 21 together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein 1 or 2 double bonds and optionally containing therein a moiety selected from the group consisting of (a) oxygen,
  • R 4 is defined above, 5') alkanoyloxy, 6') carboxaldehyde, 7') cycloalkyl, 8') cycloalkenyl, 9') halo, 10') nitro, 11') perfluoroalkyl, 12') perfluoroalkoxy,
  • X is hydroxyl or sulfhydryl
  • Y is hydrogen
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising adminstering to the mammal a pharmaceuticlly acceptable amount of a compound of formula I.
  • alkanoyl denotes an alkyl group attached to the parent molecular group through a carbonyl group.
  • the alkanoyl groups of this invention can be optionally substituted.
  • alkanoyloxy denotes an alkanoyl group attached to the parent molecular group through an oxygen atom.
  • the alkanoyloxy groups of this invention can be optionally substituted.
  • alkyl denotes a radical formed by the removal of one hydrogen atom from a straight or branched saturated hydrocarbon of one to twelve carbon atoms.
  • Representative hydrocarbon groups include methyl, ethyl, n-propyl, w ⁇ -propyl, n- butyl, sec-butyl, tert-butyl, and the like.
  • the alkyl groups of this invention can be optionally substituted.
  • alkoxy denotes a lower alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom and includes such groups as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and the like.
  • the alkoxy groups of this invention can be optionally substituted.
  • aminoacyl group denotes a radical derived from naturally or unnaturally occuring amino acids.
  • Representative aminoacyl groups include glycyl, alanyl, valyl, leucyl, wo-leucyl, methionyl, seryl, threonyl, cysteinyl, phenylalanyl, homophenylalanyl, and O-methyltyrosinyl in the racemic, 6 or L configurations.
  • aryl denotes a mono- or bicyclic- carbocyclic ring system having one or two aromatic rings.
  • Aryl groups are exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, and indenyl.
  • Bicyclic aryl groups of this invention can be attached to the parent molecular group through a saturated or unsaturated part of the group.
  • the aryl groups of this invention can be optionally substituted.
  • arylalkoxy denotes an aryl group, as defined herein, attached to the parent molecular group through an alkoxy group.
  • the arylalkoxy groups of this invention can be optionally substituted.
  • arylalkyl denotes an aryl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the arylalkyl groups of this invention can be optionally substituted.
  • aryloxy denotes an aryl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • the aryloxy groups of this invention can be optionally substituted.
  • aryloyl denotes an aryl group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • the aryloyl groups of this invention can be optionally substituted.
  • aryloyloxy denotes an aryloyl group, as defined herein, attached to the parent molecular group through an oxygen atom.
  • the aryloyloxy groups of this invention can be optionally substituted.
  • aryloyloxy alkyl denotes an aryloyloxy group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the aryloyloxyalkyl groups of this invention can be optionally substituted.
  • aryloyloxyalkylcarbonyl denotes an aryloyloxy group, as defined herein, attached to the parent molecular group through a carbonyl group.
  • the aryloyloxyalkylcarbonyl groups of this invention can be optionally substituted.
  • aryloyloxyalkylcarbonylalkyl denotes an aryloyloxyalkylcarbonyl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the aryloyloxyalkylcarbonylalkyl groups of this invention can be optionally substituted.
  • arylsulfonyl denotes an aryl group, as defined herein, attached to the parent molecular group through an -SO2- group.
  • the arylsulfonyl groups of this invention can be optionally substituted.
  • arylsulfonylalkyl denotes an arylsulfonyl group, as defined herein, attached to the parent molecular group through an alkyl group.
  • the arylsulfonylalkyl groups of this invention can be optionally substituted.
  • benzyl denotes a phenyl group, as defined herein, attached to the parent molecular group through a methyl group.
  • the benzyl groups of this invention can be optionally substituted.
  • Carboxaldehyde denotes -CHO.
  • carbonyl denotes -C(O)-.
  • carboxy denotes -CO 2 H.
  • cycloalkyl denotes a radical derived by the removal of a single hydrogen atom from a saturated cyclic or bicyclic hydrocarbon and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and the like.
  • the cycloalkyl groups of this invention can be optionally substituted.
  • (cycloalkyl)alkyl denotes a cycloalkyl group as just defined, attached to the parent molecular moiety through an alkyl group as defined above and includes such representative groups as cyclopropylmethyl, cyclopentylethyl, 2-methyl-3-cyclopentylbutyl, cyclohexylmethyl, and the like.
  • the (cycloalkyl)alkyl groups of this invention can be optionally substituted.
  • cycloalkenyl denotes a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbon atoms having at least one carbon-carbon double bond. The cycloalkenyl groups of this invention can be optionally substituted.
  • halo denotes -F, -Cl, -Br or -I.
  • heterocycle denotes any 5-, 6-or 7-membered saturated ring containing from one to three heteroatoms independently selected from the group consisting of 1, 2, or 3 nitrogens, one oxygen and one nitrogen, and one sulfur and one nitrogen; wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized.
  • heterocycle also includes and to 5-, 6-, or 7-membered aromatic rings having in the ring one, two, or three heteroatoms selected from N, O, and S, and also including benzo fused analogs of these 5-, 6-, or 7-membered heterocyclic aromatic rings.
  • heterocycles of this invention include, pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, thienyl, triazolyl 1,3,4-thiadiazolyl, and tetrazolyl, and the like.
  • heterocycle also includes compounds of formula
  • Y* is selected from the group consisting of -C(O)- and
  • R is selected from the group consisting of hydrogen and alkyl.
  • heterocycle also includes bicyclic or tricyclic rings, wherein any of the aformentioned heteroaryl rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl ring.
  • heteroaryls include benzo[b]furanyl, benzo[b] thienyl, benzimidazolyl, cinnolinyl, imidazo[4,5-c]pyridinyl, quinazolinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3- b]pyridinyl,indolizinyl, and imidazo[l,2-a]pyridine and can be attached to the parent molecular group through either the heretoaryl group or the aryl, cycloalkyl, or cycloalkenyl group to which it is fused.
  • the heterocycle groups of this invention can be optionally substituted.
  • hydroxy denotes -OH.
  • nitro denotes -NO 2 .
  • nitrogen-protecting group denotes groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used nitrogen-protecting groups are disclosed in Greene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1991)).
  • Common N-protecting groups comprise (a) acyl groups such as formyl, acetyl, propionyl, pivaloyl, tert- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, and 4- nitrobenzoyl, (b) sulfonyl groups such as benzenesulfonyl, and p ⁇ r ⁇ -toluenesulfonyl, (c) carbamate forming groups such as benzyloxycarbonyl, /?
  • Preferred nitrogen-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert- butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • perfluoroalkoxy denotes a perfluoroalkyl group attached to the parent molecular group through an oxygen atom.
  • perfluoroalkyl denotes an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
  • phenyl denotes a radical formed by the removal of one hydrogen atom from a benzene ring.
  • the phenyl groups of this invention can be optionally substituted.
  • prodrug denotes compounds that are rapidly transformed in vivo to yield the parent compounds of formula I, as for example, by hydrolysis in blood.
  • T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Prodrugs as Novel DeUvery Systems," Vol. 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups may be found on pages 14-21 of Bior ever sible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press (1987).
  • prodrug ester group denotes any of several ester-forming groups that are hydrolyzed under physiological conditions.
  • Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthahdyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters includes formates, acetates, propionates, butryates, acrylates and ethylsuccinates.
  • sulfhydryl denotes -SH.
  • thiocarbonyl denotes -C(S)-.
  • the compounds of the invention have at least one chiral center designated by the numeral "1."
  • Y is hydrogen
  • the compounds also possess at least one additional chiral center designated by the numeral "2" in the generic formula.
  • preferred compounds of the present invention are those in which the chirality at the site designated "1" is R and the chirality at the site designated "2" is S.
  • the "R” and “S” stereochemical designators follow the convention established by R. S. Cahn, et al, Angewandt Chemie. Int. Ed. Engl.. 5: 385-415 (1966).
  • Diastereomers having the preferred (Site 1)R and (Site 2)S stereochemistry can be synthesized by judicious choice of optically pure starting materials, asymmetric synthesis, or may be separated from mixtures of diastereomers by methods well known in the art as, for example, by reverse phase HPLC techniques.
  • R is -SR where R is lower alkyl, most preferably, methyl or ethyl.
  • Another preferred sub-group of compounds of the invention are compounds of 2 formula I where R is cycloalkyl, preferably cyclohexyl.
  • Another preferred sub-group of compounds of the invention are compounds of
  • Another preferred sub-group of compounds of the present invention is defined by structural formula I above where X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl group, with carbonyl being particularly preferred.
  • a preferred sub-group of compounds of the invention are defined by structural 3 formula I where R is an aminoacyl group derived from a naturally occurring amino acid, where the nitrogen atom at the N-terminus of the aminoacyl group is attached to the immediately adjacent carbonyl group of the parent molecular moiety, and the C-terminus, or carboxyl functionality of the aminoacyl residue is optionally and preferably capped by a carboxyl blocking group.
  • Carboxyl blocking groups are well known to practitioners of the organic chemical arts, and are described in some detail in Chapter 5, pages 224-276 of "Protective Groups in
  • Such carboxyl protecting groups include esters such as substituted methyl esters, substituted ethyl esters, substituted benzyl esters, silyl esters, oxazoles, 2-alkyl-l,3- oxazolines, 4-alkyl-5-oxo- 1 ,3-oxazolidines, 5-alkyl-4-oxo- 1 ,3-dioxalanes, ortho esters, and amides such as N,N-dialkyl amides, pyrrolidinyl amides, piperidinyl amides, 5,6- dihydropiperidinyl amides, o-nitroanilides, and hydrazides such as N-phenylhydrazides and
  • N, N'-dialkylhydrazides N, N'-dialkylhydrazides .
  • Recombinant methionine aminopeptidase-2 (MetAP2) was expressed as a secreted protein with a baculovirus system and purified from the insect cell culture supernatant as previously described by R. L. Kendal, et al, J. Biol. Chem.. 267(29): 20667-20673 (1992) and Xuan Li, et al, Biochem. And Biophvs. Res. Comm.. 227: 152-159 (1996), the contents of which are incorporated herein by reference.
  • Assays for MetAP2 enzyme activity and MetAP2 inhibition were performed in 96- well microtiter plates. Compounds to be tested for MetAP2 inhibition were dissolved in dimethyl-sulfoxide at 10 mM and diluted ten-fold in assay buffer (50 nM ⁇ EPES, p ⁇ 7.4, 100 mM ⁇ aCl). Ten microliters of solution of each compound to be tested for inhibition were introduced into each cell of the plate, with each compound being tested in triphcate. Zero inhibition of enzyme activity was taken to be the result obtained in cells in which 10 mL of assay buffer was placed, and 100 percent inhibition of enzyme activity was taken to be the result obtained in cells in which 10 mM of fumagillin (Sigma Chemical Co., St. Louis, MO, USA, Catalog No. F-6771) in assay buffer was placed.
  • compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluoro-hydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • disorders caused by undesirable angiogenesis are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention is meant a sufficient amount of the compound to inhibit angiogenesis, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • a well-known technique utilized by medical practitioners is to "dose titrate" the patient; that is, to start with dose lower than that required to obtain the desired effect, and to gradually increase the dose until the dseired therapeutic benefit is obtained.
  • the total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.11 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 500 mg of the compound(s) of this invention per day in single or multiple doses.
  • 3-amino-2-hydroxy-carboxylic acids used as starting materials for the synthesis of compounds of the present invention are available from appropriately substituted alpha-aminoacids by conversion to the corresponding aminoaldehyde, formation of the corresponding cyanohydrin, and hydrolysis. Protection of the free amino group, for example with a tert-butyl carbamate group, followed by couphng with an appropriate amine, amino acid derivative, or alcohol and deprotection provides the target compounds.
  • the coupling partners may be purchased from commercial sources or prepared using known chemical transformations. Subsequent conversion of the 3-amino-2- hydroxy compounds to compounds of the present invention are by standard methods well known to practitioners of the organic chemical arts and are illustrated by the Examples which appear below.
  • Example 1A A solution of N-(tert-butoxycarbonyl)-L-methionine (12.47 g, 50 mmol) and RED-
  • Example IB A solution of the product of example 1 A (9.05 g, 38.5 mmol), sulfur trioxide pyridine complex (30.64 g, 192.5 mmol) and triethylamine (26.8 mL, 192.5 mmol) in DMSO (30 mL) was stirred at ambient temperature for 30 minutes, cooled to 0 °C, then treated sequentially with water (20 mL) and saturated aqueous KHSO4 (120 mL), and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO4 and brine, dried (MgSO4), and concentrated to give a colorless syrup (9.00 g).
  • Example ID A solution of the product of example IC (5.81 g, 32.4 mmol), BOC-ON (9.58 g,
  • Example IE A solution of example ID (2.79 g, 10 mmol), L-alanine ethylester hydrochloride
  • Example IF A solution of the product of example IE (0.40 g, 1.1 mmol), in hydrogen chloride saturated dioxane (8 mL) was stirred at ambient temperature for 1 hour, evaporated to dryness, suspended in ethyl ether then concentrated and vacuum dried to give the title compound (0.24 g).
  • Example 2 (2RS.3S.l'S)-N-(fl-Ethylcarboxamido)ethyl)-3-amino-2-hvdroxy-5- (methylthio)pentanamide hvdrochloride
  • the product of example ID and alanine ethylamide were processed as in examples
  • Example 3A N-(tert-butoxycarbonyl)-D-methionine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-(methylthio)pentanoic acid.
  • Example 3B The product of example 3 A and L-alanine ethylamide were processed as in example 2 to provide the title compound.
  • MS (ESI+Q1MS) m/e 278 (M+H) + , 300 (M+Na)+;
  • Example 12 A N-(tert-butoxycarbonyl)-D-ethionine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-(ethylthio)pentanoic acid.
  • Example 12B The product of example 12 A and L-alanine ethylester hydrochloride were processed as in example 2 to provide the title compound.
  • Example 16 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride
  • MS (ESI+Q1MS) m/e 307 (M+H) + 325 (M+Na) + ; *H NMR (300 MHz, DMSO-d 6 ) ⁇ 4.46 (d.
  • Example 17 (2RS.3R.1 'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-heptanamide hydrochloride
  • Example 17A N-(tert-butoxycarbonyl)-D-norleucine was processed as in examples .1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-heptanoic acid.
  • Example 18 (2RS,3R)-3-amino-2-hvdroxy-5-(methylthio)pentanoic acid N-(tert-butoxycarbonyl)-D-methionine was processed as in examples 1 A through IC to provide (2RS,3R) 3-amino-2-hydroxy-5-(methylthio)pentanoic acid.
  • MS (APCI) m e 180 (M+H) + ;
  • Example 20A N-(tert-Butoxycarbonyl)-D-phenylalanine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoic acid.
  • Example 20B The product of example 20A and ethyl 3-amino-propionate were processed as in example 2 to provide the title compound.
  • MS (ESI+Q1MS) m/e 295 (M+H) + , 317 (M+Na) + l H NMR (300 MHz, MeOH-d 4 ) ⁇ 1.19-1.26 (m, 3H), 2.49-2.58 (m, 2H), 2.80-3.10 (m, 2H), 3.41-3.53 (m, 2H), 3.78-3.85 (m, IH), 4.03 (d, 0.6H), 4.07-4.16 (m, 2H), 4.27 (d, 0.4H), 7.25-7.40 (m, 5H); 3.10-3.19 (m, IH), 4.02 (d, IH), 4.29 (m, IH), 7.10-7.27 (m, 5H).
  • Example 21 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdroxy-4-phenyl-butanamide hydrochloride
  • the product of example 20A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound.
  • Example 22 (2RS.3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide hydrochloride
  • the product of example 20A and 4-phenylbutylamine were processed as in example
  • N-(tert-Butoxycarbonyl)-D-cyclohexylalanine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl- butanoic acid.
  • Example 25 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cvclohexyl-butanamide hydrochloride
  • the product of example 23 A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound.
  • MS (ESI+Q1MS) m/e 335 (M+Na-H) + ; l U NMR (300 MHz, MeOH-d 4 ) ⁇ 0.82-1.88 (m, 18H, includes 1.25,t, 3H), 2.34-2.39 (m,
  • example 20A The product of example 20A and L-alanine ethyl ester hydrochloride were processed as in example IE to provide the title compound.
  • Example 27 (2RS.3R)-3-amino-2-hvdroxy-N-(4-methoxyphenethyl)-5-(methylsulfanyl)pentanamide hydrochloride
  • the product of example 23 A and l-amino-2-(4-methoxyphenyl)ethane were processed as in example 2 to provide the title compound.
  • Example 31 (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride
  • the product of example 13 and methyl chloroformate were reacted in tetrahydrofuran in the presence of triethylamine and purified on silica gel column chromatography, eluting with 0.5-0.75 % methanol in chloroform to provide the title compound.
  • Example 32 (2RS.3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide
  • the product of example 3A and l-amino-2-(3-pyridyl)ethane were processed as in example 2 to provide the title compound.
  • Example 38 (2RS.3R)-N-((phenylbutyryl)-3-formylamino-2-hvdroxy-4-ethylthio)pentanamide
  • the product of example 13 and formic acid-acetic anhydride in methylene chloride in the presence of triethylamine were processed as in example IE, and purified by silica gel, eluting with 2% methanol in chloroform to provide the title compound.
  • MS (ESI+Q1MS) m e 353 (M+ H) + , 375 (M+ Na) + , 727 (2M+ Na) +
  • Example 39 (2RS.3RVN-Methyl-N-( ⁇ ethoxycarbonylmemyl)-3-amino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride
  • the product of example 12 A and sarcosine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • Example 42 (2RS.3R.rR)-N-((l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4-cvcIohexyl)butanamide hydrochloride
  • the product of example 23 A and D-alanine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 301 (M+ H) + , lH NMR (300 MHz, MeOH-d 4 ) ⁇ 4.54-4.42 (m, IH), 4.28-4.16 (m, 2H), 3.76-3.57 (m, 2H), 1.82-0.83 (m, 19H ).
  • Example 43 (2RS.3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cvclohexyDbutanamide hydrochloride
  • the product of example 23A and alpha aminoisobutyric acid ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • Example 44 (2RS.3R)-N-((Phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4- ethylthio)pentanamide hydrochloride
  • the product of example 13 and methyl bromoacetate were reacted in dimethylsulfoxide in the presence of sodium hydride and processed as in example IE to provide the title compound.
  • Example 45A N-(tert-Butoxycarbonyl)-S-benzyl-D-cysteine was processed as in Example 1 A through IB to prepare N-(tert-butoxycarbonyl)-S-benzyl-D-cysteinal.
  • Example 45C The product of example 45B (3.40g) was dissolved in 50 mL of methanol in an ice bath and hydrogen chloride gas was bubbled through the reaction mixture until saturated. It was then stirred at 0 °C for 3 hours and at room temperature for one over night. Solvent was evaporated dryness and 20 mL of water was added to the residue. 10%-Sodium hydrogen carbonate was added to the mixture to adjust pH over 9, an oil was extracted with ethyl acetate (50 mLx2). The combined ethyl acetate layer was washed with 10%- sodium hydrogen carbonate (2X), brine (3X), quickly dried over sodium sulfate anhydrous. Ethyl acetate was removed by evaporation to yield 1.77g of dark brown oil.
  • Example 45D The product of example 45C was treated with lN-lithium hydroxide in methanol- water to provide its free carboxylic acid derivatives and coupled with L-alanine ethyl ester as in example IE and deprotection was carried out according to the method described in example IF to provide the title compound.
  • Example 46 (2RS.3R.rS)-N-((2-hvdroxy-l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4- cyclohexyDbutanamide hydrochloride
  • the product of example 23 A and L-serine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 317 (M+ H) + , 633 (2M+ H) + , *H NMR (300 MHz, MeOH-d 4 ) ⁇ 4.45-4.55 (m, IH), 4.26-4.18 (m, 3H), 4.00-3.87 (m,
  • N-(tert-Butoxycarbonyl)-L-alaninol (438 mg, 2.5mmol) was dissolved in 5 mL of methylene chloride in an ice bath and acetyl chloride (0.294 mL, 3.75 mmol), followed by triethylamine (0.7mL, 5 mmol) were added. It was then reacted at 0 °C for 1 hour and at room temperature for 2 days.
  • Example 47B The product of example 47 A (380 mg) was processed as in example IF to yield
  • Example 51 (2RS.3R.2'R)- ⁇ -((2-propionyloxypropyl)-3-amino-2-hvdroxy-4-cvcIohexyl)butanamide hydrochloride
  • N-(tert-butoxycarbonyl)-L- alaninol N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-D-alaninol.
  • Example 53 f2RS.3R.rS)-N-((l-benzyloxycarbonylethyl)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide hydrochloride
  • the product of example 23 A and L-alanine benzyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 363 (M+ H) + , 725 (2M+ H) + , !H NMR (300 MHz, MeOH-d 4 ) ⁇ 7.38-7.32 (m, 5H), 5.21-5.17 (m, 2H), 4.57-4.48 (m,
  • Example 54A N-(tert-Butoxycarbonyl)-L-alanine amide (3.76g, 20 mmol) was suspended in 70 mL of methylene chloride in an ice bath and triethyloxonium hexafluorophosphate (4.97g, 20 mmol) was added. It was stirred at 0 oC for 30 minutes and at room temperature for one over night. Methylene chloride layer was washed with water (2x), 10%-sodium hydrogen carbonate (2x), water (2x), dried over sodium sulfate anhydrous. It was then evaporated to dryness, dried under high vaccum to yiels 2.72 g of iminoether. MS (ESI+Q1MS) m/e 217 (M+ H) + , 433 (2M+ H) + , 455 (2M+ ⁇ a) +
  • Example 54B The product of example 54A (2.72g, 12.6 mmol) was dissolved in 40 mL of ethanol and L-cysteine ethyl ester hydrochloride (2.57g, 13.86 mmol) was added. It was stirred at room temperature for 2 days. Ethanol was removed by evaporation, and the residue was dsirectiy purified by silica gel column chromatography, eluting with 30% ethyl acetate in hexane to yield 2.91 g of pure thizoline analogue. MS (ESI+Q1MS) m e 303 (M+ H) + , 325 (M+ Na) + ,
  • Example 54C To the product of example 54B (604mg, 2 mmol) in a 50 mL of round bottle flask were addwd copper (I) bromide (316 mg, 1.1 mmol) and copper (II) acetate anhydrous (0.40g, 2.2 mmol). The flask was evacuated with argon repeatedly and 15 mL of benzene was added via syringe. While stirring at 60 °C, tert-butyl perbenzoate was carefully added in a period of 15 minutes, and gently refluxed for 4 hours.
  • the crude product was directly purified by silica gel column chromatography, eluting eith 30 % ethyl acetate in hexane to yield 390 mg of pure thiazole derivative.
  • the obtained product (320 mg ) was treated according to the method as in example IF and coupled with the product of example 23 A as in example IE to give N-(tert-butoxycarbonyl) derivative of the title compound (220 mg).
  • Example 54D The product of example 54C (60 mg) was processed as in example IF to yield the title compound.
  • Example 55 (2RS.3R) N-(monodansylcadaveno)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide dihydrochloride
  • the product of example 23A and monodansyl cadaverive were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 519 (M+ H) + ; !H NMR (300 MHz, MeOH-d 4 ) ⁇ 8.90 (d, IH), 8.58 (d, IH), 8.36 (d, IH), 8.06 (d, IH),
  • Example 57 (2RS.3R) N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4-cvclohexy butanamide dihydrochloride
  • the product of example 23A and 2-(2-aminoethylamino)-5-nitro-pyridine were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 366 (M+ H) + , 731 (2M+ H) + ;
  • Example 61 A The product of example 23 A and L-alanine benzyl ester hydrochloride were processed as in example IE to yield N-(tert-butoxycarbonyl) drivative (3.80 g), which was hydrogenated in 50 mL of ethanol in the presence of 0.3g of 10% palladium on charcoal as a catalyst for 3.5 hours. The mixture was passed through celite 545 and evaporated to dryness to yield (2RS,3R) N-[(3-tert-butoxycarbonylamino-2-hydroxy-4- cyclohexyl)butanoyl-L-alanine (3.16g)
  • Example 6 IB The product of example 61 A and l-(2-aminoethyl)-2-methyl-5-nitro imidazole were processed as in examples IE and IF to yield the title compound.
  • MS (ESI+Q1MS) m/e 425 (M+ H) + , 849 (2M+ H) + , !H ⁇ MR (300 MHz, MeOH-d 4 ) ⁇ 8.58, 8.56 (both s, total IH), 4.73-4.57 (m, 2H), 4.26-
  • Example 62 ((2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- nitropyridylaminoethvDamide dihydrochloride
  • the product of example 61 A and 2-(2-aminoethylamino)-5-nitro-pyridine were processed as in examples IE and IF to yield the title compound.
  • MS (ESI+Q1MS) m/e 437 (M+ H) + , 873 (2M+ H) + , 1H ⁇ MR (300 MHz, MeOH-d 4 ) ⁇ 8.94-8.37 (br. m, IH), 7.92-7.75 (m, IH), 7.62-7.50
  • Example 65 ((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(5- methoxytrvptamine)amide hydrochloride
  • the product of example 61 A and 5-methoxy tryptamine were processed as in examples IE and IF to yield the title compound.
  • Example 66 (Y2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(3-O- methoxydopamine)amide hydrochloride
  • the product of example 61 A and 3-O-methoxydopamine hydrochloride were processed as in examples IE and IF to yield the title compound.
  • Example 67 (( " 2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(2- benzimidazolemethvDamide hydrochloride
  • the product of example 61 A and 2-(aminomethyl)benzimidazole dihydrochloride monohydrate were processed as in examples IE and IF to yield the title compound.
  • Example 72 f(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoylL-alanyl-(l-ethylpyrazole)amide hydrochloride
  • the product of example 61 A and 5-amino-l-ethylpyrazole were processed as in examples IE and IF to yield the title compound.
  • Example 73 ((2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide hydrochloride
  • the product of example 23 A and ethyl isonipecotate were processed as in examples IE and IF to yield the title compound.
  • MS (ESI+Q1MS) m/e 341 (M+ H) + , l H NMR (300 MHz, MeOH-d 4 ) ⁇ 4.14 (q, 2H), 3.73-3.48 (m, 2H), 0.83-1.93 (m, 20H).
  • Example 75 (2RS.3R)- 3-amino-2-hvdroxy-4-cyclohexyl)hutanoyl-(4-carboxyl-2-( 1 'amino)ethyl thizole hydrochloride
  • the product of example 54C (0.2g, 0.414 mmol) was treated with lN-lithium hydroxide (0.5 mL, 0.5 mmol) in methanol for 3 hours. 8 mL of water was added to the mixture, and methanol was removed by evaporation. The aqueous layer was washed with ethyl acetate, and acidified by an addition of 10 % potassium hydrogen sulfate.
  • Example 79 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)but ⁇ noyl-monodansylcadaverine amide dihydrochloride
  • the product of example 12 A and monodansyl cadaverine were processed as in examples IE and IF to yield the title compound.
  • Example 80A Following example 77, the product of example 23 A and N-benzyloxycarbonyl-1,4- diaminobutane hydrochloride were coupled as in examples IE to yield the both protected compound.
  • the product (260 mg) was hydrogenated in 10 mL of ethanol in the presence of 30 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same method described in Example 61A to yield 200 mg.
  • Example 80B The product of example 80A (92.8 mg, 0.25 mmol) was dissolved in 5 mL of methylene chloride in an ice bath, and diisopropylethylamine (0.048 mL, 0.275 mmol) and p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol) were added. It was reacted at 0 °C for 3 hours and at room temperature for over night. Methylene chloride was removed and the residue was purified by silica gel column chromatography, eluting with 15-30% acetone in hexane. The obtained product was processed as in example IF to yield the title compound
  • Example 81 A Following example 77, the product of example 23 A and benzyl N-(2- aminoethyl)carbamate hydrochloride were coupled as in example IE to yield the protected compound. The product (220 mg) was hydrogenated in 10 mL of ethanol in the presence of 20 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same method described in example 61 A to yield 130 mg. MS (ESI+Q1MS) m/e 344 (M+ H) +
  • Example 8 IB The product of example 81 A (42.8 mg, 0.125 mmol) and p-toluenesulfonyl chloride (23.8 mg, 0.125 mmol) were processed as in example 80B to yield the title compound (20 mg). MS (ESI+Q1MS) m/e 426 (M+ H) ⁇ 448 (M+Na) + , 533 (M+ Na) + ;
  • Example 83 (2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(2-aminoethyl)amide dihydrochloride
  • the product of example 81 A (60 mg) was processed as in example IF to yield the title compound (45 mg).
  • Example 84 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(4-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide hydrochloride
  • the product of example 81 A and m-(trifluoromethyl)benzenesulfonyl chloride were processed as in example 80B to yield the title compound.
  • Example 86 (2RS.3R)-N-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4-cvclohexyl-2- hydroxybutanamide hydrochloride
  • the product of example 81 A and 4-acetamidobenzenesulfonyl chloride were processed as in example 80B to yield the title compound.
  • MS (APCI) m/e 469 (M+ H) + ; !H NMR (300 MHz, DMSO-d 6 ) ⁇ 7.72 (m, 4H), 7.41 (m, IH), 5.93 (d, IH), 3.79 (m,
  • Example 87 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(T2- naphthylsulfonyl amino)butyl)butanamide hydrochloride
  • the product of example 81 A and 2-naphthylsulfonyl chloride were processed as in example 80B to yield the title compound.
  • Example 89 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine benzyl ester hydrochloride
  • the product of example 23A and amino isobutyric acid benzyl ester were processed as in examples IE and IF to yield the title compound.
  • Example 90A N-(tert-Butoxycarbonyl)-L-alanine (0.945g, 5 mmol) was dissolved in 10 mL of methanol and 2 mL of water was added, and pH was then adjusted to 7.0 by an addition of 20% cesium carbonate. The mixture was eveporated to dryness, re-evaporated twice from 5 mL of N,N-dimethylformamide, and suspended into 10 mL of N,N-dimethylformamide. Cyclohexyl bromide (0.677 mL, 5.5 mmol) was added and stirred at room temperature for over night.
  • Example 90B The product of example 23A and the product of example 90A were processed as in examples IE and IF to yield the title compound.
  • Example 97 (2RS.3R)-3-amino-4-cvclohexyl-N-(2,4-dichlorobenzyl)-2-hvdroxybutanamide hydrochloride
  • the product of example 23A and 2,4-dichlorobenzylamine were processed as in example 101 to provide the title compound.
  • Example 101 f2RS.3R.rRSV3-amino-4-cvclohexyl-2-hvdroxy-N-(l-( , l-naphthyl)ethyl)hutanamide hydrochloride
  • the product of example 23 A (2.4g, 8.64mmol) was dissolved in N,N- dimethylacetamide to give 48ml (solution A).
  • l-Hydroxy-7-azabenzotriazole (HOAT- 1.92g, 13.2mmol), O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU-4.8g, 13.4mmol), and disopropylethylamine (2.4ml, 13.4mmol) were dissolved in N,N-dimethylacetamide to make 48ml (solution B).
  • Solution A was distributed equally into 48 individual reactors.
  • Solution B was then added to these same reactors in equal portions. The reactors were shaken lOmin at room temperature.
  • Example 102 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(2-oxo-l-pyrrolidinyl)propyl)butanamide hydrochloride
  • the product of example 23A and l-(3-aminopropyl)-2-pyrrolidone were processed as in examples IE and IF to provide the title compound.
  • MS (ESI+Q1MS) m/e 326 (M+ H) + , 651 (2M+ H) + ; *H NMR (300 MHz, MeOH-d 4 ) ⁇ 4.24 (d, 0.4H), 4.15 (d, 0.6H), 3.54-3.41 (m, 2H),
  • Example 103 (2RS .3R)-3-amino-4-cyclohexyl-N-( 1.2-dimethylpropyl)-2-hydroxybutanamide hydrochloride
  • the product of example 23 A and 1,2-dimethylpropylamine were processed as in example 101 to provide the title compound.
  • MS (ESI+Q1MS) m/e 271 (M+H) + , 293 (M+Na) +
  • Example 106 A The product of example 20A and L-alanine benzyl ester were processed as in examples IE to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4- cyclohexyl)butanoyl-L-alanine benzyl ester.
  • 0.5g of the above product was hydrogenated in 20 mL of isopropyl alcohol in the presence of 20 mg of 10%-palladium on charcoal to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine (0.4g).
  • Example 109 (2RS,3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide hydrochloride
  • the product of example 23 A and 3-phenyl-l-propylamine were processed as in example 101 to provide the title compound.
  • Example 111 2.81 (m, 2H), 2.05 (m, IH), 0.90-1.90 (m, 16H).
  • Example 114 butyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)acetate hydrochloride
  • the product of example 23A and glycine n-butyl ester were processed as in example 101 to provide the title compound.
  • MS (APCI) m e 315 (M+H) + 1H NMR (300MHz, MeOH-d 4 ) ⁇ 4.16 (m, 2H), 4.02 (m, IH), 3.50 (m, IH), 0.90-1.85 (m,
  • Example 116 (2RS.3R)-3-amino-4-cvcIohexyl-N-(2.4-dimethoxyphenyl)-2-hydroxybutanamide hydrochloride
  • the product of example 23A and 2, 4-dimethoxy aniline were processed as in example 101 to provide the title compound.
  • Example 120 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hvdroxybutanamide hydrochloride
  • the product of example 23 A and 2-fluorobenzylamine were processed as in example 101 to provide the title compound.
  • MS (APCI) m/e 309 (M+H) + , 616 (2M+H) + 1H NMR (300MHz, MeOH-d 4 ) ⁇ 7.32 (m, 2H), 7.11 (m, 2H), 4.5 (q, 2H), 4.14 (d, IH),
  • Example 121 (2RS.3R)-3-amino-4-cvclohexyl-N-( , 4-fluoro-3-(trifluoromethyl)benzyl)-2- hydroxybutanamide hydrochloride
  • the product of example 23A and 3-(trifluoromethyl)-4-fluorobenzylamine were processed as in example 101 to provide the title compound.
  • Example 123 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(tetrahvdro-2-furanylmethyl)butanamide hydrochloride
  • the product of example 23 A and tetrahydrofurfurylamine were processed as in example 101 to provide the title compound.
  • Example 126 tert-butyl (2RS,3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)acetate hydrochloride
  • the product of example 23A and glycine tert-butyl ester were processed as in example 101 to provide the title compound.
  • Example 130 methyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3-methylbutanoate hydrochloride
  • the product of example 23A and L-valine methyl ester were processed as in example 101 to provide the title compound.
  • the product of example 23 A and (S)-l -amino- l-(2-naphthyl)ethane were processed as in example 24 to provide the title compound.
  • Example 132 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(Y 1 R)- 1 -(2-naphthyl)ethyl)butanamide hydrochloride
  • the product of example 23A and (R)-l-amino-l-(2-na ⁇ hthyl)ethane were processed as in example 24 to provide the title compound.
  • Example 133 (2RS.3R -3-amino-4-cvclohexyl-2-hvdroxy-N-f(lS)-l-(l-naphthvDethyl)butanamide hydrochloride
  • the product of example 23A and (S)-l-amino-l-(l-naphthyl)ethane were processed as in example 24 to provide the title compound.

