SK16282000A3 - 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
SK16282000A3
SK16282000A3 SK1628-2000A SK16282000A SK16282000A3 SK 16282000 A3 SK16282000 A3 SK 16282000A3 SK 16282000 A SK16282000 A SK 16282000A SK 16282000 A3 SK16282000 A3 SK 16282000A3
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SK
Slovakia
Prior art keywords
amino
cyclohexyl
hydroxy
give
nmr
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SK1628-2000A
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Slovak (sk)
Inventor
Richard A. Craig
Jack Henkin
Megumi Kawai
Linda Lijewski Lynch
Jyoti Patel
George S. Sheppard
Jieyi Wang
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Abbott Laboratories
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority claimed from US09/303,807 external-priority patent/US6242494B1/en
Publication of SK16282000A3 publication Critical patent/SK16282000A3/en

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    • C07D207/02—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
    • 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • C07C235/02—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
    • 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
    • C07C235/16—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 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C237/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
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    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract

A class of substituted beta -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

Substituované beta-aminokyselinové inhibítory metionínaminopeptidázy-2Substituted beta-amino acid inhibitors of methionine aminopeptidase-2

Oblasť technikyTechnical field

Predložený vynález sa týka organických zlúčenín majúcich biologickú aktivitu, prípravkov obsahujúcich zlúčeniny a lekárskych spôsobov ošetrenia. Podrobne sa predložený vynález týka skupiny substituovaných beta-aminokyselín a ich farmaceutický prijateľných solí, farmaceutických prípravkov obsahujúcich tieto zlúčeniny a spôsobov ošetrenia patologických stavov vznikajúcich z angiogenézy alebo závislých na angiogenéze.The present invention relates to organic compounds having biological activity, compositions containing the compounds, and medical methods of treatment. In particular, the present invention relates to a group of substituted beta-amino acids and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds, and methods of treating pathologies resulting from or dependent on angiogenesis.

Doterajší stav technikyBACKGROUND OF THE INVENTION

Angiogenéza je základný proces, ktorým sa tvoria nové krvné cievy a je dôležitý pre rôzne normálne telesné aktivity (napr. reprodukcia, vznik a reparácia zranení). Aj keď nie je úplne známy mechanizmus, má sa všeobecne za to, že sa jedná o komplexné vzájomné pôsobenie molekúl, ktoré stimulujú a inhibujú rast endoteliálnych buniek, primárnych buniek kapilárnych krvných ciev. V normálnom stave sa tieto molekuly vyskytujú na udržanie mikrovaskularity v kľudovom stave (tzn. bez kapilárneho rastu) v dlhších intervaloch, ktoré môžu trvať týždne a v niektorých prípadoch aj roky. Avšak pokiaľ je treba (napr. počas liečenia zranenia), môžu tieto rovnaké bunky podliehať rýchlej proliferácii a premeniť sa v rozmedzí 5 dní. (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 fundamental process by which new blood vessels form and is important for various normal physical activities (eg, reproduction, origin and repair of injuries). Although the mechanism is not fully understood, it is generally believed to be a complex interaction of molecules that stimulate and inhibit the growth of endothelial cells, primary cells of capillary blood vessels. In the normal state, these molecules occur to maintain microvascularity at rest (i.e., without capillary growth) at longer intervals, which may take weeks and in some cases years. However, if necessary (e.g., during wound healing), the same cells may undergo rapid proliferation and may change within 5 days. (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)).

Napriek tomu angiogenéza je v normálnych podmienkach vysoko riadený proces, mnohé ochorenia (opisované ako „angiogénne ochorenia“) sú poháňané perzistentnou neriadenou angiogenézou. Inak povedané, neriadená angiogenéza môže buď spôsobovať jednotlivé ochorenia priamo alebo exascerbovať doterajšie patologické stavy. Napríklad bolo preukázané, že očná neovaskularizácia je najbežnejšou príčinnou sleposti a prevláda približne u 20 ochorení očí. Za určitých súčasných podmienok, napr. artritída, vznikajúce nové kapilárne krvné ·· • · · • · ·· ··· ·· ··· cievy napadajú kĺby a ničia chrupavku. Pri diabetes, nové kapiláry vznikajúce v sietnici napadajú sklovec, krvácajú a spôsobujú slepotu. Rast a metastázy pevných nádorov závisia tiež na angiogenéze (Folkman, J., Cancer Research, 46, 467 - 473 (1986), Folkman, J., Journal of the National Cancer Inštitúte, 82, 4 - 6 (1989). Bolo dokázané, že napr. u nádorov, ktoré sa zväčšia na veľkosť väčšiu než 2 mm, sa musí objaviť ich vlastné krvné zásobenie a musí sa tiež vytvárať indukciou rast nových kapilárnych krvných ciev. Ako náhle sa raz tieto nové krvné cievy uchytia v nádore, poskytnú prostriedky nádorovým bunkám na vstúpenie do obehu a metastázujú do vzdialených miest, napr. do pečene, pľúc alebo kostí (Weidner, N., et al., The New England Journal of Medicíne, 324, 1 - 8 (1991).However, angiogenesis is a highly controlled process under normal conditions, many diseases (described as "angiogenic diseases") are driven by persistent, uncontrolled angiogenesis. In other words, uncontrolled angiogenesis can either cause individual diseases directly or exaserbate prior pathological conditions. For example, ocular neovascularization has been shown to be the most common cause of blindness and is predominant in approximately 20 eye diseases. Under certain current conditions, e.g. arthritis, emerging new capillary blood vessels attack the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed and cause blindness. Solid tumor growth and metastasis also depend on angiogenesis (Folkman, J., Cancer Research, 46, 467-473 (1986), Folkman, J., Journal of the National Cancer Institute, 82, 4-6 (1989). that, for example, tumors that grow to a size greater than 2 mm must have their own blood supply and also be produced by inducing the growth of new capillary blood vessels. Once these new blood vessels become attached to the tumor, tumor cells to enter the circulation and metastasize to distant sites, e.g., the liver, lungs or bones (Weidner, N., et al., The New England Journal of Medicine, 324, 1-8 (1991)).

Vzhľadom na túto kľúčovú úlohu, ktorú hrá neovaskularizácia pri vzniku nádoru a jeho metastáz a pri ďalších podobných stavoch ochorení, ako je napr. artritída, zápal, degenerácia makuly starobou a diabetická retinopatia, sa pre klinický potenciál hľadajú agens, ktoré inhibujú angiogenézu.In view of this key role played by neovascularization in tumor formation and metastasis and other similar disease states such as e.g. arthritis, inflammation, macular degeneration, and diabetic retinopathy are seeking agents that inhibit angiogenesis for clinical potential.

D. Ingber, et al., in Náture, 348: 555 - 557 publikuje, že fumagilín, prírodný produkt hubovitého pôvodu a jeho syntetického analóga, ť?-(chlóracetylkarbamoyl)fumagilol, tiež známy ako AGM-1470 alebo TNP-470, reaguje ako silný inhibítor angiogenézy, s TNP-470, ktorý je 50-krát silnejší než jeho prírodný prekurzor.D. Ingber, et al., In Nature, 348: 555-557 discloses that fumagiline, a natural product of fungal origin and its synthetic analogue, β- (chloroacetylcarbamoyl) fumagilol, also known as AGM-1470 or TNP-470, reacts as a potent inhibitor of angiogenesis, with TNP-470, which is 50 times more potent than its natural precursor.

Ny Sin, et al., Proc. Natl. Acad. Sci. USA 94: 6099 - 6103 (1997) a Eric C. Griffith, et al., Chemistry and Biology, 4(6): 461 - 471 (1997) publikujú, že AGM-1470 i ovalicín, sekviterpén izolovaný z huby Pseudorotium ocalis, sa viaže na bežný bifunkčný proteín, metionínaminopeptidáza typ-2, MetAP2 a usudzujú, že MetAP2 hrá rozhodujúcu úlohu pri proliferácii endoteliálnych buniek a môže slúžiť ako perspektívny cieľ na vývoj nových antiangiogénnych liečiv.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) disclose that both AGM-1470 and ovalicin, a sequiterpene isolated from the fungus Pseudorotium ocalis, it binds to the common bifunctional protein, methionine aminopeptidase type-2, MetAP2, and concludes that MetAP2 plays a critical role in endothelial cell proliferation and can serve as a promising target for the development of new anti-angiogenic drugs.

J. Abe, et al., Cancer Research, 54: 3407 - 3412 (1994) publikuje, že fumagilín a jeho derivát TNP-470 sú účinné pri inhibovaní neovaskularizácie zadržaním cyklu endoteliálnych buniek v neskoršej Gi fázy.J. Abe, et al., Cancer Research, 54: 3407-3412 (1994) discloses that fumagiline and its TNP-470 derivative are effective in inhibiting neovascularization by retention of the endothelial cell cycle in the later Gi phase.

·«·· · ·· · ·· ··· ···· ··· • · · · · · · • ···· · » · · ··· · · · · · ·· ··· ·· ··· ·· ·· · · «« «« «« «« «« «« «« «« «« «« «« · · ··· ·· ·

Rovnako sa v literatúre pevne zaviedla náhodná nadväznosť medzi inhibíciou MetAP2 a výslednou inhibíciou proliferácie a neovaskularizácie endoteliálnych buniek. Je potrebné po objavení nových látok , ktoré inhibujú MetAP2, pre ich potenciál ako nových liečiv pri boji proti angiogenéze alebo neovaskularizácii a rôznych stavov ochorení, napr. artritíde, zápalu, degenerácii makuly oka, diabetickej retinopatii a rastu nádoru, ktorého rozvoj závisí na neovaskularizácii. Zlúčeniny predloženého vynálezu sú zo štruktúrneho hľadiska nové, reverzibilné inhibítory MetAP2, ktoré vykazujú zdokonalené farmaceutické vlastnosti a znižujú vedľajšie účinky vzhľadom na súčasné známe ireverzibilné inhibítory, napr. fumagillin a TNP-470.Likewise, a random link between MetAP2 inhibition and resulting inhibition of endothelial cell proliferation and neovascularization has been firmly established in the literature. It is necessary, after the discovery of new substances that inhibit MetAP2, for their potential as new drugs in combating angiogenesis or neovascularization and various disease states, e.g. arthritis, inflammation, macular degeneration, diabetic retinopathy, and tumor growth whose development depends on neovascularization. The compounds of the present invention are structurally novel, reversible MetAP2 inhibitors that exhibit improved pharmaceutical properties and reduce side effects relative to currently known irreversible inhibitors, e.g. fumagillin and TNP-470.

Podstata vynálezuSUMMARY OF THE INVENTION

Vo svojom základnom uskutočnení poskytuje predložený vynález zlúčeninu majúcu účinok na inhibíciu metionínaminopeptidázy typu 2 (MetAP2 alebo MetAP2-2) majúcu vzorec I:In its basic embodiment, the present invention provides a compound having an activity for inhibiting methionine aminopeptidase type 2 (MetAP2 or MetAP2-2) having the formula I:

R1 X y (CHakR 1 X y (CHak

R3 R 3

O) alebo jej farmaceutický prijateľné soli, estery alebo jej prekurzory liečiv, kde malé čísla označujú chirálne centrá v zlúčenine;O) or a pharmaceutically acceptable salt, ester, or prodrug thereof, wherein small numbers indicate chiral centers in the compound;

index m je 1 - 3 substituent R1 je vybraný zo skupiny pozostávajúcej z (1) atómu vodíka, (2) alkylu, (3) karboxaldehydu, (4) alkanoylu, kde alkanoyl môže byť prípadne substituovaný hydroxylom. a ·«·· ·· · ·· • ·· · · ·· · · · • · · · · · · • ···· ···· ··· · · · · · ·· ··· ·· ··· ·· · 4 (5) -(CH2)nCO2R4, kde index n je O - 6 a substituent R4 je vybraný zo skupiny pozostávajúcej z (a) atómu vodíka, (b) alkylu, (c) cykloalkylu, (d) (cykloalkyl)alkylu, (e) arylu, a (f) arylalkylu, kde bod (c) a (d) môže byť prípadne substituovaný 1,2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej z (i) alkylu, (ii) alkoxy skupiny, a (iii) arylu, a kde bod (e) a (f) môže byť prípadne substituovaný 1,2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej z (i) alkylu, (ii) alkanoylu, (iii) alkoxy skupiny, (iv) -CO2R4 , kde substituent R4 je vybraný zo skupiny pozostávajúcej z (a) atómu vodíka, (b) alkylu, (c) cykloalkylu, (d) (cykloalkyl)alkylu, (e) arylu, a (f) arylalkylu, (v) alkanoyloxy skupiny, (vi) karboxaldehydu, ···m is 1-3 R 1 is selected from the group consisting of (1) a hydrogen atom, (2) alkyl, (3) carboxaldehyde, (4) alkanoyl, wherein the alkanoyl may be optionally substituted with hydroxyl. a · «·· ·········································· 4 (5) - (CH 2 ) n CO 2 R 4 , wherein the index n is 0-6 and the substituent R 4 is selected from the group consisting of (a) a hydrogen atom, (b) alkyl, (c) cycloalkyl, (d) (cycloalkyl) alkyl, (e) aryl, and (f) arylalkyl, wherein (c) and (d) may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of ( i) alkyl, (ii) alkoxy, and (iii) aryl, and wherein (e) and (f) may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (i) alkyl, (ii) alkanoyl, (iii) alkoxy groups, (iv) -CO 2 R 4 , wherein R 4 is selected from the group consisting of (a) a hydrogen atom, (b) alkyl, (c) cycloalkyl, (d) (cycloalkyl) alkyl (e) aryl, and (f) arylalkyl, (v) alkanoyloxy groups, (vi) carboxaldehyde, ···

(vii) cykloalkylu, (viii) cykloalkenylu, (ix) halogénu, (x) nitro skupiny, (xi) perfluóralkylu, (xii) perfluóralkoxy skupiny, (xiii) arylsulfonylalkylu, (xiv) aryloylalkyloxykarbonylalkylu, (xv) -NR6R6, kde substituenty R6 a R6' sú nezávisle vybrané zo skupiny pozostávajúcej z (ľ) atómu vodíka, (2‘) alkylu prípadne substituovaného alkoxy skupinou, (3’) arylu, (41) arylalkylu, a (51) a /V-chrániace skupiny, (xvi) -SO2NR6R6', kde substituenty R6 a R6' sú definované vyššie, a(vii) cycloalkyl, (viii) cycloalkenyl, (ix) halogen, (x) nitro groups, (xi) perfluoroalkyl, (xii) perfluoroalkoxy groups, (xiii) arylsulfonylalkyl, (xiv) aryloylalkyloxycarbonylalkyl 6, (xv) -NR 6 - (xv) -NR 6 wherein R 6 and R 6 'are independently selected from the group consisting of (I') a hydrogen atom, (2 ') alkyl optionally substituted with an alkoxy group, (3') aryl, (4 L ) arylalkyl, and (5 L ) and N-protecting groups, (xvi) -SO 2 NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, and