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Abstract

A class of substituted β-amino acids are potent inhibitors of methionine aminopeptidase type 2 (MetAP2) and are thus useful in inhibiting angiogenesis and disease conditions which depend upon angiogenesis for their development such as diabetic retinopathy, tumor growth, and conditions of inflammation. Pharmaceutical compounds containing the compounds and methods of inhibiting methionine aminopeptidase-2, and angiogenesis are also disclosed.

Description

SUBSTITUTED BETA-AMINO ACID INHIBITORS OF METHIONINE AMINOPEPTIDASE-2
Field of the Invention
The present invention relates to organic compounds having biological activity, to compositions containing the compounds, and to medical methods of treatment. More particularly, the present invention concerns a class of substituted beta-amino acids and their pharmaceutically acceptable salts, pharmaceutical compositions containing the compounds, and methods of treating pathological conditions arising from or dependent upon angiogenesis.
Background of the Invention Angiogenesis is the fundamental process by which new blood vessels are formed and is essential to a variety of normal body activities (such as reproduction, development and wound repair). Although the process is not completely understood, it is believed to involve a complex interplay of molecules which both stimulate and inhibit the growth of endothelial cells, the primary cells of the capillary blood vessels. Under normal conditions, these molecules appear to maintain the microvasculature in a quiescent state (i.e. one of no capillary growth) for prolonged periods which may last for as long as weeks or in some cases, decades. When necessary, however, (such as during wound repair), these same cells can undergo rapid proliferation and turnover within a 5 day period. (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267: 10931-10934 (1987), and Folkman, J. and Klagsbrun, M., Science, 235: 442-447 (1987)).
Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as "angiogenic diseases") are driven by persistent unregulated angiogenesis. Otherwise stated, unregulated angiogenesis may either cause a particular disease directly or exascerbate an existing pathological condition. For example, ocular neovacularization has been implicated as the most common cause of blindness and dominates approximately 20 eye diseases. In certain existing conditions such as arthritis, newly formed capillary blood vessels invade the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed, and cause blindness. Growth and metastasis of solid tumors are also angiogenesis-dependent (Folkman, J., Cancer Research, 46: 467-473 (1986), Folkman, J., Journal ofthe National Cancer Institute, 82: 4-6 (1989)). It has been shown for example that tumors which enlarge to greater than 2 mm, must obtain their own blood supply and do so by inducing the growth of new capillary blood vessels. Once these new blood vessels become embedded in the tumor, they provide a means for tumor cells to enter the circulation and metastasize to distant sites, such as liver, lung or bone (Weidner, N., et al., The New England Journal of Medicine, 324: 1-8 (1991)).
Because of this pivotal role played by neovasculurization in tumor formation and metastasis and in such other disease conditions as arthritis, inflammation, maccular degeneration of age, and diabetic retinopathy, agents which inhibit angiogenesis have been the subject of active current research for their clinical potential. D. Ingber, et al, in Nature. 348: 555-557 report that fumagillin, a natural product of fungal origin, and its synthetic analog, O-(chloroacetylcarbamoyl)fumagillol, also known as AGM-1470 or TNP-470, act as potent inhibitors of angiogenesis, with TNP-470 being 50-fold more potent than its natural precursor.
Ny Sin et al, Proc. Natl. Acad. Sci. USA 94: 6099-6103 (1997) and Eric C. Griffith, et al, Chemistry and Biology. 4(6): 461-471 (1997) report that both AGM-1470 and ovalicin, a sequiterpene isolated from the fungus Pseudoroήum ocalis bind to a common bifunctional protein, type 2 methionine aminopeptidase, MetAP2, and conclude that MetAP2 plays a critical role in the proliferation of endothelial cells and may serve as a promising target for the development of new anti-angiogenic drugs. J. Abe, et al, Cancer Research. 54: 3407-3412 (1994) report that fumagillin, and its derivative TNP-470, are effective in inhibiting neovascularization by arresting the endothelial cell cycle in the late Gi phase.
The literature has thus established a casual link between inhibition of MetAP2 and the resultant inhibition of endothelial cell proliferation and neovascularization. There is a need for discovery of new agents which inhibit MetAP2 for their potential as new drugs in combating angiogenesis or neovascularization and disease conditions such as arthritis, inflammation, macular degeneration of the eye, diabetic retinopathy, and tumor growth which depend upon neovasculaturization for their development. Compounds of the current invention are structurally novel, reversible inhibitors of MetAP2 which may display improved pharmaceutical properties and diminished side effects relative to the currently known irreversible inhibitors such as fumagillin and TNP-470.
Summary of The Invention
In its principle embodiment, the present invention provides a compound having activity for inhibiting methionine aminopeptidase type 2 (MetAP2 or MetAP2-2) having the structural, formula I
Figure imgf000005_0001
I, or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein the small numerals denote chiral centers in the compound;
m is 1-3;
R1 is selected from the group consisting of (1) hydrogen,
(2) alkyl,
(3) carboxaldehyde,
(4) alkanoyl, where the alkanoyl can be optionally substituted with hydroxyl, and (5) -(CH2)nCO2R , where n is 0-6, and R4 is selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) cycloalkyl,
(d) (cycloalkyl)alkyl, (e) aryl, and
(f) arylalkyl, where (c) and (d) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i) alkyl,
(ii) alkoxy, and
(ϋi) aryl, and where (e) and (f) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl, (iii) alkoxy,
(iv) -CO2R4 , where R4 is selected from the group consisting of,
(a) hydrogen,
(b) alkyl, (c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) aryl, and
(f) arylalkyl, (v) alkanoyloxy,
(vi) carboxaldehyde, (vii) cycloalkyl, (viii) cycloalkenyl, (ix) halo, (x) nitro,
(xi) perfluoroalkyl, (xii) perfluoroalkoxy, (xiii) arylsulfonylalkyl, (xiv) aryloylalkyloxycarbonylalkyl, (xv) -NR6R^ , where R6 and R6' are independently selected from the group consisting of
(1') hydrogen,
(2') alkyl optionally substituted with alkoxy,
(3') aryl, (4') arylalkyl, and
(5') a nitrogen-protecting group, (xvi) -SO2NR6R6', where R6 and R6' are defined above, and (xvii) -C(O)NR6R6', where R6 and R6' are defined above;
R2 is selected from the group consisting of
(1) alkyl,
(2) cycloalkyl, (3) (cycloalkyl)alkyl,
(4) -C(H)(SR15)(SR15'), where R15 and R15' are alkyl, or R15 and R15', together with the sulfurs to which they are attached, are a 1,3-dithiolane ring or a 1,3-dithiane ring,
(5) aryl,
(6) arylalkyl, and (7) -SR5, where R^ is selected from the group consisting of
(a) alkyl,
(b) cycloalkyl,
(c) (cycloalkyl)alkyl, and (d) benzyl, where the benzyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy, (iv) -C02R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl, (ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) -NR6R6 , where R6 and R6' are defined above, (xiv) -SO2NR6R6', where R6 and R6' are defined above, and
(xv) -C(O)NR6R6', where R6 and R6' are defined above;
R3 is selected from the group consisting of (1) an aminoacyl group optionally capped with a carboxyl protecting group,
(2) -N(R6)(CH2)PR7, where p is 0-6, R6 is defined above, and R7 is selected from the group consisting of
(a) hydrogen,
(b) alkyl, where the alkyl can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
(i) oxo, (ii) thioxo, (iii) alkoxy,
(iv) -CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde, (vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl, (xii) perfluoroalkoxy,
(xiii) -NR6R6 , where R6 and R6' are defined above,
(xiv) -SO2NR6R6', where R6 and R6' are defined above,
(xv) -C(O)NR6R6', where R6 and R6' are defined above,
(xvi) aryl, (xvii) hydroxy, and
(xviii) heterocycle,
(c) cycloalkyl, where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i) alkyl,
(ii) halo, (iii) oxo, and (iv) aryl,
(d) aryl, where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) -CO2R4, where R4 is defined above, (v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo, (x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy, (xiii) -NR^R^ , where R^ and R^' are defined above, (xiv) -SO2NR6R6', where R6 and R6' are defined above, (xv) -C(O)NR6R6', where R6 and R6' are defined above, (xvi) aryloxy, (xvii) arylalkoxy,
(xvi) aryl, (xvii) hydroxy, and
(xviii) heterocycle, (e) -CO2R4, where R4 is defined above,
(f) -CONR6R^, where R6 is defined above, and R^ is selected from the group consisting of (i) hydrogen (ϋ) alkyl, (iii) aryl, and
(iv) heterocycle, where (ii)-(iv) can be optionally substituted with one, two, or three groups independently selected from the group consisting of (1') alkyl,
(2') alkanoyl, (3') alkoxy,
(4') -CO2R4, where R4 is defined above, (5') alkanoyloxy, (6') carboxaldehyde,
(7') cycloalkyl, (8') cycloalkenyl, (9') halo, (10') nitro, (If) perfluoroalkyl,
(12') perfluoroalkoxy,
(13') -NR6R6', where R6 and R6'are defined above, (14') -SO2NR6R6', where R6 and R6' are defined above, (15') -C(O)NR6R6', where R6 and R6' are defined above, (16') aryloxy,
(17') arylalkoxy, (18') aryl, (19') hydroxy, and
(20') heterocycle, (g) heterocycle, where the heterocycle can be optionally substituted with one, two, or three groups independently selected from the group consisting of
(i) alkyl,
(ii) alkanoyl,
(iii) alkoxy, (iv) -CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl, (ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) -NR6R6', where R6 and R6' are defined above, (xiv) -SO2NR6R6', where R6 and R6' are defined above,
(xv) -C(O)NR6R6', where R6 and R6' are defined above,
(xvi) aryloxy,
(xvii) arylalkoxy,
(xviii) aryl, (xix) hydroxy, and
(xix) heterocycle,
(h) -NR6R8, where R6 and R8 are defined above, and (i) -N(R6)SO2R12, where R6 is defined previously, and R12 is selected from the group consisting of
(i) alkyl,
(ii) aryl,
(iii) arylalkyl, (iv) heterocycle, and
(v) (heterocycle)alkyl, where (ii)-(v) can be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of
(1') alkyl,
(2') alkanoyl, (3') alkoxy,
(4') -CO2R4, where R4 is defined above,
(5') alkanoyloxy,
(6') carboxaldehyde,
(7') cycloalkyl, (8') cycloalkenyl,
(9") halo,
(10') nitro,
(11') perfluoroalkyl,
(12') perfluoroalkoxy, (13') -NR6R6', where R6 and R6' are defined above,
(14') -SO2NR6R6', where R6 and R6' are defined above,
(15') -C(O)NR6R6', where R6 and R6' are defined above,
(16') aryloxy,
(17') arylalkoxy, (18') aryl,
(19') hydroxy, and
(20') heterocycle,
(3) -O(CH2)pR7 where p and R7 are defined above, and
(4) -NR^R21, where R2^ and R21, together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein 1 or 2 double bonds and optionally containing therein a moiety selected from the group consisting of (a) oxygen,
(b) nitrogen and
(c) -S(0)x-, wherein x is 0-2, where the ring formed by R ^ and R21 can be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of
(1') alkyl, (2') alkanoyl, 3') alkoxy,
4') -CO2R4, where R4 is defined above, 5') alkanoyloxy, 6') carboxaldehyde, 7') cycloalkyl, 8') cycloalkenyl, 9') halo, 10') nitro, 11') perfluoroalkyl, 12') perfluoroalkoxy,
13') -NR6R6', where R6 and R6' are defined above, 14') -SO2NR6R6', where R6 and R6' are defined above, 15') -C(O)NR6R6', where R6 and R6' are defined above, 16') aryloxy, 17') arylalkoxy, 18') aryl, 19') hydroxy, and (20') heterocycle;
X is hydroxyl or sulfhydryl;
and
Y is hydrogen;
or
X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention provides a method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising adminstering to the mammal a pharmaceuticlly acceptable amount of a compound of formula I.
Detailed Description Definition of Terms When used throughout this specification and the appended claims, the following terms have the ascribed meanings.
The term "alkanoyl," as used herein, denotes an alkyl group attached to the parent molecular group through a carbonyl group. The alkanoyl groups of this invention can be optionally substituted.
The term "alkanoyloxy," as used herein, denotes an alkanoyl group attached to the parent molecular group through an oxygen atom. The alkanoyloxy groups of this invention can be optionally substituted.
The term "alkyl," as used herein, denotes a radical formed by the removal of one hydrogen atom from a straight or branched saturated hydrocarbon of one to twelve carbon atoms. Representative hydrocarbon groups include methyl, ethyl, n-propyl, wσ-propyl, n- butyl, sec-butyl,
Figure imgf000013_0001
tert-butyl, and the like. The alkyl groups of this invention can be optionally substituted.
The term "alkoxy," as used herein, denotes a lower alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom and includes such groups as methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy, and the like. The alkoxy groups of this invention can be optionally substituted.
The term "aminoacyl group, " as used herein, denotes a radical derived from naturally or unnaturally occuring amino acids. Representative aminoacyl groups include glycyl, alanyl, valyl, leucyl, wo-leucyl, methionyl, seryl, threonyl, cysteinyl, phenylalanyl, homophenylalanyl, and O-methyltyrosinyl in the racemic, 6 or L configurations.
The term "aryl," as used herein, denotes a mono- or bicyclic- carbocyclic ring system having one or two aromatic rings. Aryl groups are exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, and indenyl. Bicyclic aryl groups of this invention can be attached to the parent molecular group through a saturated or unsaturated part of the group. The aryl groups of this invention can be optionally substituted.
The term "arylalkoxy," as used herein, denotes an aryl group, as defined herein, attached to the parent molecular group through an alkoxy group. The arylalkoxy groups of this invention can be optionally substituted.
The term "arylalkyl," as used herein, denotes an aryl group, as defined herein, attached to the parent molecular group through an alkyl group. The arylalkyl groups of this invention can be optionally substituted.
The term "aryloxy," as used herein, denotes an aryl group, as defined herein, attached to the parent molecular group through an oxygen atom. The aryloxy groups of this invention can be optionally substituted. The term "aryloyl," as used herein, denotes an aryl group, as defined herein, attached to the parent molecular group through a carbonyl group. The aryloyl groups of this invention can be optionally substituted.
The term "aryloyloxy," as used herein, denotes an aryloyl group, as defined herein, attached to the parent molecular group through an oxygen atom. The aryloyloxy groups of this invention can be optionally substituted.
The term "aryloyloxy alkyl," as used herein, denotes an aryloyloxy group, as defined herein, attached to the parent molecular group through an alkyl group. The aryloyloxyalkyl groups of this invention can be optionally substituted. The term "aryloyloxyalkylcarbonyl," as used herein, denotes an aryloyloxy group, as defined herein, attached to the parent molecular group through a carbonyl group. The aryloyloxyalkylcarbonyl groups of this invention can be optionally substituted.
The term "aryloyloxyalkylcarbonylalkyl," as used herein, denotes an aryloyloxyalkylcarbonyl group, as defined herein, attached to the parent molecular group through an alkyl group. The aryloyloxyalkylcarbonylalkyl groups of this invention can be optionally substituted.
The term "arylsulfonyl," as used herein, denotes an aryl group, as defined herein, attached to the parent molecular group through an -SO2- group. The arylsulfonyl groups of this invention can be optionally substituted. The term "arylsulfonylalkyl," as used herein, denotes an arylsulfonyl group, as defined herein, attached to the parent molecular group through an alkyl group. The arylsulfonylalkyl groups of this invention can be optionally substituted.
The term "benzyl," as used herein, denotes a phenyl group, as defined herein, attached to the parent molecular group through a methyl group. The benzyl groups of this invention can be optionally substituted.
The term "carboxaldehyde," as used herein, denotes -CHO. The term "carbonyl," as used herein, denotes -C(O)-. The term "carboxy," as used herein, denotes -CO2H.
The term "cycloalkyl," as used herein, denotes a radical derived by the removal of a single hydrogen atom from a saturated cyclic or bicyclic hydrocarbon and includes such groups as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl, and the like. The cycloalkyl groups of this invention can be optionally substituted.
The term "(cycloalkyl)alkyl" denotes a cycloalkyl group as just defined, attached to the parent molecular moiety through an alkyl group as defined above and includes such representative groups as cyclopropylmethyl, cyclopentylethyl, 2-methyl-3-cyclopentylbutyl, cyclohexylmethyl, and the like. The (cycloalkyl)alkyl groups of this invention can be optionally substituted. The term "cycloalkenyl," as used herein, denotes a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbon atoms having at least one carbon-carbon double bond. The cycloalkenyl groups of this invention can be optionally substituted.
The term "halo," as used herein, denotes -F, -Cl, -Br or -I. The term "heterocycle" as used herein denotes any 5-, 6-or 7-membered saturated ring containing from one to three heteroatoms independently selected from the group consisting of 1, 2, or 3 nitrogens, one oxygen and one nitrogen, and one sulfur and one nitrogen; wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The term "heterocycle," as used herein, also includes and to 5-, 6-, or 7-membered aromatic rings having in the ring one, two, or three heteroatoms selected from N, O, and S, and also including benzo fused analogs of these 5-, 6-, or 7-membered heterocyclic aromatic rings. Representative heterocycles of this invention include, pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, thienyl, triazolyl 1,3,4-thiadiazolyl, and tetrazolyl, and the like.
The term "heterocycle," as used herein, also includes compounds of formula
Figure imgf000015_0001
, wherein Y* is selected from the group consisting of -C(O)- and
30 31 30 31 -(C(R )(R ))v-, wherein R and R are independently selected from the group consisting of hydrogen and alkyl, and v is 1, 2, or 3, and Z* is selected from the group consisting of -CH2-, -O-, -CH2S(O) , -CH2O-, -CH2NR35-, and -NR35-, wherein, at each
35 occurence, R is selected from the group consisting of hydrogen and alkyl.
The term "heterocycle," as used herein, also includes bicyclic or tricyclic rings, wherein any of the aformentioned heteroaryl rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl ring. These heteroaryls include benzo[b]furanyl, benzo[b] thienyl, benzimidazolyl, cinnolinyl, imidazo[4,5-c]pyridinyl, quinazolinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, thieno[2,3- b]pyridinyl,indolizinyl, and imidazo[l,2-a]pyridine and can be attached to the parent molecular group through either the heretoaryl group or the aryl, cycloalkyl, or cycloalkenyl group to which it is fused. The heterocycle groups of this invention can be optionally substituted.
The term "hydroxy," as used herein, denotes -OH. The term "nitro," as used herein, denotes -NO2.
The term "nitrogen-protecting group," as used herein, denotes groups intended to protect an amino group against undersirable reactions during synthetic procedures. Commonly used nitrogen-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1991)). Common N-protecting groups comprise (a) acyl groups such as formyl, acetyl, propionyl, pivaloyl, tert- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, and 4- nitrobenzoyl, (b) sulfonyl groups such as benzenesulfonyl, and pαrα-toluenesulfonyl, (c) carbamate forming groups such as benzyloxycarbonyl, /? r -chlorobenzyloxycarbonyl, p- methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, α,α-dimethyl- 3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, (d) arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and (e) silyl groups such as trimethylsily. Preferred nitrogen-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert- butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "oxo," as used herein, denotes (=O). The term "perfluoroalkoxy," as used herein, denotes a perfluoroalkyl group attached to the parent molecular group through an oxygen atom.
The term "perfluoroalkyl," as used herein, denotes an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
The term "phenyl," as used herein, denotes a radical formed by the removal of one hydrogen atom from a benzene ring. The phenyl groups of this invention can be optionally substituted.
The term "prodrug" denotes compounds that are rapidly transformed in vivo to yield the parent compounds of formula I, as for example, by hydrolysis in blood. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in "Prodrugs as Novel DeUvery Systems," Vol. 14 of the A.C.S. Symposium Series, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups may be found on pages 14-21 of Bior ever sible Carriers in Drug Design: Theory and Application, edited by E.B. Roche, Pergamon Press (1987).
The term "prodrug ester group" denotes any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthahdyl, indanyl and methoxymethyl, as well as other such groups known in the art.
The term "pharmaceutically acceptable ester" denotes esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters includes formates, acetates, propionates, butryates, acrylates and ethylsuccinates.
The term "sulfhydryl," as used herein, denotes -SH. The term "thiocarbonyl," as used herein, denotes -C(S)-.
The term "thioxo," as used herein, denotes =S.
As shown in generic chemical structural formula I above, the compounds of the invention have at least one chiral center designated by the numeral "1." When Y is hydrogen, the compounds also possess at least one additional chiral center designated by the numeral "2" in the generic formula. While compounds having either the "R," "S," or "R,S" chirality at either site are described, preferred compounds of the present invention are those in which the chirality at the site designated "1" is R and the chirality at the site designated "2" is S. The "R" and "S" stereochemical designators follow the convention established by R. S. Cahn, et al, Angewandt Chemie. Int. Ed. Engl.. 5: 385-415 (1966). Diastereomers having the preferred (Site 1)R and (Site 2)S stereochemistry can be synthesized by judicious choice of optically pure starting materials, asymmetric synthesis, or may be separated from mixtures of diastereomers by methods well known in the art as, for example, by reverse phase HPLC techniques.
While compounds having a structure corresponding to the generic formula I given above are considered to fall within the scope of the present invention, a preferred sub-
2 5 5 group of compounds is defined by structural formula I where R is -SR where R is lower alkyl, most preferably, methyl or ethyl.
Another preferred sub-group of compounds of the invention are compounds of 2 formula I where R is cycloalkyl, preferably cyclohexyl. Another preferred sub-group of compounds of the invention are compounds of
2 formula I where m is one and R is lower alkyl, preferably n-propyl. Another preferred sub-group of compounds of the invention are compounds of formula I where X is hydroxy or sulfhydryl, and Y is hydrogen, with X is hydroxyl being particularly preferred.
Another preferred sub-group of compounds of the present invention is defined by structural formula I above where X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl group, with carbonyl being particularly preferred.
A preferred sub-group of compounds of the invention are defined by structural 3 formula I where R is an aminoacyl group derived from a naturally occurring amino acid, where the nitrogen atom at the N-terminus of the aminoacyl group is attached to the immediately adjacent carbonyl group of the parent molecular moiety, and the C-terminus, or carboxyl functionality of the aminoacyl residue is optionally and preferably capped by a carboxyl blocking group.
Carboxyl blocking groups are well known to practitioners of the organic chemical arts, and are described in some detail in Chapter 5, pages 224-276 of "Protective Groups in
Organic Synthesis," Second Edition, by T. W. Greene and P. G. M. Wuts, Kohn Wiley &
Sons, Inc., New York, 1991, the contents of which are incorporated herein by reference.
Such carboxyl protecting groups include esters such as substituted methyl esters, substituted ethyl esters, substituted benzyl esters, silyl esters, oxazoles, 2-alkyl-l,3- oxazolines, 4-alkyl-5-oxo- 1 ,3-oxazolidines, 5-alkyl-4-oxo- 1 ,3-dioxalanes, ortho esters, and amides such as N,N-dialkyl amides, pyrrolidinyl amides, piperidinyl amides, 5,6- dihydropiperidinyl amides, o-nitroanilides, and hydrazides such as N-phenylhydrazides and
N, N'-dialkylhydrazides .
Specific examples of individual compounds falling within the scope of the present invention include, but are not limited to
(2RS,3S,l'S)-Ν-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3S,l'S)-N-((l-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide, (2RS,3R, 1 'S)-N-(( l-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-((2-phenylethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-N-((3-phenylpropyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R) N-(2-(4-methoxyphenyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide,
(2RS,3R)-N-(2-(4-sulfonamidophenyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide, (2RS,3R)-N-(2-(2-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(2-(4-phenoxyphenyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide,
(2RS,3R,rS)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide, (2RS,3R)-N-(4-phenyl)butyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carboethoxy)ethyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carbobenzyloxy)ethyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-heptanamide,
(2RS,3R)-3-amino-2-hydroxy-5-(methylthio)pentanoic acid,
(2RS,3R)-N-(2-(4-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-phenyl-butanamide, (2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-cyclohexyl- butanamide,
(2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-cyclohexyl-butanamide, (2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cyclohexyl- butanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-phenyl- butanamide,
(2RS,3R)-3-amino-2-hydroxy-N-(4-methoxyphenethyl)-5- (methylsulfanyl)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-acetylamino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-amino-2-hydroxy-4-cyclohexyl)butan amide, (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-3-amino-2-hydroxy-N-methyl-5-(methylsulfanyl)-N- phenethylpentanamide,
(2RS,3R,l'S)-N-((2-carboxyethyl)-3-amino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-N-(( 1 -methyl- 1-ethoxycarboxyethyl) 3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R, 1 'S)-N-(( 1 -(2-hydroxy)- 1 -ethoxycarboxyethyl) 3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-tert-butoxycarbonylamino-2-hydroxy-4- ethylthio)pentanamide, (2RS,3R)-N-((phenylbutyryl)-3-formylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-N-Methyl-N-((ethoxycarbonylmethyl)-3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((Phenylbutyryl)-3-hydroxymethylcarbonylamino-2-hydroxy-4- ethylthio)pentan amide, (2RS ,3R, 1 'R)-N-(( 1 -ethoxycarbonylethyl)-3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R,l'R)-N-((l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butan amide,
2RS,3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-((Phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R, 1 'S)-N- (( 1 -ethoxycarbonylethyl)-3-amino-2-hydroxy-4- benzylthio)butanamide, (2RS,3R,rS)-N-((2-hydroxy-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,l'S)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2'S)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide, (2RS,3R,2'S)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R, 2'R)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,2'R)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,2'R)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,l'S)-N-((l-benzyloxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R, 1 'S)-N-(4-ethoxycarbonyl-2-( 1 '-aminoethyl)thizole)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R) N-(monodansylcadaveno)-3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R) N-(2-methyl-5-nitro imidazole-ethyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide di,
(2RS,3R) N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide di,
(2RS,3R) N-(5-methoxy-tryptaminyl) 3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R) N-(3-O-methyl-dopaminyl) 3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R) N-(2-aminomethylbenzimidazolyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-methyl-5- nitroimidazolyl-ethyl)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- nitropyridylaminoethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl- (ethylisonipecotate)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2- pyrrolidinopropyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- methoxytryptamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(3-O- methoxydopamine)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2- benzimidazolemethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-phenyl-pyrazole- 3)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-hydroxy-5-nitro- l)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-bromothizole- 2)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(4-nitro-2- hydroxyphenyl- 1 )amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoylL-alanyl-( 1 - ethylpyrazole)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(3-imidazolylpropyl)amide,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-carboxyl-2-(l'amino)ethyl thizole, ethyl (2RS,3R,2'S)-2-((-3-(acetylamino)-4-cyclohexyl-2- hydroxybutanoyl)amino)propanoate,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4- benzyloxycarbonylamino)butylamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-beta-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-monodansylcadaverine amide, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-(4- toluenesulfonyl)aminobutyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-4- toluenesulfonylaminoethyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-aminobutyl)amide , (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-aminoethyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-(((3,4- dimethoxyphenyl)sulfonyl)amino)butyl)-2-hydroxybutanamide, (2RS,3R)-N-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4- cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-((2- naphthylsulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-sulfonamide benzyl ester,
(2RS ,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclohexyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 2- ((phenylsulfonyl)methyl)benzyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclopropyl ester(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-tert-butylbenzyl ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4- methoxycarbonylbenzyl ester, (2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4- trifluoromethylbenzyl ester,
(2RS ,3R)- 3-amino- 2-hydroxy-4-cycl ohexyl)butanoyl-L- alanine- (4-(methyl)phenyl acetic acid phenacyl ester),
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenyl)butanamide, methyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-4- methylpentanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-furylmethyl)-2-hydroxybutanamide, (2RS,3R,l'RS)-3-amino-4-cyclohexyl-2-hydroxy-N-(l-(l- naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(2-oxo- 1 - pyrrohdinyl)propyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,2-dimethylpropyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenylbutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l,2,3,4-tetrahydro-l- naphthalenyl)butanamide, (2RS,3R)-3-amino-N-(4-(tert-butyl)cyclohexyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dichlorophenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethylhexyl)-2-hydroxybutanamide, butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate, 2RS,3R)-3-amino-N-(l,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-5- (trifluoromethyl)phenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-decyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-((lR,4S)bicyclo(2.2.1)hept-2-yl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l-(4-fluorophenyl)ethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(tetrahydro-2- furanylmethyl)butanamide, ethyl (2RS,3R)-(4-((-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-l- piperidinecarboxylate,
(2RS,3R)-3-amino-N-(l,3-benzodioxol-5-yl 4-cyclohexyl-2-hydroxybutanamide, tert-butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate, methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- phenylpropanoate, methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- methylpentanoate, methyl (2RS,3R,2*S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)hexanoate, methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- methylbutanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lS)-l-(2- naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lR)-l-(2- naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lS)-l-(l- naphthyl)ethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lR)- 1-(1- naphthyl)ethyl)butanamide, ethyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- fluoropropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-hydroxy-l- (hydroxymethyl)ethyl)butanamide,
4-(tert-butyl)benzyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
4-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)- 3-hydroxypropanoate, 3-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-
3-hydroxypropanoate,
4-(trifluoromethyl)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
3-(trifluoromethoxy)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenyl)butan amide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenyl)butanamide, (2RS,3R)-3-amino-N-(4-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-(tert-butyl)phenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)phenyl)butanamide, 2RS ,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dichlorophenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-bromophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-(tert-butyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyl)benzyl)butanamide, (2RS,3R)-3-amino-N-(2-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5- nitrophenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenoxyphenyl)butanamide, (((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)(2,5- dimethoxybenzyl)chloronium ,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dichlorophenethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(3-fluorophenethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3,4-bis(benzyloxy)phenethyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-
(trifluoromethoxy)phenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methylphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dimethylphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-iodo-2-methylphenyl)butanamide, (2RS,3R)-3-amino-N-(4-anilino-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-chloro-2-methoxy-5-methylphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-N-(5-(acetylamino)-2-methoxyphenyl)-3-amino-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxydibenzo(b,d)furan-3- yl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2,4-dimethoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-diethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-phenoxyphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methyl-5-nitrophenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxybenzyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylbenzyl)butanamide, (2RS,3R)-3-amino-N-(3-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxybenzyl)butanamide, (2RS,3R)-3-amino-N-(4-bromobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methylbenzyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenethylbutanamide, (2RS,3R)-3-amino-N-(4-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamid, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenethyl)butanamide, (2RS,3R)-3-amino-N-(4-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)phenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-bromophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-N-(l-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-N-(2-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-cycloheptyl-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(cyclohexylmethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N,4-dicyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-cyclopentyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-cyclobutyl-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -methyl-3- phenylpropyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l-methyl-2-(3-
(trifluoromethyl)phenyl)ethyl)butan amide,
(2RS ,3R)-3-amino-4-cyclohexyl-N-( 1 ,5-dimethylhexyl)-2-hydroxybutanamide, (2RS ,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -methylhexyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isopropoxypropyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isobutoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(4- morpholinyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,3-diphenylpropyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(l,4-dimethylpentyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-( 1 - naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-(( 1 S)- 1 -( 1 - naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5- (trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy( 1 , 1 '-biphenyl)-3- yl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro-l,4-benzodioxin-6-yl)-2- hydroxybutanamide, (2RS,3R)-3-amino-N-(3-(benzyloxy)phenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3-ethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3,4,5-trimethoxyphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2-(2-fluorophenyl)-l-methylethyl)-2- hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2-(4-fluorophenyl)- 1 , 1 -dimethylethyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro- lH-inden- 1 -yl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(( 1 S,2R)-2- phenylcyclopropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 , 1 ,3,3- tetramethylbutyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,3-dimethylbutyl)-2-hydroxybutanamide, methyl 4-((.(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- thiophenecarboxylate,
(2RS,3R)-N-(l-(l-adamantyl)ethyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-( (S)-(-)-(l- naphthyl)ethyl)amide,
(2RS ,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3- (trifluoromethoxy)benzyl)butanamide, (2RS,3R)-3-amino-N-(3,5-bis(trifluoromethyl)benzyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2- (trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4- (trifluoromethoxy)benzyl)butanamide,
(2RS,3R)-3-amino-N-(6-chloro-3-pyridinyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(6-methyl-2-pyridinyl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5- methylphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-4- methylphenyl)butanamide,
2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy-2-naphthyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-thienylmethyl)butanamide,
(2RS,3R)-3-amino-N-butyl-4-cyclohexyl-2-hydroxy-N-methylbutanamide, (2RS,3R)-3-amino-4-cyclohexyl-l-(2,6-dimethyl-4-morpholinyl)-2-hydroxy-l- butanone,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N,N-bis(methoxymethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-l-[3,4-dihydro-2(lH)-isoquinolinyl]-2-hydroxy- 1-butanone,
(2RS,3R)-3-amino-l-(l-azepanyl)-4-cyclohexyl-2-hydroxy-l-butanone,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-l-[4-phenyl-3,6-dihydro-l(2H)- pyridinyl]- 1-butanone
(2RS,3R)-3-amino-N-benzyl-N-butyl-4-cyclohexyl-2-hydroxybutanamide (2RS,3R)-3-amino-4-cyclohexyl-l-[(2R,6S)-2,6-dimethylmorpholinyl]-2-hydroxy-
1-butanone,
(2RS,3R)-3-amino-N-[(2-chloro-2,3,5-cyclohexatrien-l-yl)methyl]-4-cyclohexyl- 2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-N-(l,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxy-N- methylbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-N-ethyl-2- hydroxybutanamide, ethyl 3-[[(2RS,3R)-3-amino-4-cyclohexyl-2- hydroxybutanoyl](benzyl)amino]propanoate, and
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy- 1 -(1 -piperidinyl)- 1 -butanone.
or a pharmaceutically acceptable salt, ester, or prodrug thereof.
Biological Assay
The ability of compounds of the present invention to inhibit methionine aminopeptidase 2 was evaluated using the following assay.
Recombinant methionine aminopeptidase-2 (MetAP2) was expressed as a secreted protein with a baculovirus system and purified from the insect cell culture supernatant as previously described by R. L. Kendal, et al, J. Biol. Chem.. 267(29): 20667-20673 (1992) and Xuan Li, et al, Biochem. And Biophvs. Res. Comm.. 227: 152-159 (1996), the contents of which are incorporated herein by reference.
Assays for MetAP2 enzyme activity and MetAP2 inhibition were performed in 96- well microtiter plates. Compounds to be tested for MetAP2 inhibition were dissolved in dimethyl-sulfoxide at 10 mM and diluted ten-fold in assay buffer (50 nM ΗEPES, pΗ 7.4, 100 mM ΝaCl). Ten microliters of solution of each compound to be tested for inhibition were introduced into each cell of the plate, with each compound being tested in triphcate. Zero inhibition of enzyme activity was taken to be the result obtained in cells in which 10 mL of assay buffer was placed, and 100 percent inhibition of enzyme activity was taken to be the result obtained in cells in which 10 mM of fumagillin (Sigma Chemical Co., St. Louis, MO, USA, Catalog No. F-6771) in assay buffer was placed.