(xvii) -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie;(xvii) -C (O) NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above;

substituent R2 je vybraný zo skupiny pozostávajúcej z (1) alkylu, (2) cykloalkylu, (3) (cykloalkyl)alkylu, (4) -C(H)(SR15)(SR15), kde substituenty R15 a R15' sú alkyl, alebo substituenty R15 a R13', dohromady s atómami síry, ku ktorým sú pripojené, sú 1,3-ditiolánový kruh alebo 1,3ditiánový kruh, (5) arylu, (6) arylalkylu, ···· (7) -SR5, kde substituent R5 je vybraný zo skupiny pozostávajúcej z (a) alkylu, (b) cykloalkylu, (c) (cykloalkyl)alkylu, a (d) benzylu, kde benzyl môže byť prípadne substituovaný 1,2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej z (i) alkylu, (ii) alkanoylu, (iii) alkoxy skupiny, (iv) -CO2R4, kde substituent R4 je definovaný vyššie, (v) alkanoyloxy skupiny, (vi) karboxaldehydu, (vii) cykloalkylu, (viii) cykloalkenylu, (ix) halogénu, (x) nitro skupiny, (xi) perfluóralkylu, (xii) perfluóralkoxy skupiny, (xiii) -NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xiv) -SO2NR6R6', kde substituenty R6 a R6' sú definované vyššie, aR 2 is selected from the group consisting of (1) alkyl, (2) cycloalkyl, (3) (cycloalkyl) alkyl, (4) -C (H) (SR 15 ) (SR 15 ), wherein R 15 and R 15 are substituted. 15 'are alkyl, or the substituents R 15 and R 13 ', taken together with the sulfur atoms to which they are attached, are a 1,3-dithiolane ring or a 1,3-dithiane ring, (5) aryl, (6) arylalkyl, ··· (7) -SR 5 , wherein R 5 is selected from the group consisting of (a) alkyl, (b) cycloalkyl, (c) (cycloalkyl) alkyl, and (d) benzyl, wherein benzyl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (i) alkyl, (ii) alkanoyl, (iii) alkoxy, (iv) -CO 2 R 4 , wherein R 4 is as defined above, (v) alkanoyloxy group, (vi) carboxaldehyde, (vii) cycloalkyl, (viii) cycloalkenyl, (ix) halogen, (x) nitro groups, (xi) perfluoroalkyl, (xii) perfluoroalkoxy groups, (xiii) -NR 6 R 6 ', wherein R 6 and R 6 are substituents 6 'are as defined above, (xiv) -SO 2 NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, and

(xv) -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie;(xv) -C (O) NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above;

substituent R3 je vybraný zo skupiny pozostávajúcej z (1) aminoacylovej skupiny prípadne chránenej karboxylom, (2) -N(R6)(CH2)PR7, kde index p je 0 - 6, substituent R6 je definovaný vyššie aR 3 is selected from the group consisting of (1) an optionally carboxy-protected aminoacyl group, (2) -N (R 6 ) (CH 2 ) p R 7 , wherein the index p is 0-6, R 6 is as defined above, and

Ί substituent R7 je vybraný zo skupiny pozostávajúcej z (a) atómu vodíka, (b) alkylu, kde alkyl môže byť prípadne substituovaný 1,2,3 alebo 4 substituentami nezávisle vybranými zo skupiny pozostávajúcej z (i) oxo skupiny, (ii) tioxo skupiny, (iii) alkoxy skupiny, (iv) -CO2R4, kde substituent R4 je definovaný vyššie, (v) alkanoyloxy skupiny, (vi) karboxaldehydu, (vii) cykloalkylu, (viii) cykloalkenylu, (ix) halogénu, (x) nitro skupiny, (xi) perfluóralkylu, (xii) perfluóralkoxy skupiny, (xiii) -NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xiv) -SC>2NR6R6', kde substituenty R6 a R6’ sú definované vyššie, (xv) -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xvi) arylu, (xvii) hydroxy skupiny, a (xviii) heterocyklu, (c) cykloalkylu, kde aryl môže byť prípadne substituovaný 1,2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej z (i) alkylu, (ii) halogénu, (iii) oxo skupiny, a (iv) arylu, (d) arylu, kde aryl môže byť prípadne substituovaný 1,2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej z • · · ··· · · · ·· ··· ·· ··· ·· ·· (i) alkylu, (ii) alkanoylu, (iii) alkoxy skupiny, (iv) -CO2R4, kde substituent R4 je definovaný vyššie, (v) alkanoyloxy skupiny, (vi) karboxaldehydu, (vii) cykloalkylu, (viii) cykloalkenylu, (ix) halogénu, (x) nitro skupiny, (xi) perfluóralkylu, (xii) perfluóralkoxy skupiny, (xiii) -NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xiv) -SO2NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xv) -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xvi) aryloxy skupiny, (xvii) arylalkoxy skupiny, (xvi) arylu , (xvii) hydroxy skupiny, a (xviii) heterocyklu, (e) -CO2R4, kde substituent R4 je definovaný vyššie, (f) -CONR6R8, kde substituent R6 je definovaný vyššie a substituent R8 je vybraný zo skupiny pozostávajúcej z (i) atómu vodíka (ii) alkylu, (iii) arylu, a (iv) heterocyklu, kde (ii) -(iv) môžu byť prípadne substituované 1, 2 alebo 3 skupinami nezávisle vybranými zo skupiny pozostávajúcej z (ľ) alkylu, (2') alkanoylu, (3') alkoxy skupiny, (41 * *) -CO2R4 *, kde substituent R4 je definovaný vyššie, (5') alkanoyloxy skupiny, (6') karboxaldehydu, (7') cykloalkylu, (8') cykloalkenylu, (91) halogénu, (10') nitro skupiny, (1 ľ) perfluóralkylu, (12') perfluóralkoxy skupiny, (13') -NR6R6', kde substituenty R6 a R6' sú definované vyššie, (14’) -SC>2NR6R6', kde substituenty R6 a R6' sú definované vyššie, (15’) -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie, (16') aryloxy skupiny, (17') arylalkoxy skupiny, (18') arylu, (19') hydroxy skupiny, a (20') heterocyklu, (g) heterocyklu, kde heterocyklus môže byť prípadne substituovaný 1, 2 alebo 3 skupinami nezávisle vybranými zo skupiny pozostávajúcej z (i) alkylu, (ii) alkanoylu, (iii) alkoxy skupiny, (iv) -CO2R4, kde substituent R4 je definovaný vyššie, (v) alkanoyloxy skupiny, (vi) karboxaldehydu, (vii) cykloalkylu, (viii) cykloalkenylu, (ix) halogénu, «··· ·· · ·· • ·· · · ·· · · · • · · · · · · • · · · · ···· ··· · · · · · ·· ··· ·· ··· ·· * (x) nitro skupiny, (xi) perfluóralkylu, (xii) perfluóralkoxy skupiny, (xiii) -NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xiv) -SO2NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xv) -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie, (xvi) aryloxy skupiny, (xvii) arylalkoxy skupiny, (xviii) arylu, (xix) hydroxy skupiny, a (xix) heterocyklu, (h) -NR6R8, kde substituenty R6 a R8 sú definované vyššie a (i) -N(R6)SO2R12, kde substituent R6 je definovaný vyššie a substituent R12 je vybraný zo skupiny pozostávajúcej z (i) alkylu, (ii) arylu, (iii) arylalkylu, (iv) heterocyklu, a (v) (heterocyklus)alkylu, kde (ii) -(v) môžu byť prípadne substituované 1,2 alebo 3 skupinami nezávisle vybranými zo skupiny pozostávajúcej z (ľ) alkylu, (21) alkanoylu, (31 *) alkoxy skupiny, (41) -CO2R4, kde substituent R4 je definovaný vyššie, (51) alkanoyloxy skupiny, (6‘) karboxaldehydu, (7') cykloalkylu, (8') cykloalkenylu, (9') halogénu, ···· · ·· · ·· • ·· · · ·· · · · • · · · · · · • · · · · · · · · ·· t·· · · ·· ··· ·· ··· ·· · (101) nitro skupiny, (1 ľ) perfluóralkylu, (12') perfluóralkoxy skupiny, (13') -NR6R6', kde substltuenty R6 a R6' sú definované vyššie, (141) -SO2NR6R6', kde substltuenty R6 a R6' sú definované vyššie, (15') -C(O)NR6R6', kde substltuenty R6 a R6' sú definované vyššie, (161) aryloxy skupiny, (171) arylalkoxy skupiny, (181) arylu, (19') hydroxy skupiny, a (20') heterocyklu, (3) -O(CH2)PR7, kde index p a substituent R7 sú definované vyššie a (4) -NR20R21, kde substltuenty R20 a R21, dohromady s dusíkovým atómom, ku ktorému sú pripojené, sú 3-členný až 7-členný kruh prípadne obsahujúci 1 alebo 2 dvojité väzby a prípadne obsahujúci časť vybranú zo skupiny pozostávajúcej z (a) atómu kyslíka, (b) atómu dusíka a (c) -S(O)X-, kde index x je 0 - 2, kde kruh tvorený substituentom R20 a R21 môže byť prípadne substituovaný 1,2 alebo 3 skupinami nezávisle vybranými zo skupiny pozostávajúcej z (ľ) alkylu, (21) alkanoylu, (31) alkoxy skupiny, (41) -CO2R4, kde substituent R4 je definovaný vyššie, (5‘) alkanoyloxy skupiny, (6') karboxaldehydu, (7') cykloalkylu, (8') cykloalkenylu, a · · t·· ·· • a ··· ·· ··· ·· (91) halogénu, (10') nitro skupiny, (1 ľ) perfluóralkylu, (12') perfluóralkoxy skupiny, (13') -NRÔR6', kde substituenty R6 a R6' sú definované vyššie, (14‘) -SO2NR6R6', kde substituenty R6 a R6' sú definované vyššie, (15') -C(O)NR6R6', kde substituenty R6 a R6' sú definované vyššie, (161) aryloxy skupiny, (17') arylalkoxy skupiny, (18') arylu, (19') hydroxy skupiny, a (201) heterocyklu;R R 7 is selected from the group consisting of (a) a hydrogen atom, (b) alkyl, wherein the alkyl may be optionally substituted with 1,2,3 or 4 substituents independently selected from the group consisting of (i) an oxo group, (ii) thioxo groups, (iii) alkoxy groups, (iv) -CO 2 R 4 , wherein R 4 is as defined above, (v) alkanoyloxy groups, (vi) carboxaldehyde, (vii) cycloalkyl, (viii) cycloalkenyl, (ix) halogen, (x) nitro groups, (xi) perfluoroalkyl, (xii) perfluoroalkoxy groups, (xiii) -NR 6 R 6 'wherein R 6 and R 6 ' are as defined above, (xiv) -SC> 2NR 6 R 6 ' wherein R 6 and R 6 'are as defined above, (xv) -C (O) NR 6 R 6 ', wherein R 6 and R 6 'are as defined above, (xvi) aryl, (xvii) hydroxy groups, and (xviii) heterocycle, (c) cycloalkyl, wherein the aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of (i) alkyl, (ii) halogen, (iii) oxo, and (iv) aryl, (d) aryl, wherein the aryl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of: (ii) alkanoyl, (iii) alkoxy, (iv) -CO 2 R 4 , wherein R 4 is as defined above, (v) alkanoyloxy, (vi) carboxaldehyde, (vii) cycloalkyl, (viii) cycloalkenyl, (ix) halogen, (x) nitro groups, (xi) perfluoroalkyl, (xii) perfluoroalkoxy groups, (xiii) -NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (xiv) -SO 2 NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (xv) -C (O) NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (xvi) aryloxy groups, (xvii) arylalkoxy groups, (xvi) aryl, (xvii) hydroxy groups, and (xviii) heterocycle, (e) -CO 2 R 4 wherein R 4 is as defined above, (f) -CONR 6 R 8 wherein R 6 is as defined above and R 8 is selected from the group consisting of (ii) alkyl, (iii) aryl, and (iv) heterocycle wherein (ii) - (iv) may be optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of (I ') alkyl, (2 ') alkanoyl, (3') alkoxy, (4 ' * * ) -CO 2 R 4 * , wherein R 4 is as defined above, (5') alkanoyloxy, (6 ') carboxaldehyde, ( 7 ') cycloalkyl, (8') cycloalkenyl, (9 1) halogen, (10 ') nitro, (I' 1) perfluoroalkyl, (12 ') perfluoroalkoxy, (13') -NR 6 R 6 'wherein the substituents R 6 and R 6 'are as defined above, (14') -SC> 2NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (15 ') -C (O) NR 6 R 6 ', wherein the substituents R 6 and R 6 'are as defined above, (16') aryloxy groups, (17 ') arylalkoxy groups, (18') aryl, (19 ') hydroxy groups, and (20') heterocycle, (g) heterocycle wherein the heterocycle may be optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of (i) alkyl, (ii) alkanoyl, (iii) alkoxy groups, (iv) -CO 2 R 4 , wherein R 4 is as defined above, (v) alkanoyloxy groups, (vi) carboxaldehyde, (vii) cycloalkyl, (viii) cycloalkenyl, (ix) halogen; ··· ······················································· (X) nitro groups, (xi) perfluoroalkyl, (xii) perfluoroalkoxy groups, (xiii) -NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (xiv) -SO 2 NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (xv) -C (O) NR 6 R 6 ', wherein R 6 and R 6 ' are as defined above, (xvi) aryloxy groups, (xvii) arylalkoxy groups, (xviii) aryl, (xix) hydroxy groups, and (xix) heterocycle, (h) -NR 6 R 8 wherein R 6 and R 8 are as defined above, and (i) -N (R 6) 6 ) SO 2 R 12 wherein R 6 is as defined above and R 12 is selected from the group consisting of (i) alkyl, (ii) aryl, (iii) arylalkyl, (iv) heterocycle, and (v) (heterocycle) alkyl, wherein (ii) - (v) may be optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of (1 ') alkyl, (2 L ) alkanoyl, ( (3 1 * ) alkoxy groups, (4 1 ) -CO 2 R 4 wherein R 4 is as defined above, (5 1 ) alkanoyloxy groups, (6 ') carboxaldehyde, (7') cycloalkyl, (8 ') cycloalkenyl, (9 ') halogen, · · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 (10 1 ) nitro groups, (1 ') perfluoroalkyl, (12') perfluoroalkoxy groups, (13 ') -NR 6 R 6 ', wherein the substituents R 6 and R 6 'are as defined above, (14 L ) -SO 2 NR 6 R 6 ', wherein the substituents R 6 and R 6 'are as defined above, (15') -C (O) NR 6 R 6 ', wherein the substituents R 6 and R 6' 'are as defined above, (16 L ) aryloxy groups, (17 L ) arylalkoxy groups, (18 L ) aryl, (19') hydroxy groups, and (20 ') heterocycle, (3) -O (CH 2) p R 7 where the index pa R 7 is as defined above and (4) -NR 20 R 21 , wherein the substituents R 20 and R 21 , together with the nitrogen atom to which they are attached, are a 3-membered to 7-membered ring optionally containing 1 or 2 double bonds and optionally comprising a moiety selected from the group consisting of (a) an oxygen atom, (b) a nitrogen atom, and (c) -S (O) X -, wherein the index x is 0-2, wherein the ring formed by R 20 and R 21 may optionally substituted by 1,2 or 3 groups independently selected from the group consisting of (I ') alkyl, (2 1) alkanoyl, (1 3) alkoxy, (4 1) -CO 2 R 4 wherein R 4 is as defined above, ( 5 ') alkanoyloxy groups, (6') carboxaldehyde, (7 ') cycloalkyl, (8') cycloalkenyl, and (9 L ) halogen, (10 ') nitro groups, (11') perfluoroalkyl, (12 ') perfluoroalkoxy groups, (13') -NR Ô R 6 'wherein R 6 and R 6 ' are as defined above, (14 ') -SO 2 NR 6 R 6 ', wherein the substituents R 6 ' 6 and R 6 'are as defined above, (15') -C (O) NR 6 R 6 ', wherein the substituents R 6 and R 6 ' are as defined above, (16 L ) aryloxy groups, (17 ') arylalkoxy groups, (18 ') aryl, (19') hydroxy, and (20 L ) heterocycle;

X je hydroxyl alebo sulfanyl; aX is hydroxyl or sulfanyl; and

Y je atóm vodíka; aleboY is hydrogen; or

X a Y, spojené dohromady s atómom uhlíka, ku ktorému sú pripojené, vytvárajú karbonyl alebo tiokarbonyl.X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl.

V ďalšom uskutočnení poskytuje predložený vynález farmaceutický prípravok obsahujúci zlúčeninu vzorca I alebo farmaceutický prijateľnou soľ, ester alebo jej prekurzor liečiva v kombinácii s farmaceutický prijateľným nosičom.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.

V ďalšom uskutočnení poskytuje predložený vynález spôsob inhibície angiogenézy u cicavcov, pri potrebe takého ošetrenia, zahŕňajúceho aplikovanie farmaceutický prijateľného množstva zlúčeniny vzorca I pre cicavcov.In another embodiment, the present invention provides a method of inhibiting angiogenesis in a mammal in need of such treatment comprising administering to the mammal a pharmaceutically acceptable amount of a compound of Formula I.

Definícia termínovDefinition of terms

V tomto opise a priložených patentových nárokoch majú termíny nasledujúci význam.In this specification and the appended claims, the terms have the following meaning.

···· ·· · ·· • ·· · · ·· · · · • · · · · · · • · · · · · · · · • · · β ♦ · ·· ·· ··· ·· ··· ·· ·········· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ·

Termín alkanoyl“, ako je používaný tu, sa vzťahuje na alkylovú skupinu pripojenú na východiskovú molekulovú skupinu cez karbonylovú skupinu. Alkanoylové skupiny vynálezu môžu byť prípadne substituované.The term alkanoyl, as used herein, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. The alkanoyl groups of the invention may be optionally substituted.

Termín alkanoyloxy“, ako je používaný tu, sa vzťahuje na alkanoylovú skupinu pripojenú na východiskovú molekulovú skupinu cez atóm kyslíka. Alkanoyloxy skupiny vynálezu môžu byť prípadne substituované.The term alkanoyloxy, as used herein, refers to an alkanoyl group attached to the parent molecular moiety through an oxygen atom. The alkanoyloxy groups of the invention may be optionally substituted.

Termín alkyl“, ako je používaný tu, sa vzťahuje na radikál vytvorený odstránením jedného atómu vodíka z rozvetveného alebo nerozvetveného nasýteného uhľovodíka majúceho jeden až 12 atómov. Názorné uhľovodíkové skupiny zahŕňajúce metyl, etyl, n-propyl, izo-propyl, n-butyl, sefc-butyl, izo-butyl terc-butyl, apod. Alkylové skupiny vynálezu môžu byť prípadne substituované.The term alkyl, as used herein, refers to a radical formed by the removal of one hydrogen atom from a branched or unbranched saturated hydrocarbon having from one to 12 atoms. Illustrative hydrocarbon groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl tert-butyl, and the like. The alkyl groups of the invention may be optionally substituted.

Termín alkoxy“, ako je používaný tu, sa vzťahuje na vyššie definovanú nižšiu alkylovú skupinu pripojenú na východiskovú molekulovú časť cez atóm kyslíka a zahŕňajúcu napr. skupiny metoxy, etoxy, n-propoxy, n-butoxy, tercbutoxy, apod. Alkoxy skupiny vynálezu môžu byť prípadne substituované.The term alkoxy, as used herein, refers to a lower alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom and including, e.g. methoxy, ethoxy, n-propoxy, n-butoxy, tert-butoxy groups, and the like. The alkoxy groups of the invention may be optionally substituted.

Termín aminoacylová skupina“, ako je používaný tu, sa vzťahuje na radikál odvodený od prirodzene alebo neprirodzene sa vyskytujúcej aminokyseliny. Názorné aminoacylové skupiny zahŕňajú glycyl, alanyl, valyl, leucyl, izoleucyl, metionyl, seryl, treonyl, cysteinyl, fenylalanyl, homofenylalanyl a 0metyltyrozinyl v racemáte, δ alebo L konfigurácii.The term "aminoacyl group" as used herein refers to a radical derived from a naturally or unnaturally occurring amino acid. Illustrative aminoacyl groups include glycyl, alanyl, valyl, leucyl, isoleucyl, methionyl, seryl, threonyl, cysteinyl, phenylalanyl, homophenylalanyl and 0-methyltyrosinyl in the racemate, δ or L configuration.

Termín aryl“, ako je používaný tu, sa vzťahuje na monocyklické alebo bicyklické karbocyklické kruhové systémy majúce jeden alebo dva aromatické kruhy. Arylové skupiny zahŕňajú napr. fenyl, naftyl, 1,2-dihydronaftyl, 1,2,3,4tetrahydronaftyl, fluórenyl, indanyl, a indenyl. Bicyklické arylové skupiny tohto vynálezu môžu byť pripojené na východiskovú molekulovú skupinu cez nasýtenú alebo nenasýtenú časť skupiny. Arylové skupiny vynálezu môžu byť prípadne substituovanéThe term aryl ', as used herein, refers to monocyclic or bicyclic carbocyclic ring systems having one or two aromatic rings. Aryl groups include e.g. phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4tetrahydronaphthyl, fluorenyl, indanyl, and indenyl. The bicyclic aryl groups of the invention may be attached to the parent molecular moiety through a saturated or unsaturated moiety. The aryl groups of the invention may be optionally substituted

Termín arylalkoxy“, ako je používaný tu, sa vzťahuje na vyššie definovanú arylovú skupinu pripojenú na východiskovú molekulovú skupinu cez al• I ···· • · ·· • · · · • · · ··· ·· ·· • · · • · • · • · koxy skupinu. Arylalkoxy skupiny tohto vynálezu môžu byť prípadne substituované.The term "arylalkoxy", as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an α 1 I al “al al al al al al al al al al al al A alkoxy group. The arylalkoxy groups of this invention may be optionally substituted.

Termín arylalkyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú arylovú skupinu pripojenú na východiskovú molekulovú skupinu cez alkylovú skupinu. Arylalkylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "arylalkyl", as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group. The arylalkyl groups of this invention may be optionally substituted.

Termín aryloxy“, ako je používaný tu, sa vzťahuje na vyššie definovanú arylovú skupinu pripojenú na východiskovú molekulovú skupinu cez atóm kyslíka. Aryloxy skupiny tohto vynálezu môžu byť prípadne substituované.The term "aryloxy", as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The aryloxy groups of this invention may be optionally substituted.

Termín aryloyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú arylovú skupinu pripojenú na východiskovú molekulovú skupinu cez karbonylovú skupinu. Aryloylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "aryloyl", as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group. The aryloyl groups of the invention may be optionally substituted.

Termín aryloyloxy“, ako je používaný tu, sa vzťahuje na vyššie definovanú aryloylovú skupinu pripojenú na východiskovú molekulovú skupinu cez atóm kyslíka. Aryloyloxy skupiny tohto vynálezu môžu byť prípadne substituované.The term "aryloyloxy" as used herein refers to an aryloyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The aryloyloxy groups of this invention may be optionally substituted.

Termín aryloyloxyalkyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú aryloyloxy skupinu pripojenú na východiskovú molekulovú skupinu cez alkylovú skupinu. Aryloyloxyalkylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "aryloyloxyalkyl", as used herein, refers to an aryloyloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group. The aryloyloxyalkyl groups of this invention may be optionally substituted.

Termín aryloyloxyalkylkarbonyl“, ako je používaný tu, sa vzťahuje na vyššie definovanou aryloyloxy skupinu pripojenou na východiskovú molekulovú skupinu cez karbonylovú skupinu. Aryloyloxyalkylkarbonylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "aryloyloxyalkylcarbonyl", as used herein, refers to an aryloyloxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group. The aryloyloxyalkylcarbonyl groups of this invention may be optionally substituted.

Termín aryloyloxyalkylkarbonylalkyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú aryloyloxyalkylkarbonylovú skupinu pripojenú na východiskovú molekulovú skupinu cez alkylovú skupinu. Aryloyloxyalkylkarbonylalkylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "aryloyloxyalkylcarbonylalkyl", as used herein, refers to an aryloyloxyalkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group. The aryloyloxyalkylcarbonylalkyl groups of this invention may be optionally substituted.

···· » ·· · ·· • ·· · · ·· · · · • « · · · · · • ···· ···· ··· · · · · · • a ··· ·· ··· ························································ · ··· ··

Termín arylsulfonyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú arylovú skupinu pripojenú na východiskovú molekulovú skupinu cez SO2- skupinu. Arylsulfonylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "arylsulfonyl" as used herein refers to an aryl group, as defined herein, appended to the parent molecular moiety through an SO 2 group. The arylsulfonyl groups of this invention may be optionally substituted.

Termín arylsulfonylalkyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú arylsulfonylovú skupinu pripojenú na východiskovú molekulovú skupinu cez alkylovú skupinu. Arylsulfonylalkylové skupiny tohto vynálezu môžu byť prípadne substituované.The term "arylsulfonylalkyl", as used herein, refers to an arylsulfonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group. The arylsulfonylalkyl groups of this invention may be optionally substituted.

Termín benzyl“, ako je používaný tu, sa vzťahuje na vyššie definovanú fenylovú skupinu pripojenú na východiskovú molekulovú skupinu cez metylovú skupinu. Benzylové skupiny tohto vynálezu môžu byť prípadne substituované.The term benzyl, as used herein, refers to a phenyl group, as defined herein, appended to the parent molecular moiety through a methyl group. The benzyl groups of the invention may be optionally substituted.

Termín karboxaldehyd“, ako je používaný tu, sa vzťahuje na -CHO.The term carboxaldehyde, as used herein, refers to -CHO.

Termín karbonyl“, ako je používaný tu, sa vzťahuje na -C(O)-.The term carbonyl ', as used herein, refers to -C (O) -.

Termín karboxy“, ako je používaný tu, sa vzťahuje na -CO2H.The term carboxy ', as used herein, refers to -CO 2 H.

Termín cykloalkyl“, ako je používaný tu, sa vzťahuje na radikál derivovaný odstránením jediného atómu vodíka z nasýteného cyklického alebo bicyklického uhľovodíka a zahŕňa napr. skupiny cyklopropyl, cyklobutyl, cyklopentyl, cyklohexyl, adamantyl, norbornyl, apod. Cykloalkylové skupiny tohto vynálezu môžu byť prípadne substituované.The term cycloalkyl, as used herein, refers to a radical derived by removal of a single hydrogen atom from a saturated cyclic or bicyclic hydrocarbon and includes, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, norbornyl groups, and the like. The cycloalkyl groups of this invention may be optionally substituted.

Termín (cykloalkyl)alkyl sa vzťahuje na práve definovanú cykloalkylovú skupinu pripojenú na východiskovú molekulovú časť cez vyššie definovanú alkylovú skupinu a zahŕňa názorné skupiny napr. cyklopropylmetyl, cyklopentyletyl, 2-metyl-3-cyklopentylbutyl, cyklohexylmetyl, apod. (Cykloalkyl)alkylové skupiny vynálezu môžu byť prípadne substituované.The term (cycloalkyl) alkyl refers to a just defined cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above, and includes illustrative groups e.g. cyclopropylmethyl, cyclopentylethyl, 2-methyl-3-cyclopentylbutyl, cyclohexylmethyl, and the like. The (cycloalkyl) alkyl groups of the invention may be optionally substituted.

Termín cykloalkenyl“, ako je používaný tu, sa vzťahuje na monovalentný cyklický alebo bicyklický uhľovodík so štyrmi až dvanástimi atómami uhlíka majúcich aspoň dvojitú väzbu uhlík-uhlík. Cykloalkenylové skupiny tohto vynálezu môžu byť prípadne substituované.The term cycloalkenyl, as used herein, refers to a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbon atoms having at least a carbon-carbon double bond. The cycloalkenyl groups of this invention may be optionally substituted.

···· · ·· · ·· • ·· · · ·· · · · • · · · · · · ··· ··· ·· ·· ··· ·· ··· ······ · ························································

Termín halogén“, ako je používaný tu, sa vzťahuje na -F, -Cl, -Br alebo -I.The term halogen ', as used herein, refers to -F, -Cl, -Br, or -I.

Termín heterocyklus, ako je používaný tu, sa vzťahuje na akýkoľvek 5členný, 6-členný alebo 7-členný nasýtený kruh obsahujúci jeden až tri heteroatómy nezávisle vybrané zo skupiny pozostávajúcej z 1,2 alebo 3 atómov dusíka, jedného kyslíka a jedného dusíka a jedného atómu síry a jedného atómu dusíka; kde heteroatómy dusík a síra môžu byť prípadne oxidované a heteroatóm dusíka môže byť prípadne kvaternizovaný. Termín heterocyklus“, ako je používaný tu, tiež zahŕňa 5-členné, 6-členné alebo 7-čIenné aromatické kruhy majúce v kruhu jeden, dva alebo tri heteroatómy vybrané z N, O a S, a tiež zahŕňajúce benzo kondenzovaný analóg týchto 5-členných, 6-členných alebo 7členných heterocyklických aromatických kruhov. Názorné heterocykly vynálezu zahŕňajú, pyrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morfolinyl, piperazinyl, tiomorfolinyl, pyridyl, pyrimidinyl, chinolyl, furyl, benzofuryl, tienyl, tiazolyl, pyrimidyl, indolyl, imidazolyl, izotiazolyl, izoxazolyl, oxadiazolyl, oxazolyl, 1,2,3-oxadiazolyl, tienyl, triazolyl 1,3,4-tiadiazolyl a tetrazolyl, apod.The term heterocycle, as used herein, refers to any 5-membered, 6-membered or 7-membered saturated ring containing one to three heteroatoms independently selected from the group consisting of 1,2 or 3 nitrogen atoms, one oxygen and one nitrogen and one atom sulfur and one nitrogen atom; wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The term heterocycle 'as used herein also includes 5-membered, 6-membered or 7-membered aromatic rings having one, two or three heteroatoms selected from N, O and S in the ring, and also including a benzo fused analog of these 5- membered, 6-membered or 7-membered heterocyclic aromatic rings. Illustrative heterocycles of the invention include, pyrrolidinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl morpholinyl, piperazinyl, thiomorpholinyl, pyridyl, pyrimidinyl, quinolyl, furyl, benzofuryl, thienyl, thiazolyl, pyrimidyl, indolyl, imidazolyl, isothiazolyl, isoxazolyl, oxoxazolyl, oxoxyl, oxo, 2,3-oxadiazolyl, thienyl, triazolyl 1,3,4-thiadiazolyl and tetrazolyl, and the like.

Termín heterocyklus“, ako je používaný tu, tiež zahŕňa zlúčeniny vzorcaThe term "heterocycle" as used herein also includes compounds of the formula

kde Y* je vybraný zo skupiny pozostávajúcej z -C(O)- a -(C(R30)(R31))v -,kde substituenty R30 a R31 sú nezávisle vybrané zo skupiny pozostávajúcej z atómu vodíka a alkylu a index v je 1,2 alebo 3 a Z* je vybraný zo skupiny pozostávajúcej z -CH2-, -0-, -CH2S(O)t-, -CH20-, -CH2NR35 a -NR35-, kde, v každom prípade, substituent R35 je vybraný zo skupiny pozostávajúcej z atómu vodíka a alkylu.wherein Y * is selected from the group consisting of -C (O) - and - (C (R 30 ) (R 31 )) -, wherein R 30 and R 31 are independently selected from the group consisting of hydrogen and alkyl, and the index v is 1, 2 or 3 and Z * is selected from the group consisting of -CH 2 -, -O-, -CH 2 S (O) t -, -CH 2 O-, -CH 2 NR 35 and -NR 35 wherein, in each case, R 35 is selected from the group consisting of hydrogen and alkyl.