A mixture totaling 90 μL per well, and made up of of 84 mL of assay buffer, 1 μL of L-amino acid oxidase (Sigma Catalog No. A-9378, -11 mg/mL), 1 μL of horseradish peroxidase (Sigma Catalog No. P-8451, dissolved in assay buffer at a concentration of 10 mg mL), 1 μL of the tripeptide Met-Ala-Ser (Bachem), dissolved in assay buffer at concentration of 50 mM), 1 mL of ort/iσ-dianisidine (Sigma Catalog No. D-1954, freshly made solution in water at a concentration of 10 mg,mL), and MetAP2 at a final concentration of 4 μg/mL was rapidly mixed and added to each cell containing test or control compound. The absorbence at 450 nanometers was measured every 20 seconds over a period of twenty minutes using an automaic plate reader (Molecular Devices, CA, USA). The Vmax in mOD/min, calculated for each well was used to represent MetAP2 activity. The IC50 for each inhibitor was obtained by plotting the remaining MetAP2 activity versus inhibitor concentration. The results of these tests appear in Table 1.
Table 1
Inhibition of MetAP2 Activity by
Representative Compounds of the Invention Example IC5o(μM) Example IC50(μM)
1 11. 126 13.
2 47. 127 28.
3 10. 128 14.
4 2.4 129 27.
5 2.6 130 4.3
6 3.0 131 0.99
7 2.0 132 4.1
8 2.3 133 0.27 9 2.3 134 3.1
10 3.6 135 3.2
11 2.6 136 1.8
12 0.86 137 8.4 5
13 1.1 138 1.6
14 0.72 139 1.7
15 0.72 140 2.2
16 0.78 141 3.7
17 1.4 142 0.40 10
18 0.15 143 0.87
19 1.6 144 2.1
20 5.8 145 1.2
21 14. 146 1.5
22 3.4 147 1.0 15
23 1.3 148 0.52
24 1.0 149 0.93
25 1.9 150 3.1
26 4.7 151 0.43 27 1.7 152 2.4
28 100 153 0.37
29 100 154 1.9
30 1.1 155 052
31 100 156 3.9
32 1.4 157 1.6
33 2.5 158 2.8
34 3.1 159 1.5
35 0.11 160 0.90
10
36 0.14 161 0.62
37 16. 162 1.2
38 100 163 0.48
39 5.1 164 0.65
40 81 165 0.26
15
41 .09 166 0.59
42 2.8 167 3.3
43 6.8 168 1.5
44 13 169 3.3 45 5.2 170 1.0
46 1.1 171 0.95
47 1.5 172 5.0
48 1.5 173 0.58
49 2.2 174 1.5
50 3.7 175 2.1
51 5.0 176 3.4
52 6.1 177 2.0
53 1.8 178 11.
10
54 2.6 179 4.9
55 2.7 180 2.0
56 12. 181 9.8
57 3.1 182 8.0
58 3.5 183 8.7
15
59 1.5 184 0.43
60 18. 185 1.8
61 13. 186 1.1
62 7.6 187 1.2 63 20. 188 1.6
64 19 189 1.5
65 5.6 190 1.3
66 10. 191 2.5
67 13. 192 1.2
68 3.8 193 2.5
69 5.3 194 1.4
70 5.4 195 1.3
71 12. 196 0.82
10
72 9.2 197 0.58
73 6.8 198 0.84
74 30. 199 1.0
75 9.4 200 1.5
76 100 201 0.71
15
77 3.3 202 8.3
78 1.8 203 4.9
79 0.10 204 3.8
80 1.3 205 2.5 81 1.8 206 10.
82 38. 207 4.1
83 26. 208 2.7
84 3.3 209 14.
85 3.2 210 2.3
86 1.7 211 2.4
87 2.7 212 1.7
88 2.2 213 2.6
89 6.6 214 2.8
90 2.3 215 1.3
91 2.3 216 1.8
92 1.4 217 1.8
93 5.4 218 0.46
94 0.91 219 1.8
95 5.2 220 5.5
96 2.9 221 5.4
97 3.0 222 0.20
98 0.58 223 0.88 99 35 224 0.43
100 5.9 225 0.35
101 0.31 226 0.97
102 13 227 0.88
103 100 228 0.93
104 28 229 1.2
105 19. 230 34.
106 100 231 2.5
107 1.2 232 100
108 0.63 233 2.7
109 1.7 235 0.97
110 1.0 236 1.9
111 8.2 237 5.1
112 1.5 238 2.7
113 5.5 239 4.2
114 20. 240 0.76
115 1.5 241 0.96
116 0.67 242 1.6 117 0.87 243 1.1
118 16. 244 1.5
119 8.9 245 1.2
120 1.1 246 0.39
121 2.6 247 0.57
122 2.8 248 1.0
123 2.7 249 0.41
124 7.0
125 0.45
Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluoro-hydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
Therapeutic Administration According to the methods of treatment of the present invention, disorders caused by undesirable angiogenesis are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of the compound to inhibit angiogenesis, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. However, a well-known technique utilized by medical practitioners is to "dose titrate" the patient; that is, to start with dose lower than that required to obtain the desired effect, and to gradually increase the dose until the dseired therapeutic benefit is obtained.
The total daily dose of the compounds of this invention administered to a human or other mammal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.11 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 1 mg to about 500 mg of the compound(s) of this invention per day in single or multiple doses.
General Synthetic Methods
As shown in Reaction Scheme 1, 3-amino-2-hydroxy-carboxylic acids used as starting materials for the synthesis of compounds of the present invention are available from appropriately substituted alpha-aminoacids by conversion to the corresponding aminoaldehyde, formation of the corresponding cyanohydrin, and hydrolysis. Protection of the free amino group, for example with a tert-butyl carbamate group, followed by couphng with an appropriate amine, amino acid derivative, or alcohol and deprotection provides the target compounds. The coupling partners may be purchased from commercial sources or prepared using known chemical transformations. Subsequent conversion of the 3-amino-2- hydroxy compounds to compounds of the present invention are by standard methods well known to practitioners of the organic chemical arts and are illustrated by the Examples which appear below. Scheme 1
Figure imgf000042_0001
Figure imgf000042_0002
Figure imgf000042_0003
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
Example 1
(2RS.3S. S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide hvdrochloride
Example 1A A solution of N-(tert-butoxycarbonyl)-L-methionine (12.47 g, 50 mmol) and RED-
AL (50 mmol) in dry toluene (125 mL) was stirred at 0 °C for 30 minutes, then at ambient temperature for 1 hour. The mixture was treated with aqueous Rochelle salt and extracted with ethyl ether. The extract was washed sequentially with brine and aqueous ΝaHCθ3, dried (MgSO4), and concentrated to give a colorless syrup (9.05 g). Example IB A solution of the product of example 1 A (9.05 g, 38.5 mmol), sulfur trioxide pyridine complex (30.64 g, 192.5 mmol) and triethylamine (26.8 mL, 192.5 mmol) in DMSO (30 mL) was stirred at ambient temperature for 30 minutes, cooled to 0 °C, then treated sequentially with water (20 mL) and saturated aqueous KHSO4 (120 mL), and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO4 and brine, dried (MgSO4), and concentrated to give a colorless syrup (9.00 g).
Example IC
A solution of the product of example IB (9.00 g, 38.5 mmol), and sodium bisulfite (3.80 g, 36.6 mmol) in water (200 mL) was stirred at 5 °C for 72 hours, warmed to ambient temperature, then treated with potassium cyanide (2.51 g, 38.6 mmol) in ethyl acetate (250 mL) for 4 hours. The separated ethyl acetate layer was washed sequentially with water and brine, dried (MgSO4), and concentrated to give a colorless syrup, which was dissolved in dioxane (75 mL) and 12 N HC1 (75 mL), then heated at reflux for 16 h. The mixture was concentrated in vacuo and redissolved in water (8 mL) and acetone (300 mL), the pH adjusted to 5.5 with 1 N NaOH, and the resulting solid collected by filtration and dried to provide 5.81 g solid material. MS (ESI+Q1MS) m/e 180: (M+ H)+, 202 (M+ Na)+; (ESI-Q1MS) m/e: 178 (M- H)- 1H NMR (300 MHz, D2O) δ 4.25 (d, 0.5H), 4.14 (d, 0.5H), 3.78 (m, 0.5H), 3.66 (m,
0.5H), 2.65 (m, 2H), 2.13 (s, 1.5H), 2.09 (s, 1.5H), 1.93 (m, 2H).
Example ID A solution of the product of example IC (5.81 g, 32.4 mmol), BOC-ON (9.58 g,
38.9 mmol) and triethylamine (6.77 mL, 48.6 mmol) in water (70 mL) and dioxane (70 mL) was stirred at 45 °C for 5 hours, diluted with ethyl acetate and 10% aqueous KHSO4 then extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (MgSO4), and concentrated to give (2RS,3S) 3-(tert-butoxycarbonylamino)-2- hydroxy-5-(methylthio)pentanoic acid. (4.05 g).
MS (ESI+Q1MS) m e 280: (M+ H)+, 302 (M+ Na)+, 581 (2M+ Na)+; (ESI-Q1MS) m/e 278: (M- H)-.
Example IE A solution of example ID (2.79 g, 10 mmol), L-alanine ethylester hydrochloride
(1.84 g, 12 mmol), EDCI (2.30 g, 12 mmol), HOBT (1.84 g, 12 mmol) and NMM (1.32 mL, 12 mmol) in CH2CI2 (35 mL) was stirred at ambient temperature for 16 hours, evaporated to dryness, redissolved in ethyl acetate then washed sequentially with aqueous NaHCO3, brine, 10% aqueous KHSO4 and brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel with 50% ethyl acetate/toluene to provide the designated compound (2.74g). MS (ESI+Q1MS) m/e 379 (M+H)+ 396 (M+Na)+, 279 (M+H-BOQ+.
Example IF A solution of the product of example IE (0.40 g, 1.1 mmol), in hydrogen chloride saturated dioxane (8 mL) was stirred at ambient temperature for 1 hour, evaporated to dryness, suspended in ethyl ether then concentrated and vacuum dried to give the title compound (0.24 g).
MS (ESI+Q1MS) m/e 279 (M+H)+ 557 (2M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.46 (d. 0.6H), 8.43 (d, 0.4H), 8.14 (br. 1H), 7.97 (br.,
1H), 6.63 (d, 0.6H), 6.51 (d, 0.4H), 4.05-4.38 (m, 5H), 2.42-2.67 (m, 2H), 2.04 (s, 1.8H), 2.01 (s, 1.2H), 1.65-1.96 (m, 2H), 1.35 (d, 0.6H), 1.33 (d,1.2H), 1.17-1.23 (dt, 1.8H).
Example 2 (2RS.3S.l'S)-N-(fl-Ethylcarboxamido)ethyl)-3-amino-2-hvdroxy-5- (methylthio)pentanamide hvdrochloride The product of example ID and alanine ethylamide were processed as in examples
IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 278 (M+H)+ 300 (M+Na)+; lH NMR (300 MHz, D2O) δ 4.28-4.52 (m, 2H),. 3.83-3.88 (m, 0.5H), 3.72-3.78 (m,
0.5H), 3.22 (q, 2H), 2.52-2.73 (m, 2H), 1.83-2.17 (m, 5H), 1.41 (d, 3H), 1.11 (t, 1.5H), 1.10 (t, 1.5H).
Example 3 (2RS.3R.rS)-N-((l-Ethylcarboxamido)ethyl)-3-amino-2-hvdroxy-5- (methylthio)pentanamide hydrochloride
Example 3A N-(tert-butoxycarbonyl)-D-methionine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-(methylthio)pentanoic acid.
Example 3B The product of example 3 A and L-alanine ethylamide were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 278 (M+H)+, 300 (M+Na)+;
*H NMR (300 MHz, D20) δ 4.27-4.52 (m, 2H), 3.85-3.92 (m, 0.5H), 3.74-3.81 (m, 0.5H), 3.17-3.26 (m, 2H), 2.52-2.74 (m, 2H), 1.85-2.17 (m, 5H), 1.42 (d, 3H), 1.12 (t, 3H).
Example 4 (2RS.3R.rS)-N-f(l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide hydrochloride
The product of example 3 A and L-alanine ethylester hydrochloride were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 279 (M+H)+, 301 (M+Na)+; *H NMR (300 MHz, D2O) δ 4.37-4.53 (m, 2H), 4.24 (q, 2H), 3.86-3.93 (m, 0.4H), 3.73- 3.78 (m, 0.6H), 2.53-2.77 (m, 2H), 1.89-2.17 (m, 5H), 1.48 (d, 3H), 1.28 (t, 3H).
Example 5 (2RS,3R)-N-((2-phenylethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide hydrochloride
The product of example 3A and l-amino-2-phenylethane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 283 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 8.20 (m, IH), 7.80 (m, 2H), 7.30 (m, 2H), 7.21 (m, 3H), 6.50 (m, IH), 4.09 (m, IH), 3.40 (m, 3H), 2.79 (m, 2H), 2.53 (m, 2H), 2.04 (s, 3H), 1.68 (m, 2H).
Example 6 (2RS.3R)-N-((3-Dhenylpropyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide hydrochloride
The product of example 3 A and l-amino-3-phenylpropane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 297 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.20 (m, IH), 7.82 (m, 2H), 7.28 (m, 5H), 6.54 (d, 0.6H), 6.47 (d, 0.4H), 4.09 (m, IH), 3.40 (m, 2H), 2.68 (m, 2H), 2.57 (m, 2H), 2.05 (s, 1.8H), 1.98 (s, 1.2H), 1.68 (m, 2H). Example 7 f2RS.3R)-N-(4-phenylbutyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide hydrochloride
The product of example 3 A and l-amino-4-phenylbutane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 311 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.18 (m, IH), 7.82 (m, 2H), 7.22 (m, 5H), 6.45 (m, IH), 4.09 (m, IH), 3.39 (m, IH), 3.15 (m, 2H), 2.56 (m, 4H), 2.03 (s, 3H), 1.80 (m, 2H), 1.51 (m, 4H).
Example 8
(2RS.3R) N-(2-(4-methoxyphenyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide hydrochloride The product of example 3A and l-amino-2-(4-methoxyphenyl)ethane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 313 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.17 (m, IH), 7.87 (bds, 2H), 7.12 (s, 2H), 6.86 (d,
2H), 6.5 (m, IH), 4.1 (m, IH), 3.72 (s, 3H), 3.30 (m, 2H), 2.70 (m, 2H), 2.54 (m, 2H), 2.05 (s, 3H), 1.78 (m, 2H).
Example 9
(2RS.3R)-N-(2-(4-sulfonamidoρhenyl)ethylV3-amino-2-hvdroxy-5- (methylthio)pentanamide hydrochloride The product of example 3 A and l-amino-2-(4-sulfonamidophenyl)ethane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 362 (M+H)+;
JH NMR (300 MHz, DMSO-d6) δ 8.24 (m, IH), 7.84 (m, 2H), 7.75 (d, 2H), 7.42 (d, 2H),
7.32 (s, 2H), 6.52 (d, IH), 4.09 (m, IH), 3.70 (m, IH), 3.45 (m, IH), 2.86 (m, 2H), 2.58 (m, 2H), 2.04 (s, 3H), 1.67 (m, 2H).
Example 10
(2RS.3R)-N-(2-(2-pyridyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio pentønamide dihydrochloride The product of example 3 A and l-amino-2-(2-pyridyl)ethane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 284 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 8.74 (m, IH), 8.38 (m, 2H), 8.10 (m, IH), 7.90 (m, 2H), 7.78 (m, 2H), 4.09 (m, IH), 3.70 (m, 2H), 3.57 (m, 2H), 3.49 (m, 2H), 2.57 (m, IH), 2.04 (s, 3H), 1.80 (m, 2H).
Example 11
(2RS.3R)-N-(2-(4-phenoxyphenyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio pentanamide hydrochloride The product of example 3 A and l-amino-2-(4-phenoxyphenyl)ethane were processed as in example 2 to provide the title compound. MS (APCI+) m/e 375 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.17 (m, IH), 7.69 (m, 2H), 7.39 (m, 2H), 7.23 (m,
2H), 7.13 (m, IH), 6.98 (m, 4H), 6.50 (m, IH), 4.09 (m, IH), 3.38 (m,3H), 2.75 (m, 2H), 2.56 (m, 2H), 2.04 (s, 3H), 1.74 (m, 2H).
Example 12
(2RS.3R.l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride
Example 12 A N-(tert-butoxycarbonyl)-D-ethionine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-5-(ethylthio)pentanoic acid.
Example 12B The product of example 12 A and L-alanine ethylester hydrochloride were processed as in example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 293 (M+H)+, 585 (2M+H)+; lH ΝMR (300 MHz, D20) δ 4.37-4.53 (m, 2H), 4.24 (q, 2H), 3.87-3.92 (m, 0.4H), 3.73-
3.79 (m, 0.6H), 2.68-2.82 (m, 2H), 2.52-2.65 (m, 2H), 1.91-2.16 (m, 2H), 1.47 (d, 3H), 1.20-1.30 (m, 6H).
Example 13 (2RS.3R)-Ν-(4-phenyl)butyl -3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride
The product of example 12A and l-amino-4-phenylbutane were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 325 (M+H)+, 347 (M+Na)+, 649 (2M+H)+, 671 (2M+Na)+; !H NMR (300 MHz, DMSO-d6) δ 7.16-7.31 (m, 5H), 6.77 (br., IH), 5.22 (br.d., 0.6H), 5.01 (br.d., 0.4H), 4.23 (d. 0.4H), 4.12 (d, 0.6H), 3.94 (br.m. IH), 3.24-3.36 (m, 2H), 2.46-2.68 (m, 6H), 1.94-2.16 (m, 2H), 1.47-1.62 (m, 4H), 1.19-1.28 (m, 3H).
Example 14
(2RS.3R)-N-(3-(carboethoxy)ethyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride The product of example 12 A and ethyl 3-amino-propionate were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m e 293 (M+H)+;, 315 (M+Na)+; lH NMR (300 MHz, D2O) δ 4.45 (d. 0.4H), 4.31 (d, 0.6H), 4.17 (q, 2H), 3.81-3.87 (m,
0.4H), 3.67-3.77 (m, 0.6H), 3.44-3.63 (m, 2H), 2.52-2.74 (m, 6H), 1.75-2.12 (m, 2H), 1.19-1.28 (m, 6H).
Example 15
(2RS.3R)-N-(3-(carbobenzyloxy)ethyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride The product of example 12A and benzyl 3-amino-propionate were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 355 (M+H)+ 377 (M+Na)+;
!H NMR (300 MHz, DMSO-d6) δ 7.45 (br.m., 5H), 5.18 (s, 2H), 4.41 (d. 0.4H), 4.21 (d, 0.6H), 3.46-3.87 (m, 3H), 2.43-2.72 (m, 6H), 1.70-2.03 (m, 2H), 1.16-1.26 (m, 3H).
Example 16 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride The product of example 12A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 307 (M+H)+ 325 (M+Na)+; *H NMR (300 MHz, DMSO-d6) δ 4.46 (d. 0.4H), 4.32 (d, 0.6H), 4.17 (q, 2H), 3.83-3.88 (m, 0.4H), 3.71-3.80 (m, 0.6H), 3.20-3.41 (m, 2H), 2.58-2.79 (m, 2H), 2.52-2.55 (m, 2H), 2.44 (t, 2H), 1.81-2.13 (m, 4H), 1.20-1.29 (m, 6H).
Example 17 (2RS.3R.1 'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-heptanamide hydrochloride Example 17A N-(tert-butoxycarbonyl)-D-norleucine was processed as in examples .1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-heptanoic acid.
Example 17B
The product of example 17 A and L-alanine ethyl ester hydrochloride were processed as in example IE to provide the title compound.donnerg MS (APCI) m/e 295 (M+H)+ ; *H ΝMR (300 MHz, DMSO-d6) δ 8.39 (m, IH), 7.89 (m, IH), 7.74 (m, IH), 6.48 (m, IH), 4.13 (m, IH), 4.08 (m, 3H), 3.60 (m, IH), 1.34 (m, 9H), 1.19 (m, 3H), 0.88 (m, 3H).
Example 18 (2RS,3R)-3-amino-2-hvdroxy-5-(methylthio)pentanoic acid N-(tert-butoxycarbonyl)-D-methionine was processed as in examples 1 A through IC to provide (2RS,3R) 3-amino-2-hydroxy-5-(methylthio)pentanoic acid. MS (APCI) m e 180 (M+H)+ ;
!H ΝMR (300 MHz, DMSO-d6) δ 7.52 (bs, 2H), 3.64 (d, IH), 3.50 (m, IH), 3.30 (m, 2H), 2.58 (m, 2H), 2.03 (s, 3H).
Example 19
(2RS.3R)-Ν-(2-(4-pyridvI)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide The product of example 3A and l-amino-2-(4-pyridyl)ethane were processed as in example 2 to provide the title compound. MS (APCI) m/e 284 (M+H)+ ; l NMR (300 MHz, DMSO-d6) δ 8.78 (m, 2H), 8.32 (m, IH), 8.10 (m, IH), 7.90 (m,
IH), 7.84 (m, 2H), 4.22 (m, IH), 4.08 (m, IH), 3.49 (m, 2H), 3.04 (m, 2H), 2.55 (m, 2H), 2.04 (s, 3H), 1.75 (m, 2H).
Example 20 (2RS.3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-phenyl-butanamide hydrochloride
Example 20A N-(tert-Butoxycarbonyl)-D-phenylalanine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenyl-butanoic acid.
Example 20B The product of example 20A and ethyl 3-amino-propionate were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 295 (M+H)+ , 317 (M+Na)+ lH NMR (300 MHz, MeOH-d4) δ 1.19-1.26 (m, 3H), 2.49-2.58 (m, 2H), 2.80-3.10 (m, 2H), 3.41-3.53 (m, 2H), 3.78-3.85 (m, IH), 4.03 (d, 0.6H), 4.07-4.16 (m, 2H), 4.27 (d, 0.4H), 7.25-7.40 (m, 5H); 3.10-3.19 (m, IH), 4.02 (d, IH), 4.29 (m, IH), 7.10-7.27 (m, 5H).
Example 21 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hvdroxy-4-phenyl-butanamide hydrochloride The product of example 20A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound.
MS (ESI+Q1MS) m/e 309 (M+H)+ , 325 (M+NH4)+ 1H NMR (300 MHz, MeOH-d4) δ 1.23 (dt, 3H), 1.75-1.87 (m, 2H), 2.32-2.38 (m, 2H),
2.82-3.38 (m ), 3.79-3.86 (m, IH), 4.05-4.15 (m, 3H), 4.28 (d, 0.3H), 7.25-7.40 (m, 5H).
Example 22 (2RS.3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide hydrochloride The product of example 20A and 4-phenylbutylamine were processed as in example
2 to provide the title compound.
MS (ESI+Q1MS) m/e 327 (M+H)+ , 653 (2M+H)+
JH NMR (300 MHz, MeOH-d4) δ 1.47-1.69 (m, 4H), 2.65 (t, 2H), 2.80-3.39 (m ), 3.75-
3.84 (m, IH), 4.03 (d, 0.7H), 4.29 (d, 0.3H), 7.08-7.39 (m, 10H).
Example 23 (2RS.3R,rS)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hvdroxy-4-cvclohexyl-butanamide hydrochloride
Example 23A
N-(tert-Butoxycarbonyl)-D-cyclohexylalanine was processed as in examples 1 A through ID to provide (2RS,3R) 3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl- butanoic acid.
Example 23B
The product of example 23A and L-alanine ethyl ester hydrochloride were processed as in example IE to provide the title compound. MS (ESI+Q1MS) m/e 301 (M+H)+ , 601 (2M+H)+
!H NMR (300 MHz, MeOH-d4) δ 0.90-1.82 (m, 19H, includes 1.27,t, 3H; 1.45, d, 3H)
3.57-3.65 (m, 3H), 4.15-4.23 (m, 3H), 4.45 (q, 2H);
Example 24
(2RS.3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-cvclohexyl-butanamide hydrochloride The product of example 23A and ethyl 3-amino-propionate were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m e 301 (M+H)+ , 323 (M+Na)+ lH NMR (300 MHz, MeOH-d4) δ 0.93-1.84 (m, 16H, includes 1.26,t, 3H) 2.55-2.61 (m,
2H), 3.47-3.54 (m, 2H), 4.11-4.24 (m, 3H).
Example 25 (2RS.3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cvclohexyl-butanamide hydrochloride The product of example 23 A and ethyl 4-amino-butyrate were processed as in example 2 to provide the title compound. MS (ESI+Q1MS) m/e 335 (M+Na-H)+; lU NMR (300 MHz, MeOH-d4) δ 0.82-1.88 (m, 18H, includes 1.25,t, 3H), 2.34-2.39 (m,
2H), 3.18-3.38 (m, overlapped with MeOH peak), 3.57-3.67 (m, 2H), 4.08-4.25 (m, 3H).
Example 26
(2RS.3R.rS)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-phenyl-butanamide hydrochloride
The product of example 20A and L-alanine ethyl ester hydrochloride were processed as in example IE to provide the title compound.
MS (ESI+Q1MS) m e 295 (M+ H)+;
*H NMR (300 MHz, MeOH-d4) δ 1.25 (dt, 3H), 1.44 (d, 3H), 2.83-3.17 (m, 2H), 3.76- 3.83 (m, IH), 4.08-4.21 (m, 3H), 4.35-4.47 (m, IH), 7.25-7.40 (m, 5H).
Example 27 (2RS.3R)-3-amino-2-hvdroxy-N-(4-methoxyphenethyl)-5-(methylsulfanyl)pentanamide hydrochloride The product of example 23 A and l-amino-2-(4-methoxyphenyl)ethane were processed as in example 2 to provide the title compound. MS (APCI) m/e 313 (M+H)+ ; lH NMR (300 MHz, DMSO-d6) δ 8.24 (m, IH), 7.82 (m, 2H), 7.12 (d, 2H), 6.86 (d, 2H), 6.53 (d, IH), 4.08 (m, IH), 3.72 (s, 3H), 3.38 (m, 2H), 2.70 (m, 2H), 2.54 (m, 2H), 2.04 (s, 3H), 1.75 (m, 2H).
Example 28
(2RS.3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hvdroxy-5-
(ethylthio)pentanamide The product of examplel2A and 4-phenylbutyl amine were processed as in example IE to provide the title compound. MS (APCI-Q1MS) m/e 459 (M+2NH4-H)+
!H NMR (300 MHz, MeOH-d4) δ 1.16-1.25 (dt, 3H), 1.39 (s, 0.4x9H), 1.43 (s, 0.6x9H),
1.52-1.84 (m, 6H), 2.43-2.55 (m, 3H), 3.14-3.26 (m, IH), 3.99 (brd, 0.6H), 4.09 (brd, 0.4H), 7.10-7.27 (m, 5H);
Example 29
(2RS,3R)-N-((2-phenylbutyl)-3-acetylamino-2-hvdroxy-5-(ethylthio)pentanamide
The product of example 13 and acetic anhydride were reacted in methylene chloride in the presence of triethylamine and purified on silica gel column chromatography, eluting with 1 % methanol in chloroform to provide the title compound. MS (ESI+Q1MS) m/e 367 (M+H)+ , 389 (M+Na)+ , 733 (2M+H)+ , 755 (2M+Na)+ lH NMR (300 MHz, MeOH-d4) δ 1.23 (t, 3H), 1.48 -1.68 (m, 4H), 1.73-1.93 (m, 5H, includes, 1.87, s, 3H), 2.49-2.57 (m, 4H), 2.63 (t, 2H), 3.10-3.19 (m, IH), 4.02 (d, IH), 4.29 (m, IH), 7.10-7.27 (m, 5H);
Example 30
(2RS.3R)-N-((phenylbutyryl)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide hydrochloride The product of example 23A and 4-phenylbutyl amine were processed as in examples IE and IF to provide the title compound.
MS (ESI+Q1MS) m/e 333 (M+ H)+, 665 (2M+ H)+ *H NMR (300 MHz, CDC13) δ 7.14-7.30 (m, 5H), 5.04 (br. 0.7H), 4.82 (br.d, 0.3H), 4.17
(br., 0.3H), 4.04 (br.d, 0.7H), 3.86 (br.m, IH), 3.22-3.36 (m, 2H), 2.63 (t, 2H), 0.80-1.83
(m, 19H).
Example 31 (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride The product of example 13 and methyl chloroformate were reacted in tetrahydrofuran in the presence of triethylamine and purified on silica gel column chromatography, eluting with 0.5-0.75 % methanol in chloroform to provide the title compound.
MS (ESI+Q1MS) m e 383 (M+ H)+ , 400 (M+ NH4)+
!H NMR (300 MHz, CDC13) δ 7.16-7.30 (m, 5H), 6.73 (br.d, IH), 5.18 and 5.35 (both br. d.,total IH), 4.25 (br.d, 0.3H), 4.14 (d, 0.7H), 3.97-4.07 (m, IH), 3.59 and 3.67 (both s, total 3H), 3.23-3.37 (m, 2H), 2.45-2.68 (m, 6H), 1.90-2.12 (m, 2H), 1.52-1.71 (m, 6H), 1.25 (dt, 3H).
Example 32 (2RS.3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hvdroxy-5-(methylthio)pentanamide The product of example 3A and l-amino-2-(3-pyridyl)ethane were processed as in example 2 to provide the title compound. MS (APCI) m/e 284 (M+H)+ ;
*H NMR (300 MHz, DMSO-d6) δ 8.74 (m, IH), 8.38 (m, 2H), 8.10 (m, IH), 7.90 (m, 2H), 7.78 (m, 2H), 4.09 (m, IH), 3.70 (m, 2H), 3.57 (m, 2H), 3.49 (m, 2H), 2.57 (m, IH), 2.04 (s, 3H), 1.80 (m, 2H).
Example 33
(2RS.3R)-3-amino-2-hvdroxy-N-methyl-5-(methylsulfanyl)-N-phenethylpentanamide hydrochloride The product of example 3A and l-(N-methylamino)-2-phenylethane were processed as in example 2 to provide the title compound. MS (APCI) m/e 297 (M+H)+ ;
*H ΝMR (300 MHz, DMSO-d6) δ 7.88 (m, IH), 7.76 (m, 2H), 7.37 (m, 5H), 6.38 (m,
IH), 4.42 (m, IH), 4.23 (s, 3H), 3.70 (m, 4H), 3.49 (m, 3H), 3.05 (m, IH), 2.92 (m, IH), 2.04 (m, 3H).
Example 34
(,2RS.3R.rS)-Ν-((2-carboxyethyl)-3-amino-2-hvdroxy-4-ethylthio)pentanamide hydrochloride Following example 12B an intermediate product tert-butoxycarbonyl derivative was obtained. This was saponified by lN-lithium hydroxide in methanol-water to obtain N- protected carboxylic acid derivative, which was then treated in the same method described in example IF provide the title compound. MS (ESI+Q1MS) m/e 265 (M+ H)+, 287 (M+ Νa)+ ,529 (2M+ H)+ , 551 (2M+Na)+ *H NMR (300 MHz, D2O) δ 2.75-2.50 (m, 4H), 2.12-1.90 (m, 2H), 1.40 (d, 3H), 1.24 (dt, 3H);
Example 35 (2RS ,3R)-N-(Y 1 -methyl- 1 -ethoxycarboxyethyl) 3-amino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride
The product of example 12A and alpha aminoisobutyric acid ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
MS (ESI+Q1MS) m/e 307 (M+ H)+ lH NMR (300 MHz, MeOH-d4) δ 4.26-4.14 (m, 3H), 3.77-3.53 (m, 4H), 2.77-2.55 (m,
4H), 2.14-1.84 (m, 2H), 1.54-1.51 (m, 6H), 1.29-1.22 (m, 6H);
Example 36 (2RS .3R.1 'S)-N-(( 1 -(2-hvdroxy)- 1 -ethoxycarboxyethyl) 3-amino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride
The product of example 12A and L-serine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 309 (M+ H)+
!H NMR (300 MHz, D2O) δ 4.67-4.63, (m, IH) 4.57 (d, 0.3), 4.44 (d, 0.7H), 4.24-4.15 (m, 2H), 4.06-3.87 (3H), 3.76-3.84 (m, IH), 2.52-2.83 (m, 4H), 2.18-1.93 (m, 2H), 1.32- 1.20 (m, 6H);
Example 37 (2RS.3R)-N-((phenylbutyryl)-3-tert-butoxycarbonylamino-2-hvdroxy-4- ethylthio)pentanamide
The product of example 12 A and 4-phenylbutyl amine were processed as in example IE to provide the title compound. MS (ESI+Q1MS) m e 439 (M+ H)+
!H NMR (300 MHz, CDC13) δ 7.30-7.15 (m, 5H), 7.03 (t, IH), 3.34-3.26 (m, 2H), 2.73- 2.47 (m, 6H), 1.98-1.85 (m, 2H), 1.73-1.53 (m, 6H), 1.46 (s, 9H), 1.28-1.21 (m, 3H).
Example 38 (2RS.3R)-N-((phenylbutyryl)-3-formylamino-2-hvdroxy-4-ethylthio)pentanamide The product of example 13 and formic acid-acetic anhydride in methylene chloride in the presence of triethylamine were processed as in example IE, and purified by silica gel, eluting with 2% methanol in chloroform to provide the title compound. MS (ESI+Q1MS) m e 353 (M+ H)+ , 375 (M+ Na)+ , 727 (2M+ Na)+
*H NMR (300 MHz, MeOH-d4) δ 7.26-7.11 (m, 5H), 4.44-4.38 (m, IH), 4.05 (d, 0.7H),
4.00 (d, 0.3H), 3.27-3.12 (m, 2H), 2.63-2.49 (m, 4H), 1.93-1.30 (m, 8H), 1.26-1.20 (m, 3H).
Example 39 (2RS.3RVN-Methyl-N-(ϊethoxycarbonylmemyl)-3-amino-2-hvdroxy-4- ethylthio)pentanamide hydrochloride The product of example 12 A and sarcosine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m e 293 (M+ H)+ lH NMR (300 MHz, D2O) δ 4.22-4.27 (m, IH), 3.76 (s, 3H), 3.24-2.98 (m, 2H), 2.83- 2.54 (m, 6H), 2.23-1.92 (m, 4H), 1.31-1.19 (m, 6H).
Example 40
(2RS.3R)-N-r(Phenylbutyryl)-3-hvdroxymethylcarbonylamino-2-hydroxy-4- ethylthio)pentanamide hydrochloride The product of example 13 and glycolic acid were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 383 (M+ H)+ , 405 (M+ Na)+, 787 (2M+ Na)+
JH NMR (300 MHz, MeOH-d4) δ 8.01 (br.t, IH), 7.68 (d, IH), 7.26-7.13 (m, 5H), 4.43-
4.32 (m, IH), 3.94-3.85 (m, IH), 3.78-3.65 (m, IH), 3.26-3.15 (m, 2H), 3.24-2.98 (m, 2H), 2.64-2.48 (m, 6H), 1.97-1.49 (m, 6H), 1.22 (t, 3H).
Example 41
(2RS.3R,rR)-N-((l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4-ethylthio)pentanamide hydrochloride The product of example 12A and D-alanine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 293 (M+ H)+ ,
*H NMR (300 MHz, MeOH-d4) δ 4.55-4.15 (m, 4H), 3.76-3.67 (m, 2H), 2.75-2.51 (m,
4H), 2.05-2.17 (m, IH), 1.97-1.85 (m, IH), 1.45 (t, 3H), 1.31-1.22 (m, 6H).