Termín heterocyklus“, ako je používaný tu, tiež zahŕňa bicyklické alebo tricyklické kruhy, kde akékoľvek vyššie zmienené heteroarylové kruhy sú kon···· · ·· · ·· • ·· · · ·· · • · · · · · I • ·· · · · ·· ·· ··· ·· ··· ·· · denzované na jeden alebo dva kruhy nezávisle vybrané zo skupiny pozostávajúcej z arylového kruhu, cykloalkylového kruhu, cykloalkenylového kruhu a iného monocyklického heteroarylového kruhu. Tieto heteroaryly zahŕňajú benzo[b]furanyl, benzo[b]tienyl, benzimidazolyl, cinolinyl, imidazo[4,5cjpyridinyl, chinazolinyl, tieno[2,3-c]pyridinyl, tieno[3,2-b]pyridinyl, tieno[2,3-b]pyridinyl, indolizinyl, a imidazo[l,2-a]pyridín a môžu byť pripojené na východiskovú molekulovú skupinu cez buď heretoarylovú skupinu alebo arylovú, cykloalkylovú alebo cykloalkenylovú skupinu, ku ktorej sú kondenzované. Heterocyklické skupiny tohto vynálezu môžu byť prípadne substituované.The term heterocycle 'as used herein also includes bicyclic or tricyclic rings, wherein any of the above-mentioned heteroaryl rings are conjugated. 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, cinolinyl, imidazo [4,5-c] pyridinyl, quinazolinyl, thieno [2,3-c] pyridinyl, thieno [3,2-b] pyridinyl, thieno [2] , 3-b] pyridinyl, indolizinyl, and imidazo [1,2-a] pyridine and may be attached to the parent molecular moiety through either a heretoaryl group or an aryl, cycloalkyl or cycloalkenyl group to which they are fused. The heterocyclic groups of this invention may be optionally substituted.

Termín hydroxy“, ako je používaný tu, sa vzťahuje na -OH.The term hydroxy 'as used herein refers to -OH.

Termín nitro“, ako je používaný tu, sa vzťahuje na -NO2.The term nitro ', as used herein, refers to -NO2.

Termín N-chrániaca skupina“, ako je používaný tu, sa vzťahuje na skupiny, ktoré sú zamerané na chránenie amino skupiny proti nežiaducim reakciám počas syntézy. Bežne používané Ύ-chrániace skupiny sú uvedené v knihe Greene, Protective Groups In Organic Synthesis, (John Wiley & Sons, New York (1991)). Bežné JV-chrániace skupiny zahŕňajú (a) acylové skupiny, napr. formyl, acetyl, propionyl, pivaloyl, ŕerc-butylacetyl, 2-chlóracetyl, 2-brómacetyl, trifluóracetyl, trichlóracetyl, ftalyl, o-nitrofenoxyacetyl, α-chlórbutyryl, benzoyl, 4-chlórbenzoyl, 4-brómbenzoyl a 4-nitrobenzoyl, (b) sulfonylové skupiny, napr. benzénsulfonyl a para-toluénsulfonyl, (c) skupiny tvoriace karbamát, napr. benzyloxykarbonyl, para-chlórbenzyloxykarbonyl, p-metoxybenzyloxykarbonyl, p-nitro-benzyloxykarbonyl, 2-nitrobenzyloxykarbonyl, p-brómbenzyloxykarbonyl, 3,4-dimetoxy-benzyloxykarbonyl, 3,5-dimetoxybenzyloxykarbonyl, 2,4-dimetoxybenzyloxykarbonyl, 4-metoxybenzyloxykarbonyl, 2-nitro-4, 5-dimetoxybenzyloxykarbonyl, 3,4,5-trimetoxybenzyloxykarbonyl, l-(pbifenylyl)-l-metyletoxykarbonyl, a a, a-dimety 1-3,5-dimetoxybenzyloxykarbonyl, benzhydryloxykarbonyl, /erc-butyloxykarbonyl, diizo-propylmetoxykarbonyl, izopropyloxykarbonyl, . etoxykarbonyl, metoxykarbonyl, alyloxykarbonyl, 2,2,2,-trichlóretoxykarbonyl, fenoxykarbonyl, 4-nitrofenoxykarbonyl, cyklo-pentyloxykarbonyl, adamantyloxykarbonyl, cyklohexyloxykarbonyl a fenyl-tiokarbonyl, (d) arylalkylové skupiny, napr. benzyl, trifenylmetyl a benzyloxymetyl a (e) silylové skupiny, napr. trimetylsilyl. Výhodné JV-chrániace ···· · ·· · ·· • ·· · · ·· · • · · · · · · • · · · ···· ··· ··· ·· ·· ··· ·· ··· ·· · skupiny sú formyl, acetyl, benzoyl, pivaloyl, /erc-butylacetyl, fenylsulfonyl, benzyl, ŕerc-butyloxykarbonyl (Boe) a benzyloxykarbonyl (Cbz).The term N-protecting group, as used herein, refers to groups that are aimed at protecting an amino group against undesired reactions during synthesis. Commonly used chrá-protecting groups are listed in Greene, Protective Groups In Organic Synthesis, (John Wiley & Sons, New York (1991)). Common N-protecting groups include (a) acyl groups, e.g. formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-bromobenzoyl, sulfonyl groups, e.g. benzenesulfonyl and para-toluenesulfonyl; (c) carbamate-forming groups, e.g. benzyloxycarbonyl, para-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitro-benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 4-dimethoxybenzyloxy nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, aa,? -dimethyl 1-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, tert-butyloxycarbonyl isopropyloxycarbonyl,. ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2, -trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl and phenylthiocarbonyl, (d) arylalkyl groups. benzyl, triphenylmethyl and benzyloxymethyl; and (e) silyl groups, e.g. trimethylsilyl. Advantageous JV-Protectors ··································· Groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boe) and benzyloxycarbonyl (Cbz).

Termín oxo“, ako je používaný tu, sa vzťahuje na (=0).The term oxo ', as used herein, refers to (= 0).

Termín perfluóralkoxy“, ako je používaný tu, sa vzťahuje na perfluóralkylovú skupinu pripojenú na východiskovú molekulovú skupinu cez atóm kyslíka.The term perfluoroalkoxy, as used herein, refers to a perfluoroalkyl group attached to the parent molecular moiety through an oxygen atom.

Termín perfluóralkyl“, ako je používaný tu, sa vzťahuje na alkylovú skupinu, v ktorej všetky atómy vodíka boli nahradené atómami fluoridu.The term perfluoroalkyl, as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.

Termín fenyl“, ako je používaný tu, sa vzťahuje na radikál vytvorený odstránením jedného atómu vodíka z benzénového kruhu. Fenylové skupiny tohto vynálezu môžu byť prípadne substituované.The term phenyl, as used herein, refers to a radical formed by the removal of one hydrogen atom from the benzene ring. The phenyl groups of the invention may be optionally substituted.

Termín prekurzor liečiva sa vzťahuje na zlúčeniny, ktoré sa rýchlo transformujú in vivo, čím sa získajú východiskové zlúčeniny vzorca I, napr. hydrolýzou v krvi. T. Higuchi a V. Stella poskytujú ďalší informácie o prekurzoroch liečiv v knihe Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Šerieš, American Chemical Society (1975). Príklady esterov použiteľných ako prekurzory liečiv pre zlúčeniny obsahujúce karboxylové skupiny môžu byť nájdené na stranách 14-21 knihy Bioreversible Carriers in Drug Design: Theory and Application, edited by E. B. Roche, Pergamon Press (1987).The term prodrug refers to compounds that rapidly transform in vivo to give starting compounds of formula I, e.g. hydrolysis in the blood. T. Higuchi and V. Stella provide further information on prodrugs in Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S Symposium Šeresh, American Chemical Society (1975). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of Bioreversible Carriers in Drug Design: Theory and Application, edited by E. B. Roche, Pergamon Press (1987).

Termín esterová skupina prekurzoru liečiva sa vzťahuje na akékoľvek rozličné skupiny tvoriace ester, ktoré sú hydrolyzované za fyziologických podmienok. Príklady esterových skupín prekurzorov liečiva zahŕňajú pivoyloxymetyl, acetoxymetyl, ftalidyl, indanyl a metoxymetyl, ako i ďalšie skupiny známe zo súčasného stavu techniky.The term prodrug ester group refers to any of the various ester-forming groups that are hydrolyzed under physiological conditions. Examples of drug prodrug ester groups include pivoyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as other groups known in the art.

Termín farmaceutický prijateľný ester sa vzťahuje na estery, ktoré sa hydrolyzujú in vivo a zahŕňajú tie, ktoré sa ľahko odštiepia v ľudkom tele a opustia tak východiskovú zlúčeninu alebo jej soľ. Vhodné esterové skupiny zahŕňajú napr. tie, ktoré sú odvodené od farmaceutický prijateľných alifatických ···· · ·· · ·· · • ·· · · ·· · · ·· • · ··· · · · • ···· · · · · · ··· ··· ··· ·· ··· ·· ··· ·· ··· karboxylových kyselín, hlavne alkánových, alkénových, cykloalkánových a alkándiových, v ktorých každá alkylová alebo alkenylová časť nemá výhodne viac ako 6 atómov uhlíka. Príklady jednotlivých esterov zahŕňajú formiáty, acetáty, propionáty, butyráty, akryláty a etylsukcináty.The term pharmaceutically acceptable ester refers to esters that hydrolyze in vivo and include those that are readily cleaved in the human body leaving the parent compound or salt thereof. Suitable ester groups include e.g. those derived from pharmaceutically acceptable aliphatic aliphatic aliphatic; Carboxylic acids, in particular alkanoic, alkene, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety preferably has no more than 6 carbon atoms. Examples of individual esters include formates, acetates, propionates, butyrates, acrylates and ethyl succinates.

Termín sulfanyl“, ako je používaný tu, sa vzťahuje na -SH.The term sulfanyl, as used herein, refers to -SH.

Termín tiokarbonyl“, ako je používaný tu, sa vzťahuje na -C(S)-.The term thiocarbonyl, as used herein, refers to -C (S) -.

Termín tioxo“, ako je používaný tu, sa vzťahuje na =S.The term thioxo ', as used herein, refers to = S.

Ako je uvedené vyššie v generickom chemickom štruktúrnom vzorci I majú zlúčeniny vynálezu aspoň jedno chirálne centrum označené číselne napr.As mentioned above in the generic chemical structural formula I, the compounds of the invention have at least one chiral center designated numerically e.g.

„1“. Pokiaľ Y je atóm vodíka majú zlúčeniny tiež aspoň jedno ďalšie chirálne centrum označené číslom „2“ v generickom vzorci. Zatiaľ čo zlúčeniny majúce buď “R,“ “S“ alebo “R,S“ chiralitu podľa svojej konfigurácie, výhodné zlúčeniny predloženého vynálezu sú také, v ktorých chiralita v polohe označenej “1“ je R a chiralita v polohe označenej “2“ je S. Stereochemické označenie “R“ a “S“ je podľa ustanovenej konvencie R.S.Cahn, et al., Angewandt Chemie, Int."1". When Y is a hydrogen atom, the compounds also have at least one additional chiral center designated by the number "2" in the generic formula. While compounds having either "R," "S" or "R, S" chirality according to their configuration, preferred compounds of the present invention are those wherein the chirality at the "1" position is R and the chirality at the "2" position is S. The stereochemical designations "R" and "S" are according to established convention RSCahn, et al., Angewandt Chemie, Int.

Ed. Engl., 5: 385-415(1966).Ed. Engl., 5: 385-415 (1966).

Diastereoizoméry majúce výhodnú stereochémiu (poloha 1) R a (poloha 2) S môžu byť syntetizované na základe uváženého výberu opticky čistých východiskových látok, asymetrickej syntézy alebo môžu byť separované zo zmesí diastereoizomérov spôsobmi, ktoré sú dobre známe v súčasnom stave techniky, napr. HPLC s reverznými fázami.Diastereoisomers having preferred stereochemistry (position 1) R and (position 2) S may be synthesized based on a deliberate choice of optically pure starting materials, asymmetric synthesis, or may be separated from mixtures of diastereoisomers by methods well known in the art, e.g. Reversed phase HPLC.

Zatiaľ čo zlúčeniny so štruktúrou odpovedajúcou vyššie uvedenému generickému vzorcu I spadajú do rozsahu vynálezu, výhodná podskupina zlúčeniny je definovaná štruktúrnymi vzorcami I, kde substituent R2 je -SRJ, kde substituent R5 je nižší alkyl, najvýhodnejšie, metyl alebo etyl.While compounds having a structure corresponding to the above generic formula I are within the scope of the invention, a preferred subgroup of the compound is defined by structural formulas I wherein R 2 is -SR J , where R 5 is lower alkyl, most preferably methyl or ethyl.

Ďalšia výhodná podskupina zlúčenín vynálezu sú zlúčeniny vzorca I, kde substituent R2 je cykloalkyl, výhodne čyklohexyl.Another preferred subgroup of compounds of the invention are compounds of formula I wherein R 2 is cycloalkyl, preferably cyclohexyl.

Ďalšia výhodná podskupina zlúčenín vynálezu sú zlúčeniny vzorca I, kde index m je jedna a substituent R2 je nižší alkyl, výhodne n-propyl.Another preferred subgroup of the compounds of the invention are compounds of formula I wherein m is one and R 2 is lower alkyl, preferably n-propyl.

···· · ·· · ·· • ·· · · ·· · · ····· · ·· · ·· · · · · ·

9 9 9 9 9 99 9 9 9 9

9 9 9 9 9 9 9 99 9 9 9 9

999 99 999 99 999999 99 999 99 999

Ďalšia výhodná podskupina zlúčenín vynálezu sú zlúčeniny vzorca I, kde X je hydroxy skupina alebo sulfanyl a Y je atóm vodíka, zvlášť výhodne je X hydroxyl.Another preferred subgroup of compounds of the invention are compounds of formula I wherein X is hydroxy or sulfanyl and Y is hydrogen, particularly preferably X is hydroxyl.

Ďalšia výhodná podskupina zlúčenín vynálezu sú zlúčeniny vzorca I, kde X a Y, spojené dohromady s atómom uhlíka, ku ktorému sú pripojené, vytvárajú karbonylovú alebo tiokarbonylovú skupinu, zvlášť výhodne karbonylovú skupinu.Another preferred subgroup of compounds of the invention are compounds of formula I wherein X and Y, taken together with the carbon atom to which they are attached, form a carbonyl or thiocarbonyl group, particularly preferably a carbonyl group.

Ďalšia výhodná podskupina zlúčenín vynálezu sú zlúčeniny vzorca I, kde substituent R3 je aminoacylová skupina odvodená od prirodzene vyskytujúcej sa aminokyseliny, kde dusíkový atóm na Y-konci aminoacylovej skupiny je pripojený na priamo susednú karbonylovú skupinu materskej molekulovej časti a C-koniec alebo karboxylová funkčná skupina aminoacylového zvyšku je prípadne a výhodne chránená skupinou chrániacou karboxyl.Another preferred subgroup of compounds of the invention are compounds of formula I, wherein R 3 is an aminoacyl group derived from a naturally occurring amino acid, wherein the nitrogen atom at the Y-terminus of the aminoacyl group is attached to the directly adjacent carbonyl group of the parent molecular moiety. the aminoacyl group is optionally and preferably protected with a carboxyl protecting group.