Example 42 (2RS.3R.rR)-N-((l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4-cvcIohexyl)butanamide hydrochloride The product of example 23 A and D-alanine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 301 (M+ H)+ , lH NMR (300 MHz, MeOH-d4) δ 4.54-4.42 (m, IH), 4.28-4.16 (m, 2H), 3.76-3.57 (m, 2H), 1.82-0.83 (m, 19H ).
Example 43 (2RS.3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cvclohexyDbutanamide hydrochloride The product of example 23A and alpha aminoisobutyric acid ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound.
MS (ESI+Q1MS) m/e 315 (M+ H)+ , 629 (2M+ H)+ ,
!H NMR (300 MHz, MeOH-d4) δ 4.23-4.09 (m, 3H), 3.76-3.57 (m, IH), 1.82-0.82 (m,
22H).
Example 44 (2RS.3R)-N-((Phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4- ethylthio)pentanamide hydrochloride The product of example 13 and methyl bromoacetate were reacted in dimethylsulfoxide in the presence of sodium hydride and processed as in example IE to provide the title compound.
MS (ESI+Q1MS) m e 397 (M+ H)+ , 419 (M+ Na)+,
!H NMR (300 MHz, CDC13) δ 8.01(s, IH), 7.31-7.16 (m, 5H), 6.53 (br. IH), 4.35-4.25 (m, IH), 3.85-3.71 (m, 4H), 3.33-3.25 (m, 2H), 2.68-2.48 (m, 6H), 1.97-1.49 (m, 6H), 1.22 (t, 3H), 1.99-1.50 (m, 8H), 1.28-1.19 (m, 3H).
Example 45 (2RS.3R. S)-N-((l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4-benzylthio)butanamide hydrochloride
Example 45A N-(tert-Butoxycarbonyl)-S-benzyl-D-cysteine was processed as in Example 1 A through IB to prepare N-(tert-butoxycarbonyl)-S-benzyl-D-cysteinal.
Example 45B
The product of example 286491.1A (3.56g, 12.1 mmol) was suspended in ice-cold water (70 mL) and sodium bisulfite (1.26g, 12.1 mmol) was added, and stirred at 0 °C for 1.5 hours, and was then kept in a refrigerator for one over night. Ethyl acetate (70 mL) and potassium cyanide (0.79g, 12.1 mmol) were added and vigorously stirred for 4 hours. The separated ethyl acetate layer was washed sequentially with water and brine, dried (MgSO4), and concentrated to give a colorless syrup to provide 3.40 g solid material.
Example 45C The product of example 45B (3.40g) was dissolved in 50 mL of methanol in an ice bath and hydrogen chloride gas was bubbled through the reaction mixture until saturated. It was then stirred at 0 °C for 3 hours and at room temperature for one over night. Solvent was evaporated dryness and 20 mL of water was added to the residue. 10%-Sodium hydrogen carbonate was added to the mixture to adjust pH over 9, an oil was extracted with ethyl acetate (50 mLx2). The combined ethyl acetate layer was washed with 10%- sodium hydrogen carbonate (2X), brine (3X), quickly dried over sodium sulfate anhydrous. Ethyl acetate was removed by evaporation to yield 1.77g of dark brown oil. This was processed as in Example ID, and purified by silica gel column chromatography, eluting with 12.5 % acetone in hexane to yield 0.12g of (2RS, 3R)-3-(tert- butoxycarbonylamino)-2-hydroxy-4-benzylthio-butanoic acid methyl ester.
Example 45D The product of example 45C was treated with lN-lithium hydroxide in methanol- water to provide its free carboxylic acid derivatives and coupled with L-alanine ethyl ester as in example IE and deprotection was carried out according to the method described in example IF to provide the title compound.
MS (ESI+Q1MS) m/e 341 (M+ H)+ , 363 (M+ Νa)+, 681 (2M+ H)+, *H NMR (300 MHz, MeOH-d4) δ 7.38-7.22 (m, 5H), 4.51-4.38 (m, 2H), 4.23-4.05 (m,
2H), 3.76-3.56 (m, 4H), 2.86-2.77 (m, IH), 2.72-2.61 (m, IH), 1.46-1.38 (m, 3H), 1.32- 1.16 (m, 3H).
Example 46 (2RS.3R.rS)-N-((2-hvdroxy-l-ethoxycarbonylethyl)-3-amino-2-hvdroxy-4- cyclohexyDbutanamide hydrochloride The product of example 23 A and L-serine ethyl ester hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 317 (M+ H)+ , 633 (2M+ H)+, *H NMR (300 MHz, MeOH-d4) δ 4.45-4.55 (m, IH), 4.26-4.18 (m, 3H), 4.00-3.87 (m,
2H), 3.69-3.63 (m, IH), 0.94-1.83 (m, 16H, includes 1.29 t, 3H). Example 47 (2RS.3R.rS)-N-((2-acetoxypropyl)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide hydrochloride
Example 47 A
N-(tert-Butoxycarbonyl)-L-alaninol (438 mg, 2.5mmol) was dissolved in 5 mL of methylene chloride in an ice bath and acetyl chloride (0.294 mL, 3.75 mmol), followed by triethylamine (0.7mL, 5 mmol) were added. It was then reacted at 0 °C for 1 hour and at room temperature for 2 days. The mixture was diluted with 25 mL of ethyl acetate and the organic layer was washed with 10%-sodium hydrogen carbonate (3x), brine (2x), dried over magnesium sulfate anhydrous, and then evaporated to dryness to yield 380 mg of N- (tert-butoxycarbonyl)-O-acetyl-L-alaninol.
Example 47B The product of example 47 A (380 mg) was processed as in example IF to yield
0.26g of its corresponding salt. This (0.26g, 1.69 mmol) was coupled with the product of example 23 A (509mg, 1.69 mmol) according to the method described in example IE and purified by silica gel column eluting with 15% acetone in hexane to yield 0.35 g of N-(tert- butoxycarbonyl) derivative. The obtained product (0.35 g) was processed as in example IF to give the title product (290mg).
MS (ESI+Q1MS) m/e 301 (M+ H)+ , 601 (2M+ H)+, H NMR (300 MHz, MeOH-d4) δ 4.26-3.97 (m, 4H), 3.74-3.56 (m, 2H), 2.05, 2.03
(2.05, s, major, 2.03 s, minor, total 3H), 1.83-0.94 (m, 16H).
Example 48
(2RS.3R.2'S)-N-((2-propionyloxypropyl)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide hydrochloride Following the procedure of example 47 A, but replacing acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-L-alaninol. This was followed the procedure described in example 47B to give the title compound. MS (ESI+Q1MS) m/e 315 (M+ H)+ , 629 (2M+ H)+, lH NMR (300 MHz, MeOH-d4) δ 4.25-3.97 (m, 4H), 3.74-3.56 (m, 2H), 2.40-2.32 (m,
2H), 1.83-0.94 (m, 19H).
Example 49
(2RS.3R.2'S)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4-cvclohexyl)butanamide hydrochloride Following the procedure of example 47 A, but replacing acetyl chloride with benzoyl chloride, provided N-(tert-butoxycarbonyl)-O-benzoyl-L-alaninol. This was followed the procedure described in example 47B to give the title compound. MS (ESI+Q1MS) m/e 363 (M+ H)+ , 725 (2M+ H)+, 747 (2M+ Νa)+, lH NMR (300 MHz, MeOH-d4) δ 8.07-8.02 (m, 2H), 7.65-7.58 (m, IH), 7.52-7.45 (m,
2H), 4.44-4.07 (m, 4H), 3.60-3.54 (m, IH), 1.78-0.82 (m, 16H).
Example 50
(2RS.3R. 2'R)-N-((2-benzoyloxypropyl)-3-amino-2-hvdroxy-4-cyclohexyl)butanamide hydrochloride
Following the procedure of example 47 A, but replacing N-(tert-butoxycarbonyl)-L- alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with benzoyl chloride, provided N-(tert-butoxycarbonyl)-O-benzoyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound. MS (ESI+Q1MS) m/e 363 (M+ H)+ , 725 (2M+ H)+,
!H ΝMR (300 MHz, MeOH-d4) δ 8.07-8.02 (m, 2H), 7.65-7.58 (m, IH), 7.53-7.44 (m,
2H), 4.43-4.12 (m, 4H), 3.62-3.48 (m, IH), 1.74-0.82 (m, 16H).
Example 51 (2RS.3R.2'R)-Ν-((2-propionyloxypropyl)-3-amino-2-hvdroxy-4-cvcIohexyl)butanamide hydrochloride Following the procedure of example 47 A, but replacing N-(tert-butoxycarbonyl)-L- alaninol with N-(tert-butoxycarbonyl)-D-alaninol and acetyl chloride with propionyl chloride, provided N-(tert-butoxycarbonyl)-O-propionyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound. MS (ESI+Q1MS) m/e 315 (M+ H)+ , 629 (2M+ H)+, *H ΝMR (300 MHz, MeOH-d4) δ 4.23-4.00 (m, 4H), 3.62-3.53 (m, IH), 2.43-2.32 (m,
2H), 1.82-0.94 (m, 19H).
Example 52
(2RS.3R,2'R)-Ν-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cvclohexyl)butanamide hydrochloride Following the procedure of example 47 A, but replacing N-(tert-butoxycarbonyl)-L- alaninol with N-(tert-butoxycarbonyl)-D-alaninol, provided N-(tert-butoxycarbonyl)-O- acetyl-D-alaninol. This was followed the procedure described in example 47B to give the title compound. MS (ESI+Q1MS) m/e 301 (M+ H)+ , 601 (2M+ H)+, !H NMR (300 MHz, MeOH-d4) δ 4.25-3.99 (m, 4H), 3.74-3.54 (m, 2H), 2.06, 2.04 (2.04, s, major, 2.06 s, minor, total 3H), 1.83-0.82 (m, 16H).
Example 53 f2RS.3R.rS)-N-((l-benzyloxycarbonylethyl)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide hydrochloride The product of example 23 A and L-alanine benzyl ester hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 363 (M+ H)+ , 725 (2M+ H)+, !H NMR (300 MHz, MeOH-d4) δ 7.38-7.32 (m, 5H), 5.21-5.17 (m, 2H), 4.57-4.48 (m,
IH), 4.27-4.15 (m, IH), 3.63-3.56 (m, IH), 1.82-0.87 (m, 16H).
Example 54 f2RS.3R.rS)-N-(4-ethoxycarbonyl-2-(l'-aminoethyl)thizole)-3-amino-2-hvdroxy-4- cvclohexyDbutanamide hydrochloride
Example 54A N-(tert-Butoxycarbonyl)-L-alanine amide (3.76g, 20 mmol) was suspended in 70 mL of methylene chloride in an ice bath and triethyloxonium hexafluorophosphate (4.97g, 20 mmol) was added. It was stirred at 0 oC for 30 minutes and at room temperature for one over night. Methylene chloride layer was washed with water (2x), 10%-sodium hydrogen carbonate (2x), water (2x), dried over sodium sulfate anhydrous. It was then evaporated to dryness, dried under high vaccum to yiels 2.72 g of iminoether. MS (ESI+Q1MS) m/e 217 (M+ H)+ , 433 (2M+ H)+, 455 (2M+Νa)+
Example 54B The product of example 54A (2.72g, 12.6 mmol) was dissolved in 40 mL of ethanol and L-cysteine ethyl ester hydrochloride (2.57g, 13.86 mmol) was added. It was stirred at room temperature for 2 days. Ethanol was removed by evaporation, and the residue was dsirectiy purified by silica gel column chromatography, eluting with 30% ethyl acetate in hexane to yield 2.91 g of pure thizoline analogue. MS (ESI+Q1MS) m e 303 (M+ H)+ , 325 (M+ Na)+,
Example 54C To the product of example 54B (604mg, 2 mmol) in a 50 mL of round bottle flask were addwd copper (I) bromide (316 mg, 1.1 mmol) and copper (II) acetate anhydrous (0.40g, 2.2 mmol). The flask was evacuated with argon repeatedly and 15 mL of benzene was added via syringe. While stirring at 60 °C, tert-butyl perbenzoate was carefully added in a period of 15 minutes, and gently refluxed for 4 hours. The crude product was directly purified by silica gel column chromatography, eluting eith 30 % ethyl acetate in hexane to yield 390 mg of pure thiazole derivative. The obtained product (320 mg ) was treated according to the method as in example IF and coupled with the product of example 23 A as in example IE to give N-(tert-butoxycarbonyl) derivative of the title compound (220 mg).
Example 54D The product of example 54C (60 mg) was processed as in example IF to yield the title compound.
MS (ESI+Q1MS) m/e 384 (M+ H)+ , 767 (2M+ H)+,
*H NMR (300 MHz, MeOH-d4) δ 8.38 , 8.34 (8.34, s, major, 8.38, s, minor both IH),
5.51-5.27 (m, IH), 4.43-4.23 (m, 4H), 3.71-3.57 (m, IH), 1.70, d, 3H), 1.86-0.88 (m, 19H, includes 1.37 t, 3H).
Example 55 (2RS.3R) N-(monodansylcadaveno)-3-amino-2-hvdroxy-4-cvclohexyl)butanamide dihydrochloride The product of example 23A and monodansyl cadaverive were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 519 (M+ H)+ ; !H NMR (300 MHz, MeOH-d4) δ 8.90 (d, IH), 8.58 (d, IH), 8.36 (d, IH), 8.06 (d, IH),
7.87 (q, 2H), 4.23 (d, 0.3H), 4.12 (d, 0.7H), 3.72-3.44 (m, 8H), 3.23-2.97 (m, 2H), 2.87 (t, 2H), 1.81-0.77 (m, 19H).
Example 56
(2RS.3R) N-(2-methyl-5-nitro imidazole-ethyl) 3-amino-2-hvdroxy-4- cvclohexyDbutan amide dihydrochloride The product of example 23 A and l-(2-aminoethyl)-2-methyl-5-nitro imidazole were processed as in examples IE and IF to provide the title compound.
MS (ESI+Q1MS) m/e 354 (M+ H)+ , 707 (2M+ H)+ ;
!H NMR (300 MHz, MeOH-d4) δ 8.63 (mn, IH), 8.52, 8.50 (both s, total IH), 4.75-4.56
(m, 2H), 4.11 (d, 0.4H), 4.00 (d, 0.6H), 3.96-3.72 (m, 2H), 3.63-3.53 (m, 2H), 2.72 (s, 3H), 1.82-0.77 (m, 13H).
Example 57 (2RS.3R) N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4-cvclohexy butanamide dihydrochloride The product of example 23A and 2-(2-aminoethylamino)-5-nitro-pyridine were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 366 (M+ H)+ , 731 (2M+ H)+;
*H NMR (300 MHz, MeOH-d4) δ 8.94 (br.d, IH), 8.41 (br. IH), 7.90 (d, IH), 7.77 (d,
IH), 7.61-7.49 (m, 2H), 6.98 (br., IH), 4.28 (d, 0.4H), 4.18 (d, 0.6H), 3.96-3.72 (m, 2H), 3.77-3.42 (m, 6H), 2.72 (s, 3H), 1.80-0.77 (m, 13H).
Example 58
(2RS.3R) N-(5-methoxy-trvptaminyl) 3-amino-2-hvdroxy-4-cvclohexyl)butanamide dihydrochloride
The product of example 23 A and 5-methoxy tryptamine were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 374 (M+ H)+ , 747 (2M+ H)+ ,
*H NMR (300 MHz, MeOH-d4) δ 7.91 (m, IH), 7.78 (d, IH), 7.63-7.52 (m, 2H), 7.25-
7.06 (m, IH), 4.24 (d, 0.3H), 4.13 (d, 0.7H), 3.93-3.82 (m, 4H, includes 3.84, s, 3H), 3.75-3.44 (m, 4H), 3.00-2.87 (m, 2H), 1.76-0.66 (m, 13H).
Example 59
(2RS,3R) N-(3-O-methyl-dopaminyl) 3-amino-2-hvdroxy-4-cvclohexyI)butanamide hydrochloride
The product of example 23A and 3-O-methyl dopamine hydrochloride were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 351 (M+ H)+ , 701 (2M+ H)+ ; lH NMR (300 MHz, MeOH-d4) δ 7.90-7.74 (m, IH), 7.60-7.46 (m, IH), 6.84-6.65 (m,
3H), 4.21 (d, 0.3H), 4.10 (d, 0.7H), 3.85 (s, 3H), 3.62-3.34 (m, 4H), 2.75 (t, 2H), 1.82- 0.76 (m, 13H).
Example 60
(2RS.3R) N-(2-aminomethylbenzimidazolyl) 3-amino-2-hydroxy-4-cvclohexyl)butanamide hydrochloride
The product of example 23A and 2-(aminomethyl)benzimidazole dihydrochloride monohydrate were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 331 (M+ H)+ , 661 (2M+ H)+ ;
*H NMR (300 MHz, MeOH-d4) δ 7.92-7.47 (m, 5H), 4.46 (d, 0.3H), 4.39 (d, 0.7H),
3.77-3.56 (m, 2H), 1.84-0.83 (m, 13H). Example 61 ((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanvH2-methyl-5- nitroimidazolyl-ethvDamide hydrochloride
Example 61 A The product of example 23 A and L-alanine benzyl ester hydrochloride were processed as in example IE to yield N-(tert-butoxycarbonyl) drivative (3.80 g), which was hydrogenated in 50 mL of ethanol in the presence of 0.3g of 10% palladium on charcoal as a catalyst for 3.5 hours. The mixture was passed through celite 545 and evaporated to dryness to yield (2RS,3R) N-[(3-tert-butoxycarbonylamino-2-hydroxy-4- cyclohexyl)butanoyl-L-alanine (3.16g)
Example 6 IB The product of example 61 A and l-(2-aminoethyl)-2-methyl-5-nitro imidazole were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 425 (M+ H)+ , 849 (2M+ H)+ , !H ΝMR (300 MHz, MeOH-d4) δ 8.58, 8.56 (both s, total IH), 4.73-4.57 (m, 2H), 4.26-
4.17 (m, 2H), 3.84-3.56 (m, 4H), 2.77 (s, 3H), 1.85-0.82 (m, 16H includes 1.34, d).
Example 62 ((2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- nitropyridylaminoethvDamide dihydrochloride The product of example 61 A and 2-(2-aminoethylamino)-5-nitro-pyridine were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 437 (M+ H)+ , 873 (2M+ H)+ , 1H ΝMR (300 MHz, MeOH-d4) δ 8.94-8.37 (br. m, IH), 7.92-7.75 (m, IH), 7.62-7.50
(m, IH), 4.37-4.17 (m, 3H), 3.78-3.50 (m, 5H), 1.85-0.80 (m, 16H).
Example 63
((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(ethylisonipecotate)amide hydrochloride
The product of example 61 A and ethyl isonipecotate were processed as in examples
IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 412 (M+ H)+ , 823 (2M+ H)+ ;
*H ΝMR (300 MHz, MeOH-d4) δ 4.41-3.93 (m, 4H), 3.76-3.57 (m, 3H), 3.00-2.82 (m,
IH), 2.72-2.53 (m, IH), 2.08-1.92 (m, 2H), 1.85-0.80 (m, 23H). Example 64
(f2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(2-pyrrolidinopropyl)amide hydrochloride The product of example 61 A and l-(3-aminopropyl)-2-pyrrolidone were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 397 (M+ H)+ , 793 (2M+ H)+ , lH NMR (300 MHz, MeOH-d4) δ 4.38-4.24 (m, 2H), 3.74-3.56 (m, 2H), 3.52-3.43 (m,
2H), 3.27-3.08 (m, 2H), 2.41 (t, 2H), 2.12-2.00 (m, 2H), 1.84-1.70 (m, 8H), 1.53-0.91 (m, 10H includes 1.42, d, 3H).
Example 65 ((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(5- methoxytrvptamine)amide hydrochloride The product of example 61 A and 5-methoxy tryptamine were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 455 (M+ H)+ , 889 (2M+ H)+ ;
*H NMR (300 MHz, MeOH-d4) δ 4.38-4.24 (m, 2H), 3.74-3.56 (m, 2H), 3.52-3.43 (m,
2H), 3.27-3.08 (m, 2H), 2.41 (t, 2H), 2.12-2.00 (m, 2H), 1.84-1.70 (m, 8H), 1.53-0.91 (m, 10H includes 1.42, d, 3H).
Example 66 (Y2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(3-O- methoxydopamine)amide hydrochloride The product of example 61 A and 3-O-methoxydopamine hydrochloride were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 422 (M+ H)+ , 843 (2M+ H)+ ;
!H NMR (300 MHz, MeOH-d4) δ 6.80-6.63 (m, 4H), 4.38-4.16 (m, 2H), 3.84 (s, 3H),
3.67-3.56 (m, IH), 3.44-3.35 (m, 2H), 2.72 (t, 2H), 1.85-0.82 (m, 16H includes 1.34, d, 3H).
Example 67 (("2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(2- benzimidazolemethvDamide hydrochloride The product of example 61 A and 2-(aminomethyl)benzimidazole dihydrochloride monohydrate were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 402 (M+ H)+ , 803 (2M+ H)+ ; lH NMR (300 MHz, MeOH-d4) δ 7.90-7.46 (m, 5H), 4.54-4.44 (m, IH), 4.24 (d, 0.7H), 3.75-3.48 (m, 2H), 1.80-0.83 (m, 16H includes 1.50, d, 3H).
Example 68 ((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(5-phenyl-pyrazole-3)amide hydrochloride
The product of example 61 A and 3-amino-5-phenyl pyrazole were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 414 (M+ H)+ , 827 (2M+ H)+ ; *H NMR (300 MHz, MeOH-d4) δ 7.92-7.46 (m, 5H), 6.80 (br., IH), 4.64-4.56 (m, IH),
4.33 (d, 0.3H), 4.24 (d, 0.7H), 3.75-3.56 (m, 2H), 1.84-0.93 (m, 16H).
Example 69 ((2RS.3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-L-alanyl-r2-hvdroxy-5-nitro-l)amide hydrochloride
The product of example 61 A and 2-amino-4-nitrophenol were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 409 (M+ H)+ , 817 (2M+ H)+ , lH NMR (300 MHz, MeOH-d4) δ 9.03-8.96 (m, IH), 7.98-7.77 (m, 2H), 7.47-7.60 (m, IH), 4.55-4.65 (m, IH), 4.33 (d, 0.3H), 4.23 (d, 0.7H), 3.75-3.55 (m, 2H), 1.84-0.69 (m, 16H).
Example 70
((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(5-bromothizole-2)amide hydrochloride
The product of example 61 A and 2-amino-5-bromothiazole hydrobromide were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 433 (M+ H)+ , 867 (2M+ H)+ ;
*H NMR (300 MHz, MeOH-d4) δ 7.42 (s, IH), 4.65-4.57 (m, IH), 4.31 (d, 0.3H), 4.20 (d, 0.7H), 3.76-3.49 (m, 2H), 1.84-0.76 (m, 16H).
Example 71 ((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanyl-(4-nitro-2-hvdroxyphenyl-
Pamide hydrochloride The product of example 61 A and 2-amino-5-nitrophenol were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 409 (M+ H)+ , 817 (2M+ H)+
!H NMR (300 MHz, D2O) δ 8.08-7.98 (m, IH), 7.85-7.68 (m, 2H), 4.68-4.57 (m, IH),
3.76-3.49 (m, 2H), 1.88-0.80 (m, 16H).
Example 72 f(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoylL-alanyl-(l-ethylpyrazole)amide hydrochloride The product of example 61 A and 5-amino-l-ethylpyrazole were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 366 (M+ H)+ ;
!H NMR (300 MHz, D2O) δ 7.74-7.70 (br., IH), 7.55 (br., IH), 4.52-3.98 (m, 4H), 3.71- 3.62 (m, IH), 1.76-0.86 (m, 19H).
Example 73 ((2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide hydrochloride The product of example 23 A and ethyl isonipecotate were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 341 (M+ H)+, lH NMR (300 MHz, MeOH-d4) δ 4.14 (q, 2H), 3.73-3.48 (m, 2H), 0.83-1.93 (m, 20H).
Example 74
((2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(3-imidazolylpropyl)amide dihydrochloride The product of example 23A and l-(3-aminopropyl)imidazole were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 309 (M+ H)+, 617 (2M+ H)+ ; lH NMR (300 MHz, MeOH-d4) δ 9.04 (s, IH), 7.73 (s, IH), 7.60 (s, IH), 4.35-4.21 (m,
3H), 3.42-3.16 (m, 2H), 2.18-2.07 (m, 2H), 0.82-1.83 (m, 15H).
Example 75 (2RS.3R)- 3-amino-2-hvdroxy-4-cyclohexyl)hutanoyl-(4-carboxyl-2-( 1 'amino)ethyl thizole hydrochloride The product of example 54C (0.2g, 0.414 mmol) was treated with lN-lithium hydroxide (0.5 mL, 0.5 mmol) in methanol for 3 hours. 8 mL of water was added to the mixture, and methanol was removed by evaporation. The aqueous layer was washed with ethyl acetate, and acidified by an addition of 10 % potassium hydrogen sulfate. The product was extracted with ethyl acetate (15 mL x2), and ethyl acetate layer was washed with brine (2x), dried over magnesium sulfate anhydrous. Evaporation of solvent gave 160 mg, which was then precessed as in example IF to obtain the title compound (120 mg). MS (ESI+Q1MS) m/e 356 (M+ H)+, 378 (M+ Na)+, 711 (2M+ H)+, 733 (2M+ Na)+ ; 1H NMR (300 MHz, D2O) δ 8.20 (s, IH), 5.40-5.29 (m, IH), 4.34 (d, 0.3H), 4.27 (d, 0.7H), 3.69-3.53 (m, 2H), 1.72-0.73 (m, 16H).
Example 76 ethyl (2RS.3R.2'SV2-(T-3-(acetylamino)-4-cvclohexyl-2- hvdroxybutanoyl)amino)propanoate
The product of example 23 (0.050g, 0.15 mmol), diisopropylethylamine (0.055mL, 0.31 mmol) and acetyl chloride (0.012 mL, 0.16 mmol) in dichloromethane was stirred at 0°C for 2 hours, washed sequentially with aqueous sodium bicarbonate, water and brine, dried (MgSO4), and concentrated to give the title compound. MS (APCI) m/e 343 (M+ H)+ ;
*H NMR (300 MHz, MeOH-d4) δ 7.81 (m, IH), 7.32 (m, 2H), 5.92 (d, IH), 4.30 (m,
IH), 4.11 (m, 4H), 3.95 (m, IH), 3.73 (m, 2H), 3.38 (m, IH), 1.78 (s, 3H), 1.63 (6H), 1.32 (m, 2H), 1.23 (m, 9H), 0.89 (m, IH).
Example 77
(2RS,3R)-3-arnino-2-hvdroxy-4-cvclohexyl)butanoyl-(4- benzyloxycarbonylamino)butylamide hydrochloride
The product of example 23 A and N-benzyloxycarbonyl-l,4-diaminobutane hydrochloride were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 406 (M+ H)+, 428 (M+ Na)+, 811 (2M+ H)+ ;
!H NMR (300 MHz, MeOH-d4) δ 7.39-7.27 (m, 5H), 5.06 (s, 2H), 4.23 (d, 0.3H), 4.14
(d, 0.7H), 3.73-3.56 (m, 2H), 3.27-3.08 (m, 4H), 1.84-0.80 (m, 17H).
Example 78 (2RS ,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-beta-alanine benzyl ester hydrochloride
The product of example 23A and benzyl N-(2-aminoethyl)carbamate hydrochloride were processed as in examples IE and IF to yield the title compound.
MS (ESI+Q1MS) m/e 378 (M+ H)+, 400 (M+ Na)+ 1H NMR (300 MHz, MeOH-d4) δ 7.39-7.27 (m, 5H), 5.07 (s, 2H), 4.22 (d, 0.3H), 4.14
(d, 0.7H), 3.76-3.56 (m, 2H), 3.45-3.15 (m, 4H overlapped with MeOH peak ), 1.84-0.91 (m, 13H). Example 79 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butønoyl-monodansylcadaverine amide dihydrochloride The product of example 12 A and monodansyl cadaverine were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m e 511 (M+ H)+, 533 (M+ Na)+ ; *H NMR (300 MHz, MeOH-d4) δ 8.87 (d, IH), 8.55 (d, IH), 8.35 (d, IH), 8.02 (d, IH),
7.88-7.82 (m, 2H), 4.26 (d, 0.4H), 4.18 (d, 0.6H), 3.70-3.56 (m, 2H), 3.43 (s, 6H), 3.22- 2.98 (m, 2H), 2.87 (t, 2H), 2.73-2.63 (m, 2H), 2.59-2.46 (m, 2H), 2.12-1.78 (m, 3H), 1.50-1.34 (m, 4H), 1.29-1.18 (m, 4H).
Example 80 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(4-(4- toluenesulfonvDaminobutvDamide hydrochloride
Example 80A Following example 77, the product of example 23 A and N-benzyloxycarbonyl-1,4- diaminobutane hydrochloride were coupled as in examples IE to yield the both protected compound. The product (260 mg) was hydrogenated in 10 mL of ethanol in the presence of 30 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same method described in Example 61A to yield 200 mg. MS (ESI+Q1MS) m/e 372 (M+ H)+
Example 80B The product of example 80A (92.8 mg, 0.25 mmol) was dissolved in 5 mL of methylene chloride in an ice bath, and diisopropylethylamine (0.048 mL, 0.275 mmol) and p-toluenesulfonyl chloride (47.7 mg, 0.25 mmol) were added. It was reacted at 0 °C for 3 hours and at room temperature for over night. Methylene chloride was removed and the residue was purified by silica gel column chromatography, eluting with 15-30% acetone in hexane. The obtained product was processed as in example IF to yield the title compound
(70 mg).
MS (ESI+Q1MS) m/e 426 (M+ H)+, 448 (M+Νa)+, 533 (M+ Na)+ ;
*H NMR (300 MHz, MeOH-d4) δ 7.73 (d, 2H), 7.37 (d, 2H), 4.22 (d, 0.4H), 4.13 (d,
0.6H), 3.74-3.56 (m, 2H), 3.25-3.07 (m, IH), 2.84 (t, 2H), 2.43 (s, 3H), 1.84-0.81 (m, 17H).
Example 81 (2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(2-4-toluenesulfonylaminoethyl)amide hydrochloride
Example 81 A Following example 77, the product of example 23 A and benzyl N-(2- aminoethyl)carbamate hydrochloride were coupled as in example IE to yield the protected compound. The product (220 mg) was hydrogenated in 10 mL of ethanol in the presence of 20 mg of 10%-palladium on charcoal for 3 hours. It was treated in the same method described in example 61 A to yield 130 mg. MS (ESI+Q1MS) m/e 344 (M+ H)+
Example 8 IB The product of example 81 A (42.8 mg, 0.125 mmol) and p-toluenesulfonyl chloride (23.8 mg, 0.125 mmol) were processed as in example 80B to yield the title compound (20 mg). MS (ESI+Q1MS) m/e 426 (M+ H)\ 448 (M+Na)+, 533 (M+ Na)+ ;
1H NMR (300 MHz, MeOH-d4) δ 7.73 (d, 2H), 7.38 (d, 2H), 4.23 (d, 0.4H), 4.15 (d,
0.6H), 3.76-3.56 (m, 2H), 3.25-3.07 (m, IH), 3.02-2.93 (m, 2H), 2.84 (t, 2H), 2.43 (s, 3H), 1.84-0.92 (m, 13H).
Example 82
(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(4-aminobutyl)amide dihydrochloride The product of example 80A (100 mg) was processed as in example IF to yield the title compound (70 mg).
MS (ESI+Q1MS) m/e 272 (M+ H)+ ; *H NMR (300 MHz, MeOH-d4) δ 4.28 (d, 0.4H), 4.16 (d, 0.6H), 3.77-3.56 (m, 2H),
3.46-3.14 (m, 2H overlapped with MeOH peak), 2.96 (t, 2H), 1.84-0.80 (m, 17H).
Example 83 (2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-(2-aminoethyl)amide dihydrochloride The product of example 81 A (60 mg) was processed as in example IF to yield the title compound (45 mg).
MS (ESI+Q1MS) m/e 244 (M+ H)+ ; lH NMR (300 MHz, MeOH-d4) δ 4.33 (d, 0.2H), 4.24 (d, 0.8H), 3.75-3.56 (m, 3H),
3.48-3.38 (m, IH), 3.18-3.03 (m, 2H), 1.84-0.92 (m, 13H).
Example 84 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(4-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide hydrochloride The product of example 81 A and m-(trifluoromethyl)benzenesulfonyl chloride were processed as in example 80B to yield the title compound. MS (APCI) m/e 480 (M+ H)+ ;
*H NMR (300 MHz, DMSO-d6) δ 8.08 (m, 4H), 7.86 (m, 2H), 7.73 (m, IH), 6.41 (d, IH), 3.99 (m, IH), 3.70 (m, 2H), 3.49 (m, IH), 3.06 (m, 2H), 2.76 (m, 2H), 1.65 (m, 4H), 1.40 (m, 5H), 1.15 (m, 3H), 0.84 (m, 3H).
Example 85
(2RS.3R)-3-amino-4-cvclohexyl-N-(4-(((3.4-dimethoxyphenyl)sulfonyl)amino)butyl)-2- hydroxybutanamide hydrochloride The product of example 81 A and 3,4-dimethoxybenzenesulfonyl chloride were processed as in example 80B to yield the title compound. MS (APCI) m/e 472 (M+ H)+ ;
!H NMR (300 MHz, DMSO-d6) δ 8.10 (m, IH), 7.92 (m, IH), 7.73 (m, IH), 7.44 (m, IH), 7.42 (m, IH), 7.12 (m, IH), 6.42 (m, IH), 3.98 (m, IH), 3.84 (s, 3H), 3.81 (s, 3H), 3.70 (m, 2H), 3.49 (m, IH), 3.08 (m, 2H), 2.67 (m, 2H), 1.65 (m, 4H), 1.40 (m, 5H), 1.18 (m, 3H), 0.84 (m, 3H).
Example 86 (2RS.3R)-N-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4-cvclohexyl-2- hydroxybutanamide hydrochloride The product of example 81 A and 4-acetamidobenzenesulfonyl chloride were processed as in example 80B to yield the title compound. MS (APCI) m/e 469 (M+ H)+ ; !H NMR (300 MHz, DMSO-d6) δ 7.72 (m, 4H), 7.41 (m, IH), 5.93 (d, IH), 3.79 (m,
3H), 3.04 (m, 2H), 2.73 (s, 3.H), 2.68 (m, IH), 2.09 (s, 3H), 1.60 (m, 2H), 1.24 (m, 4H), 1.13 (m, 5H), 0.85 (m, 3H).
Example 87 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(T2- naphthylsulfonyl amino)butyl)butanamide hydrochloride The product of example 81 A and 2-naphthylsulfonyl chloride were processed as in example 80B to yield the title compound. MS (APCI) m/e 462 (M+ H)+ ; *H NMR (300 MHz, DMSO-d6) δ 8.61 (s, IH), 8.15 (m, 2H), 8.04 (m, 2H), 7.82 (m, IH), 7.70 (m, 4H), 6.41 (m, IH), 3.99 (m, IH), 3.69 (m, 2H), 3.50 (m, IH), 3.04 (m, 2H), 2.77 (m, 2H), 1.64 (m, 4H), 1.42 (5H), 1.14 (m, 3H), 0.85 (m, 3H).