Skupiny chrániace karboxyl sú dobre známe odbornej verejnosti a sú detailnejšie opísané v kapitole 5 na strane 224 - 276 knihy „Protective Groups in Organic Synthesis,“ Second Edition, autorov T. W. Greene a P. G. M. Wuts, Kohn Wiley & Sons, Inc., New York, 1991, obsah je tu uvedený ako odkaz. Skupiny chrániace karboxyl zahŕňajú napr. estery, napr. substituované metylestery, substituované etylestery, substituované benzylestery, silylestery, oxazoly, 2-alkyl-l,3-oxazolíny, 4-alkyl-5-oxo-l,3-oxazolidíny, 5-alkyl-4-oxo-l,3dioxalány, ortoestery a amidy, napr. Υ,Υ-dialkylamidy, pyrolidinylamidy, piperidinylamidy, 5,6-dihydropiperidinylamidy, o-nitroanilidy a hydrazidy, napr. N-fenylhydrazidy a Ν,Ν'-dialkylhydrazidy.Carboxyl protecting groups are well known to those of ordinary skill in the art and are described in more detail in Chapter 5 on pages 224-276 of the book "Protective Groups in Organic Synthesis," Second Edition, by TW Greene and PGM Wuts, Kohn Wiley & Sons, Inc., New York, 1991, the contents of which are incorporated herein by reference. Carboxyl protecting groups include e.g. esters, e.g. substituted methyl esters, substituted ethyl esters, substituted benzyl esters, silyl esters, oxazoles, 2-alkyl-1,3-oxazolines, 4-alkyl-5-oxo-1,3-oxazolidines, 5-alkyl-4-oxo-1, 3dioxalanes, orthoesters and amides, e.g. Υ, Υ-dialkylamides, pyrrolidinylamides, piperidinylamides, 5,6-dihydropiperidinylamides, o-nitroanilides and hydrazides, e.g. N-phenylhydrazides and Ν, Ν'-dialkylhydrazides.

Špecifické príklady jednotlivých zlúčenín spadajúcich do rozsahu predloženého vynálezu zahŕňajú, ale nie je to nijak limitované:Specific examples of individual compounds within the scope of the present invention include, but are not limited to:

(2RS,3S,l’S)-Y-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamid, (2RS,3S, l’S)-Y-((l-etylkarboxamido)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamid, (2RS,3R,l’S)-Y-((l-etylkarboxamido)etyI)-3-amino-2-hydroxy-5-(metyltio)pentánamid ···· · ·· · ·· • ·· · · ·· · · • · · · · · · ··· ··· · · R· ··· ·· ··· ·· (2RS,3R, ľS)-.V-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamid, (2RS,3R)-JV-((2-fenyletyl)-3-amino-2-hydroxy-5-(metyltio)pentánamid, (2RS,3R)-JV-((3-fenylpropyl)-3-amino-2-hydroxy-5-(metyltio)pentánamid, (2RS,3R)-JV-(4-fenylbutyl)-3-amino-2'hydroxy-5-(metyltio)pentánamid, (2RS,3R)-jV-(2-(4-metoxyfenyl)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamid, (2RS,3R)-ň/-(2-(4-sulfónamidofenyl)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamid, (2RS,3R)-JV-(2-(2-pyridyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamid, (2RS,3R)-/V-(2-(4-fenoxyfenyI)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamid, (2RS,3R,l’S)-7\í-((l-etoxykarbonyI)etyl)-3-amino-2-hydroxy-5(etyltio)pentánamid, (2RS,3R)-JV-((4-fenyl)butyl)-3-amino-2-hydroxy-5-(etyltio)pentánamid, (2RS,3R)-J^-(3-(karboetoxy)etyl)-3-amino-2-hydroxy-5-(etyltio)pentánamid, (2RS,3R)-7V-(3-(karbobenzyloxy)etyl)-3-amino-2-hydroxy-5(etyltio)pentánamid, (2RS,3R)-JV-(3-(karboetoxy)propyl)-3-amino-2-hydroxy-5-(etyltio)pentánamid, (2RS,3R, 1 ’ S)-7V-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-heptánamid, (2RS,3R)-3-amino-2-hydroxy-5-(metyltio)pentánová kyselina, (2RS,3R)-JV-(2-(4-pyridyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamid, (2RS,3R)-JV-(2-(karboetoxy)etyl)-3-amino-2-hydroxy-4-fenyl-butánamid, (2RS,3R)-Y-(3-(karboetoxy)propyl)-3-amino-2-hydroxy-4-fenyl-butánamid, (2RS,3R)-JV-(4-fenylbutyl)-3-amino-2-hydroxy-4-fenyl-butánamid, (2RS,3R,l’S)-jV-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-4cyklohexylbutánamid, (2RS,3R)-JV-(2-(karboetoxy)etyl)-3-amino-2-hydroxy-4-cyklohexyl-butánamid, (2RS,3R)-7V-(3-(karboetoxy)propyl)-3-amino-2-hydroxy-4cyklohexylbutánamid, (2RS,3R, l’S)-7V-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-4-fenyl-butánamid, (2RS,3R)-3-amino-2-hydroxy-/V-(4-metoxyfenetyl)-5(metylsulfanyl)pentánamid, ···· · ·· · ·· • ·· · · ·· · · • · · · · · · • 1«·· ···· · ··· ·· ··· ·· (2RS,3R)-AT-((2-fenylbutyl)-3-/erc-butoxykarbonylamino-2-hydroxy-5(etyltio)-pentánamid, (2RS,3R)-7V-((2-fenylbutyl)-3-acetylamino-2-hydroxy-5-(etyltio)pentánamid, (2RS,3R)-JV-((fenylbutyryI)-3-amino-2-hydroxy-4-cyklohexyl)butánamid, (2RS,3R)-/V-((fenylbutyryl)-3-metoxykarbonylamino-2-hydroxy-4etyltio)pentánamid, (2RS,3R)-Ar-(2-(3-pyridyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamid, (2RS,3R)-3-amino-2-hydroxy-/7-metyl-5-(metylsulfanyl)-7V-fenetylpentánamid, (2RS,3R,l’S)-/V-((2-karboxyetyl)-3-amino-2-hydroxy-4-etyltio)pentánamid, (2RS,3R)-Aľ-(( 1-metyl-1-etoxykarboxyetyl)-3-amino-2-hydroxy-4etyltio)pentánamid, (2RS.3R, l’S)-7V-((l-(2-hydroxy)-l-etoxykarboxyetyl)-3-amino-2-hydroxy-4etyltio)pentánamid, (2RS,3R)-7V-((fenylbutyryl)-3-/erc-butoxykarbonylamino-2-hydroxy-4-etyltio)pentánamid, (2RS,3R)-7V-((fenylbutyryl)-3-formy lamino-2-hydroxy-4-etyltio)pentánamid, (2RS,3R)-/V-Metyl-y-((etoxykarbonylmetyl)-3-amino-2-hydroxy-4etyltio)pentánamid, (2RS, 3 R)-JV-((Fenylbutyryl)-3-hydroxy metylkarbony lamino-2-hydroxy-4etyltio)pentánamid, (2RS,3R, l’R)-JV-((l-etoxykarbonyletyl)-3-amino-2-hydroxy-4etyltio)pentánamid, (2RS,3R, 1 'R)-JV-((l-etoxykarbonyletyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R)-/V-((1-metyl-l-etoxykarbonyletyl)-3-amino-2-hydroxy-4-cyklohexyl) butánamid, (2RS, 3R)-JV-((Feny lbutyryl)-3-metoxy karbonyl mety lamino-2-hy droxy-4etyltio)-pentánamid, (2RS,3R, l’S)-JV-((l-etoxykarbonyletyl)-3-amino-2-hydroxy-4benzy ltio)butánamid, (2RS,3R,l’S)-/V-((2-hydroxy-l-etoxykarbonyletyl)-3-amino-2-hydroxy-4cyklohexyl)-butánamid, (2RS,3R, l’S)-JV-((2-acetoxypropyI)-3-amino-2-hydroxy-4cyklohexyl)butánamid, ···· a · a a aa a aa a a aa a a a aa ata aa aaa a· a (2RS,3R,2’S)-JV-((2-propionyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R,2’S)-/V-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R,2’R)-JV-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R,2’R)-/V-((2-propionyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R,2’R)-/V-((2-acetoxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R, 1 ’ S)-A-((l-benzyloxykarbonyletyl)-3-amino-2-hydroxy-4-cyklohexyl)butánamid, (2RS,3R, l’S)-y-(4-etoxykarbonyl-2-(ľ-aminoetyl)tiazol)-3-amino-2-hydroxy4-cyklohexyl)-butánamid, (2RS,3R)-JV-(monodansylkadaveno)-3-amino-2-hydroxy-4cyklohexyl)butánamid, di (2RS,3R)-JV-(2-metyl-5-nitro-imidazol-etyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, di (2RS,3R)-/V-(5-nitropyridyl-2-aminoetyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R)-JV-(5-metoxy-tryptaminyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R)-.W-(3-0-metyl-dopaminyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, (2RS,3R)-JV-(2-aminometylbenzimidazolyl)-3-amino-2-hydroxy-4cyklohexyl)butánamid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyI)butanoyl-L-alanyl-(2-metyl-5nitroimidazolyl-etyl)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(5nitropyridy l-aminoetyl)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(etylizonipekotát)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoylL-alanyl-(2-pyrolidino-propyl)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(5-metoxy24 ···· ·· ·· · ·· • ·· · · ·· » · • · ··· · f ·(2RS, 3S, 1'S) -Y - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-5 (methylthio) pentanamide, (2RS, 3S, 1'S) -Y - ((1-ethylcarboxamido) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide, (2RS, 3R, 1'S) -Y - ((1-ethylcarboxamido) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide ··· · ··· · · · · · · · · · · · · · · · · · · · · (2RS, 3R (1S) - N - ((1-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 (2RS, 3R) -N- (2- (4-methoxyphenyl) ethyl) -3-amino-2-hydroxy-5 (methylthio) -phenylbutyl) -3-amino-2'hydroxy-5- (methylthio) pentanamide 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, 1'S) -7H- ( (1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-5 (ethylthio) pentanamide, (2RS, 3R) -N - ((4-phenyl) butyl) -3-amino-2-hydroxy-5- ( (2RS, 3R) -N- (3- (carboethoxy) ethyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide, (2RS, 3R) -7H- (3- (carbobenzyloxy) ethyl) (ethyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide, (2RS, 3R) -N- (3- (carboethoxy) propyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide, (2RS, 3R, 1'S) - N - ((1-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) -Y- (3- (carboethoxy) propyl) -3-amino-2-hydroxy-4-phenyl-butanamide, ( 2RS, 3R) -N- (4-phenylbutyl) -3-amino-2-hydroxy-4-phenylbutanamide, (2RS, 3R, 1'S) -N - ((1-ethoxycarbonyl) ethyl) -3-amino- 2-hydroxy-4cyclohexylbutanamide, (2RS, 3R) -N- (2- (carboethoxy) ethyl) -3-amino-2-hydroxy-4-cyclohexylbutanamide, (2RS, 3R) -7H- (3- (carboethoxy) ) propyl) -3-amino-2-hydroxy-4cykloh (2RS, 3R, 1'S) -7H - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-4-phenylbutanamide, (2RS, 3R) -3-amino-2-hydroxy-. N - (4-Methoxyphenethyl) -5 (methylsulfanyl) pentanamide, 1 · 1 · 1 · 1 (2RS, 3R) -AT - ((2-phenylbutyl) -3- tert -butoxycarbonylamino-2-hydroxy-5 (ethylthio) pentanamide, (2RS, 3R) -7V - ((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, 1'S) - N - ((2-carboxyethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide, (2RS, 3R) - N 1 - ((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-ethyl) io) pentanamide, (2RS, 3R) -7 N - ((phenylbutyryl) -3- tert -butoxycarbonylamino-2-hydroxy-4-ethylthio) pentanamide, (2RS, 3R) -7 N - ((phenylbutyryl) -3-forms) lamino-2-hydroxy-4-ethylthio) pentanamide, (2RS, 3R) - N-Methyl-γ - ((ethoxycarbonylmethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide, (2RS, 3 R) -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-4cyclohexyl) butanamide, (2RS, 3R) - N - ((1-methyl-1-ethoxycarbonylethyl) (2RS, 3R) -N - ((Phenylbutyryl) -3-methoxycarbonylmethylamino-2-hydroxy-4-ethylthio) -pentanamide, (2RS, 3-amino-2-hydroxy-4-cyclohexyl) butanamide; 3R, 1'S) -N - ((1-ethoxycarbonylethyl) -3-amino-2-hydroxy-4-benzylthio) butanamide, (2RS, 3R, 1'S) - N - ((2-hydroxy-1-ethoxycarbonylethyl) -3 -amino-2-hydroxy-4cyclohexyl) -butanamide, (2RS, 3R, 1'S) -N - ((2-acetoxypropyl) -3-amino-2-hydroxy-4cyclohexyl) butanamide, ··· a · aa aa a aa aa aa aaa aa ata aa aaa a · And (2RS, 3R, 2'S) -N - ((2-propionyloxypropyl) -3-amino-2-hydroxy-4cyclohexyl) butanamide, (2RS, 3R, 2'S) - N - ((2-benzoyloxypropyl) -3 -amino-2-hydroxy-4cyclohexyl) butanamide, (2RS, 3R, 2'R) -N - ((2-benzoyloxypropyl) -3-amino-2-hydroxy-4cyclohexyl) butanamide, (2RS, 3R, 2'R) N - ((2-propionyloxypropyl) -3-amino-2-hydroxy-4cyclohexyl) butanamide, (2RS, 3R, 2'R) - N - ((2-acetoxypropyl) -3-amino-2- (2RS, 3R, 1'S) -A - ((1-benzyloxycarbonylethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide, (2RS, 3R, 1'S) -y- (hydroxy-4-cyclohexyl) butanamide; 4-Ethoxycarbonyl-2- (1'-aminoethyl) thiazole) -3-amino-2-hydroxy-4-cyclohexyl) butanamide, (2RS, 3R) -N- (monodansylcadaveno) -3-amino-2-hydroxy-4cyclohexyl) butanamide di (2RS, 3R) -N- (2-methyl-5-nitro-imidazol-ethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide, di (2RS, 3R) - N - (5-nitropyridyl) (2RS, 3R) -N- (5-methoxy-tryptaminyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide, (2RS, 3R) -2-aminoethyl) -3-amino-2-hydroxy-4cyclohexyl) butanamide; N- (3-O-methyl-dopaminyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide, (2R) S, 3R) -N- (2-aminomethylbenzimidazolyl) -3-amino-2-hydroxy-4cyclohexyl) 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-nitropyridyl-1-aminoethyl) amide, ((2RS, 3R) 3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (ethyl isonipecotate) amide, ((2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl- (2-pyrrolidino) -propyl) amide, ((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl- (5-methoxy24) ··· ··· · · · ··· · · · ··· · f ·

1···· · « · I · • · · · · é ·· ··· ·· ··· ·· ·· tryptamín)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(3-0-metoxydopamín)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(2benzimidazol-metyl)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(5-fenylpyrazol-3)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(2-hydroxy-5nitro-l)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyI-L-alanyl-(5-brómtiazol2)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(4-nitro-2hydroxyfenyl-l)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl-(letylpyrazol)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(etylizonipekotát)amid, ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(3imidazolylpropyl)amid, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-karboxy 1-2-(1amino)etyltiazol, etyl-(2RS,3R,2’S)-2-((-3-(acetylamino)-4-cyklohexyl-2hydroxybutanoyl)amino)propanoát, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4benzyloxykarbonylamino)butylamid, benzylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-beta-alanínu, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-monodansylkadaverín amid, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-(4-toluénsulfonyl)aminobutyl)-amid, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(2-4-toluénsulfony 1aminoetyl)amid, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-aminobutyl)amid, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(2-aminoetyl)amid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-A/-(4-(((3···· · ·· · ·· · ··· · ··· · · · · (trifluórmetyl)fenyl)sulfonyl)amino)butyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-JV-(4-(((3,4dimetoxyfenyl)sulfonyl)amino)butyl)-2-hydroxybutánamid, (2RS,3R)-jV-(4-(((4-(acetylamino)fenyl)sulfonyl)amino)butyl)-3-amino-4cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(4-((2naftylsulfonyl)amino)butyl)butánamid, benzylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanín-4sulfónamidu, benzylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu, cyklohexylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-Lalanínu,1 (Tryptamine) 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-benzimidazol-methyl) amide, ((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl- (5-phenylpyrazol-3) amide, ((2RS, 3R) -3-amino-2-hydroxy-4 -cyclohexyl) butanoyl-L-alanyl- (2-hydroxy-5-nitro-1) amide, ((2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl- (5-bromothiazole2) amide, ((2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl- (4-nitro-2-hydroxyphenyl-1) amide, ((2RS, 3R) -3-amino-2 (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl (ethyl isonipecotate) amide, ((2RS, 3R) -hydroxy-4-cyclohexyl) butanoyl-L-alanyl- (letylpyrazole) amide 3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (3-imidazolylpropyl) amide, (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl- (4-carboxy-1-2- (1-amino) Ethylthiazole, ethyl- (2RS, 3R, 2'S) -2 - ((- 3- (acetylamino) -4-cyclohexyl-2-hydroxybutanoyl) amino) propane oate, (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl- (4benzyloxycarbonylamino) butylamide, (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl-beta- alanine, (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl monodansylcadaverine amide, (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl- (4- (4 (2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (2-4-toluenesulfonylaminoethyl) amide, (2RS, 3R) -3-amino-2- (toluenesulfonyl) aminobutyl) amide (2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (2-aminoethyl) amide, (2RS, 3R) -3- hydroxy-4-cyclohexyl) butanoyl- (4-aminobutyl) amide 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-Y- (4 - ((2-naphthylsulfonyl) amino) butyl) -butane mid, (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, (2RS, 3R) -3-amino-2-hydroxy-4-cyclohexyl) butanoyl-Llanine cyclohexyl ester,

2-((fenylsulfonyl)metyl)benzylester (2RS,3R)-3-amino-2-hydroxy-4cyklohexyl)butanoyl-L-a!anínu, cyklopropylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-Lalanínu,(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-lalanine 2 - ((phenylsulfonyl) methyl) benzyl ester, (2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl cyclopropyl ester butanoyl-L-alanine,

4-/erc-butylbenzylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoylL-alanínu,(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine tert-butyl benzyl ester,

4-metoxykarbonylbenzylester (2RS,3R)-3-amino-2-hydroxy-4cyklohexyl)butanoyl-L-alanínu,(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine 4-methoxycarbonylbenzyl ester,

4-trifluórmetylbenzylester (2RS,3R)-3-amino-2-hydroxy-4cyklohexyl)butanoyl-L-alanínu, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu-(fenacylester 4(metyl)fenyloctovej kyseliny), (2RS,3R)-3-amino-4-cyklohexyl-/V-(2,4-dichlórbenzyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3-metoxyfenyl)butánamid, metyl-(2RS,3R,2’R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-4metylpentanoát, (2RS,3R)-3-amino-4-cyklohexyl-/V-(2-furylmetyl)-2-hydroxybutánamid, (2RS,3R, l’RS)-3-amino-4-cyklohexyl-2-hydroxy-/V-(l-(lnaftyl)etyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(3-(2-oxo-l pyrolidinyl)propyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-/V-(l,2-dimetylpropyl)-2-hydroxybutánamid, ·· • · · • · (2RS,3R)-3-amino-2-hydroxy-4-cykIohexyl)butanoyl-L-alanín, benzylester (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanín, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanín, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-fenylbutánamid, (2RS,3R)-3-amino-/V-(2-chlórfenetyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-TV-(3-fenylpropyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-//-(l,2,3,4-tetrahydro-lnaftalenyl)butánamid, (2RS,3R)-3-amino-JV-(4-(/erc-butyl)cyklohexyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-/V-(3,5-dichlórfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-/V-(2-etylhexyl)-2-hydroxybutánamid, butyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)acetát, (2RS,3R)-3-amino-jV-( 1,3-benzodioxol-5-yl mety l)-4-cyklohexy 1-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-/V-(2,4-dimetoxyfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(3-metoxy-5(trifluórmetyl)fenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-ÄT-decyl-2-hydroxybutánamid, (2RS,3R)-3-amino-/V-((lR,4S)bicyklo(2,2,l)hept-2-yl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-jV-(2-fluórbenzyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-AT-(4-fluór-3-(trifluórmetyl)benzyl)-2hydroxy-butánamid, (2RS,3R)-3-amino-4-cyklohexyl-/V-(l-(4-fluórfenyl)etyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(tetrahydro-2furanylmetyl)butánamid, etyl-(2RS,3R)-(4-((-3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-lpiperidínkarboxylát, (2RS,3R)-3-amino-/V-( 1,3-benzodioxol-5-yl)-4-cyklohexyl-2hydroxybutánamid,(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) phenylacetic acid phenacylester), (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, 1'RS) -3-amino-4-cyclohexyl-2-hydroxy- N - (1- (lnaphthyl) ethyl) butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-Y- (3- (2-oxo-1-pyrrolidinyl) propyl) butanamide, (2RS, 3R) (3-Amino-4-cyclohexyl- N - (1,2-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 -phenylbu (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-1H - (1,2,3,4-tetrahydro-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- (1,3-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 - ((1R, 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-hydroxy-butanamide, (2RS, 3R) -3-amino-4-cyclohexyl- N - ( 1- (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) -1-piperidinecarboxylate, (2RS, 3R) -3-amino- N - (1,3-benzodioxol-5-yl) -4- cyclohexyl-2hydroxybutánamid,

Zerc-butyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)acetát, metyl-(2RS, 3R)-2-((3-amino-4-cy klohexyl-2-hy droxy butanoyl)amino)-327 ·· ··· • · · ·· • · · · · · · :: : ·: :Tert-Butyl (2RS, 3R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) acetate, methyl (2RS, 3R) -2 - ((3-amino-4-cyclohexyl-2) -hyroxy-butanoyl) amino) -327 ::::::

• · ··· ·· · fenylpropanoát, metyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3metylpentanoát, metyI-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)hexanoát, metyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3metylbutanoát, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-((lS)-l-(2naftyl)etyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-((lR)-l-(2naftyl)etyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Ä/-((lS)-l-(lnaftyl)etyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-((lR)-l-(lnaftyl)etyl)butánamid, etyl-(2RS,3R,2’R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3fluórpropanoát, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/'/-(2-hydroxy-l(hydroxymetyl)etyl)-butánamid,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 - ((1S) -1- (2-naphthyl) ethyl) butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy- N - ((1R) -1- (2naphthyl) ethyl) butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-N - ((1S) -1- (1naphthyl) ethyl) butanamide (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N - ((1R) -1- (lnaphthyl) 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 (hydroxymethyl) ethyl) ) butanamide.

4-(íerc-butyl)benzyl-(2RS,3R,2’R)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)-3-hydroxypropanoát, 4-nitrobenzyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)-3-hydroxy propanoát,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-hydroxy propanoate,

3- nitrobenzyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)3-hydroxypropanoát,3-nitrobenzyl- (2RS, 3R, 2'S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) 3-hydroxypropanoate,

4- (trifluórmetyl)benzyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)-3-hydroxypropanoát,4- (trifluoromethyl) benzyl- (2RS, 3R, 2'S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate,

3-(trifluórmetoxy)benzyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)-3-hydroxypropanoát, (2RS, 3R)-3-amino-4-cyklohexy l-A/-(4-fluórfenetyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(4-metylfenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-?/-(4-fluórfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(4-metoxyfenyl)butánamid, (2RS,3 R)-3-amino-4-cyklohexy l-2-hydroxy-/V-(2-metoxy fény l)butánamid, ···· · ·· · ·· ··· ···· r · · • · · · · · · ··· · < · · · • a aaa ·· ·· ·· · (2RS,3R)-3-amino-N-(4-chlórfenyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-/V-(3-chlórfenyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-7V-(2-chlórfenyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-.W-(4-(/erc-butyl)fenyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-W-(3(trifluórmetyl)fenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(4(trifluórmetyl)fenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2V-(3,4-dichlórfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-Á/-(2,4-dichlórfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-/V-(4-brómfenyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-7V-(4-(/erc-butyl)benzyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(3(trifluórmetyl)benzyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-y-(4(trifluórmetyl)benzyl)butánamid, (2RS,3R)-3-amino-/V-(2-chlórbenzyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-y-(2-metoxy-5nitrofenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2V-(3,5-dimetoxyfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-y-(3-fenoxyfenyl)butánamid, (((2RS,3R)-3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)(2,5dimetoxybenzyl)chlorónium, (2RS,3R)-3-amino-4-cyklohexyl-Áf-(2,4-dichlórfenetyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-AT-(2,6-dichlórfenetyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-/V-(3-fluórfenetyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-2V-(3,4-bis(benzyloxy)fenetyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-2V-(4-fenoxyfenetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-W-(2(trifluórmetoxy)fenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-y-(3(trifluórmetoxy)fenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7^-(2-metylfenyl)butánamid, • · ·· · ·· · ·· • ·· ···· · · · • · · · · · · • · « m W b··· ··· · « · 4 ·· ··» ·· ··· «· · (2RS,3R)-3-amino-4-cyklohexyl-A/-(2,6-di mety lfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(4-jód-2-metylfenyl)butánamid, (2RS,3R)-3-amino-JV-(4-anilino-2-metoxyfenyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2V-(2-etoxyfenyl)-2-hydroxybutánamid, (2RS, 3R)-3-amino-2V-(4-chlór-2-metoxy-5-mety lfenyl)-4-cyklohexy 1-2hydroxy-butánamid, (2RS,3R)-3-amino-4-cyklohexyl-JV-(2,5-dimetoxyfenyl)-2-hydroxybutánamid, (2RS,3R)-7V-(5-(acetylamino)-2-metoxy fény l)-3-amino-4-cyklohexy 1-2hydroxy-butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-jV-(2-metoxydibenzo(b, d)furan-3yl)butánamid, (2RS,3R)-3-amino-jV-(5-chlór-2,4-dimetoxyfenyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-AT-(2,5-dietoxyfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-JV-(5-(/ez'c-butyl)-2-metoxyfenyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(2-fenoxyfenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(2-metyl-5-nitrofenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-2V-(4-fenoxyfenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7\í-(4-metoxybenzyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(4-metylbenzyl)butánamid, (2RS,3R)-3-amino-JV-(3-chlórbenzyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(3-metoxybenzyl)butánamid, (2RS,3R)-3-amino-/V-(4-brómbenzyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-2V-(3-metylbenzyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-fenetylbutánamid, (2RS,3R)-3-amino-/V-(4-chlórbenzyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-A-(4-metylfenetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(4-metoxyfenetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(3-metoxyfenetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(2-metoxyfenetyl)butánamid, (2RS,3R)-3-amino-2V'-(4-chlórfenetyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-/V-(3-chlórfenetyl)-4-cyklohexyl-2-hydroxybutánamid, ·· ·· ·· · · · (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(3(trifluórmetyl)fenetyl)butánamid, (2RS,3R)-3-amino-jV-(4-brómfenetyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-7V-(l-adamantyl)-3-amino-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-JV-(2-adamantyl)-3-amino-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-Aľ-cykloheptyl-4-cy klohexy 1-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cy klohexy l-7y-(cyklohexylmetyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-N,4-dicyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2V-cyklopentyl-2-hydroxybutánamid, (2RS,3R)-3-amino-JV-cyklobutyI-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-jV-(l-mety 1-3fenylpropyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7\/-(l-metyl-2-(3(trifluórmetyl)fenyl)etyl)-butánamid, (2RS,3R)-3-amino-4-cyklohexyl-/ý-(l,5-dimetylhexyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(l-metylhexyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7^-(3-izopropoxypropyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3-izobutoxypropyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7'/-(4-(4-morfolinyl)fenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-Y-(3,3-difenylpropyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-Y-(l,4-dimetylpentyl)-2-hydroxybutánamid, (2RS, 3R)-3-amino-4-cyklohexy Ι-2-hydroxy-Y-mety l-7V-( 1 -nafty lmetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7^-metyl-/V-((lS)-l-(l-naftyl)etyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-2V-(2-metoxy-5-(trifluórmetyl)fenyl)-butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(4-metoxy(l, ľ-bifenyl)-3yl)butánamid, (2RS, 3R)-3-amino-4-cy klohexy 1-Ύ-(2,3-dihydro-1,4-benzodioxi n-6-yl)-2hydroxy-butánamid, (2RS,3R)-3-amino-/V-(3-(benzyloxy)fenyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cy klohexy 1-jV-(3-etoxyfenyl)-2-hydroxybutánamid, «··· · ·· · ·· · • ·· · · ·· 9 · ·· • · · · · · · · · ··· · 4 · · · · ·· ··· ·· ··· ·· ··· (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-.y-(3,4,5-trimetoxyfenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-W-(2-(2-fluórfenyl)-l-metyletyl)-2hydroxybutánamid, (2RS,3R)-3-amino-4-cykIohexyl-2V-(2-(4-fluórfenyl)-l,l-dimetyletyl)-2hydroxy-butánamid, (2RS, 3 R)-3-amino-4-cyklohexyl-A-(2,3-dihydro-1 H-inden- 1-y l)-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-.W-((lS,2R)-2fenylcyklopropyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(l,l,3,3tetrametylbutyl)butánamid, (2RS,3R)-3-amino-4-cyklohexy 1-//-( 1,3-dimetylbutyl)-2-hydroxybutánamid, metyl-4-(((2RS,3R)-3-amino-4-cyklohexyl-2-hydroxybutanoyI)amino)-3tiofénkarboxylát, (2RS,3R)-/V-(l-(l-adamantyl)etyl)-3-amino-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-((S)-(-)-(lnaftyl)etyl)amid, (2RS,3 R)-3-amino-4-cyklohexyl-2-hydroxy-7/-( 1 -nafty lmetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-//-(3(trifluórmetoxy)benzyl)butánamid, (2RS,3R)-3-amino-//-(3,5-bis(trifluórmetyI)benzyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-(trifluórmetyl)benzy l)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-//-(4-(trifluórmetoxy)benzyl)butánamid, (2RS,3R)-3-amino-/V-(6-chIór-3-pyridinyl)-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-N-(6-metyl-2-pyridinyl)butánamid, (2RS,3R)-3-amino-/V-(5-chlór-2-metoxyfenyl)-4-cyklohexyl-2hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-metoxy-5-metylfenyl)butánamid, (2RS,3R)-3-amino-//-(4-chlór-2,5-dimetoxyfenyl)-4-cyklohexyl-2hydroxybutánamid, ···· φ ·· • ·· · · · ·· • · · • · ·· ··· ·· ··· (2RS,3R)-3-amino-4-cyklohexyl-/V-(2,3-dimetoxyfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-7V-(3,4-dimetoxyfenyl)-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(3-metoxy-4metylfenyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(4-metoxy-2-naftyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(2-tienylmetyl)butánamid, (2RS,3R)-3-amino-7V-butyl-4-cyklohexyl-2-hydroxy-7V-metylbutánamid, (2RS,3R)-3-amino-4-cyklohexyl-l-(2,6-dimetyl-4-morfolinyl)-2-hydroxy-lbutanón, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7^,iV-bis(metoxymetyl)butánamid, (2RS,3R)-3-amino-4-cyklohexyl-l-[3,4-dihydro-2(lH)-izochinolinyl]-2hydroxy-l-butanón, (2RS,3R)-3-amino-l-(l-azepanyl)-4-cyklohexyl-2-hydroxy-l-butanón, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-l-[4-fenyl-3,6-dihydro-l(2H)pyridinyl]-l-butanón, (2RS,3R)-3-amino-7V-benzyl-/V-butyl-4-cyklohexyl-2-hydroxybutánamid, (2RS,3R)-3-amino-4-cyklohexyl-l-[(2R,6S)-2,6-dimetylmorfolinyl]-2-hydroxy1- butanón, (2RS,3R)-3-amino-2V-[(2-chlór-2,3,5-cyklohexatrien-l-yl)metyl]-4-cyklohexyl2- hydroxy-/V-metylbutánamid, (2RS,3R)-3-amino-y-(l ,3-benzodioxol-5-ylmetyl)-4-cyklohexyl-2-hydroxy-JVmetylbutánamid, (2RS,3R)-3-amino-4-cyklohexyl-2\í-(2,4-dichlórbenzyl)-/V-etyl-2hydroxybutánamid, etyl- 3-[[(2RS,3R)-3-amino-4-cyklohexyl-2-hydroxybutanoyl](benzyl)aminojpropanoát, (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-l-(l -piperidinyl)-l-butanón.3- (Trifluoromethoxy) benzyl (2RS, 3R, 2'S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate, (2RS, 3R) -3-amino-4-cyclohexyl 1A 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, (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2-methoxyphenyl) butanamide, ··· ··· ··· ··· And aaa (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 (trifl) (2RS, 3R) -3-Amino-4-cyclohexyl-N- (3,4-dichlorophenyl) -2-hydroxybutanamide, (2RS, 3R) -3-Amino-4-cyclohexyl-N- (2-methyl-phenyl) butanamide; - (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-γ- (4 (trifluoromethyl) benzyl) butanamide, (2RS, 3R) -3-amino- N - (2-chlorobenzyl) -4 -cyclohexyl-2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-γ- (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-γ- (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 , 3 R) -3-amino-4-cyclohexyl-N- (2,6-dichlorophenethyl) -2-hydroxy (2RS, 3R) -3-Amino-4-cyclohexyl-N- (3-fluorophenethyl) -2-hydroxybutanamide, (2RS, 3R) -3-amino-2H- (3,4-bis (benzyloxy)) (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4-phenoxyphenethyl) butanamide, (2RS, 3R) -3-Amino-4-cyclohexyl- (phenethyl) -4-cyclohexyl-2-hydroxybutanamide; 2-hydroxy-N- (2 (trifluoromethoxy) phenyl) butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-γ- (3 (trifluoromethoxy) phenyl) butanamide, (2RS, 3R) - 3-Amino-4-cyclohexyl-2-hydroxy-7 - [(2-methylphenyl) butanamide], (2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,6- (methylsulfonyl) -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-2H- (2-ethoxyphenyl) -2-hydroxybutanamide, (2RS, 3R) -3-Amino-N- (4-chloro-2-methoxy-5-methylphenyl) -4-cyclohexy-2-hydroxybutanes d, (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-AT- (2,5 (2RS, 3R) -3-Amino- N - (5- (tert -butyl) -2-methoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide, (2RS, 3R) -3-diethoxyphenyl) -2-hydroxybutanamide -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-2H- (4-phenoxyphenyl) butanamide, (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-7H- (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-2H- (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, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-Y- ( 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) -7- (1-adamantyl) -3-amino-4-cyclohexyl- 2-hydroxybutanamide, (2RS, 3R) -N- (2-adamantyl) -3-amino-4-cyclohexyl-2-hydroxyb utánamid, (2RS, 3R) -3-amino-L-cycloheptyl-4-cyclohexyl-1-2 hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-l 7y- (cyclohexylmethyl) -2 -hydroxybutanamide, (2RS, 3R) -3-amino-N, 4-dicyclohexyl-2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2H-cyclopentyl-2-hydroxybutanamide, (2RS, 3R) 3-amino-N-cyclobutyl-4-cyclohexyl-2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-N- (1-methyl-1-3-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- (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-7 '- (4- (4-morpholinyl) phenyl) butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-Y - (3,3-Diphenylpropyl) -2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-Y- (1,4-di) methylpentyl) -2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-Y-methyl-N- (1-naphthylmethyl) butanamide, (2RS, 3R) -3-amino 4-Cyclohexyl-2-hydroxy-7H-methyl- N - ((1S) -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-Y- (4-methoxy (1,1'-biphenyl) - 3yl) butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-6- (2,3-dihydro-1,4-benzodioxin-6-yl) -2-hydroxy-butanamide, (2RS, 3R) -3-amino- N - (3- (benzyloxy) phenyl) -4-cyclohexyl-2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-N- (3-ethoxyphenyl) -2 -hydroxybutanamide, 9 · 9 · 4 · 4 · 4 · 4 · 4 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- (3,4,5-trimethoxyphenyl) butanamide, (2RS, 3R) -3-amino- 4-Cyclohexyl-N- (2- (2-fluorophenyl) -1-methylethyl) -2-hydroxybutanamide, (2RS, 3R) -3-amino-4-cyclohexyl-N- (2- (4-fluorophenyl) -1,11); dimethylethyl) -2hydro xy-butanamide, (2RS, 3R) -3-amino-4-cyclohexyl-N- (2,3-dihydro-1H-inden-1-yl) -2-hydroxybutanamide, (2RS, 3R) -3-amino- 4-cyclohexyl-2-hydroxy-N - ((1S, 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-1H - (1,3-dimethylbutyl) -2-hydroxybutanamide, methyl 4 - (((2RS, 3R) -3-amino- 4-cyclohexyl-2-hydroxybutanoyl) amino) -3-thiophenecarboxylate, (2RS, 3R) -N- (1- (1-adamantyl) ethyl) -3-amino-4-cyclohexyl-2-hydroxybutanamide, (2RS, 3R) (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-3-amino-2-hydroxy-4-cyclohexyl) butanoyl - ((S) - (-) - (1-naphthyl) ethyl) amide 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) benzy (l) 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 - (2R) -methoxy-5-methylphenyl) butanamide, (2RS, 3R) -3-amino- N - (4-chloro-2,5-dimethoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide, ···· φ ·· · ··· (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-1- (2,6-dimethyl-4-morpholinyl) -2-hydroxy-1-butanone, (2RS, 3R) -3-amino-4-cyclohexyl-2- (2RS, 3R) -3-Amino-4-cyclohexyl-1- [3,4-dihydro-2 (1H) -isoquinolinyl] -2-hydroxy-1-butanone, hydroxy-N, N-bis (methoxymethyl) butanamide, (2RS, 3R) -3-Amino-1- (1-azepanyl) -4-cyclohexyl-2-hydroxy-1-butanone, (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-1- [4-phenyl-3,6-dihydro-1 (2H) -pyridinyl] -1-butanone, (2RS, 3R) -3-amino-N-benzyl- N -butyl-4-cyclohexyl-2-hydroxybutanamide, ( 2RS, 3R) -3-amino-4-cyclohexyl-1 - [(2R, 6S) -2,6-dimethylmorpholinyl] -2-hydroxy-1-butanone, (2RS, 3R) -3-amino-2H - [(2 (2-chloro-2,3,5-cyclohexatrien-1-yl) methyl] -4-cyclohexyl-2-hydroxy- N -methylbutanamide, (2RS, 3R) -3-amino-γ- (1,3-benzodioxole-5- (2RS, 3R) -3-Amino-4-cyclohexyl-2H- (2,4-dichlorobenzyl) - N -ethyl-2-hydroxybutanamide, ethyl-3-ylmethyl) -4-cyclohexyl-2-hydroxy-N-methylbutanamide [[(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxybutanoyl] (benzyl) amino] propanoate, (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-1- (1-piperidinyl) -l-butanone.