Example 88
(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine 4-sulfonamide benzyl ester hydrochloride The product of example 23 A and 4-(2-aminoethyl)benzenesulfonamide were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 384 (M+ H)+ ; lH NMR (300 MHz, MeOH-d4) δ 4.20 (d,), 4.10 (d,), 3.75-3.56 (m, 3H), 3.85-3.37 (m,
2H), 2.93 (t, 2H), 1.8-0.91 (m, 15H).
Example 89 (2RS,3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine benzyl ester hydrochloride The product of example 23A and amino isobutyric acid benzyl ester were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 377 (M+ H)+, 753 (2M+H)+ ; 1H NMR (300 MHz, MeOH-d4) δ 7.39-7.30 (m, 5H), 5.17 (s, 2H), 4.22 (d, 0.3H), 4.08 (d, 0.7H), 3.76-3.46 (m, 2H), 1.81-0.74 (m, 19H).
Example 90 (2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine cyclohexyl ester hydrochloride
Example 90A N-(tert-Butoxycarbonyl)-L-alanine (0.945g, 5 mmol) was dissolved in 10 mL of methanol and 2 mL of water was added, and pH was then adjusted to 7.0 by an addition of 20% cesium carbonate. The mixture was eveporated to dryness, re-evaporated twice from 5 mL of N,N-dimethylformamide, and suspended into 10 mL of N,N-dimethylformamide. Cyclohexyl bromide (0.677 mL, 5.5 mmol) was added and stirred at room temperature for over night. The mixture was diluted with 40 mL of ethyl acetate, the organic layer was washed with brine (2x), 10% sodiun hydrogen carbonate (2x), brine (2x), dried over magnesium sulfate anhydrous. It was then evapotated to dryness to yield 0.97 g of Ν-(tert-butoxycarbonyl)-L- alanine cyclohexyl ester. All was processed as in example IF to obtain L-alanine cyclohexyl ester hydrochloride (0.68 g). Example 90B The product of example 23A and the product of example 90A were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 355 (M+ H)+, 709 (2M+H)+.; lH NMR (300 MHz, MeOH-d4) δ 4.46-4.35 (m, IH), 4.28 (d, 0.3H), 4.17 (d, 0.7H),
3.78-3.56 (m, 2H), 0.74-1.81 (m, 27H includes 1.45 d, 3H).
Example 91 (2RS .3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine 2-
((phenylsulfonvDmethvDbenzyl ester hydrochloride Following the procedure of example 90 A, but replacing cyclohexyl bromide with 1- bromomethyl-2-[(phenylsulfonyl)methyl]benzene, followed by the procedure of example IF provided the desired title compound. MS (ESI+Q1MS) m/e 517 (M+ H)+, 539 (M+Na)+, 1033 (2M+H)+ ;
!H NMR (300 MHz, MeOH-d4) δ 7.75-7.68 (m, 3H), 7.62-7.53 (m, 2H), 7.46-7.32 (m,
2H), 7.27-7.18 (m, IH), 7.06-6.98 (m, IH), 5.22-5.18 (m, 2H), 4.69-4.66 (m, 2H), 4.54- 4.44 (m, IH), 4.27 (d, 0.3H), 4.16 (d, 0.7H), 3.76-3.54 (m, 2H), 1.83-0.74 (m, 16H).
Example 92
(2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl")butanoyl-L-alanine cyclopropyl ester hydrochloride Following the procedure of example 90A, but replacing cyclohexyl bromide with cyclopropyl bromide, and followed by the procedure of example IF provided the desired title compound.
MS (ESI+Q1MS) m/e 315 (M+ H)+, 629 (2M+H)+ ; lH NMR (300 MHz, MeOH-d4) δ 5.06-4.97 (m, IH), 4.45-4.36 (m, IH), 4.17 (d, 0.7H),
3.63-3.57 (m, IH), 1.84-0.90 (m, 20H).
Example 93
(2RS,3R)-3-amino-2-hydroxy-4-cvclohexyl)butanoyl-L-alanine 4-tert-butylbenzyl ester hydrochloride Following the procedure of example 90A, but replacing cyclohexyl bromide with 4- tert-butylbenzyl bromide, followed by the procedure of example IF provided the desired title compound.
MS (ESI+Q1MS) m/e 419 (M+ H)+, 837 (2M+H)+ ; *H NMR (300 MHz, MeOH-d4) δ 7.42-7.28 (m, 4H), 5.15 (s, 2H), 4.56-4.47 (m, IH),
4.28 (d, 0.3H), 4.16 (d, 0.7H), 3.74-3.55 (m, 2H), 1.84-0.90 (m, 25H includes 1.32 s, 9H and 1.45 d, 3H).
Example 94
(2RS.3R)- 3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine 4-methoxycarbonylbenzyl ester hydrochloride Following the procedure of example 90A, but replacing cyclohexyl bromide with 4- methoxycarbonylbenzyl bromide, followed by the procedure of example IF provided the desired title compound.
MS (ESI+Q1MS) m e 421 (M+ H)+, 841 (2M+H)+ ;
!H NMR (300 MHz, MeOH-d4) δ 8.04-7.46 (m, 4H), 5.26 (s, 2H), 4.62-4.51 (m, IH),
4.29 (d, 0.3H), 4.16 (d, 0.7H), 3.90 (s, 3H), 3.75-3.55 (m, 2H), 0.66-1.79 (m, 16H).
Example 95
(2RS ,3R)- 3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine 4-trifluoromethylbenzyl ester hydrochloride Following the procedure of example 90A, but replacing cyclohexyl bromide with 4- trifluoromethylbenzyl bromide, followed by the procedure of example IF provided the desired title compound.
MS (ESI+Q1MS) m/e 431 (M+ H)+, 861 (2M+H)+ ; lH NMR (300 MHz, MeOH-d4) δ 7.70-7.56 (m, 4H), 5.27 (s, 2H), 4.62-4.52 (m, IH),
4.31 (d, 0.3H), 4.16 (d, 0.7H), 3.76-3.56 (m, 2H), 1.81-0.66 (m, 16H).
Example 96
(2RS.3R)- 3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine-(4-(methyl)phenyl acetic acid phenacyl ester) hydrochloride Following the procedure of example 294115.1 A, but replacing cyclohexyl bromide with 4-(bromomethyl)phenyl acetic acid phenacyl ester, followed by the procedure of example IF provided the desired title compound. MS (ESI+Q1MS) m/e 539 (M+ H)+ ; *H NMR (300 MHz, MeOH-d4) δ 7.96-7.32 (m, 9H), 5.46-5.17 (m, 4H), 4.59-4.48 (m,
IH), 4.28 (d, 0.3H), 4.16 (d, 0.7H), 3.84 (s, 2H), 3.76-3.54 (m, 2H), 1.80-0.75 (m, 16H).
Example 97 (2RS.3R)-3-amino-4-cvclohexyl-N-(2,4-dichlorobenzyl)-2-hvdroxybutanamide hydrochloride The product of example 23A and 2,4-dichlorobenzylamine were processed as in example 101 to provide the title compound. MS (ESI+QlMS) m/e 359 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.47 (d, IH), 7.39 (d, IH), 7.30 (dd, IH), 4.54(q, 2H),
4.13 (d, IH), 3.49 (m, IH), 3.0 (br s, IH), 0.82-1.80 (m, 13H).
Example 98 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-methoxyphenyl)butanamide hydrochloride
The product of example 23A and 3-methoxyaniline were processed as in example
101 to provide the title compound.
MS (ESI+Q1MS) m/e 307 (M+H)+, 329 (M+Na)+ 1H NMR (300MHz, MeOH-d4) δ 7.37 (t, IH), 7.23 (dd, IH), 7.16 (m, IH), 6.72 (m, IH),
4.24 (d, IH), 3.79 (s, 3H), 3.66 (m, IH), 0.80-1.85 (m, 13H).
Example 99 methyl (2RS.3R,2'R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-4- methylpentanoate hydrochloride
The product of example 23 A and L-leucine methyl ester were processed as in example 101 to provide the title compound.
MS (ESI+Q1MS) m e 329 (M+H)+, 351 (M+Na)+
1H NMR (300MHz, MeOH-d4) δ 4.50 (m, IH), 4.10 (d, IH), 3.73 (s, 3H), 3.39 (m, IH), 1.2-1.81 (m, 13H), 0.9-1.0 (m, 9H).
Example 100
(2RS.3R)-3-amino-4-cvclohexyl-N-(2-furylmethyl)-2-hvdroxybutanamide hydrochloride
The product of example 23 A and furfurylamine were processed as in example 101 to provide the title compound.
MS (ESI+Q1MS) m/e 281 (M+H)+, 303 (M+Na)+
1H NMR (300MHz, MeOH-d4) δ 7.42 (m, IH), 6.35 (m, IH), 6.28 (d, IH), 4.47 (q, 2H),
4.13 (d, IH), 3.51 (m, IH), 0.90-1.80 (m, 13H).
Example 101 f2RS.3R.rRSV3-amino-4-cvclohexyl-2-hvdroxy-N-(l-(,l-naphthyl)ethyl)hutanamide hydrochloride The product of example 23 A (2.4g, 8.64mmol) was dissolved in N,N- dimethylacetamide to give 48ml (solution A). l-Hydroxy-7-azabenzotriazole (HOAT- 1.92g, 13.2mmol), O-(7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU-4.8g, 13.4mmol), and disopropylethylamine (2.4ml, 13.4mmol) were dissolved in N,N-dimethylacetamide to make 48ml (solution B). Solution A was distributed equally into 48 individual reactors. Solution B was then added to these same reactors in equal portions. The reactors were shaken lOmin at room temperature. To one of these reactors, l-(l-naphthyl)ethylamine( 0.04ml, 0.275mmol) was added and the mixture was shaken ca. 75h. Dichloromethane (5ml) and water (5ml) were added to the reaction and shaken. The aqueous layer was removed and the reactor placed on a liquid phase extractor to wash twice with IN hydrochloric acid, once with water, and finally, twice with 2Ν sodium carbonate. Any residual water was removed and the solvent was concentrated to dryness. The residue was dissolved in dichloromethane (1ml) and placed on a solid phase extractor to be eluted on a lg silica gel cartridge with 13% ethyl acetate in hexane. The appropriate fractions were collected and dried down. The residue was dissolved in 4M hydrochloric acid in dioxane (1ml) to cleave the protecting group. After one hour, the solvent was concentrated to dryness. 48 amines were processed at one time in batch mode. Based on HPLC purity, the material was either submitted as is, or sent for preparative HPLC purification prior to submission.
MS (ESI+Q1MS) m/e 355 (M+H)+, 377 (M+Na)+
1H NMR (300MHz, MeOH-d4) δ 8.16 (m, IH), 7.89 (d, IH), 7.81 (d, IH), 7.44-7.63 (m,
4H), 5.90 (q, IH), 4.08 (dd, IH), 3.48 (m, IH), 2.98 (br s, IH), 0.85-1.91 (m, 17H).
Example 102 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(2-oxo-l-pyrrolidinyl)propyl)butanamide hydrochloride The product of example 23A and l-(3-aminopropyl)-2-pyrrolidone were processed as in examples IE and IF to provide the title compound. MS (ESI+Q1MS) m/e 326 (M+ H)+ , 651 (2M+ H)+ ; *H NMR (300 MHz, MeOH-d4) δ 4.24 (d, 0.4H), 4.15 (d, 0.6H), 3.54-3.41 (m, 2H),
3.27-3.15 (m, 2H), 2.44-2.34 (m, 2H), 2.12-2.02 (m, 2H), 1.86-0.72 (m, 19H).
Example 103 (2RS .3R)-3-amino-4-cyclohexyl-N-( 1.2-dimethylpropyl)-2-hydroxybutanamide hydrochloride The product of example 23 A and 1,2-dimethylpropylamine were processed as in example 101 to provide the title compound. MS (ESI+Q1MS) m/e 271 (M+H)+, 293 (M+Na)+
1H NMR (300MHz, MeOH-d4) δ 4.28 (d, IH), 3.74 (m, IH), 1.05-1.80 (m, 13H), 0.88-
0.94 (m, 11H).
Example 104 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine hydrochloride
The product of example 61 A was processed as in example IF to yield the title compound.
MS (ESI-Q1MS) m/e 271 (M- H)+, 307 (M+Na- H)+, 543 (2M-H)+, 565 (2M+Na-H)+ ; H NMR (300 MHz, D2O) δ 4.28-4.47 (m, 2H), 3.86-3.62 (m, 2H), 1.75-0.78 (m, 16H).
Example 105 (2RS.3R)-3-amino-2-hvdroxy-4-cvclohexyl)butanoyl-L-alanine benzyl ester hydrochloride
The product of example 20A and L-alanine benzyl ester were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 357 (M+H)+, 713 (2M+H)+ ; lH NMR (300 MHz, D2O) δ 7.39-7.17 (m, 10H), 5.16 (s, 2H), 4.53-4.43 (m, IH), 4.35 (d, 0.3H), 4.07 (d, 0.7H), 3.82-3.63 (m, 2H), 3.12-2.76 (m, 2H),1.45 (d, 3H).
Example 106 (2RS,3R)-3-amino-2-hvdroxy-4-cyclohexyl)butanoyl-L-alanine hydrochloride
Example 106 A The product of example 20A and L-alanine benzyl ester were processed as in examples IE to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4- cyclohexyl)butanoyl-L-alanine benzyl ester. 0.5g of the above product was hydrogenated in 20 mL of isopropyl alcohol in the presence of 20 mg of 10%-palladium on charcoal to yield (2RS,3R)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine (0.4g).
Example 106B
The product of example 106.1 A was processed as in example IF to yield the title compound. MS (ESI+Q1MS) m/e 267 (M+H)+, 289 (M+Na)+,533 (2M+H)+, 555 (2M+Na)+ ;
!H NMR (300 MHz, D2O) δ 7.46-7.27 (m, 5H), 4.52-4.13 (m, 2H), 4.03-3.85 (m, 2H),
3.19-2.88 (m, 2H), 1.45-1.38 (dt, 3H).
Example 107
(2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-phenylbutanamide hydrochloride
The product of example 23A and aniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 277 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.64 (m, 2H), 7.35 (m, 2H), 7.14 (m, IH), 4.22 (d, IH),
3.61 (m, IH), 0.91-1.85 (m, 13H).
Example 108
(2RS,3R)-3-amino-N-(2-chlorophenethyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 2-(2-chlorophenyl)ethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.2-7.4 (m, 4H), 4.04 (d, IH), 3.00 (m, IH), 0.9-1.81 (m, 13H).
Example 109 (2RS,3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide hydrochloride The product of example 23 A and 3-phenyl-l-propylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 319 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.12-7.3 (m, 5H), 4.1 (d, IH), 3.25 (m, IH), 2.65 (m,
6H), 0.90-1.90 (m, 13H).
Example 110
(2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-α.2.3,4-tetrahvdro-l- naphthalenvDbutanamide hydrochloride
The product of example 23 A and 1,2,3,4-tetrahydro-l-naphthylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 3661 (2M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.15 (m, 4H), 5.12 (m, IH), 4.14 (m, IH), 3.58 (m, IH),
2.81 (m, 2H), 2.05 (m, IH), 0.90-1.90 (m, 16H). Example 111
("2RS.3R)-3-amino-N-(4-(tert-butyl)cvclohexyl)-4-cvclohexyI-2-hydroxybutan amide hydrochloride
The product of example 23A and l-amino-4-(l,l-dimethylethyl)cyclohexane were processed as in example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+, 677.3 (2M+H)+
1H NMR (300MHz, MeOH-d4) δ 4.03 (d, IH), 3.62 (m, 1H),3.49 (m, IH), 0.90-2.00 (m,
22H), 0.89 (m, 9H).
Example 112
(2RS.3R)-3-amino-4-cvclohexyl-N-(3.5-dichlorophenyl)-2-hydroxybutanamide hydrochloride
The product of example 23 A and 3,4-dichloroaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 345 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.74 (d, 2H), 7.20 (t, IH), 4.23 (d, IH), 3.58 (m, IH),
0.92-1.85 (m, 13H).
Example 113 f2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethylhexyl)-2-hvdroxybutanamide hydrochloride
The product of example 23A and 2-ethylhexylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 313 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 4.03 (dd, IH), 3.13(m, IH), 0.89-1.85 (m, 29H).
Example 114 butyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)acetate hydrochloride The product of example 23A and glycine n-butyl ester were processed as in example 101 to provide the title compound. MS (APCI) m e 315 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 4.16 (m, 2H), 4.02 (m, IH), 3.50 (m, IH), 0.90-1.85 (m,
19H), 0.95 (t, 3H).
Example 115 (2RS.3R)-3-amino-N-(1.3-benzodioxol-5-ylmethyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23A and piperonylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 335 (M+H)+, (669 (2M+H)+
1H NMR (300MHz, MeOH-d4) δ 6.80 (m, 2H), 5.92 (s, IH), 4.32 (q, 2H), 4.11 (d, IH),
3.50 (m, IH), 0.85-1.80 (m, 13H).
Example 116 (2RS.3R)-3-amino-4-cvcIohexyl-N-(2.4-dimethoxyphenyl)-2-hydroxybutanamide hydrochloride The product of example 23A and 2, 4-dimethoxy aniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 673 (2M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.09 (d, IH), 6.63 (d, IH), 6.51 (dd, IH), 4.27 (d, IH),
3.89 (s, 3H), 3.79 (s, 3H), 3.67 (m, IH), 0.95-1.87 (m, 13H).
Example 117 (2RS,3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(3-methoxy-5- (trifluoromethvDphenvDbutanamide hydrochloride
The product of example 23A and 3-methoxy-5-(trifluoromethyl)aniline were processed as in example 101 to provide the title compound. MS (APCI) m e 375 (M+H)+, 748 (2M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.55 (m, IH), 7.47 (t, IH), 6.85 (m, IH), 4.10 (d, IH), 3.45 (m, IH), 0.80-1.75 (m, 13H).
Example 118
(2RS.3R -3-amino-4-cvclohexyl-N-decyl-2-hvdroxybutanamide hydrochloride
The product of example 23 A and undecylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 681 (2M+H)+
1H NMR (300MHz, MeOH-d4) δ 3.85 (d, IH), 3.22 (m, 2H), 3.13 (m, IH), 0.85-1.85 (m,
32H).
Example 119 (2RS.3R)-3-amino-N-((lR.4S)hicvclo(2.2.1)hept-2-yl)-4-cvclohexyl-2-hvdroxybutanamide
The product of example 23 A and 2-aminonorbornane were processed as in example
101 to provide the title compound.
MS (APCI) m e 295 (M+H)+, 589 (2M+H)+ 1H NMR (300MHz, MeOH-d4) δ 4.05 (t, IH), 3.66 (m, IH), 3.51 (m, IH), 2.30 (br s, IH),
2.22 (m, IH), 0.90-1.80 (m, 21H).
Example 120 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hvdroxybutanamide hydrochloride The product of example 23 A and 2-fluorobenzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 309 (M+H)+, 616 (2M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.32 (m, 2H), 7.11 (m, 2H), 4.5 (q, 2H), 4.14 (d, IH),
3.52 (m, IH), 0.87-1.80 (m, 13H).
Example 121 (2RS.3R)-3-amino-4-cvclohexyl-N-(,4-fluoro-3-(trifluoromethyl)benzyl)-2- hydroxybutanamide hydrochloride The product of example 23A and 3-(trifluoromethyl)-4-fluorobenzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 377 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.64 (m, 2H), 7.29 (t, IH), 4.45 (q, 2H), 4.12 (d, IH),
3.49 (m, IH), 0.80-1.80 (me, 13H).
Example 122
(2RS.3R)-3-amino-4-cvclohexyl-N-(l-(4-fluorophenyl)ethyl)-2-hydroxybutanamide hydrochloride
The product of example 23A and 4-fluoro-a-methylbenzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 645 (2M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.36 (m, 2H), 7.04 (t, 2H), 5.06 (m, IH), 4.05 (d, IH),
3.47 (m, IH), 0.80-1.85 (m, 17H).
Example 123 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(tetrahvdro-2-furanylmethyl)butanamide hydrochloride The product of example 23 A and tetrahydrofurfurylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 285 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 4.07 (m, IH), 3.88 (m, IH), 3.75 (m, IH), 3.48 (m, IH),
1.92 (m, IH), 0.90-185 (m, 19H).
Example 124 ethyl (2RS.3R)-(4-((-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-l- piperidinecarboxylate hydrochloride
The product of example 23 A and ethyl 4-amino-l-piperidinecarboxylate were processed as in example 101 to provide the title compound.
MS (APCI) m/e 356 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 4.1 (q, 2H), 4.05 (t, IH), 3.91 (m, IH), 3.48 (m, IH),
2.94 (m, 2H), 1.26-1.90 (m, 17H), 1.25 (t, 3H), 0.95 (m, 2H).
Example 125 (2RS.3R)-3-amino-N-(1.3-benzodioxol-5-yl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23A and 3,4-methylenedioxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 321 (M+H)+, 640 (2M+H)+ 'H NMR (300MHz, MeOH-d4) δ 7.32 (d, IH), 7.00 (dd, IH), 6.77 (dd, IH), 5.94 (s, 2H), 4.25 (d, IH), 3.68 (m, IH), 0.90-1.85 (m, 13H).
Example 126 tert-butyl (2RS,3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)acetate hydrochloride The product of example 23A and glycine tert-butyl ester were processed as in example 101 to provide the title compound.
MS (APCI) m/e 315 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 4.10 (d, IH), 3.91 (q, 2H), 3.45 (m, IH), 1.48 (s, 9H),
0.90-1.85 (m, 13H).
Example 127 methyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3- phenylpropanoate hydrochloride
The product of example 23 A and phenylalanine methyl ester were processed as in example 101 to provide the title compound. MS (APCI) m/e 363 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.23 (m, 5H), 4.74 (m, IH), 4.17 (d, IH), 3.73 (s, 3H),
3.47 (m, IH), 3.01-3.25 (m, 2H), 0.70-1.78 (m, 13H).
Example 128 methyl (2RS,3R,2'S)-2-((3-amino-4-cvclohexyl-2-hydroxybutanoyl)amino)-3- methylpentanoate hydrochloride
The product of example 23A and L-isoleucine methyl ester were processed as in example 101 to provide the title compound.
MS (APCI) m/e 657 (2M+H)+ 1H NMR (300MHz, MeOH-d4) δ 4.41 (m, 2H), 4.33 (d, IH), 4.17 (m, IH), 3.95 (s, 3H),
3.73 (d, 2H), 0.90-1.78 (m, 22H).
Example 129 methyl (2RS.3R.2'S)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)hexanoate hydrochloride
The product of example 23A and L-norleucine methyl ester were processed as in example 101 to provide the title compound.
MS (APCI) m/e 657 (2M+H)+
1H NMR (300MHz, MeOH-d4) δ 4.44 (m, IH), 4.13 (d, IH), 3.74 (s, 3H), 3.45 (m, IH), 0.90-1.82 (m, 22H).
Example 130 methyl (2RS.3R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3-methylbutanoate hydrochloride The product of example 23A and L-valine methyl ester were processed as in example 101 to provide the title compound.
MS (APCI) m/e 315 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 4.36 (d, 2H), 4.05 (d, IH), 3.72 (s, 3H), 2.20 (m, 2H),
0.98 (s, 3H), 0.96 (s, 3H), 0.87-1.84 (m, 13H).
Example 131 f2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-('('lS)-l-(2-naphthvDethyl)butanamide The product of example 23 A and (S)-l -amino- l-(2-naphthyl)ethane were processed as in example 24 to provide the title compound. MS (ESI) m e 355 (M+H)+;
!H NMR (300 MHz, DMSO-d6) δ 8.63 (d, IH), 7.88 (m, 2H), 7.78 (m, 3H), 7.54 (dd, IH), 7.48 (m, 2H), 6.46 (d, IH), 5.13 (m, IH), 4.02 (m, IH), 3.28 (m, IH), 1.58 (m, 2H), 1.52 (d, 3H), 1.38-1.06 (m, 9H), 0.77 (m, IH), 0.63 (m, IH); Anal, calcd for C22H30N2O2SΗCI: C, 67.59; H, 7.99; N, 7.17. Found: C, 67.42; H,
8.03; N, 7.08.
Example 132 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(Y 1 R)- 1 -(2-naphthyl)ethyl)butanamide hydrochloride The product of example 23A and (R)-l-amino-l-(2-naρhthyl)ethane were processed as in example 24 to provide the title compound. MS (ESI) m/e 355 (M+H)+; !H NMR (300 MHz, DMSO-d6) δ 8.67 (d, IH), 7.83 (m, 5H), 7.56 (dd, IH), 7.48 (m,
2H), 6.49 (d, IH), 5.13 (m, IH), 4.09 (t, IH), 3.28 (m, IH), 1.58 (m, 2H), 1.50 (d, 3H), 1.38-1.06 (m, 9H), 0.77 (m, IH), 0.63 (m, IH).
Example 133 (2RS.3R -3-amino-4-cvclohexyl-2-hvdroxy-N-f(lS)-l-(l-naphthvDethyl)butanamide hydrochloride The product of example 23A and (S)-l-amino-l-(l-naphthyl)ethane were processed as in example 24 to provide the title compound. MS (ESI) m/e 355 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, IH), 8.13 (d, IH), 7.94 (dd, IH), 7.81 (m,
3H), 7.60 (d, IH), 7.52 (m, 2H), 6.47 (d, IH), 5.77 (m, IH), 3.99 (t, IH), 3.23 (m, IH), 1.61 (m, 2H), 1.57 (d, 3H), 1.38-1.11 (m, 9H), 0.78-0.60 (m, 2H); Anal, calcd for C22H3θN2θ2S»HCl: C, 67.59; H, 7.99; N, 7.17. Found: C, 67.25; H,
7.92; N, 6.96.
Example 134 (2RS,3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(Y 1 R)- 1 -f 1 -naphthvDethvDbutanamide hydrochloride
The product of example 23A and (R)-l-amino-l-(l-naphthyl)ethane were processed as in example 24 to provide the title compound. MS (ESI) m/e 355 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.71 (d, IH), 8.14 (d, IH), 7.94 (dd, IH), 7.82 (d, IH),
7.79 (bds, 2H), 7.60 (d, IH), 7.52 (m, 2H), 6.43 (d, IH), 5.76 (m, IH), 4.11 (t, IH, J=5 Hz), 3.23 (m, IH), 1.61 (m, 2H), 1.53 (d, 3H), 1.38-1.11 (m, 9H), 0.81 (m, IH), 0.63 (m, IH);
Anal, calcd for C22H3θN2θ2S«HCl«0.33 H2O: C, 66.58; H, 8.04; N, 7.06. Found: C,
66.46; H, 8.07; N, 6.81.
Example 135 ethyl (2RS.3R.2'R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)aminoV3- fluoropropanoate trifluoroacetate
Example 135 A Hδ-fluoro-DL- alanine was processed as in example ID to provide the title compound.
MS (APCI+) m/e 208 (M+H)+.
Example 135B The product of example 135 A was processed as in example 137 A to provide the title compound.
MS (APCI+) m e 236 (M+H)+.
Example 135C The product of example 135B was processed as in example IF to provide the title compound.
MS (APCI+) m/e 136 (M+H)+.
Example 135D The product of example 23 A and the product of example 135C were processed as in example IE to provide the title compound. MS (APCI+) m/e 419 (M+H)+.
Example 135E A solution of example 135D (0.27 g, 0.62 mmol) in dichloromethane (3 mL) containing trifluoroacetic acid (2 mL) was stirred at ambient temperature for 3 hours, evaporated to dryness, suspended in ethyl ether, then concentrated and vacuum dried to give the title compound (0.24 g).
MS (APCI) m/e 336 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 7.75 (m, 2H), 6.43 (m, IH), 6.18 (m, 2H), 5.84 (m, IH), 4.26 (m, IH), 4.13 (m, 3H), 3.38 (m, IH), 1.67 (m, 8H), 1.28 (m, IH), 1.19 (m, 3H), 1.10 (m, 2H).
Example 136 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(2-hydroxy-l- (hvdroxymethyDethvDbutanamide trifluoroacetate
Example 136 A N-(Benzyloxycarbonyl)-O-(t-butyl)-L- Serine was processed as in example 1 A to provide the title compound. MS (ESI+QlMS) m/e 282 (M+H)+
Example 136B The product of example 136 A was processed as in example 106.1 A to provide the title compound. MS (APCI+) m/e 311 (M+H)+
Example 136C The product of example 23 A and the product of example 136B were processed as in examples IE and 135B to provide the title compound. MS (APCI) m/e 275 (M+H)+ ;
*H ΝMR (300 MHz, D2O) δ 7.64 (m, 2H), 6.49 (m, IH), 4.70 (m, IH), 4.04 (m, 2H), H), 3.78 (m, 2H), 3.42 (m, 2H), 3.35 (m, 2H), 1.64 (m, 4H), 1.41 (m, 3H), 1.22 (m, 3H), 0.89 (m, IH).
Example 137 4-(tert-butvI)benzvH2RS.3R.2'R)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3- hydroxypropanoate trifluoroacetate
Example 137 A
A solution of N-(t-butyloxycarbonyl)-O-(t-b«ty/)-L- Serine (0.54 g, 2.1 mmol) and DCC (0.47g, 2.2mmol) in CH2C12 (5 mL) was stirred at 0 °C for 15 minutes, treated with para-t-bxityl benzyl alcohol (0.33 g, 2.0 mmol) and catalytic DMAP and stirred for 16 hours. The solution was evaporated to dryness and the residue was purified by flash chromatography on silica gel with 5% ethyl acetate/toluene to provide the designated compound (0.49g). MS (APCI+) m/e 311 (M+H)+
Example 137B The product of example 137 A was processed as in examples IF, IE, and 135B to provide the title compound. MS (APCI) m/e 435 (M+H)+ ;
*H NMR (300 MHz, D2O) δ 7.72 (m, 2H), 7.41 (m, 3H), 7.28 (m, IH), 5.40 (s, 2H), 5.14 (m, 2H), 4.89 (m, IH), 4.70 (m, 2H), 4.12 (m, IH), 3.76 (m, IH), 1.64 (m, 6H), 1.42 (m, 2H), 1.28 (s, 9H), 1.14 (m, IH), 0.84 (m, 2H).
Example 138
4-nitrobenzyl (2RS,3R.2'S)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3- hydroxypropanoate trifluoroacetate
Example 138A N-BOC-O-(t-Butyl)-L- Serine and 4-nitro-benzyl alcohol were processed as in example 137 A to provide the title compound.
Example 138B The product of example 23 A and the product of example 138 were processed as in example 138B to provide the title compound. MS (APCI) m/e 424 (M+H)+;
*H ΝMR (300 MHz, DMSO-d6) δ 8.86 (m, IH), 8.23 (d, 2H), 7.67 (m, IH), 7.63 (d, 2H), 5.32 (s, 2H), 4.93 (m, IH), 4.76 (m, 2H), 4.48 (m, IH), 4.13 (m, IH), 3.78 (m, 2H), 1.62 (m, 6H), 1.40 (m, 2H), 1.18 (m, 3H).
Example 139 3-nitrobenzyl (2RS.3R.2'S)-2-((3-amino-4-cvclohexyl-2-hvdroxybutanoyl)amino)-3- hydroxypropanoate trifluoroacetate N-BOC-O-(t-Butyl)-L-Serine and 3-nitro-benzyl alcohol were processed as in examples 137 A and 137B to provide the title compound. MS (APCI) m/e 424 (M+H)+; iH NMR (300 MHz, DMSO-d6) δ 8.80 (m, IH), 8.24 (m, IH), 7.86 (m, IH), 7.70 (m, 2H), 5.32 (m, 2H), 4.91 (m, IH), 4.74 (m, 2H), 4.13 (m, IH), 3.32 (m, 2H), 1.63 (m, 6H), 1.40 (m, 2H), 1.15 (m, 2H) 0.80 (m, IH).
Example 140
4- rifluoromethyl)benzvU2RS.3R.2'S)-2-((3-amino-4-cvclohexyl-2- hydroxybutanoyl)amino)-3-hvdroxypropanoate trifluoroacetate N-BOC-O-(t-Butyl)-L-Serine and 4-(trifluoromethyl)benzyl alcohol were processed as in examples 137 A and 137B to provide the title compound. MS (APCI) m/e 447 (M+H)+; lH NMR (300 MHz, DMSO-d6) δ 8.82 (m, IH), 7.74 (m, 3H), 7.58 (m, IH), 5.28 (s, 2H),
4.91 (m, IH), 4.48 (m, IH), 4.23 (m, 2H), 4.21 (m, IH), 3.83 (m, 2H), 1.65 (m, 6H), 1.40 (m, 2H), 1.18 (m, 2H), 0.79 (m, IH).
Example 141
3-αrifluoromethoxy)benzvH2RS.3R.2'SV2-((3-amino-4-cvclohexyl-2- hvdroxybutanoyl)amino)-3-hvdroxypropanoate trifluoroacetate N-BOC-O-(t-Butyl)-L-Serine and 3-(trifluoromethoxy)benzyl alcohol were processed as in examples 137 A and 137B to provide the title compound. MS (APCI) m/e 463 (M+H)+;
*H NMR (300 MHz, DMSO-d6) δ 8.78 (m, IH), 7.73 (m, 2H), 7.50 (m, IH), 7.37 (m,
3H), 5.24 (m, 2H), 4.90 (m, IH), 4.83 (m, 2H), 4.11 (m, IH), 4.05 (m, IH), 3.99 (m, 2H), 1.62 (m, 6H), 1.40 (m, 2H), 1.15 (m, 2H), 0.82 (m, IH).
Example 142
(2RS.3R)-3-amino-4-cvclohexyI-N-(4-fluorophenethyl)-2-hydroxybutanamide hydrochloride
The product of example 23A and4-fluoro phenethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 323 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 7.25 (m, 2H), 7.00 (m, 2H), 4.10 (d, IH), 3.60 (m,
2H),3.40 (m, 2H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 143 (2RS.3R)-3-amino-4-cvclohexyI-2-hvdroxy-N-(4-methylphenyl)butanamide
The product of example 23 A and -toluidine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 291 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.52 (d, 2H), 7.16 (d, 2H), 4.28 (d, IH), 3.65 (m, IH),
2.31 (s, 3H), 0.92-1.86 (m, 13H).
Example 144
(2RS,3R)-3-amino-4-cvclohexyl-N-(4-fluorophenyl)-2-hvdroxybutanamide The product of example 23 A and 4-fluoroaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 295 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.65 (q, 2H), 7.07 (t, 2H), 4.29 (d, IH), 3.74 (m, IH),
0.92-1.88 (m, 13H).
Example 145
(2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(4-methoxyphenyl)butanamide
The product of example 23 A and p-anisidine were processed as in example 101 to provide the title compound. MS (APCI) m/e 307 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.54 (d, 2H), 6.90 (d, 2H), 4.29 (d, IH), 3.80 (s, 3H),
3.67 (m, IH), 0.92-1.88 (m, 13H).