alebo ich farmaceutický prijateľné soli, estery alebo prekurzory liečiv.or pharmaceutically acceptable salts, esters or prodrugs thereof.

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Biologický testBiological test

Schopnosť zlúčenín predloženého vynálezu inhibovať metionínaminopeptidázu-2 sa stanovila pomocou nasledujúceho testu.The ability of the compounds of the present invention to inhibit methionine aminopeptidase-2 was determined using the following assay.

Rekombinantná metionínaminopeptidáza-2 (MetAP2) sa exprimovala ako sekrétovaný proteín bakulovírusovým systémom a čistila od insektného supernatantu bunkovej kultúry vyššie opísaným spôsobom R.L. Kendalom, et al., J. Biol. Chem., 267(29): 20667 - 20673 (1992) a Xuanom Li, et al., Biochem. And Biophys. Res. Comm., 227: 152 - 159 (1996), obsah tu je uvedený ako odkaz.Recombinant methionine aminopeptidase-2 (MetAP2) was expressed as a secreted protein by the baculovirus system and purified from the insect cell culture supernatant as described above by R.L. Kendal, et al., J. Biol. Chem., 267 (29): 20667-20673 (1992) and Xuan Li, et al., Biochem. And Biophys. Res. Comm., 227: 152-159 (1996), the contents of which are incorporated herein by reference.

Stanovenie enzýmovej aktivity MetAP2 a inhibície MetAP2 sa vykonávalo na mikrotitračných platniach s 96 jamkami. Zlúčeniny, ktoré sa testovali na inhibíciu MetAP2 sa rozpustili v dimetylsulfoxide na 10 mM a desaťkrát sa zriedili v pufre (50 nM HEPES, pH 7,4, 100 mM NaCl). Desať mikrolitrov roztoku každej zlúčeniny, ktorá sa testovala na inhibíciu, sa zaviedlo do každej jamky platne, každá zlúčenina sa testovala trikrát. Za nulovú hodnotu inhibície enzýmovej aktivity sa vzal výsledok, ktorý sa zobral od buniek, v ktorých bolo umiestnené 10 ml pufru a za 100% hodnotu inhibície enzýmovej aktivity sa vzal výsledok, ktorý sa zobral od buniek, v ktorých bolo umiestnené 10 mM fumagilínu (Sigma Chemical Co., St. Louis, MO, USA, Catalog No. F-6771) v 10 ml pufru.Determination of MetAP2 enzyme activity and MetAP2 inhibition was performed in 96-well microtiter plates. Compounds that were tested for MetAP2 inhibition were dissolved in dimethylsulfoxide to 10 mM and diluted ten times in buffer (50 nM HEPES, pH 7.4, 100 mM NaCl). Ten microliters of each compound tested for inhibition was introduced into each well of the plate, each compound tested three times. The zero inhibition value of the enzyme activity was taken from the cells in which 10 ml of buffer was placed and the 100% inhibition value of the enzyme activity was taken from the cells in which 10 mM fumagiline was placed (Sigma Chemical Co., St. Louis, MO, USA, Catalog No. F-6771) in 10 ml of buffer.

Zmes 90 μΐ (celkové množstvo na jednu skúmavku) a 84 ml pripraveného pufru, 1 μΐ L-aminokyselinovej oxidázy (Sigma Catalog No. A-9378, ~ llmg/ml), 1 μΐ peroxidázy z chrenu dedinského (Sigma Catalog No. P-8451, rozpustenej v pufri s koncentráciou 10 mg/ml), 1 μΐ tripeptidu Met-Ala-Ser (Bachem), rozpúšťaného v pufri s koncentráciou 50 mM), 1 ml orto-dianizidínu (Sigma Catalog No. D-1954, čerstvo pripravený roztok vo vode v koncentrácii lOmg/ml) a MetAP2 v konečnej koncentrácii 4 pg/ml sa rýchlo mieša a pridá do každej bunky obsahujúcej testovanú alebo kontrolnú zlúčeninu. Každých 20 sekúnd po dobu 20 minút sa merala absorbancia pri 450 nanometroch pomocou automatického platňového detektora (Molecular Devices, CA, USA). Pre každú skúmavku sa vypočítala hodnota Vmax v mOD/min uvádzajúca aktivitu MetAP2.Mixture of 90 μΐ (total per tube) and 84 ml of prepared buffer, 1 μΐ of L-amino acid oxidase (Sigma Catalog No. A-9378, ~ 11mg / ml), 1 μΐ of horseradish peroxidase (Sigma Catalog No. P- 8451, dissolved in 10 mg / ml buffer, 1 μΐ of Met-Ala-Ser tripeptide (Bachem), dissolved in 50 mM buffer, 1 ml of ortho-dianisidine (Sigma Catalog No. D-1954, freshly prepared solution in water (10mg / ml) and MetAP2 at a final concentration of 4µg / ml are mixed rapidly and added to each cell containing the test or control compound. Absorbance at 450 nanometers was measured every 20 seconds for 20 minutes using an automated plate detector (Molecular Devices, CA, USA). The Vmax value in mOD / min indicating MetAP2 activity was calculated for each tube.

·· ·· · ·· ·· · ·· • · • · · · • · • · • ·· • • · · • ·· · · * * • · • • · • : t : t • • • · • · ··· · · · • · • · ··» ·· » • · • · • •

Hodnota IC50 stanovená pre každý inhibítor sa získala grafickým znázornením zostávajúcej aktivity MetAP2 oproti koncentrácii inhibítora. Výsledky týchto testov sú uvedené v tabuľke 1.The IC 50 value determined for each inhibitor was obtained by graphing the remaining MetAP2 activity versus inhibitor concentration. The results of these tests are shown in Table 1.

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Tabuľka 1Table 1

Inhibície aktivity MetAP2 reprezentatívnymi zlúčeninami predloženého vynálezuInhibition of MetAP2 activity by representative compounds of the present invention

Príklad Example ICa,(|LM) ICa (| LM) Príklad Example 1 1 11. 11th 126 126 13. 13th 2 2 47. 47th 127 127 28. 28th 3 3 10. 10th 128 128 14. 14th 4 4 2.4 2.4 129 129 27. 27th 5 5 2.6 2.6 130 130 4.3 4.3 6 6 3.0 3.0 131 131 0.99 0.99 7 7 2.0 2.0 132 132 4.1 4.1 8 8 2.3 2.3 133 133 0.27 00:27

···· • • ···· • • • • · • • • · • ·· • · • · · · • · • · • ·· • • · · • ·· • · • 1 · · • · • 1 ·· · · ·· · · ··· · · · ·· · · ··· · · · ·· · · • · • ·

9 9 2.3 2.3 134 134 3.1 3.1 10 10 3.6 3.6 135 135 3.2 3.2 11 11 2.6 2.6 136 136 1.8 1.8 12 12 0.86 0.86 137 137 8.4 8.4 13 13 1.1 1.1 138 138 1.6 1.6 14 14 0.72 0.72 139 139 1.7 1.7 15 15 0.72 0.72 140 140 2.2 2.2 16 16 0.78 0.78 141 141 3.7 3.7 17 17 1.4 1.4 142 142 0.40 00:40 18 18 0.15 00:15 143 143 0.87 0.87 19 19 1.6 1.6 144 144 2.1 2.1 20 20 5.8 5.8 145 145 1.2 1.2 21 21 14. 14th 146 146 1.5 1.5 22 22 3.4 3.4 147 147 1.0 1.0 23 23 1.3 1.3 148 148 0.52 00:52 24 24 1.0 1.0 149 149 0.93 0.93 25 25 1.9 1.9 150 150 3.1 3.1 26 26 4.7 4.7 151 151 0.43 00:43

·· ··· ·· ··· ···· ··· ·· ··· ··

27 27 1.7 1.7 152 152 2.4 2.4 28 28 100 100 153 153 0.37 00:37 29 29 100 100 154 154 1.9 1.9 30 30 1.1 1.1 155 155 052 052 31 31 100 100 156 156 3.9 3.9 32 32 1.4 1.4 157 157 1.6 1.6 33 33 2J 2J 158 158 2.8 2.8 34 34 3.1 3.1 159 159 1.5 1.5 35 35 0.11 00:11 160 160 0.90 0.90 36 36 0.14 00:14 161 161 0.62 0.62 37 37 16. 16th 162 162 1.2 1.2 38 38 100 100 163 163 0.48 00:48 39 39 5.1 5.1 164 164 0.65 0.65 40 40 81 81 165 165 0.26 00:26 41 41 .09 .09 166 166 0.59 00:59 42 42 2.8 2.8 167 167 3.3 3.3 43 43 6.8 6.8 168 168 1.5 1.5 44 44 13 13 169 169 3.3 3.3