Example 146 (2RS,3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(2-methoxyphenyl)butanamide
The product of example 23 A and o-anisidine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 307 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.28 (dd, IH), 7.03-7.15 (m, 2H), 6.94 (td, IH), 4.34 (d, IH), 3.91 (s, 3H), 3.77 (m, IH), 0.96-1.89 (m, 13H).
Example 147 (2RS.3R)-3-amino-N-(4-chlorophenyl)-4-cvclohexyl-2-hvdroxybutanamide The product of example 23A and 4-chloroaniline were processed asάn example 101 to provide the title compound. MS (APCI) m/e 311 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.67 (d, 2H), 7.33 (d, 2H), 4.30 (d, 2H), 3.74 (m, IH), 0.92-1.86 (m, 13H).
Example 148 (2RS.3R)-3-amino-N-(3-chlorophenyl)-4-cvclohexyl-2-hvdroxybutanamide
The product of example 23 A and 3-chloroaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 311 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.87 (t, IH), 7.15 (qd, IH), 7.32 (t, IH), 7.14 (qd, IH), 4.31 (d, IH), 3.73 (m, IH), 0.93-1.87 (m, 13H).
Example 149
(2RS.3R)-3-amino-N-(2-chlorophenyl)-4-cyclohexyl-2-hvdroxybutanamide
The product of example 23A and 2-chloroaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 311 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.33 (dd, IH), 7.48 (dd, IH), 7.34 (dt, IH), 7.16 (dt,
IH), 4.40 (d, IH), 3.80 (m, IH), 2.69 (s, IH), 0.96-1.88 (m, 13H).
Example 150
(2RS.3R)-3-amino-N-(4-(tert-butyl)phenyl)-4-cvclohexyl-2-hvdroxybutanamide
The product of example 23A and 4-tert-butylaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 333 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.57 (d, 2H), 7.54 (d, 2H), 4.28 (d, IH), 3.72 (m, IH),
1.33 (s, 9H), 0.92-1.88 (m, 13H).
Example 151
(2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(trifluoromethyl)phenyl)butanamide The product of example 23 A and 3-(trifluoromethyl)aniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 345 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.16 (s, IH), 7.86 (d, IH), 7.54 (t, IH), 7.43 (d, IH),
4.33 (d, IH), 3.77 (m, IH), 0.93-1.87 (m, 13H).
Example 152 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(trifluoromethyl)phenyl)butanamide
The product of example 23 A and 4-(trifluoromethyl)aniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 345 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.89 (d, 2H), 7.64 (d, 2H), 4.34 (d, IH), 3.74 (m, IH),
0.95-1.87 (m, 13H).
Example 153
(2RS.3R)-3-amino-4-cvclohexyl-N-(3,4-dichlorophenyl)-2-hydroxybutan amide The product of example 23A and 3,4-dichloroaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 345 (M)+
1H NMR (300MHz, MeOH-d4) δ 8.04 (d, IH), 7.55 (dd, IH), 7.47 (d, IH), 4.32 (d, IH),
3.75 (m, IH), 0.92-1.83 (m, 13H).
Example 154 (2RS.3R)-3-amino-4-cvclohexyl-N-(2,4-dichIorophenvI)-2-hvdroxybutanamide The product of example 23 A and 2,4-dichloroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 345 (M)+
1H NMR (300MHz, MeOH-d4) δ 8.32 (d, IH), 7.55 (d, IH), 7.37 (dd, IH), 4.40 (d, IH),
3.66 (m, IH), 0.95-1.87 (m, 13H).
Example 155 (2RS.3R)-3-amino-N-(4-bromophenyl)-4-cvclohexyl-2-hvdroxybutanamide
The product of example 23 A and 4-bromoaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 356 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.62 (d, 2H), 7.47 (d, 2H), 4.30 (d, IH), 3.73 (m, IH), 0.92-1.85 (m, 13H).
Example 156 (2RS.3R)-3-amino-N-(4-(tert-butyl)benzyl)-4-cvclohexyl-2-hvdroxybutanamide The product of example 23A and 4-tertbutylbenzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 347 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.35 (d, 2H), 7.24 (d, 2H), 4.39 (q, 2H), 4.16 (d, IH), 3.58 (m, IH), 1.39 (s, 9H), 0.87-1.80 (m, 13H).
Example 157 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(trifluoromethyl)benzyl)butanamide
The product of example 23A and 3-(trifluoromethyl)benzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 359 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.64 (s, IH), 7.57 (m, 3H), 4.50 (q, 2H), 4.20 (d, IH), 3.58 (m, IH), 0.82-1.80 (m, 13H).
Example 158 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(trifluoromethyl)benzyl)butanamide The product of example 23 A and 4-(trifluoromethyl)benzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 359 (M+H)+ 'H NMR (300MHz, MeOH-d4) δ 7.63 (d, 2H), 7.51 (d, 2H), 4.50 (q, 2H), 4.20 (d, IH),
3.62 (m, IH), 0.86-1.80 (m, 13H).
Example 159
(2RS,3R)-3-amino-N-(2-chlorobenzyl)-4-cvclohexyl-2-hvdroxybutanamide The product of example 23A and 3-chlorobenzylamine were processed as in . example 101 to provide the title compound. MS (APCI) m/e 325 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.40 (m, 2H), 7.27 (m, 2H), 4.55 (q, 2H), 4.22 (d, IH),
3.61 (m, IH), 0.88-1.81 (m, 13H).
Example 160 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(2-methoxy-5-nitrophenyl)butan amide hydrochloride
The product of example 23A and 2-methoxy-5-nitroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 352 (M+H)+; !H NMR (300 MHz, MeOH-d4) δ 9.30 (d, 0.5H), 8.10 (m, IH), 7.25 (d, IH), 4.40 (d, IH), 4.08 (s, 3H), 3.82 (m, IH), 3.75 (m, IH), 3.65 (m, IH), 3.58 (m, IH), 1.75 (m, 5H), 1.40 (m, 6H), 1.05 (m, 2H). Example 161
(2RS.3R)-3-amino-4-cvclohexyl-N-(3.5-dimethoxyphenyl)-2-hvdroxybutanamide hydrochloride
The product of example 23A and 3,5-dimethoxyaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 337 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 6.92 (d, 2H), 6.60 (t, IH), 4.28 (d, IH), 3.78 (s, 6H),
3.73 (m, IH), 3.65 (m, IH), 3.58 (m, IH), 1.75 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).
Example 162 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-G-phenoxyphenyl)butanamide hydrochloride
The product of example 23 A and 3-phenoxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 369 (M+H)+;
!H NMR (300 MHz, MeOH-d4) δ 7.40 (m, 5H), 7.10 (m, 4H), 6.75 (m, IH), 4.28 (d, IH),
3.72 (m, IH), 3.66 (m, 2H), 3.58 (m, IH), 1.75 (m, 5H), 1.50 (m, 2H), 1.30 (m, 4H), 1.00 (m, 2H).
Example 163
(((2RS,3R)-3-amino-4-cyclohexyl-2-hvdroxybutanoyl)amino)(2.5- dimethoxybenzyPchloronium hydrochloride The product of example 23A and 2,5-dimethoxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 365 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 6.42 (d, 2H), 6.35 (t, IH), 4.11 (d, IH), 3.75 (s, 6H),
3.65 (m, IH), 3.55 ( , 2H), 3.40 (m, IH), 2.78 (t, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.90 ( m, 2H).
Example 164
(2RS.3R)-3-amino-4-cvclohexyl-N-(2.4-dichlorophenethyl)-2-hydroxybutanamide hydrochloride The product of example 23A and 2,4-dichloro phenethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 373 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 7.45 (d, IH), 7.30 (m, 2H), 4.00 (d, IH), 3.60 (m, 2H),
3.45 (m, 2H), 3.00 (m, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H). Example 165 f2RS.3R)-3-amino-4-cvclohexyl-N-(2,6-dichlorophenethyl)-2-hvdroxybutønamide hydrochloride The product of example 23 A and 2,6-dichloroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 373 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.38 (d, 2H), 7.20 (t, IH), 4.10 (d, IH), 3.60 (m, 3H),
3.40 (m, IH), 3.25 (m, 2H), 1.75 (m, 7H), 1.45 (m, 2H), 1.30 (m, 2H), 1.00 (m, 2H).
Example 166
(2RS,3R)-3-amino-4-cvclohexyl-N-(3-fluorophenethyl)-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 3-fluorophenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 323 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 7.30 (m, IH), 7.00 (m, 3H), 4.10 (d, IH), 3.65 (m, IH),
3.58 (m, 2H), 3.40 (m, IH), 2.85 (t, 2H), 1.75 (m, 5H), 1.60 (m, 2H), 1.45 (m, 2H), 1.28 (m, 2H), 0.95 (m, 2H).
Example 167 (2RS.3R)-3-amino-N-(3.4-bis(benzyloxy)phenethyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride The product of example 23 A and 3,4-dibenzyloxy phenethylamine were processed as in example 101 to provide the title compound. MS (APCI) m e 517 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.45 (t, 5H), 7.35 (m, 5H), 6.95 (m, 2H), 8.78 (d, IH),
5.10 (d, 4H), 4.10 (d, IH), 3.65 (m, IH), 3.55 (m, 2H), 3.40 (m, IH), 2.75 (m, 2H), 1.75 (m, 5H), 1.60 (m, 2H), 1.40 (m, 4H), 0.90 (m, 2H).
Example 168 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-phenoxyphenethyl)butanamide hydrochloride The product of example 23 A and 4-phenoxy phenethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 397 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.35 (t, 2H), 7.25 (d, 2H), 7.08 (t, IH), 6.95 (t, 4H), 4.12 (d, IH), 3.65 (m, 4H), 2.85 (m, 2H), 1.75 (m, 5H), 1.50 (m, 6H), 0.95 (m, 2H).
Example 169 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(2-(trifluoromethoxy)phenyl)butan amide hydrochloride The product of example 23A and 2-(trifluoromethoxy)aniline were processed as in example 101 to provide the title compound. MS (APCI) m e 361 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.34 (dd, IH), 7.38 (dt, 2H), 7.26 (dt, IH), 4.39 (d, IH),
3.78 (m, IH), 0.94-1.86 (m, 13H).
Example 170 (2RS,3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(trifluoromethoxy)phenyl)butanamide hydrochloride
The product of example 23A and 3-(trfluoromethoxy)aniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 361 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.85 (s, IH), 7.57 (qd, IH), 7.43 (t, IH), 7.05 (td, IH), 4.33 (d, IH), 3.76 (m, IH), 0.91-1.87 (m, 13H).
Example 171 (2RS,3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(2-methylphenyl)butanamide hydrochloride The product of example 23 A and ø-anisidine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 291 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.68 (dd, IH), 7.22 (dq, 2H), 7.13 (dq, IH), 4.37 (d,
IH), 3.74 (m, IH), 2.30 (s, 3H), 0.94-1.88 (m, 13H).
Example 172
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dimethylphenyl)-2-hvdroxybutanamide hydrochloride The product of example 23 A and 2,6-dimethylaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 305 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.14 (s, 3H), 4.38 (d, IH), 3.61 (m, IH), 2.24 (s, 6H), 0.89-1.89 (m, 13H).
Example 173 (2RS,3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(4-iodo-2-methylphenyl)butanamide hydrochloride The product of example 23A and 2-methyl-4-iodoaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 416 (M)+ 1H NMR (300MHz, MeOH-d4) δ 8.16 (d, IH), 7.47 (dd, IH), 7.03 (d, IH), 4.38 (d, IH),
3.74 (m, IH), 2.25 (s, 3H), 0.91-1.86 (m, 13H).
Example 174 (2RS.3R)-3-amino-N-(4-anilino-2-methoxyphenyl)-4-cvclohexyl-2-hydroxybutanamide hydrochloride
The product of example 23 A and l-amino-2-methoxy-4-(N-phenylamino)benzene were processed as in example 101 to provide the title compound. MS (APCI) m/e 398 (M+H)+ 1H ΝMR (300MHz, MeOH-d4) δ 8.05 (d, IH), 7.24 (t, 2H), 7.10 (d, 2H), 6.88 (m, IH), 6.78 (d, IH), 6.70 (dd, IH), 4.32 (d, IH), 3.76 (s, 3H), 3.74 (m, IH), 0.85-1.89 (m, 13H).
Example 175 (2RS.3R)-3-amino-4-cvclohexyl-Ν-(2-ethoxyphenyl)-2-hydroxybutanamide hydrochloride The product of example 23 A and 2-ethyoxyaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.30 (dd, IH), 7.09 (dt, IH), 7.03 (t, IH), 6.93 (dt, IH),
4.34 (d, IH), 4.14 (q, 2H), 3.79 (m, IH), 1.45 (t, 3H), 0.92-1.88 (m, 13H).
Example 176
(2RS.3R)-3-amino-N-(4-chloro-2-methoxy-5-methylphenyl)-4-cvclohexyl-2- hydroxybutanamide hydrochloride The product of example 23 A and 2-methoxy-4-chloro-5-toluidine were processed as in example 101 to provide the title compound. MS (APCI) m/e 355 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.24 (s, IH), 7.05 (s, IH), 4.34 (d, IH), 3.89 (s, 3H), 3.78 (m, IH), 2.30 (s, 3H), 0.94-1.89 (m, 13H).
Example 177 (2RS.3R)-3-amino-4-cvclohexyl-N-(2.5-dimethoxyphenyl)-2-hvdroxybutanamide hydrochloride The product of example 23A and 2,5-dimethoxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 337 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.00 (d, IH), 6.95 (d, IH), 6.67 (dd, IH), 4.34 (d, IH),
3.86 (s, 3H), 3.79 (m, IH), 3.75 (s, 3H), 0.94-1.86 (m, 13H).
Example 178 (2RS.3R)-N-(5-(acetylamino)-2-methoxyphenvI)-3-amino-4-cvclohexyl-2- hydroxybutanamide hydrochloride
The product of example 23 A and l-amino-2-methoxy-4-(N-acetylamino)benzene were processed as in example 101 to provide the title compound.
1H ΝMR (300MHz, MeOH-d4) δ 8.00 (d, IH), 7.54 (d, IH), 7.44 (dt, IH), 7.42 (td, IH),
4.48 (d, IH), 4.41 (d, IH), 4.06 (s, 3H), 3.83 (m, IH), 3.15 (s, 3H), 0.89-1.88 (m, 13H).
Example 179
(2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-Ν-(2-methoxydibenzo(b.d)furan-3- vDbutanamide hydrochloride
The product of example 23A and 3-amino-2-methoxydibenzofuran were processed as in example 101 to provide the title compound.
MS (APCI) m/e 397 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.67 (s, IH), 7.98 (qd, IH), 7.69 (s, IH), 7.54 (q, IH),
7.43 (qd, IH), 7.43 (dt, IH), 4.41 (d, IH), 4.06 (s, 3H), 3.84 (m, IH), 0.98-1.90 (m, 13H).
Example 180
(2RS.3R)-3-amino-N-(5-chloro-2.4-dimethoxyphenyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride The product of example 23A and 2,4-dimethoxy-5-chloroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 371 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.29 (s, IH), 6.80 (s, IH), 4.33 (d, IH), 3.95 (s, 3H), 3.90 (s, 3H), 3.74 (m, IH), 0.82-1.88 (m, 13H).
Example 181 (2RS.3R)-3-amino-4-cvclohexyl-N-(2.5-diethoxyphenyl)-2-hvdroxybutanamide hydrochloride The product of example 23 A and 2,5-diethoxyaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 365 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.00 (d, IH), 6.92 (d, IH), 6.63 (dd, IH), 4.34 (d, IH),
4.09 (q, 2H), 4.01 (q, 2H), 3.81 (m, IH), 1.42 (t, 3H), 1.36 (t, 3H), 0.93-1.89 (m, 13H).
Example 182 (2RS.3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23A and 32-methoxy-5-tert-butylaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 363 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.42 (d, IH), 7.15 (dd, IH), 6.95 (d, IH), 4.34 (d, IH), 3.89 (s, 3H), 3.76 (m, IH), 1.30 (s, 9H), 0.93-1.89 (m, 13H).
Example 183 (2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(2-phenoxyphenyl)butanamide hydrochloride The product of example 23A and 2-phenoxyaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 369 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.35 (dd, IH), 7.37 (m, 2H), 7.14 (m, 3H), 7.02 (m, 2H),
6.92 (d, IH), 4.31 (d, IH), 3.71 (m, IH), 0.89-1.81 (m, 13H).
Example 184
(2RS,3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(2-methyl-5-nitrophenyl)butanamide hydrochloride The product of example 23A and 2-methyl-5-nitroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 336 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.77 (d, IH), 8.00 (dd, IH), 7.50 (d, IH), 4.44 (d, IH), 3.79 (m, IH), 3.19 (d, IH), 3.06 (d, IH), 2.42 (s, 3H), 0.82-1.88 (m, 13H).
Example 185 (2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(4-phenoxyphenyl)butanamide hydrochloride
The product of example 23A and 4-phenoxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 369 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.63 (d, 2H), 7.34 (t, 2H), 7.09 (t, IH), 6.96 (d, 3H), 4.20 (d, IH), 3.58 (m, IH), 0.93-1.91 (m, 13H).
Example 186
(2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-methoxybenzyl)butanamide hydrochloride
The product of example 23A and 4-methoxybenzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.25 (d, 2H), 6.87 (d, 2H), 4.35 (q, 2H), 4.15 (d, IH),
3.77 (s, 3H), 3.57 (m, IH), 0.85-1.78 (m, 13H).
Example 187
(2RS.3R)-3-amino-4-cvclohexyI-2-hydroxy-N-(4-methylbenzyl)butanamide hydrochloride
The product of example 23A and 4-methylbenzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m e 305 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.20 (d, 2H), 7.12 (d, 2H), 4.38 (q, 2H), 4.11 (d, IH),
3.53 (m, IH), 2.30 (s, 3H), 0.86-1.80 (m, 13H).
Example 188
(2RS3R)-3-amino-N-(3-chlorobenzyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride The product of example 23A and 3-chlorobenzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 325 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.34 (s, IH), 7.26 (m, 3H), 4.41 (q, 2H), 4.17 (d, IH),
3.55 (m, IH), 0.87-1.80 (m, 13H).
Example 189 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-methoxybenzyl)butanamide hydrochloride
The product of example 23A and 3-methoxybenzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.22 (t, IH), 6.88 (m, 2H), 6.80 (m, IH), 4.38 (q, 2H),
3.99 (d, IH), 3.77 (s, 3H), 0.82-1.80 (m, 13H).
Example 190
(2RS.3R)-3-amino-N-(4-bromobenzyl)-4-cyclohexyl-2-hvdroxybutanamide hydrochloride The product of example 23 A and 4-bromo benzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 371 (M+H)+ ; lH NMR (300 MHz, MeOH-d4) δ 7.40 (d, 2H), 7.25 (d, 2H), 4.45 (d, IH), 4.37 (d, IH),
4.02 (d, IH), 3.35 (m, 2H),1:70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 191
(2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-methylbenzyl)butanamide hydrochloride
The product of example 23 A and 3-methyl benzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 305 (M+H)+; H NMR (300 MHz, MeOH-d4) δ 7.25 (m, 4H), 4.90 (d, IH), 4.30 (d, IH), 4.12 (d, IH),
3.55 (m, 2H), 2.35 (s, 3H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H)..
Example 192 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-phenethylbutanamide hydrochloride
The product of example 23A and phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 305 (M+H)+; lH NMR (300 MHz, MeOH-d4)δ 7.25 (m, 5H), 4.00 (d, IH), 3.50 (m, 4H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 193 (2RS.3R)-3-amino-N-(4-chlorobenzyl)-4-cvclohexyl-2-hydroxybutanamide hydrochloride The product of example 23A and 4-chlorobenzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 325 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.32 (s, 4H), 4.40 (q, 2H), 4.18 (d, IH), 3.59 (m, IH), 0.87-1.80 (m, 13H).
Example 194 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-methylphenethyl)butanamide hydrochloride The product of example 23 A and 3-methyl phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 319 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.10 (s, 4H), 4.05 (d, IH), 3.50 (m, 4H), 2.80 (t, 2H),
2.30 (s, 3H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 195 (2RS,3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(4-methoxyphenethyl)butanamide hydrochloride
The product of example 23 A and 4-methoxy phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m e 335 (M+H), 669 (2M+H)+;
!H NMR (300 MHz, MeOH-d4) δ 7.15 (d, 2H), 6.80 (d, 2H), 4.05 (d, IH), 3.75 (s, 3H), 3.50 (m, 2H), 3.40 (m, 2H), 2.78 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 196
(2RS.3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenethyI)butanamide hydrochloride The product of example 23A and 3-methoxy phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+; H NMR (300 MHz, MeOH-d4) δ 7.15 (d, 2H), 6.85 (d, 2H), 4.05 (d, IH), 3.75 (d, 3H),
3.45 (m, 4H), 2.78 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 197 (2RS,3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(2-methoxyphenethyl)butanamide hydrochloride The product of example 23A and 2-methoxy phenethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 335 (M+H)+; !H NMR (300 MHz, MeOH-d4) δ 7.19 (m, 2H), 6.90 (m, 2H), 4.05 (d, IH), 3.85 (s, 3H), 3.45 (m, 4H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 198 (2RS.3R)-3-amino-N-(4-chlorophenethyl)-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 4-chloro phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.25 (m, 4H), 3.92 (d, IH), 3.48 (m, 4H), 2.82 (t, 2H),
1.71 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 199
(2RS.3R)-3-amino-N-(3-chlorophenethyl)-4-cvclohexyl-2-hydroxybutanamide hydrochloride
The product of example 23 A and 3-chloro phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 339 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 7.25 (m, 4H), 4.05 (d, IH), 3.55 (m, 2H), 3.45 (m, 2H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 200
(2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(3-(trifluoromethyl)phenethyl)butanamide hydrochloride The product of example 23A and 3-trifluoromethyl phenethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 373 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.55 (m, 4H), 4.05 (d, IH), 3.6 (m, 2H), 3.45 (m, 2H),
2.95 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 201 (2RS.3R)-3-amino-N-(4-bromophenethyl)-4-cvclohexyl-2-hydroxybutanamide hydrochloride The product of example 23 A and 4-bromo phenethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 385 (M+H)+; !H NMR (300 MHz, MeOH-d4) δ 7.41 (d, 2H), 7.16 (d, 2H), 3.90 (d, IH), 3.50 (m, 4H), 2.80 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 202 (2RS.3R)-N-(l-adamantyl)-3-amino-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 1-adamantanamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 335 (M+H)+; !H NMR (300 MHz, MeOH-d4) δ 3.95 (d, IH), 3.45 (m, 2H), 2.09 (s, 10H), 1.75 (s, 10H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 203 (2RS.3R)-N-(2-adamantyl)-3-amino-4-cvclohexyl-2-hvdroxybutanamide hydrochloride The product of example 23 A and 2-adamantamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 335 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 4.15 (d, IH), 4.00 (s, IH), 3.55 (m, 2H), 1.80 (m, 19H),
1.40 (m, 6H), 0.90 (m, 2H).
Example 204
(2RS.3R)-3-amino-N-cvcloheptyl-4-cvclohexyl-2-hydroxybutanamide hydrochloride The product of example 23 A and cycloheptylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 297 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 4.00 (d, IH), 3.90 (m, IH), 3.41 (m, 2H), 1.50 (m,
23H), 0.90 (m, 2H).
Example 205 (2RS.3R)-3-amino-4-cvclohexyl-N-(cvclohexylmethyl)-2-hvdroxybutanamide hydrochloride
The product of example 23 A and cyclohexylmethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 297 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 4.02 (d, IH), 3.40 (m, 2H), 3.15 (m, IH), 3.00 (m, IH), 1.50 (m, 24H). Example 206
(2RS.3R)-3-amino-N.4-dicvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23A and cyclohexylamine were processed as in example
101 to provide the title compound. MS (APCI) m/e 283 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 4.05 (d, IH), 3.70 (m, IH), 3.45 (m, 2H), 1.50 (m,
21H), 0.90 (m, 2H).
Example 207 (2RS.3R)-3-amino-4-cvcIohexyl-N-cvclopentyl-2-hvdroxybutanamide hydrochloride
The product of example 23 A and cyclopentylamine were processed as in example
101 to provide the title compound.
MS (APCI) m/e 269 (M+H)+; iH NMR (300 MHz, MeOH-d4) δ 4.15 (m, IH), 3.95 (d, IH), 3.35 (m, 2H), 1.50 (m, 19H), 0.90 (m, 2H).
Example 208
(2RS.3R)-3-amino-N-cvclobutyl-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23 A and cyclobutylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 255 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 4.35 (m, IH), 4.00 (d, IH), 3.45 (m, IH), 2.30 (m, 2H),
2.05 (m, 2H), 1.75 (m, 7H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 209
(2RS ,3R)-3-amino-4-cvclohexyl-2-h vdroxy-N-( 1 -methyl-3-phenylpropyl)butanamide hydrochloride The product of example 23 A and 4-phenyl-2-aminopropane were processed as in example 101 to provide the title compound. MS (ESI) m/e 333 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.40 (m, 5H), 4.10 (d, IH), 3.90 (m, IH), 3.75 (m, IH),
3.68 (m, IH), 3.55 (m, 2H), 2.65 (m, 2H), 1.75 (m, 7H), 1.45 (m, 2H), 1.20 (m, 5H), 0.90 (m, 2H).
Example 210 ('2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(l-methyl-2-G- (trifluoromethvDphenvDethvDbutanamide hydrochloride The product of example 23A and 3(3-triflouromethylphenyl)-2-aminopropane were processed as in example 101 to provide the title compound. MS (APCI) m/e 387 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.50 (m, 4H), 4.25 (m, 2H), 4.10 (d, IH), 4.00 (d, IH),
3.50 (m, 2H), 3.00 (m, IH), 2.90 (m, 2H), 1.75 (m, 5H), 1.30 (m, 9H), 0.90 (m, 2H).
Example 211 (2RS.3R)-3-amino-4-cvclohexyl-N-(1.5-dimethylhexyl)-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 1,5-dimethylhexylamine were processed as in example 101 to provide the title compound.
MS (ESI) m/e 313 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 4.10 (m, IH), 3.95 (m, IH), 3.55 (m, 2H), 1.75 (m,
7H), 1.25 (m, 7H), 1.00 (m, 2H), 0.80 (m, 6H).
Example 212 (2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(l-methylhexyl)butanamide hydrochloride The product of example 23 A and 1-methylhexylamine were processed as in example
101 to provide the title compound. MS (ESI) m/e 299 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 4.10 (d, IH), 3.95 (m, IH), 3.55 (m, 2H), 1.75 (m, 8H),
1.45 (m, 2H), 1.35 (m, 8H), 1.15 (m, 4H), 0.80 (m, 5H).
Example 213
(2RS,3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-isopropoxypropyI)butanamide hydrochloride
The product of example 23A and 3-isopropoxypropylamine were processed as in example 101 to provide the title compound.
MS (ESI) m/e 301 (M+H)+; H NMR (300 MHz, MeOH-d4) δ 4.15 (d, IH), 3.60 (m, 2H), 3.55 (m, 4H), 1.75 (m, 6H),
1.40 (m, 8H), 1.15 (d, 6H), 1.00 (m, 2H).
Example 214 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-isobutoxypropyl)butanamide hydrochloride
The product of example 23A and 3-isobutoxypropylamine were processed as in example 101 to provide the title compound. MS (ESI) m e 315 (M+H)+;
!H NMR (300 MHz, MeOH-d4) δ 4.15 (d, IH), 3.62 (m, IH), 3.50 (t, 2H), 3.40 (m, IH),
3.20 (d, 2H), 1.80 (m, 9H), 1.45 (m, 2H), 1.30 (m, 3H), 0.90 (m, 10H).
Example 215 f2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(4-mo holinyl)phenyl)butanamide hydrochloride The product of example 23 A and 4-morpholinoaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 362 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.85 (d, 2H), 7.60 (d, 2H), 4.32 (d, IH), 4.05 (t, 4H),
3.75 (m, 2H), 3.65 (m, 2H), 3.58 (m, 4H), 1.50 (m, 11H), 1.00 (m, 2H).
Example 216 (2RS,3R)-3-amino-4-cvclohexyl-N-(3,3-diphenylpropyl)-2-hvdroxybutanamide hydrochloride
The product of example 23A and 3,3-diphenylpropylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 395 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.30 (m, 8H), 7.15 (m, 2H), 4.10 (d, IH), 4.00 (t, IH), 3.55 (m, 2H), 3.25 (m, IH), 3.15 (m, IH), 2.30 (q, 2H), 1.75 (m, 7H), 1.45 (m, 2H), 1.25 (m, 2H), 0.90 (m, 2H).
Example 217 (2RS.3R)-3-amino-4-cvclohexyl-N-(1.4-dimethylpentyl)-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 1,4-dimethylpentylamine were processed as in example 101 to provide the title compound. MS (ESI) m/e 299 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 4.10 (m, IH), 3.80 (m, IH), 3.55 (m, IH), 1.75 (m, 6H), 1.50 (m, 5H), 1.20 (m, 8H), 0.90 (m, 8H).
Example 218 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-methyl-N-(l-naphthylmethyl)butanamide hydrochloride The product of example 23 A and N-methyl-N-(l-naphthyl)methyl amine were processed as in example 24 to provide the title compound. MS (ESI) m/e 355 (M+H)+; lH ΝMR (300 MHz, DMSO-d6) δ 7.90 (m, 3H), 7.68 (d, IH), 7.52 (m, 3H), 6.51 (m, IH),
5.08 (dd, 1.2H), 4.96 (dd, 0.8H), 4.45 (m, 0.6H), 4.20 (m, 0.4H), 3.03 (s, 1.8H), 2.98 (s, 1.2H), 1.80 (m, IH), 1.63 (m, 3H), 1.43 (m, 2H), 1.31 (m, 2H), 1.17 (m, 4H), 0.81 (m, 2H); Anal, calcd for C22H3θ 2θ2S-HCW).5C2H8θ: C, 66.27; H, 8.11 ; N, 6.44. Found: C,
65.96; H, 7.82; N, 6.31.
Example 219 (2RS,3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-methyl-N-((TS)-l-(T- naphthvPethvPbutanamide hydrochloride
The product of example 23A and (S)-N-methyl-N-l-(l-naphthyl)ethyl amine were processed as in example 24 to provide the title compound. MS (ESI) m/e 369 (M+H)+; lH ΝMR (300 MHz, DMSO-d6) δ 7.90 (m, 3H), 7.68 (d, IH), 7.52 (m, 3H), 6.43 (m, IH), 4.20 (t, IH), 2.59 (s, 3H), 1.80 (m, IH), 1.63 (m, 3H), 1.53 (d, 3H), 1.43 (m, 2H), 1.31 (m, 2H), 1.17 (m, 4H), 0.81 (m, 2H); Anal, calcd for C23H32Ν2θ2S-HCM).75H2θ: C, 66.01; H, 8.31; N, 6.69. Found: C,
66.25; H, 8.09; N, 6.31.
Example 220
(2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(,2-methoxy-5-
(trifluoromethyDphenvDhutanamide hydrochloride
The product of example 23A and 2-methoxy-5-(trifluoromethoxy)aniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 375 (M+H)+
'H NMR (300MHz, MeOH-d4) δ 8.70 (d, IH), 7.44 (dd, IH), 7.20 (d, IH), 4.35 (d, IH),
4.00 (s, 3H), 3.72 (m, IH), 0.92-1.86 (m, 13H).
Example 221 (2RS.3R)-3-amino-4-cvcIohexyl-2-hvdroxy-N-(4-methoxy(l,r-biphenvP-3-yPbutanamide hydrochloride The product of example 23A and 2-methoxy-5-phenylaniline were processed as in example 101 to provide the title compound. MS (APCI) m e 383 (M+H)+;
1H NMR (300 MHz, MeOH-d4) δ 7.60 (d, 2H), 7.40 (t, 4H), 7.15 (m, IH), 7.05 (d, IH),
4.25 (d, IH), 3.95 (s, 3H), 3.55 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 222 ('2RS.3R)-3-amino-4-cvclohexyl-N-(2.3-dihvdro-1.4-benzodioxin-6-vP-2- hvdroxybutanamide hydrochloride
The product of example 23 A and 3, 4-ethylenedioxy aniline were processed as in example 101 to provide the title compound.
MS (APCI) m e 335 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.25 (s, IH), 7.00 (d, IH), 6.80 (d, IH), 4.25 (m, 5H),
3.70 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).
Example 223
(2RS,3R)-3-amino-N-(3-(benzyloxy)phenvP-4-cvclohexyl-2-hydroxybutanamide hydrochloride
The product of example 23A and 3-benzyloxyaniline were processed as in example
101 to provide the title compound.
MS (APCI) m/e 383 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 7.20 (m, 6H), 6.90 (d, IH), 6.40 (m, 2H), 5.05 (d, 2H), 4.30 (d, IH), 3.70 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).
Example 224 (2RS.3R)-3-amino-4-cvclohexyl-N-(3-ethoxyphenvP-2-hvdroxybutan amide hydrochloride The product of example 23A and 3-ethoxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 321 (M+H)+; iH NMR (300 MHz, MeOH-d4) δ 7.40 (d, IH), 7.20 (m, 2H), 6.70 (d, IH), 4.25 (d, IH),
4.00 (q, 2H), 3.70 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 1.05 (m, 2H).
Example 225 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3.4.5-trimethoxyphenyl)butanamide hydrochloride
The product of example 23 A and 3,4, 5-trimethoxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 367 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.10 (s, 2H), 4.30 (d, IH), 3.80 (m, 11H), 1.80 (m, 5H),
1.50 (m, 2H), 1.30 (m, 4H), 1.00 (m, 2H).
Example 226 (2RS.3R)-3-amino-4-cvclohexyl-N-(2-(2-fluorophenvP-l-methylethyl)-2- hvdroxybutanamide hydrochloride The product of example 23A and 3(2-flourophenyl)-2-aminopropane were processed as in example 101 to provide the title compound. MS (APCI) m/e 337 (M+H)+; lH NMR (300 MHz, DMSO) δ 7.60 (m, IH), 7.30 (m, 2H), 7.10 (m, IH), 4.10 (m, IH), 2.80 (m, 2H), 1.80 (m, 6H), 1.40 (m, IH), 1.10 (m, 8H), 0.80 (m, 2H).
Example 227 (2RS.3R)-3-amino-4-cvclohexyl-N-(2-(4-fluorophenvP-l.l-dimethylethyl)-2- hydroxybutanamide hydrochloride
The product of example 23A and 2-(4-flourophenyl)-l,l-dimethylethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 351 (M+H)+;
!H NMR (300 MHz, DMSO) δ 7.20 (m, 2H), 7.05 (m, 2H), 3.60 (d, IH), 3.00 (s, 2H), 1.65 (m, 5H), 1.40 (m, 2H), 1.20 (m, 10H), 0.80 (m, 2H).
Example 228 (2RS.3R)-3-amino-4-cyclohexyl-N-(2.3-dihvdro-lH-inden-l-vP-2-hvdroxybutan amide hydrochloride The product of example 23A and 1-aminoindane were processed as in example 101 to provide the title compound. MS (APCI) m/e 317 (M+H)+;
*H NMR (300 MHz, DMSO) δ 7.95 (m, IH), 7.20 (m, 3H), 5.30 (m, IH), 3.75 (d, IH), 3.00 (m, 2H), 2.80 (m, 2H), 2.38 (m, IH), 1.95 (m, IH), 1.70 (m, 5H), 1.20 (m, 6H), 0.90 (m, 2H).
Example 229 (2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-((lS.2R)-2-phenylcvclopropyl)butan amide hydrochloride
The product of example 23A and trans-2-phenylcyclopropylamine were processed as in example 101 to provide the title compound. MS (APCI) m e 317 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.25 (t, 2H), 7.15 (m, 3H), 4.12 (d, IH), 3.55 (m, 2H),
2.95 (m, IH), 2.15 (m, IH), 1.75 (m, 7H), 1.45 (m, 2H), 1.25 (m, 4H), 1.00 (m, 2H).
Example 230 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(1.1.3.3-tetramethylbutyl)butanamide hydrochloride The product of example 23 A and tert-octylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 313 (M+H)+; *H NMR (300 MHz, DMSO) δ 3.60 (d, IH), 2.95 (m, IH), 1.75 (m, 7H), 1.35 (s, 6H), 1.20 (m, 6H), 0.98 (s, 9H), 0.80 (m, 2H).
Example 231 (2RS.3R)-3-amino-4-cvclohexyl-N-(1.3-dimethylbutvP-2-hvdroxybutanamide hydrochloride
The product of example 23 A and 1,3-dimethylbutylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 285 (M+H)+;
4* NMR (300 MHz, DMSO) δ 3.70 (m, IH), 2.95 (m, IH), 1.80 (m, 8H), 1.40 (m, 2H), 1.20 (m, 4H), 1.05 (d, 3H), 0.85 (m, 8H).
Example 232 methyl 4-(((2RS.3R)-3-'amino-4-cvclohexyl-2-hydroxybutanoyl)amino)-3- thiophenecarboxylate hydrochloride The product of example 23A and methyl 3-aminothiophene-4-carboxylate were processed as in example 101 to provide the title compound.
MS (APCI) m/e 341 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 8.40 (s, IH), 8.10 (s, IH), 3.95 (d, IH), 3.80 (s, 3H),
3.10 (m, IH), 1.70 (m, 5H), 1.20 (m, 6H), 0.90 (m, 2H).
Example 233 (2RS.3R)-N-(l-(l-adamantvPethyP-3-amino-4-cyclohexyl-2-hydroxybutanamide hydrochloride The product of example 23A and l-(l-adamantyl)ethylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 363 (M+H)+;
*H NMR (300 MHz, DMSO) δ 3.75 (d, IH), 3.50 (m, 2H), 2.90 (m, 2H), 1.95 (s, 2H), 1.65 (m, 10H), 1.45 (m, 8H), 1.20 (m, 5H), 0.95 (d, 3H), 0.80 (m, 2H).
Example 234 (2RS3R)- 3-amino-2-hvdroxy-4-cvclohexyPbutanoyl-( (S)-(-)-α-naphthyl)ethyl)amide
The product of examplel2A and (S)-(-)-(l-naphthyl)ethylamine were processed as in examples IE and IF to yield the title compound. MS (ESI+Q1MS) m/e 347 (M+ H)+ , 693 (2M+ H)+ ;
*H NMR (300 MHz, DMSO-d6) δ 8.75-7.47 (m, 7H), 6.55 (br., IH), 4.82-4.75 (m, IH), 4.15 (d, IH), 3.60-3.33 (br.m, 3H), 2.68-2.34 (m, 3.6H), 2.18 (q, 0.4H), 1.87-1.68 (m, 2H), 1.58-1.53 (m, 3H), 1.13 (t, 0.6H), 0.98 (t, 0.4H).
Example 235 (2RS.3R)-3-amino-4-cvclohexyl-2-hydroxy-N-(l-naphthylmethyPbutanamide hydrochloride
The product of example 23A and 1-naphthylmethylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 341 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 8.15 (d, IH), 7.85 (q, 2H), 7.50 (m, 4H), 4.90 (m, 2H), 4.15 (d, IH), 3.50 (m, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 236 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-(trifluoromethoxy)benzyPbutanamide hydrochloride The product of example 23A and 3-trifluoromethoxy benzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 375 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 7.40 (t, IH), 7.30 (d, IH), 7.22 (s, IH), 7.19 (d, IH),
4.55 (d, IH), 4.40 (d, IH), 4.15 (d, IH), 3.50 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.95 (m, 2H).
Example 237 (2RS.3R)-3-amino-N-(3.5-bis(trifluoromethyl)benzvP-4-cvclohexyl-2-hvdroxybutanamide hydrochloride
The product of example 23A and 3-methylbenzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 427 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 7.95 (s, 2H), 7.85 (s, IH), 4.65 (d, IH), 4.50 (d, IH),
4.10 (d, IH), 3.40 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).
Example 238 (2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(2-(trifluoromethvPbenzvPbutanamide
The product of example 23 A and 2-trifluoromethyl benzylamine were processed as in example 101 to provide the title compound.
MS (APCI) m/e 359 (M+H)+;
!H NMR (300 MHz, MeOH-d4) δ 7.70 (d, IH), 7.58 (m, 2H), 7.45 (t, IH), 4.75 (d, IH), 4.55 (d, IH), 4.19 (d, IH), 3.55 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.95 (m, 2H).
Example 239 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-(trifluoromethoxy benzvPbutanamide hydrochloride The product of example 23A and 2-trifluoromethoxy benzylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 375 (M+H)+; *H NMR (300 MHz, MeOH-d4) δ 7.45 (d, 2H), 7.22 (d, 2H), 4.50 (d, IH), 4.38 (d, IH),
4.10 (d, IH), 3.45 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.95 (m, 2H).
Example 240 (2RS,3R)-3-amino-N-(6-chloro-3-pyridinyP-4-cvclohexyl-2-hvdroxybutanamide hydrochloride The product of example 23 A and 3-amino-6-chloropyridine were processed as in example 101 to provide the title compound. MS (APCI) m/e 312 (M+H)+; lH NMR (300 MHz, MeOH-d4) δ 8.70 (s, IH), 8.20 (d, IH), 7.40 (d, IH), 4.30 (d, IH),
3.80 (m, 2H), 1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 3H), 1.00 (m, 2H).
Example 241 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(6-methyl-2-pyridinyl)butanamide hydrochloride
The product of example 23 A and 2-amino-6-methylpyridine were processed as in example 101 to provide the title compound. MS (APCI) m/e 292 (M+H)+;
*H NMR (300 MHz, MeOH-d4) δ 8.05 (d, 2H), 7.30 (m, IH), 4.45 (d, IH), 3.70 (m, 2H),
2.60 (s, 3H), 1.80 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).
Example 242 (2RS.3R)-3-amino-N-(5-chloro-2-methoxyphenyl)-4-cvclohexyl-2-hvdroxybutan amide hydrochloride The product of example 23 A and 2-methoxy-5-chloroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 341 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.39 (d, IH), 7.11 (dd, IH), 7.02 (d, IH), 4.36 (d, IH),
3.82 (s, 3H), 3.79 (m, IH), 0.98-1.88 (m, 13H).
Example 243 (2RS.3R)-3-amino-4-cyclohexyl-2-hvdroxy-N-(2-methoxy-5-methylphenvPbutanamide hydrochloride
The product of example 23A and 2-methoxy-5-methylaniline were processed as in example 101 to provide the title compound.
MS (APCI) m/e 321 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 8.13 (s, IH), 6.92 (s, 2H), 4.33 (d, IH), 3.89 (s, 3H), 3.78 (m, IH), 2.28 (s, 3H), 0.92-1.88 (m, 13H).
Example 244 (2RS.3R)-3-amino-N-(4-chloro-2.5-dimethoxyphenvP-4-cvcIohexyl-2-hvdroxybutanamide hydrochloride The product of example 23A and 2,5-dimethoxy-4-chloroaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 370 (M)+ 1H NMR (300MHz, MeOH-d4) δ 8.23 (s, IH), 7.09 (s, IH), 4.36 (d, IH), 3.88 (s, 3H),
3.85 (s, 3H), 3.79 (m, IH), 0.97-1.88 (m, 13H).
Example 245 (-2RS.3R)-3-amino-4-cvclohexyl-N-(23-dimethoxyphenvP-2-hydroxybutanamide hydrochloride The product of example 23A and 2,3-dimethoxyaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 337 (M+H)+
1H NMR (300MHz, MeOH-d4) δ 7.93 (d, IH), 7.04 (t, IH), 6.83 (d, IH), 4.35 (d, IH), 3.88 (m, 6H), 3.79 (m, IH), 0.94-1.88 (m, 13H).
Example 246 (2RS.3R)-3-amino-4-cvclohexyl-N-(3.4-dimethoxyphenvP-2-hvdroxybutanamide hydrochloride The product of example 23A and 3,4-dimethoxyaniline processed as in example 101 to provide the title compound. MS (APCI) m/e 337 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.39 (d, IH), 7.14 (dd, IH), 6.91 (d, IH), 4.27 (d, IH),
3.83 (s, 3H), 3.81 (s, 3H), 3.72 (m, IH), 0.95-1.86 (m, 13H).
Example 247 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(3-methoxy-4-methylphenyl)butanamide hydrochloride
The product of example 23A and 3-methoxy-4-methylaniline were processed as in example 101 to provide the title compound. MS (APCI) m/e 321 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.35 (s, IH), 7.06 (d, 2H), 4.28 (d, IH), 3.82 (s, 3H), 3.72 (m, IH), 2.14 (s, 3H), 0.91-1.86 (m, 13H).
Example 248 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(4-methoxy-2-naphthyl)butanamide hydrochloride The product of example 23 A and 4-methoxy-2-naphthylamine were processed as in example 101 to provide the title compound. MS (APCI) m/e 357 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 8.13 (dd, IH), 7.82 (d, IH), 7.73 (d, IH), 7.47 (m, IH),
7.38 (m, IH), 7.24 (d, IH), 4.35 (d, IH), 4.02 (s, 3H), 3.77 (m, IH), 0.95-1.88 (m, 13H).
Example 249 (2RS.3R)-3-amino-4-cvclohexyl-2-hvdroxy-N-(2-thienylmethvPbutanamide hydrochloride
The product of example 23A and 2-(aminomethyl)thiophene were processed as in example 101 to provide the title compound. MS (APCI) m/e 297 (M+H)+ 1H NMR (300MHz, MeOH-d4) δ 7.29 (dd, IH), 7.02 (dd, IH), 6.95 (dd, IH), 4.59 (q,
2H), 4.15 (d, IH), 3.58 (m, IH), 0.82-1.80 (m, 13H).
Example 250 f2RS.3RV3-amino-N-hutyl-4-cyclohexyl-2-hvdroxy-N-methylbutanamide The product of example 23A (2.4g, 8.64mmole) was dissolved in anhydrous dichloromethane to give 24ml ( solution A). 1-Hydroxybenzotriazole hydrate (HOBT- 0.96g, 7.78mmole) and 4-(dimethylamino)-pyridine (DMAP-0.096 g, catalytic) were dissolved in 2:1 dichloromethane :N,N-dimethylform amide to make 48ml (solution B). 1- [3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI-2.30g, 12.96mmole) was dissolved in anhydrous dichloromethane to give 48ml (solution C). Solution A was distributed equally into 48 individual reactors. Solution B and solution C were added respectively to these same reactors in equal portions. The reactors were shaken 15min at room temperature. To one of these reactors, N-methylbutylamine( 0.022ml, 0.27mmol) was added and the mixture was shaken ca. 20h. Dichloromethane (2.5ml) was added to the reaction and shaken. The reactor placed on a liquid phase extractor to wash twice with IM sodium bisulfate, once with water, and finally, twice with 2Ν sodium bicarbonate. Any residual water was removed and the solvent was concentrated to dryness. The residue was dissolved in 4M hydrochloric acid in dioxane (1ml) to cleave the protecting group. After one hour, the solvent was concentrated to dryness. 48 amines were processed at one time in batch mode. Based on HPLC purity, the material was either submitted as is, or sent for preparative HPLC purification prior to submission. MS (APCI) m/e 271 (M+H)+ ; l NMR (300 MHz, MeOH-d4) δ 4.45 (t, IH), 3.45 (m, 3H), 3.14 (s, 2H), 2.95 (s, IH),
1.7 (m, 5H), 1.4 (m, 4H), 0.95 (m, 6H).
Example 251 (2RS.3RV3-amino-4-cyclohexyl-l-f2.6-dimethyl-4-morpholinyP-2-hydroxy- 1-butanone The product of example 23A and 2,6-dimethylmorpholine were processed as in Eample 250 to provide the title compound. MS (APCI) m/e 299 (M+H)+ ; lH NMR (300 MHz, MeOH-d4) δ 4.4 (m, 2H), 3.95 (m, IH), 3.55 (m, 3H), 2.85 (m, IH), 2.4 (m, IH), 1.7 (m, 5H), 1.5 (m, 3H), 1.2 (m, 9H), 0.95 (m, 2H).
Example 252 (2RS.3RV3-amino-4-cyclohexyl-2-hydroxy-N.N-bis(methoxymethyPbutanamide
The product of Example 23A and bis(2-methoxyethyl)amine were processed as in Example 250 to provide the title compound. MS (APCI) m/e 317 (M+H)+ ; lH ΝMR (300 MHz, MeOH-d4) δ 4.65 (d, IH), 3.9 (m, IH), 3.55 (m, 9H), 3.35 (m, 6H), 1.7 (m, 5H), 1.4 (m, 6H), 0.95 (m, 2H).
Example 253 (2RS.3RV3-amino-4-cvclohexyl-l-r3.4-dihvdro-2('lH)-isoquinolinvn-2-hvdroxy-l- butanone The product of example 23 A and 1, 2,3,4- tetrahydroisoquinoline were processed as in example 250 to provide the title compound. MS (APCI) m/e 317 (M+H)+ ; lH ΝMR (300 MHz, MeOH-d4) δ 7.2 (m, 4H), 4.7 (m, 2H), 4.55 (d, IH), 3.8 (m, 2H), 3.5
(m, IH), 2.95 (m, 2H), 1.7 (m, 5H), 1.4 (m, 6H), 0.95 (m, 2H).
Example 254 ( 2RS.3R)-3-amino- 1 -( 1 -azepanyP-4-cyclohexyl-2-hvdroxy- 1 -butanone The product of example 23 A and hexamethyleneimine were processed as in example 250 to provide the title compound. MS (APCI) m/e 283 (M+H)+ ; H ΝMR (300 MHz, MeOH-d4) δ 4.45 (d, IH), 3.65 (m, 2H), 3.55 (m, 3H), 1.6-1.8 (m,
13H), 0.95-1.5 (m, 8H).
Example 255 f2RS.3RV3-amino-4-cvclohexyl-2-hvdroxy- 1 -r4-phenyl-3.6-dihvdro- 1 f2HVpyridinvn- 1- butanone
The product of example 23 A and 4-phenyl-l,2,3,6-tetrahydropyridine hydrochloride were processed as in example 250 to provide the title compound.
MS (APCI) m/e 343 (M+Η)+ ; !H ΝMR (300 MHz, MeOH-d4) δ 7.35 (m, 5H), 6.15 (m, IH), 4.45 (dd, IH), 4.25 (m,
2H), 3.85 (m, 2H), 3.55 (m, IH), 2.6 (m, 2H), 1.7 (m, 5H), 0.95 -1.5 (m, 8H). Example 256
(2RS.3R)-3-amino-N-benzyl-N-butyl-4-cyclohexyl-2-hvdroxybutanamide
The product of example 23A and n-butylbenzylamine were processed as in Example 250 to provide the title compound.
MS (APCI) m/e 347 (M+H)+ ; lH ΝMR (300 MHz, MeOH-d4) δ 7.4 (m, 5H), 4.7 (m, 2H), 4.4 (dd, IH), 3.5 (m, 2H),
3.25 (m, IH), 2.1-1.7 (m, 15H), 0.92 (m, 5H).
Example 257 f2RS.3RV3-amino-4-cvclohexyl-l-rr2R.6S )-2.6-dimethylmoφholinyll-2-hvdroxy-l- hutanone The product of example 23A and cis-2,6-dimethylmorpholine were processed as in example 250 to provide the title compound. MS (APCI) m/e 299 (M+H)+ ;
1H ΝMR (300 MHz, MeOH-d4) δ 4.5 (dd, IH), 4.35 (m, IH), 3.95 (m, IH), 3.55 (m, IH),
2.9 (m, IH), 2.4 (m, IH), 1.5-1.7 (m, 8H), 0.95- 1.3 (m, 11H).
Example 258 (2RS.3RV3-amino-N-r('2-chloro-2.3.5-cvclohexatrien-l-vPmethyll-4-cvclohexyl-2- hydroxy-N-methylhutanamide The product of example 23 A and 2-chloro-N-methylbenzylamine were processed as in example 250 to provide the title compound. MS (APCI) m/e 339 (M+H)+ ; lH ΝMR (300 MHz, MeOH-d4) δ 7.35 (m, 4H), 4.75 (m, 2H), 4.4-4.55 (dd, IH), 3.5 (m,
IH), 3.14 (s, 2H), 2.99 (s, IH), 1.7 (m, 5H), 0.95- 1.5 (m, 8H).
Example 259 (2RS.3RV3-amino-N-π.3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxy-N- ethylbutanamide
The product of example 23A and N-ethyl-3,4 (methylenedioxy)aniline were processed as in example 250 to provide the title compound. MS (APCI) m/e 349 (M+H)+ ; lH ΝMR (300 MHz, MeOH-d4) δ 6.9 (d, IH), 6.83 (d, IH), 6.78 (dd, IH), 6.04 (d, 2H), 4.19 (d, IH), 3.9 m, IH), 3.5 (m, IH), 3.25 (m, IH), 1.65 (m, 5H), 1.4 (m, 2H), 1.0- 1.25 (m, 7H), 0.8 (m, 2H) Example 260 f2RS.3RV3-amino-4-cyclohexyl-N-(2.4-dichlorohenzylVN-ethyl-2-hydroxybutanamide
The product of example 23A and 2,4-dichloro-N-ethylbenzylamine were processed as in example 250 to provide the title compound. MS (APCI) m/e 387 (M+H)+ ;
*H ΝMR (300 MHz, MeOH-d4) δ 7.29-7.52 (m, 3H), 4.65 (m, 2H), 4.3-4.5 (dd, IH), 3.55
(m, 2H), 3.45 (m, IH), 1.7 (m, 5H), 1.5 (m, 2H), 1.1-1.4 (m, 7H), 0.95 (m, 2H).
Example 261 ethyl 3-rr('2RS.3RV3-amino-4-cvclohexyl-2-hydroxybutanoyll('benzyPaminolpropanoate The product of example 23 A and N-benzyl-3-aminopropionic acid ethyl ester were processed as in example 250 to provide the title compound. MS (APCI) m/e 391 (M+H)+ ; !H ΝMR (300 MHz, MeOH-d4) δ 7.3 (m, 5H), 4.7 (m, 3H), 4.1 (m, 2H), 3.4 (m, IH), 2.6 (m, 2H), 1.7 (m, 5H), 1.15-1.5 (m, 9H), 0.95 (m, 2H).
Example 262 (2RS.3RV 3-amino-4-cvclohexyl-2-hydroxy- 1 -( 1 -piperidinyP- 1 -butanone The product of example 23A and piperidine were processed as in example 250 to provide the title compound.
MS (APCI) m/e 269 (M+H)+ ;
1H ΝMR (300 MHz, MeOH-d4) δ 4.45 (d, IH), 3.7 (m, 2H), 3.5 (m, 3H), 1.7 (m, 9H), 1.5
(m, 4H), 1.3 (m, 4H), 1.0 (m, 2H).
Example 263
(2RS.3R.5'S)-Ν-r4-rN-phenylhvdantovPbutvn-3-amino-2-hvdroxy-5- (ethylthio)pentananamide hydrochloride Step (a)
Potassium tert-butoxide (112 mg) is added to a solution of Ν(epsilon)(tert- butoxycarbonyl)-L-lysine methyl ester hydrochloride (300 mg) and phenyl isocyanate (110 mL) in 5 ml of tetrahydrofuran. The resulting mixture is stirred at room temperature for one day. After a similar amount of potassium tert-butoxide is added, the resulting mixture is heated at 65-70 'C for 1 hour. The solvent is removed and ethyl acetate is added to the residue, which is washed with successive portions of brine, 10% KHS0 , brine, 10% NaHC03, and brine, and dried over anhydrous magnesium sulfate. After removal of the solvents under vacuum, the product residue is treated with 4N hydrogen chloride in dioxane for 1 hour, and again evaporated to dryness.
Step fb) The product of Step (a) of Example 12 is reacted with the product of Step (a) of this Example using the method as described in Example 2 to provide the title compound.
Example 264 f2RS.3R.5,R)-N-r4-fN-phenylhvdantoyl)-butvn-3-amino-2-hvdroxy-5- (ethylthio)pentanamide hydrochloride
Using Ν(epsilon)(tert-butoxycarbonyl)-D-lysine methyl ester hydrochloride and phenyl isocyanate, the procedure of Example 263 is used to produce the stereoisomer shown above.
Example 265
(,2RS.3R.4,R)-N-r4-(N-(2.4-dimethoxyphenvPhvdantoyl)propyll-3-amino-2-hvdroxy-5-
(ethylthio)pentanamide hydrochloride Using Ν(epsilon)(tert-butoxycarbonyl)-L-ornithine methyl ester hydrochloride and 2,4-dimethoxyphenyl isocyanate, the procedure of Example 263 is used to produce the compound shown above.
Example 266
2RS.3R.5,S)-N-r4-fN-('4-triflouromethoxyphenyl) hvdantoyl)butyl1-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride Using Ν(epsilon)(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride and 4- trifluoromethoxyphenylphenyl isocyanate, the procedure of Example 28 is used to produce the compound shown above.
Example 267 (2RS.3R.5'S.8'S)-N-r4-(3-Methyl-2.5-dioxopiperazin-2-vPbutyll-3-amino-2-hvdroxy-5-
(ethylthio)pentanamide hydrochloride Step (a)
L-alanyl-Ν'-benzyloxycarbonyllysine methyl ester hydrochloride is synthesized by standard peptide synthesis methods well known in the art. The resulting dipeptide ester (250 mg) is dissolved in toluene (20 mL), triethylamine is added, and the mixture is sealed in a tube and heated to 140°C for 12 hours. The solvent is removed, and the product is dissolved in ethyl acetate (30 ml) and washed with successive portions of brine, 10% KHS04, and brine and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum, and the resulting product is deprotected by standard techniques known in the art.
Step (b)
The product of Step (a) of Example 12 and the product of Step (a) above are processed as described in Example 2 to yield the title compound.
Utilizing the procedure of Example 32, and employing amino acids with widely differing side-chains, a number of substituted diketopiperazines can be synthesized and incorporated into compounds of the present invention by the methods detailed in the Examples above.
Example 268
(2RS.3R)-N-r4-(Phthalimido)butyll-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride Step (a)
Mono-Ν-(tert)-butoxycarbonyl-l,4-diaminobutane (190 mg) and phthalic anhydride (150 mg) are dissolved in 5 ml of toluene and gently refluxed in an oil bath (117-120°C until all of the starting material is consumed. The reaction mixture is diluted with 15 mL of ethyl acetate, and the organic layer is washed with successive portions of brine, 10% KHS04, brine, 10% NaHCO3, and brine and dried over anhydrous magnesium sulfate. The solvent is evaporated to yield the crude product which is treated with 4N hydrogen chloride in dioxane for 1 hour. The solvent is removed, taken up in diethyl ether, twice with evaporations to remove the HC1, and dried.
Step (b)
The product of Step (a) of Example 3 and the product of Step (a) above are processed as described in example 2 to provide the title compound.
Utilizing the method detailed in Step (a) of Example 268, a number of N- (aminoalkyl)phthalimides can be synthesized and incorporated into compounds of the present invention. Examples of such N-(aminoalkyl)phthalimides include compounds where q can range from one to six, inclusive, and A can be hydrogen, halogen, lower alkyl, lower alkoxy, nitro, or carboxy. Example 269 (2RS.3R)-N-(2-thien-2-ylethvP-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride The product of Step (a) of Example 12 and 2-(2-aminoethyl)thiophene are processed as described above in Example 2 to provide the title compound.
Example 270 (2RS.3R)-(N-methyl-N-propyl)-3-amino-2-hvdroxy-5-(ethylthio)pentanamide hydrochloride
The product of Step (a) of Example 12 and Ν-methyl n-propylamine are processed as described in Example 2 to provide the title compound.
In the same manner, alkylamines and dialkylamines in which the two alkyl groups are the same or are different can be converted to compounds of the present invention by the method detailed in Example 35.
Example 271 (2RS.3R)-Ν-r2-(g-AminobutyrolactamyPethyll-3-amino-2-hydroxy-5- (ethylthio)pentanamide
The product of Step (a) of Example 12 and l-amino-2- [g- aminobutyrolactamyllethane are processed as described in Example 2 to provide the title compound.
In a similar manner, aminoalkyl lactams can be incorporated into compounds of the present invention my the methods detailed in the Examples given above.
Example 272 (2RS.3S. S) N-r(l-carboxyl)ethyll 3-amino-2-thio-5-(methylthio)pentanamide hydrochloride
Example IE (0.40 g, 1.1 mmole) in 3 mL of methylene chloride containing 50 % molar excess of triethylamine at 0 °C is treated with methanesulfonyl chloride (O.lmL, 1.31 mmole). After the reaction is completed, the mixture is washed with brine, 10% KHSO4, dried over MgSO4. To a solution of mesylate (0.45 mmole) in 5 mL of THF is added a solution of -methoxybenzyl mercaptan (0.104g, 0.675 mmole) in the presence of 1Ν- ΝaOH at 0 °C under nitrogen atmosphere. After an additional 30 minutes at room temperature with stirring, the product is purified by silica gel column chromatography, eluting with 10% ethyl acetate in toluene.
Obtained 7-methoxybenzyl mercapto derivative (0.4 mmole) is dissolved in 3 mL of methanol. 2N-NaOH is added to adjust pH at around 12. The reaction is worked up according to the general procedure and the product is treated with 4N-HC1 in dioxane for 1.5 hours to obtain the title compound.
Example 273 (2RS.35.rS) N-r(l-ethoxycarbonvPethvn 3-amino-2-oxo-5-(methylthio)pentanamide hydrochloride
Example IE (0.4 g, 1.1 mmole) is oxidized by pyridinium chlorochromate (710 mg, 3.3 mmole) in 5 mL of methylene chloride until the starting material is consumed. The obtained diketone is purified on silica gel column chromatography. The resulting product is processed as described in step (f) in example 1 to yield the title compound.

Claims

WE CLAIM
1. A compound having the formula (I):
Figure imgf000122_0001
I, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the small numerals denote chiral centers in the compound;
m is 1-3;
R1 is selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) carboxaldehyde, (4) alkanoyl, where the alkanoyl can be optionally substituted with hydroxyl, and (5) -(CH )nCO2R4, where n is 0-6, and R4 is selected from the group consisting of
(a) hydrogen,
(b) alkyl, (c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) aryl, and
(f) arylalkyl, where (c) and (d) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl,
(ii) alkoxy, and (iii) aryl, and where (e) and (f) can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i) alkyl, (ii) alkanoyl,
(iii) alkoxy, (iv) -CO R4 , where R4 is selected from the group consisting of,
(a) hydrogen,
(b) alkyl, (c) cycloalkyl,
(d) (cycloalkyl)alkyl,
(e) aryl, and
(f) arylalkyl, (v) alkanoyloxy,
(vi) carboxaldehyde, (vii) cycloalkyl, (viii) cycloalkenyl, (ix) halo, (x) nitro,
(xi) perfluoroalkyl, (xii) perfluoroalkoxy, (xiii) arylsulfonylalkyl, (xiv) aryloylalkyloxycarbonylalkyl, (xv) -NR6R , where R6 and R6 are independently selected from the group consisting of
(1') hydrogen,
(2') alkyl optionally substituted with alkoxy,
(3') aryl, (4') arylalkyl, and
(5') a nitrogen-protecting group, (xvi) -SO2NR6R6', where R6 and R6' are defined above, and (xvii) -C(O)NR6R6', where R6 and R6' are defined above;
R2 is selected from the group consisting of
(1) alkyl,
(2) cycloalkyl, (3) (cycloalkyl)alkyl, (4) -C(H)(SR15)(SR15'), where R15 and R15' are alkyl, or R15 and R15', together with the sulfurs to which they are attached, are a 1,3-dithiolane ring or a 1,3-dithiane ring,
(5) aryl,
75 (6) arylalkyl, and (7) -SR^, where R5 is selected from the group consisting of
(a) alkyl,
(b) cycloalkyl,
80 (c) (cycloalkyl)alkyl, and (d) benzyl, where the benzyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl, 85 (ii) alkanoyl,
(iii) alkoxy,
(iv) -CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde, 90 (vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl, 95 (xii) perfluoroalkoxy,
(xiii) -NR6R , where R^ and R^' are defined above,
(xiv) -SO2NR6R6', where R6 and R6' are defined above, and
(xv) -C(O)NR6R6', where R6 and R6' are defined above; 100
R3 is selected from the group consisting of
(1) an aminoacyl group optionally capped with a carboxyl protecting group,
(2) -N(R6)(CH2)PR7, where p is 0-6, R6 is defined above, and R7 is selected from the group consisting of 105 (a) hydrogen,
(b) alkyl, where the alkyl can be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
(i) oxo,
(ii) thioxo, (iii) alkoxy,
(iv) -CO2R4, where R4 is defined above,
(v) alkanoyloxy,
(vi) carboxaldehyde,
(vii) cycloalkyl, (viii) cycloalkenyl,
(ix) halo,
(x) nitro,
(xi) perfluoroalkyl,
(xii) perfluoroalkoxy, (xiii) -NR6R6 , where R^ and R6 are defined above,
(xiv) -SO2NR6R6', where R6 and R6' are defined above,
(xv) -C(O)NR6R6', where R6 and R6' are defined above,
(xvi) aryl,
(xvii) hydroxy, and
(xviii) heterocycle,
(c) cycloalkyl, where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i) alkyl, (ii) halo,
(iii) oxo, and (iv) aryl,
(d) aryl, where the aryl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of (i) alkyl,
(ii) alkanoyl,
(iii) alkoxy,
(iv) -CO2R4, where R4 is defined above,
(v) alkanoyloxy, (vi) carboxaldehyde,
(vii) cycloalkyl,
(viii) cycloalkenyl,
(ix) halo, (x) nitro, 145 (xi) perfluoroalkyl,
(xii) perfluoroalkoxy,
(xiii) -NR6R6 , where R^ and R^' are defined above,
(xiv) -SO2NR6R6', where R6 and R6' are defined above,
(xv) -C(O)NR6R6', where R6 and R6' are defined above, 150 (xvi) aryloxy,
(xvii) arylalkoxy,
(xvi) aryl,
(xvii) hydroxy, and 155 (xviii) heterocycle,
(e) -CO2R4, where R4 is defined above,
(f) -CONR6R8, where R6 is defined above, and R^ is selected from the group consisting of (i) hydrogen 160 (ii) alkyl,
(iii) aryl, and
(iv) heterocycle, where (ii)-(iv) can be optionally substituted with one, two, or three 165 groups independently selected from the group consisting of d') alkyl, (2') alkanoyl, (3') alkoxy,
(4') -CO2R4, where R4 is defined above, 170 (5') alkanoyloxy,
(6') carboxaldehyde, (7') cycloalkyl, (8') cycloalkenyl, (9') halo, 175 (10') nitro,
(I T) perfluoroalkyl, (12') perfluoroalkoxy,
(13') -NR6R6', where R6 and R6'are defined above, (14') -SO2NR6R6', where R6 and R6' are defined above, 180 (15') -C(O)NR6R6', where R6 and R6' are defined above, (16') aryloxy, (17') arylalkoxy, (18') aryl, (19') hydroxy, 185 and
(20') heterocycle, (g) heterocycle, where the heterocycle can be optionally substituted with one, two, or three groups independently selected from the group consisting of (i) alkyl, 190 (ii) alkanoyl,
(iii) alkoxy,
(iv) -CO2R4, where R4 is defined above, (v) alkanoyloxy, (vi) carboxaldehyde, 195 (vii) cycloalkyl,
(viii) cycloalkenyl, (ix) halo, (x) nitro,
(xi) perfluoroalkyl, 200 (xii) perfluoroalkoxy,
(xiii) -NR6R6', where R6 and R6' are defined above, (xiv) -S02NR6R6', where R6 and R6' are defined above, (xv) -C(O)NR6R6', where R6 and R6' are defined above, (xvi) aryloxy, 205 (xvii) arylalkoxy,
(xviii) aryl, (xix) hydroxy, and
(xix) heterocycle, 210 (h) -NR6R8, where R6 and R8 are defined above, and (i) -N(R6)SO2R12, where R6 is defined previously, and R12 is selected from the group consisting of (i). alkyl, 215 (ii) aryl,
(iii) arylalkyl, (iv) heterocycle, and
(v) (heterocycle)alkyl, 220 where (ii)-(v) can be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of (1') alkyl, (2') alkanoyl, (3') alkoxy, 225 (4') -CO2R4, where R4 is defined above,
(5') alkanoyloxy, (6') carboxaldehyde, (7') cycloalkyl, (8') cycloalkenyl, 230 (9') halo,
(10') nitro, (I T) perfluoroalkyl, (12') perfluoroalkoxy,
(13') -NR6R6', where R6 and R6' are defined above, 235 (14') -SO2NR6R6', where R6 and R6' are defined above,
(15') -C(O)NR6R6', where R6 and R6' are defined above, (16') aryloxy, (17') arylalkoxy, (18') aryl, 240 (19') hydroxy, and
(20') heterocycle, (3) -O(CH2)pR7 where p and R7 are defined above, and 245 (4) -NR20R21, where R2^ and R21, together with the nitrogen atom to which they are attached, are a 3- to 7-membered ring optionally containing therein 1 or 2 double bonds and optionally containing therein a moiety selected from the group consisting of (a) oxygen, 250 (b) nitrogen and
(c) -S(O)x-, wherein x is 0-2, where the ring formed by R2^ and R2* can be optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of 255 (1') alkyl,
(2') alkanoyl,
(3") alkoxy,
(4') -CO2R4, where R4 is defined above,
(5') alkanoyloxy, 260 (6') carboxaldehyde,
(7') cycloalkyl,
(8') cycloalkenyl,
(9') halo,
(10') nitro, 265 (11') perfluoroalkyl,
(12') perfluoroalkoxy,
(13') -NR6R6', where R6 and R6' are defined above,
(14') -SO2NR6R6', where R6 and R6' are defined above,
(15') -C(O)NR6R6', where R6 and R6' are defined above, 270 (16') aryloxy,
(17') arylalkoxy,
(18') aryl,
(19') hydroxy, and 275 (20') heterocycle;
X is hydroxyl or sulfhydryl;
and 280 Y is hydrogen;
or
X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl.
285
2. A compound in accordance with Claim 1, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein Y is hydrogen and X is hydroxy.
3. A compound in accordance with Claim 2, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the stereochemistry at the chiral center designated "2" is of the S configuration.
4. A compound in accordance with Claim 2, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the stereochemistry at the chiral center designated "1" is of the R configuration.
5. A compound in accordance with Claim 4, or a pharmaceutically acceptable salt,
2 5 ester, or prodrug thereof, wherein R is -SR .
6. A compound in accordance with Claim 5, or a pharmaceutically acceptable salt, ester, or prodrug thereof, selected from the group consisting of
(2RS,3R,rS)-N-((l-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide, (2RS,3R,rS)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-((2-phenylethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-((3-phenylpropyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-N-(2-(4-methoxyphenyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-(2-(4-sulfonamidophenyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide,
(2RS,3R)-N-(2-(2-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS ,3R)-N- (2-(4-phenoxyphenyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R)-N-(4-phenyl)butyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide, (2RS,3R)-N-(3-(carboethoxy)ethyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carbobenzyloxy)ethyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide, (2RS,3R,rS)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-heptanamide,
(2RS,3R)-3-amino-2-hydroxy-5-(methylthio)pentanoic acid,
(2RS,3R)-N-(2-(4-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-3-amino-2-hydroxy-N-(4-methoxyphenethyl)-5- (methylsulfanyl)pentanamide, (2RS,3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hydroxy-5-
(ethylthio)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-acetylamino-2-hydroxy-5-(ethylthio)pentanamide, (2RS,3R)-N-((phenylbutyryl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-3-amino-2-hydroxy-N-methyl-5-(methylsulfanyl)-N- phenethylpentanamide,
(2RS,3R,l'S)-N-((2-carboxyethyl)-3-amino-2-hydroxy-4-ethylthio)pentanamide, (2RS,3R)-N-((l-methyl-l-ethoxycarboxyethyl) 3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R,l'S)-N-((l-(2-hydroxy)-l-ethoxycarboxyethyl) 3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-tert-butoxycarbonylamino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-formylamino-2-hydroxy-4-ethylthio)pentanamide, (2RS,3R)-N-methyl-N-((ethoxycarbonylmethyl)-3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-hydroxymethylcarbonylamino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R,l'R)-N-((l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide, (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4 ethylthio)pentanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- benzylthio)butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-monodansylcadaverine amide, and
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-((S)-(-)-( 1 - naphthyl)ethyl)amide.
7. A compound in accordance with Claim 4, or a pharmaceutically acceptable salt,
2 ester, or prodrug thereof, wherein R is aryl.
8. A compound in accordance with Claim 7, or a pharmaceutically acceptable salt, ester, or prodrug thereof, selected from the group consisting of
(2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-phenyl-butanamide, (2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-phenyl-butanamide, (2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-phenyl- butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester, and (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine.
9. A compound in accordance with Claim 4, or a pharmaceutically acceptable salt,
2 ester, or prodrug thereof, wherein R is cycloalkyl.
10. A compound in accordance with Claim 6, or a pharmaceutically acceptable salt, ester, or prodrug thereof, selected from the group consisting of
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-cyclohexyl- butanamide, (2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-cyclohexyl-butanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cyclohexyl- butanamide,
(2RS,3R)-N-((phenylbutyryl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R,l'R)-N-((l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexypbutanamide,
(2RS,3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexypbutanamide,
(2RS,3R,l'S)-N-((2-hydroxy-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide, (2RS,3R,rS)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2'S)-N-((2-propionyloxyproρyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,2'S)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide, (2RS,3R,2'R)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide, (2RS,3R,2'R)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,2'R)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R,l'S)-N-((l-benzyloxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butan amide,
(2RS,3R, 1 'S)-N-(4-ethoxycarbonyl-2-( 1 '-aminoethyl)thizole)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-(monodansylcadaveno)-3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R)-N-(2-methyl-5-nitro imidazole-ethyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-(5 -methoxy-tryptaminyl) 3 -amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-(3-0-methyl-dopaminyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-(2-aminomethylbenzimidazolyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-methyl-5- nitroimidazolyl-ethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- nitropyridylaminoethyPamide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl- (ethylisonipecotate)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2- pyrrolidinopropyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- methoxytryptamine)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(3-O- methoxydopamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2- benzimidazolemethyl) amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-phenyl-pyrazole- 3)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-hydroxy-5-nitro- l)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-bromothizole- 2)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(4-nitro-2- hydroxyphenyl- l)amide,
((2RS ,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoylL-alanyl-( 1 - ethylpyrazole)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide, ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(3-imidazolylpropyl)amide,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-carboxyl-2-( 1 'amino)ethyl thizole, ethyl (2RS,3R,2'S)-2-((-3-(acetylamino)-4-cyclohexyl-2- hydroxybutanoyl)amino)propanoate, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4- benzyloxycarbonylamino)butylamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-beta-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-(4- toluenesulf onyl) aminobutyl)amide, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-4- toluenesulfonylaminoethyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-aminobutyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-aminoethyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-(((3,4- dimethoxyphenyl)sulfonyl)amino)butyl)-2-hydroxybutanamide,
(2RS,3R)-N-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4- cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-((2- naphthylsulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-sulfonamide benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclohexyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 2- ((phenylsulfonyl)methyl)benzyl ester,
(2RS ,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclopropyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-tert-butylbenzyl 95 ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4- methoxycarbonylbenzyl ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L- alanine 4- trifluoromethylbenzyl ester, 100 (2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-(4-(methyl)phenyl acetic acid phenacyl ester),
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenyl)butanamide, methyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-4- 105 methylpentanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-furylmethyl)-2-hydroxybutanamide, (2RS,3R, 1 'RS)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -( 1 - naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(2-oxo-l- 110 pyrrolidinyl)propyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,2-dimethylpropyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenylbutanamide, (2RS,3R)-3-amino-N-(2-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, 115 (2RS,3R)-3-amino-4-cyclohexy 1-2- hydroxy- N-(3-phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l,2,3,4-tetrahydro-l- naphthalenyl)butanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)cyclohexyl)-4-cyclohexyl-2- hydroxybutanamide, 120 (2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethylhexyl)-2-hydroxybutanamide, butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate, (2RS,3R)-3-amino-N-(l,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2- hydroxybutanamide, 125 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-5- (trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-decyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-((lR,4S)bicyclo(2.2.1)hept-2-yl)-4-cyclohexyl-2- 130 hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-( 1 -(4-fluoroρhenyl)ethyl)-2- 135 hydroxy butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(tetrahydro-2- furanylmethyl)butanamide, ethyl (2RS,3R)-(4-((-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)- 1 - piperidinecarboxylate, 140 (2RS,3R)-3-amino-N-(l,3-benzodioxol-5-yl)-4-cyclohexyl-2-hydroxybutanamide, tert-butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate, methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- phenylpropanoate, methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- 145 methylpentanoate, methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)hexanoate, methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- methylbutanoate, 150 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lS)-l-(2- naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lR)-l-(2- naphthyl)ethyl)butanamide,
(2RS ,3R)-3-amino-4-cyclohexyl-2-hydroxy-N- (( 1 S)- 1 -( 1 - 155 naphthyl)ethyl)butaήamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lR)-l-(l- naphthyl)ethyl)butanamide, ethyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- fluoropropanoate, 160 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-hydroxy-l-
(hydroxymethyl)ethyl)butanamide,
4-(tert-butyl)benzyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
4-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)- 165 3-hydroxypropanoate,
3-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)- 3-hydroxypropanoate, 4-(trifluoromethyl)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
170 3-(trifluoromethoxy)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenyl)-2-hydroxybutanamide,
175 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenyl)butanamide, (2RS,3R)-3-amino-N-(4-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(2-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide,
180 (2RS,3R)-3-amino-N-(4-(tert-butyl)phenyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3- (trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4- (trifluoromethyl)phenyl)butanamide,
185 (2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-bromophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-(tert-butyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
190 (trifluoromethyl)benzyPbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4- (trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-N-(2-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-
195 nitrophenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenoxyphenyl)butanamide, (((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)(2,5- dimethoxybenzyl)chloronium ,
200 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenethyl)-2-hydrόxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dichlorophenethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(3-fluorophenethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3,4-bis(benzyloxy)phenethyl)-4-cyclohexyl-2- hydroxybutanamide, 205 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2- (trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3- (trifluoromethoxy)phenyl)butanamide,
210 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methylphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dimethylphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-iodo-2-methylphenyl)butanamide, (2RS,3R)-3-amino-N-(4-anilino-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
215 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-chloro-2-methoxy-5-methylphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-N-(5-(acetylamino)-2-methoxyphenyl)-3-amino-4-cyclohexyl-2-
220 hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxydibenzo(b,d)furan-3- yl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2,4-dimethoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
225 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-diethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-phenoxyphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methyl-5-nitrophenyl)butanamide,
230 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxybenzyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylbenzyl)butanamide, (2RS,3R)-3-amino-N-(3-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxybenzyl)butanamide,
235 (2RS,3R)-3-amino-N-(4-bromobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methylbenzyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenethylbutanamide, (2RS,3R)-3-amino-N-(4-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenethyl)butanamide,
240 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenethyl)butanamide, (2RS,3R)-3-amino-N-(4-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, 245 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)phenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-bromophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-N-(l-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-N-(2-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, 250 (2RS,3R)-3-amino-N-cycloheptyl-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(cyclohexylmethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N,4-dicyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-cyclopentyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-cyclobutyl-4-cyclohexyl-2-hydroxybutanamide, 255 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -methyl-3- phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -methyl-2-(3-
(trifluoromethyl)phenyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,5-dimethylhexyl)-2-hydroxybutanamide, 260 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l-methylhexyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isopropoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isobutoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(4- morpholinyl)phenyl)butanamide, 265 (2RS,3R)-3-amino-4-cyclohexyl-N-(3,3-diphenylpropyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,4-dimethylpentyl)-2-hydroxybutan amide, (2RS,3R)-3-amino-4-cyclohexy 1-2- hydro xy-N-methyl-N-( 1 - naphthylmethypbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-((lS)-l-(l- 270 naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-
(trifluoromethyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy( 1 , 1 '-biphenyl)-3- yl)butanamide, 275 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro- 1 ,4-benzodioxin-6-yl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-(benzyloxy)phenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(3-ethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3,4,5-trimethoxyphenyl)butanamide, 280 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-(2-fluorophenyl)- 1 -methylethyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-(4-fluorophenyl)- 1 , 1 -dimethylethyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro- lH-inden- l-yl)-2- 285 hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lS,2R)-2- phenylcycloρropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 , 1 ,3,3- tetramethylbutyPbutanamide, 290 (2RS,3R)-3-amino-4-cyclohexyl-N-(l,3-dimethylbutyl)-2-hydroxybutanamide, methyl 4-(((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- thiophenecarboxylate,
(2RS,3R)-N-(l-(l-adamantyl)ethyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS ,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -naphthylmethyl)butanamide, 295 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethoxy)benzyl)butanamide,
(2RS,3R)-3-amino-N-(3,5-bis(trifluoromethyl)benzyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2- 300 (trifluoromethyl)benzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4- (trifluoromethoxy)benzyl)butanamide,
(2RS,3R)-3-amino-N-(6-chloro-3-pyridinyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(6-methyl-2-pyridinyl)butanamide, 305 (2RS,3R)-3-amino-N-(5-chloro-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5- methylphenyl)butanamide,
(2RS,3R)-3-amino-N-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-2- 310 hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-4- methylphenyl)butanamide, 315 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy-2-naphthyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-thienylmethyl)butanamide,
(2RS,3R)-3-amino-N-butyl-4-cyclohexyl-2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-l-(2,6-dimethyl-4-moφholinyl)-2-hydroxy-l- butanone, 320 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N,N-bis(methoxymethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-l-[3,4-dihydro-2(lH)-isoquinolinyl]-2-hydroxy-
1-butanone,
(2RS ,3R)-3-amino- 1 -( 1 -azepanyl)-4-cyclohexyl-2-hydroxy- 1 -butanone, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-l-[4-phenyl-3,6-dihydro-l(2H)- 325 pyridinyl]- 1 -butanone,
(2RS,3R)-3-amino-N-benzyl-N-butyl-4-cyclohexyl-2-hydroxybutanamide (2RS,3R)-3-amino-4-cyclohexyl-l-[(2R,6S)-2,6-dimethylmoφholinyl]-2-hydroxy-
1 -butanone,
(2RS,3R)-3-amino-N-[(2-chloro-2,3,5-cyclohexatrien-l-yl)methyl]-4-cyclohexyl- 330 2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-N-(l,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxy-N- methylbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-N-ethyl-2- hydroxybutanamide, 335 ethyl 3-[[(2RS,3R)-3-amino-4-cyclohexyl-2- hydroxybutanoyl](benzyl)amino]propanoate, and
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-l-(l-piperidinyl)- 1-butanone.
11. A compound in accordance with Claim 4, or a pharmaceutically acceptable salt,
2 ester, or prodrug thereof, wherein R is alkyl.
12. A compound in accordance with Claim 11, or a pharmaceutically acceptable salt, ester, or prodrug thereof, which is
(2RS,3R, l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxyheptanamide.
13. A compound in accordance with Claim 2, or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein the stereochemistry at the chiral center designated "1" is of the S configuration.
14. A compound in accordance with Claim 13, or a pharmaceutically acceptable salt,
2 5 ester, or prodrug thereof, wherein R is -SR .
15. A compound in accordance with Claim 14, or a pharmaceutically acceptable salt, ester, or prodrug thereof, selected from the group consisting of
(2RS,3S,l'S)-N-[(l-ethoxycarbonyl)ethyl]-3-amino-2-hydroxy-5- (methylthio)pentanamide and
(2RS,3S,l'S)-N-[(l-ethylcarboxamido)ethyl]-3-amino-2-hydroxy-5- (methylthio)pentanamide.
16. A pharmaceutical composition comprising a compound in accordance with Claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof, in combination with a pharmaceutically acceptable carrier.
17. A method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising adminstering to the mammal a pharmaceuticUy acceptable amount of a compound of claim 1.
18. A compound or a pharmaceutically acceptable salt, ester, or prodrug thereof, selected from the group consisting of
(2RS,3S,l'S)-Ν-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide, (2RS,3S,l'S)-N-((l-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R, 1 'S)-N-(( l-ethylcarboxamido)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide,
(2RS,3R)-N-((2-phenylethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-N-((3-phenylpropyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R) N-(2-(4-methoxyphenyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide,
(2RS,3R)-N-(2-(4-sulfonamidophenyl)ethyl)-3-amino-2-hydroxy-5-
(methylthio)pentanamide,
(2RS,3R)-N-(2-(2-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-N-(2-(4-phenoxyphenyl)ethyl)-3-amino-2-hydroxy-5- (methylthio)pentanamide,
(2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R)-N-(4-phenyl)butyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide, (2RS,3R)-N-(3-(carboethoxy)ethyl)-3-amino-2-hydroxy-5-(ethylthio)pentanamide, (2RS,3R)-N-(3-(carbobenzyloxy)ethyl)-3-amino-2-hydroxy-5-
(ethylthio)pentanamide,
(2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R,rS)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-heptanamide, (2RS,3R)-3-amino-2-hydroxy-5-(methylthio)pentanoic acid,
(2RS,3R)-N-(2-(4-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide, (2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-phenyl-butanamide, (2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-phenyl-butanamide, (2RS,3R)-N-(4-phenylbutyl)-3-amino-2-hydroxy-4-phenyl-butanamide, (2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-cyclohexyl- butanamide,
(2RS,3R)-N-(2-(carboethoxy)ethyl)-3-amino-2-hydroxy-4-cyclohexyl-butanamide, (2RS,3R)-N-(3-(carboethoxy)propyl)-3-amino-2-hydroxy-4-cyclohexyl- butanamide, (2RS,3R,l'S)-N-((l-ethoxycarbonyl)ethyl)-3-amino-2-hydroxy-4-phenyl- butanamide,
(2RS,3R)-3-amino-2-hydroxy-N-(4-methoxyphenethyl)-5- (methylsulfanyl)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-tert-butoxycarbonylamino-2-hydroxy-5- (ethylthio)pentanamide,
(2RS,3R)-N-((2-phenylbutyl)-3-acetylamino-2-hydroxy-5-(ethylthio)pentanamide, (2RS,3R)-N-((phenylbutyryl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide, (2RS,3R)-N-((phenylbutyryl)-3-methoxycarbonylamino-2-hydroxy-4- ethylthio)pentanamide, (2RS,3R)-N-(2-(3-pyridyl)ethyl)-3-amino-2-hydroxy-5-(methylthio)pentanamide,
(2RS,3R)-3-amino-2-hydroxy-N-methyl-5-(methylsulfanyl)-N- phenethylpentanamide,
(2RS,3R,l'S)-N-((2-carboxyethyl)-3-amino-2-hydroxy-4-ethylthio)pentanamide, (2RS,3R)-N-((1 -methyl- 1-ethoxycarboxyethyl) 3-amino-2-hydroxy-4- ethylthio)pentanamide, (2RS ,3R, 1 'S)-N-(( 1 -(2-hydroxy)- 1 -ethoxycarboxyethyl) 3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((phenylbutyryl)-3-tert-butoxycarbonylamino-2-hydroxy-4- ethylthio)pentanamide, (2RS,3R)-N-((phenylbutyryl)-3-formylamino-2-hydroxy-4-ethylthio)pentanamide,
(2RS,3R)-N-Methyl-N-((ethoxycarbonylmethyl)-3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS,3R)-N-((Phenylbutyryl)-3-hydroxymethylcarbonylamino-2-hydroxy-4- ethylthio)pentanamide, (2RS,3R, 1 'R)-N- (( 1 -ethoxycarbonylethyl)-3-amino-2-hydroxy-4- ethylthio)pentanamide,
(2RS ,3R, 1 'R)-N-(( 1 -ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butan amide,
2RS,3R)-N-((l-methyl-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R)-N-((Phenylbutyryl)-3-methoxycarbonylmethylamino-2-hydroxy-4 ethylthio)pentanamide,
(2RS,3R,rS)-N-((l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- benzylthio)butanamide, (2RS,3R,l'S)-N-((2-hydroxy-l-ethoxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butan amide,
(2RS,3R,l'S)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,2'S)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide, (2RS,3R,2'S)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R, 2'R)-N-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,2'R)-N-((2-propionyloxypropyl)-3-amino-2-hydroxy-4- cyclohexyPbutanamide,
(2RS,3R,2'R)-N-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R,l'S)-N-((l-benzyloxycarbonylethyl)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R,l'S)-N-(4-ethoxycarbonyl-2-(l'-aminoethyl)thizole)-3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R) N-(monodansylcadaveno)-3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R) N-(2-methyl-5-nitro imidazole-ethyl) 3-amino-2-hydroxy-4- cyclohexyPbutanamide di,
(2RS,3R) N-(5-nitropyridyl-2-aminoethyl) 3-amino-2-hydroxy-4- 95 cyclohexyPbutanamide di,
(2RS,3R) N-(5-methoxy-tryptaminyl) 3-amino-2-hydroxy-4- cyclohexyl)butanamide,
(2RS,3R) N-(3-O-methyl-dopaminyl) 3-amino-2-hydroxy-4-cyclohexyl)butanamide,
(2RS,3R) N-(2-aminomethylbenzimidazolyl) 3-amino-2-hydroxy-4- 100 cyclohexyPbutanamide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-methyl-5- nitroimidazolyl-ethyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- nitropyridylaminoethyPamide, 105 ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-
(ethylisonipecotate)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2- pyrrolidinopropyl)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5- 110 methoxytryptamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(3-O- methoxydopamine)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2- benzimidazolemethyPamide, 115 ((2RS ,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-phenyl-pyrazole-
3)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(2-hydroxy-5-nitro- l)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(5-bromothizole- 120 2)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanyl-(4-nitro-2- hydroxyphenyl- 1 )amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoylL-alanyl-( 1 - ethylpyrazole)amide, 125 ((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(ethylisonipecotate)amide,
((2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(3-imidazolylpropyl)amide,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-carboxyl-2-(l'amino)ethyl thizole, ethyl (2RS,3R,2'S)-2-((-3-(acetylamino)-4-cyclohexyl-2- 130 hydroxybutanoyl)amino)propanoate,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4- benzyloxycarbonylamino)butylamide,
(2RS ,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-beta-alanine benzyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-monodansylcadaverine amide, 135 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-(4- toluenesulfonyl)aminobutyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-4- toluenesulfonylaminoethyl)amide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(4-aminobutyl)amide , 140 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-(2-aminoethyl)amide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(((3- (trifluoromethyl)phenyl)sulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-(((3,4- dimethoxyphenyl)sulfonyl)amino)butyl)-2-hydroxybutanamide, 145 (2RS,3R)-N-(4-(((4-(acetylamino)phenyl)sulfonyl)amino)butyl)-3-amino-4- cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-((2- naphthylsulfonyl)amino)butyl)butanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-sulfonamide 150 benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclohexyl ester, (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 2- ((phenylsulfonyl)methyl)benzyl ester, 155 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine cyclopropyl ester(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4-tert-butylbenzyl ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4- methoxycarbonylbenzyl ester, 160 (2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine 4- trifluoromethylbenzyl ester,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine-(4-(methyl)phenyl acetic acid phenacyl ester),
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-2-hydroxybutanamide, 165 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenyl)butanamide, methyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-4- methylpentanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-furylmethyl)-2-hydroxybutanamide,
(2RS,3R, l'RS)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -( 1 - 170 naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-(2-oxo- 1 - pyrrolidinyPpropypbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,2-dimethylpropyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine, 175 (2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine benzyl ester,
(2RS,3R)-3-amino-2-hydroxy-4-cyclohexyl)butanoyl-L-alanine,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenylbutanamide,
(2RS,3R)-3-amino-N-(2-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenylpropyl)butanamide, 180 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l,2,3,4-tetrahydro-l- naphthalenyl)butanamide,
(2RS,3R)-3-amino-N-(4-(tert-butyl)cyclohexyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dichlorophenyl)-2-hydroxybutanamide, 185 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethylhexyl)-2-hydroxybutanamide, butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate,
2RS,3R)-3-amino-N-(l,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dimethoxyphenyl)-2-hydroxybutanamide, 190 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-5-
(trifluoromethyPphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-decyl-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-((lR,4S)bicyclo(2.2.1)hept-2-yl)-4-cyclohexyl-2- hydroxybutanamide, 195 (2RS,3R)-3-amino-4-cyclohexyl-N-(2-fluorobenzyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluoro-3-(trifluoromethyl)benzyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-( 1 -(4-fluorophenyl)ethyl)-2- hydroxybutanamide, 200 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(tetrahydro-2- furanylmethyPbutanamide, ethyl (2RS,3R)-(4-((-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-l- piperidinecarboxylate, (2RS,3R)-3-amino-N-(l,3-benzodioxol-5-yl)-4-cyclohexyl-2-hydroxybutanamide, 205 tert-butyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)acetate, methyl (2RS,3R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- phenylpropanoate, methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- methylpentanoate, 210 methyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)hexanoate, methyl (2RS ,3R)-2- ((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- methylbutanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lS)-l-(2- 215 naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lR)-l-(2- naphthyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lS)-l-(l- naphthyl)ethyl)butanamide, 220 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-((lR)- 1-(1- naphthyl)ethyl)butanamide, ethyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- fluoropropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-hydroxy- 1 - 225 (hydroxymethyl)ethyPbutanamide,
4-(tert-butyl)benzyl (2RS,3R,2'R)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
4-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)- 3-hydroxypropanoate, 230 3-nitrobenzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-
3-hydroxypropanoate,
4-(trifluoromethyl)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- hydroxybutanoyl)amino)-3-hydroxypropanoate,
3-(trifluoromethoxy)benzyl (2RS,3R,2'S)-2-((3-amino-4-cyclohexyl-2- 235 hydroxybutanoyl)amino)-3-hydroxypropanoate,
(2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenethyl)-2-hydroxybutanamide, (2RS ,3R)- 3-amino-4-cyclohexyl-2-hydroxy-N- (4-methylphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(4-fluorophenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenyl)butanamide, 240 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenyl)butanamide, (2RS,3R)-3-amino-N-(4-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(2-chlorophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-(tert-butyl)phenyl)-4-cyclohexyl-2-hydroxybutanamide, 245 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethyl)phenyPbutanamide,
2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyPphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dichlorophenyl)-2-hydroxybutanamide, 250 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N-(4-bromophenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(4-(tert-butyl)benzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethy benzyl)butanamide, 255 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-
(trifluoromethyl)benzyPbutan amide,
(2RS,3R)-3-amino-N-(2-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5- nitrophenyPbutanamide, 260 (2RS,3R)-3-amino-4-cyclohexyl-N-(3,5-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-phenoxyphenyl)butanamide, (((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)(2,5- dimethoxybenzyl)chloronium ,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorophenethyl)-2-hydroxybutanamide, 265 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dichlorophenethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3-fluorophenethyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3,4-bis(benzyloxy)phenethyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenethyl)butanamide, 270 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-
(trifluoromethoxy)phenypbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
(trifluoromethoxy)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methylphenyl)butanamide, 275 (2RS,3R)-3-amino-4-cyclohexyl-N-(2,6-dimethylphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-iodo-2-methylphenyl)butanamide, (2RS,3R)-3-amino-N-(4-anilino-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-ethoxyphenyl)-2-hydroxybutanamide,
280 (2RS,3R)-3-amino-N-(4-chloro-2-methoxy-5-methylphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-dimethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-N-(5-(acetylamino)-2-methoxyphenyl)-3-amino-4-cyclohexyl-2- hydroxybutanamide,
285 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxydibenzo(b,d)furan-3- yl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2,4-dimethoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,5-diethoxyphenyl)-2-hydroxybutanamide,
290 (2RS,3R)-3-amino-N-(5-(tert-butyl)-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-phenoxyphenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methyl-5-nitrophenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-phenoxyphenyl)butanamide,
295 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxybenzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylbenzyl)butanamide, (2RS,3R)-3-amino-N-(3-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxybenzyl)butanamide, (2RS,3R)-3-amino-N-(4-bromobenzyl)-4-cyclohexyl-2-hydroxybutanamide,
300 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methylbenzyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-phenethylbutanamide, (2RS,3R)-3-amino-N-(4-chlorobenzyl)-4-cyclohexyl-2-hydroxybutanamid, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methylphenethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxyphenethyl)butanamide,
305 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxyphenethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxyphenethyl)butanamide, (2RS,3R)-3-amino-N-(4-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-(3-chlorophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-
310 (trifluoromethyPphenethyl)butanamide,
(2RS,3R)-3-amino-N-(4-bromophenethyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-N-(l-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-N-(2-adamantyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-cycloheptyl-4-cyclohexyl-2-hydroxybutanamide, 315 (2RS,3R)-3-amino-4-cyclohexyl-N-(cyclohexylmethyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-N,4-dicyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-cyclopentyl-2-hydroxybutanamide, (2RS,3R)-3-amino-N-cyclobutyl-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l-methyl-3- 320 phenylpropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-( 1 -methyl-2-(3- (trifluoromethyl)phenyl)ethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,5-dimethylhexyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l-methylhexyl)butanamide, 325 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isopropoxypropyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-isobutoxypropyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-(4- moφholinyl)phenyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,3-diphenylpropyl)-2-hydroxybutanamide, 330 (2RS,3R)-3-amino-4-cyclohexyl-N-(l,4-dimethylpentyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-( 1 - naphthylmethyPbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-methyl-N-(( 1 S)- 1-( 1 - naphthyl)ethyl)butanamide, 335 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5-
(trifluoromethyl)phenyPbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy( 1 , 1 '-biphenyI)-3- yl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro-l,4-benzodioxin-6-yl)-2- 340 hydroxybutanamide,
(2RS,3R)-3-amino-N-(3-(benzyloxy)phenyl)-4-cyclohexyl-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(3-ethoxyphenyl)-2-hydroxybutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3,4,5-trimethoxyphenyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2-(2-fluorophenyl)-l-methylethyl)-2- 345 hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2-(4-fluorophenyl)-l,l-dimethylethyl)-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dihydro- lH-inden- 1 -yl)-2- hydroxybutanamide, 350 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(( 1 S,2R)-2- phenylcyclopropyPbutanamide, (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l , 1 ,3,3- tetramethylbutyPbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(l,3-dimethylbutyl)-2-hydroxybutanamide, 355 methyl 4-(((2RS,3R)-3-amino-4-cyclohexyl-2-hydroxybutanoyl)amino)-3- thiophenecarboxylate,
(2RS,3R)-N-(l-(l-adamantyl)ethyl)-3-amino-4-cyclohexyl-2-hydroxybutanamide,
(2RS,3R)- 3-amino-2-hydroxy-4-cyclohexyl)butanoyl-( (S)-(-)-(l- naphthyl)ethyl)amide, 360 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(l-naphthylmethyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3- (trifluoromethoxy)benzyPbutanamide,
(2RS,3R)-3-amino-N-(3,5-bis(trifluoromethyl)benzyl)-4-cyclohexyl-2- hydroxybutanamide, 365 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-
(trifluoromethyl)benzyPbutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4- (trifluoromethoxy)benzyPbutanamide,
(2RS,3R)-3-amino-N-(6-chloro-3-pyridinyl)-4-cyclohexyl-2-hydroxybutanamide, 370 (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(6-methyl-2-pyridinyl)butanamide,
(2RS,3R)-3-amino-N-(5-chloro-2-methoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-methoxy-5- methylphenyPbutanamide, 375 (2RS,3R)-3-amino-N-(4-chloro-2,5-dimethoxyphenyl)-4-cyclohexyl-2- hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(2,3-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-N-(3,4-dimethoxyphenyl)-2-hydroxybutanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(3-methoxy-4- 380 methylphenyPbutanamide,
2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(4-methoxy-2-naphthyl)butanamide,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N-(2-thienylmethyl)butanamide,
(2RS,3R)-3-amino-N-butyl-4-cyclohexyl-2-hydroxy-N-methylbutanamide, 385 (2RS,3R)-3-amino-4-cyclohexyl-l-(2,6-dimethyl-4-moφholinyl)-2-hydroxy-l- butanone,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-N,N-bis(methoxymethyl)butanamide, (2RS,3R)-3-amino-4-cyclohexyl-l-[3,4-dihydro-2(lH)-isoquinolinyl]-2-hydroxy- 1 -butanone, (2RS,3R)-3-amino-l-(l-azepanyl)-4-cyclohexyl-2-hydroxy- 1-butanone,
(2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-l-[4-phenyl-3,6-dihydro-l(2H)- pyridinyl]- 1-butanone
(2RS,3R)-3-amino-N-benzyl-N-butyl-4-cyclohexyl-2-hydroxybutanamide (2RS,3R)-3-amino-4-cyclohexyl-l-[(2R,6S)-2,6-dimethylmoφholinyl]-2-hydroxy- 1-butanone,
(2RS,3R)-3-amino-N-[(2-chloro-2,3,5-cyclohexatrien-l-yl)methyl]-4-cyclohexyl- 2-hydroxy-N-methylbutanamide,
(2RS,3R)-3-amino-N-(l,3-benzodioxol-5-ylmethyl)-4-cyclohexyl-2-hydroxy-N- methylbutanamide, (2RS,3R)-3-amino-4-cyclohexyl-N-(2,4-dichlorobenzyl)-N-ethyl-2- hydroxybutanamide, ethyl 3-[[(2RS,3R)-3-amino-4-cyclohexyl-2- hydroxybutanoyl](benzyl)amino]propanoate, and (2RS,3R)-3-amino-4-cyclohexyl-2-hydroxy-l-(l-piperidinyl)- 1-butanone.
PCT/US1999/009641 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2 WO1999057098A2 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
BR9910092-4A BR9910092A (en) 1998-05-01 1999-04-30 Beta-amino acid inhibitors substituted for methionine aminopeptidase-2
EP99921611A EP1073633A2 (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
JP2000547068A JP2002513781A (en) 1998-05-01 1999-04-30 Substituted β-amino acid inhibitors of methionine aminopeptidase-2
PL99346444A PL346444A1 (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
IL13913999A IL139139A0 (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
AU38778/99A AU3877899A (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
KR1020007012124A KR20010043198A (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
SK1628-2000A SK16282000A3 (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
CA002329704A CA2329704A1 (en) 1998-05-01 1999-04-30 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2
NO20005506A NO20005506L (en) 1998-05-01 2000-11-01 Substituted beta-amino acid inhibitors for methionine aminopeptidase-2
BG104981A BG104981A (en) 1998-05-01 2000-11-24 Substituted beta-amino acid inhibitors of methionine aminopeptidase-2

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JP2003516383A (en) * 1999-12-11 2003-05-13 グラクソ グループ リミテッド Method for preparing arylethanolamine derivatives having anti-obesity and anti-diabetic properties
WO2003082838A1 (en) * 2002-04-02 2003-10-09 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences New methionine aminopeptidase inhibitor
WO2004013085A1 (en) * 2002-08-06 2004-02-12 Abbott Laboratories 3-amino-2-hrydroxyalkanoic acids and their prodrugs
WO2004033439A1 (en) * 2002-10-09 2004-04-22 Pfizer Products Inc. Thiazole compounds for the treatment of neurodegenerative disorders
US6887863B2 (en) 2000-04-14 2005-05-03 Abbott Laboratories Hydrazide and alkoxyamide angiogenesis inhibitors
US7030262B2 (en) 2002-08-06 2006-04-18 Abbott Laboratories 3-Amino-2-hydroxyalkanoic acids and their prodrugs
US7759382B2 (en) 2003-06-05 2010-07-20 Elan Pharmaceuticals, Inc. Acylated amino acid amidyl pyrazoles and related compounds
US11273142B2 (en) 2016-01-11 2022-03-15 Syndevrx, Inc. Treatment for tumors driven by metabolic dysfunction
US11612577B2 (en) 2018-10-26 2023-03-28 Syndevrx, Inc. Biomarkers of METAP2 inhibitors and applications thereof

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003516383A (en) * 1999-12-11 2003-05-13 グラクソ グループ リミテッド Method for preparing arylethanolamine derivatives having anti-obesity and anti-diabetic properties
US6887863B2 (en) 2000-04-14 2005-05-03 Abbott Laboratories Hydrazide and alkoxyamide angiogenesis inhibitors
WO2003082838A1 (en) * 2002-04-02 2003-10-09 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences New methionine aminopeptidase inhibitor
WO2004013085A1 (en) * 2002-08-06 2004-02-12 Abbott Laboratories 3-amino-2-hrydroxyalkanoic acids and their prodrugs
US7030262B2 (en) 2002-08-06 2006-04-18 Abbott Laboratories 3-Amino-2-hydroxyalkanoic acids and their prodrugs
WO2004033439A1 (en) * 2002-10-09 2004-04-22 Pfizer Products Inc. Thiazole compounds for the treatment of neurodegenerative disorders
US7759382B2 (en) 2003-06-05 2010-07-20 Elan Pharmaceuticals, Inc. Acylated amino acid amidyl pyrazoles and related compounds
US11273142B2 (en) 2016-01-11 2022-03-15 Syndevrx, Inc. Treatment for tumors driven by metabolic dysfunction
US11612577B2 (en) 2018-10-26 2023-03-28 Syndevrx, Inc. Biomarkers of METAP2 inhibitors and applications thereof

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