···· • · ·· • · ····· · · ·· · · ·

45 45 5.2 5.2 170 170 1.0 1.0 46 46 1.1 1.1 171 171 0.95 0.95 47 47 1.5 1.5 172 172 5.0 5.0 48 48 1.5 1.5 173 173 0.58 00:58 49 49 2.2 2.2 174 174 1.5 1.5 50 50 3.7 3.7 175 175 2.1 2.1 51 51 5.0 5.0 176 176 3.4 3.4 52 52 6.1 6.1 177 177 2.0 2.0 53 53 1.8 1.8 178 178 11. 11th 54 54 2.6 2.6 179 179 4.9 4.9 55 55 2.7 2.7 180 180 2.0 2.0 56 56 12. 12th 181 181 9.8 9.8 57 57 3.1 3.1 182 182 8.0 8.0 58 58 3.5 3.5 183 183 8.7 8.7 59 59 1.5 1.5 184 184 0.43 00:43 60 60 18. 18th 185 185 1.8 1.8 61 61 13. 13th 186 186 1.1 1.1 62 62 7.6 7.6 187 187 1.2 1.2

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63 63 20. 20th 188 188 1.6 1.6 64 64 19 19 189 189 1.5 1.5 65 65 5.6 5.6 190 190 1.3 1.3 66 66 10. 10th 191 191 2.5 2.5 67 67 13. 13th 192 192 1.2 1.2 68 68 3.8 3.8 193 193 2.5 2.5 69 69 5.3 5.3 194 194 1.4 1.4 70 70 5.4 5.4 195 195 1.3 1.3 71 71 12. 12th 196 196 0.82 0.82 72 72 9.2 9.2 197 197 0.58 00:58 73 73 6.8 6.8 198 198 0.84 0.84 74 74 30. 30th 199 199 1.0 1.0 75 75 9.4 9.4 200 200 1.5 1.5 76 76 100 100 201 201 0.71 0.71 77 77 3.3 3.3 202 202 8.3 8.3 78 78 1.8 1.8 203 203 4.9 4.9 79 79 0.10 00:10 204 204 3.8 3.8 80 80 1.3 1.3 205 205 2.5 2.5

1.8 1.8 206 206 10. 10th 38. 38th 207' 207 ' 4.1 4.1 26. 26th 208 208 2.7 2.7 3.3 3.3 209 209 14. 14th 3.2 3.2 210 210 2.3 2.3 1.7 1.7 211 211 2.4 2.4 2.7 2.7 212 212 1.7 1.7 2.2 2.2 213 213 2.6 2.6 6.6 6.6 214 214 2.8 2.8 2.3 2.3 215 215 1.3 1.3 2.3 2.3 216 216 1.8 1.8 1.4 1.4 217 217 1.8 1.8 5.4 5.4 218 218 0.46 00:46 0.91 0.91 219 219 1.8 1.8 5.2 5.2 220 220 5.5 5.5 2.9 2.9 221 221 5.4 5.4 3.0 3.0 222 222 0.20 00:20 0.58 00:58 223 223 0.88 0.88

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99 99 35 35 224 224 0.43 00:43 100 100 5.9 5.9 225 225 0.35 00:35 101 101 0.31 00:31 226 226 0.97 0.97 102 102 13 13 227 227 0.88 0.88 103 103 100 100 228 228 0.93 0.93 104 104 28 28 229 229 1.2 1.2 105 105 19. 19th 230 230 34. 34th 106 106 100 100 231 231 2.5 2.5 107 107 1.2 1.2 232 232 100 100 108 108 0.63 0.63 233 233 2.7 2.7 109 109 1.7 1.7 235 235 0.97 0.97 110 110 1.0 1.0 236 236 1.9 1.9 111 111 8.2 8.2 237 237 5.1 5.1 112 112 1.5 1.5 238 238 2.7 2.7 113 113 5.5 5.5 239 239 4.2 4.2 114 114 20. 20th 240 240 0.76 0.76 115 115 1.5 1.5 241 241 0.96 0.96 116 116 0.67 0.67 242 242 1.6 1.6

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117 117 0.87 0.87 243 243 1.1 1.1 118 118 16. 16th 244 244 1.5 1.5 119 119 8.9 8.9 245 245 1.2 1.2 120 120 1.1 1.1 246 246 0.39 00:39 121 121 2.6 2.6 247 247 0.57 00:57 122 122 2.8 2.8 248 248 1.0 1.0 123 123 2.7 2.7 249 249 0.41 00:41 124 124 7.0 7.0 125 125 0.45 00:45

Farmaceutické prípravkyPharmaceutical preparations

Farmaceutické prípravky predloženého vynálezu obsahujú terapeuticky účinné množstvo zlúčeniny predloženého vynálezu pripravené spoločne s jedným alebo viacerými farmaceutický prijateľnými nosičmi. Termín „farmaceutický prijateľný nosič“, ako je používaný tu, znamená netoxickú, inertnú pevnú látku, polopevnú látku alebo tekuté plnivo, riediaci roztok, látku slúžiacu na zapuzdrenie alebo pomocnú látku akéhokoľvek typu. Príklady látok, ktoré slúžia ako farmaceutický prijateľné nosiče, zahŕňajú napr. cukry, napr. laktóza, glukóza a sacharóza; škroby, napr. kukuričný škrob a zemiakový škrob; celulózu a jej deriváty, napr. sodná soľ karboxymetylcelulózy, etylcelulóza a acetát celulózy; traganth rozdrvený na prášok; slad; želatínu; mastenec; excipienty, napr. kakaové maslo a čipky z vosku; oleje, napr. arašídový olej, bavlníkový olej; šafránový olej; sézamový olej; olivový olej; kukuričný olej a sójový olej; glykoly; napr. propylénglykol; estery napr. etyloleát a etyllaurát; agar; pufrujúce činidlá, napr. hydroxid horečnatý a hydroxid hlinitý; alginovú kyselinu;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. The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulant or excipient of any type. Examples of substances that serve as pharmaceutically acceptable carriers include e.g. sugars, e.g. lactose, glucose and sucrose; starches, e.g. corn starch and potato starch; cellulose and its derivatives, e.g. carboxymethylcellulose sodium, ethylcellulose and cellulose acetate; powder crushed traganth; malt; gelatin; talc; excipients, e.g. cocoa butter and lace of wax; oils, e.g. peanut oil, cottonseed oil; saffron oil; sesame oil; olive oil; corn oil and soybean oil; glycols; e.g. propylene glycol; esters e.g. ethyl oleate and ethyl laurate; agar; buffering agents, e.g. magnesium hydroxide and aluminum hydroxide; alginic acid;

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vodu neobsahujúcu pyrogén; izotonický roztok; fyziologický roztok; etylalkohol a fostátové pufrujúce roztoky, ako i iné netoxické, zlučiteľné mazivá, napr. laurylsulfát sodný a stearát horečnatý, ako i farbiace činidlá, distribučné činidlá, látky slúžiace k pokrytiu vrstvy, sladidla, aromatizačné činidlá a činidlá uvoľňujúce vonné látky, konzervačné látky a antioxidanty môžu byť v prípravku tiež prítomné podľa zváženia toho, kto prípravok pripravuje. Farmaceutické prípravky tohto vynálezu môžu byť aplikované ľuďom a iným zvieratám perorálne, rektálne, parenterálne, intracisterálne, intravaginálne, intraperitoneálne, miestne (zásypy, masti, kvapky), bukálne alebo ako perorálne alebo nazálne spreje.pyrogen-free water; isotonic solution; saline; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic, compatible lubricants, e.g. sodium lauryl sulfate and magnesium stearate, as well as coloring agents, distributing agents, coating agents, sweeteners, flavoring and fragrance releasing agents, preservatives and antioxidants may also be present in the formulation at the discretion of the formulator. The pharmaceutical compositions of this invention may be administered to humans and other animals orally, rectally, parenterally, intracisterially, intravaginally, intraperitoneally, topically (dusting, ointments, drops), buccally or as oral or nasal sprays.

Dávky v tekutej forme na perorálnu aplikáciu zahŕňajú farmaceutický prijateľné emulzie, mikroemulzie, roztoky, suspenzie, sirupy a liečebné nápoje. Okrem aktívnych zlúčenín môžu dávky v tekutej forme obsahovať inertné riediace roztoky bežne používané v súčasnom stave techniky, napr. voda alebo iné rozpúšťadlá, solubilizujúce činidlo a emulgátory, napr. etylalkohol, izopropylalkohol, etylkarbonát, etylacetát, benzylalkohol, benzylbenzoát, propylénglykol, 1,3-butylénglykol, dimetylformamid, oleje (hlavne bavlníkové, podzemnice olejné, kukuričné, klíčkové, olivové, ricínové a sezamové oleje), glycerol, tetrahydrofurfurylalkohol, polyetylénglykoly a estery mastných kyselín sorbitanu a ich zmesi. Okrem inertných riediacich roztokov môžu perorálne prípravky zahŕňať tiež adjuvans, napr. detergenty, emulgátory a suspendačné prostriedky, prisladzujúce prostriedky, prostriedky vytvárajúce chuť a prostriedky uvoľňujúce vonné látky.Dosages in liquid form for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, dosages in liquid form may contain inert diluents commonly used in the art, e.g. water or other solvents, solubilizing agents and emulsifiers, e.g. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, groundnuts, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl ethyl ester sorbitan acids and mixtures thereof. In addition to inert diluents, oral preparations may also include an adjuvant, e.g. detergents, emulsifiers and suspending agents, sweetening, flavoring and perfuming agents.

Injektovateľné prípravky, napr. sterilné injektovateľné vodné alebo olejovité suspenzie môžu byť pripravené, v rámci technik známych v odbore, použitím vhodných detergentov alebo dispergujúcich a suspendačných prostriedkov. Sterilné injektovateľné prípravky môžu byť tiež sterilné injektovateľné roztoky, suspenzie alebo emulzie v netoxických, parenterálne vhodných riediacich roztokoch alebo rozpúšťadlách, napr. roztok v 1,3-butándiole. Medzi vhodné nosiče a rozpúšťadlá, ktoré môžu byť použité, patrí voda, fyziologický roztok, U.S.P. a izotonický roztok chloridu sodného. Navyše sterilné, pevné oleje sú konvenčné používané ako rozpúšťadlá alebo suspendačné médium. NaInjectable preparations, e.g. sterile injectable aqueous or oleaginous suspensions may be prepared, using techniques known in the art, using suitable detergents or dispersing and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, e.g. solution in 1,3-butanediol. Suitable carriers and solvents that may be used include water, saline, U.S.P. and isotonic sodium chloride solution. In addition, sterile, solid oils are conventionally employed as a solvent or suspending medium. On the

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tento účel môže byť používaný akýkoľvek nedráždivý pevný olej hlavne syntetických monoglyceridov alebo diglyceridov. Navyše mastné kyseliny, napr. olejová kyselina sú používané pri príprave injektovateľných prípravkov.any non-irritating solid oil, especially synthetic monoglycerides or diglycerides, may be used for this purpose. In addition, fatty acids, e.g. Oleic acid is used in the preparation of injectables.

Injektovateľné formulácie môžu byť sterilizované napr. filtrácia cez filter zadržujúci baktérie alebo vložením sterilizujúceho činidla vo forme sterilných, pevných prípravkov, ktoré môžu byť rozpúšťané alebo dispergované pred použitím v sterilnej vode alebo v inom, sterilnom, injektovateľnom prostriedku.Injectable formulations may be sterilized e.g. filtration through a bacteria-retaining filter or by introducing a sterilizing agent in the form of sterile, solid preparations which can be dissolved or dispersed in sterile water or other sterile injectable compositions prior to use.

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Na predĺženie účinku Lieku je často potrebné spomaliť absorbciu lieku pri podkožnej intramuskulárnej injekcii. Táto požiadavka môže byť docielená použitím tekutých suspenzií kryštalických alebo amorfných látok so zlou rozpustnosťou vo vode: Miera absorbcie lieku potom závisí na jeho miere rozpúšťania, ktorá môže závisieť na kryštalickej veľkosti a kryštalickej forme. Iným spôsobom je pomalšia absorbcia parenterálne aplikovanej formy lieku docielená rozpúšťaním alebo suspendáciou lieku v olejovitom nosiči. Injektovateľné, depotné formy sú pripravené vytvorením mikrozapúzdrených matríc lieku v biologicky degradovateľných polyméroch, napr. polyaktid-polyglykolid. Miera uvoľňovania lieku môže byť regulovaná v závislosti na pomere lieku k polyméru a k druhu jednotlivých používaných polymérov. Príklady ďalších biologicky degradovateľných polymérov zahŕňajú poly(ortoestery) a poly(anhydridy). Depotné injektovateľné preparáty sú tiež pripravované zadržovaním lieku v lipozómoch alebo mikroemulziách, ktoré sú zlučiteľné s tkanivami tela.To prolong the effect of the drug, it is often necessary to slow the absorption of the drug by subcutaneous intramuscular injection. This requirement can be achieved by using liquid suspensions of crystalline or amorphous substances with poor water solubility: The rate of absorption of a drug then depends on its dissolution rate, which may depend on crystalline size and crystalline form. Alternatively, slower absorption of the parenterally administered drug form is achieved by dissolving or suspending the drug in an oily carrier. Injectable, depot forms are prepared by forming microencapsulated drug matrices in biodegradable polymers, e.g. polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the type of polymer used. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable preparations are also prepared by retaining the drug in liposomes or microemulsions that are compatible with body tissues.

Prípravky na rektálnu alebo vaginálnu aplikáciu sú výhodné čipky, ktoré môžu byť pripravené namiešaním zlúčenín tohto vynálezu s vhodnými, nedráždivými excipientami alebo nosiče, napr. kakaové maslo, polyetylénglykoly alebo čipky z vosku, ktoré sú pevné pri pokojovej teplote, ale tekuté pri teplote tela a preto sa roztopia v konečníku alebo vo vaginálnej dutine a uvoľnia tak aktívnu zlúčeninu.Formulations for rectal or vaginal administration are preferred laces, which may be prepared by mixing the compounds of the invention with suitable, non-irritating excipients or carriers, e.g. cocoa butter, polyethylene glycols or wax lace, which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

Dávky v pevnej forme na perorálnu aplikáciu zahŕňajú kapsule, tablety, pilulky, zásypy a granule. V takýchto pevných dávkovacích formách je aktívna zlúčenina namiešaná s aspoň jedným inertným, farmaceutický prijateľným ex···· · ·· · ·· • ·· · · ·· · · · • · · · · e · ··· · · · ·· ·· ··· ·· ··· ·· · cipientom alebo nosičom, napr. citrát sodný alebo fosforečnan divápenatý a/alebo a) plnidlami alebo nastavovacími plnidlami, nar. škrob, laktóza, sacharóza, glukóza, manitol a kyselina ortokremičitá, b) spojivami, napr. karboxymetylcelulóza, algináty, želatína, polyvinylpyrolidon, sacharóza a želatína, c) zvlhčovacími prostriedkami, napr. glycerol, d) dezintegrujúcimi prostriedkami, napr. agar-agar, uhličitan vápenatý, zemiakový alebo tapiokový škrob, kyselina alginová, určité silikáty a uhličitan vápenatý, e) inhibítormi roztokov, napr. parafín, f) urýchľovačmi absorbcie, napr. kvartérne amóniové zlúčeniny, g) detergentami, napr. cetylalkohol a glycerolmonostearát, h) adsorbentami, napr. kaolín a bentonitový kaolín a (i) mazivami, napr. mastenec, stearát vápenatý, stearát horečnatý, pevné polyetylénglykoly, nátriumlaurylsulfát a ich zmesi. V prípade kapsúl, tabliet a pilúl môžu tiež dávkovacie formy obsahovať pufrujúcu látku. Pevné prípravky podobného typu môžu byť tiež upotrebené ako plnidlá v ľahko naplnených a husto naplnených želatínových kapsúl použitím takých excipientov ako laktóza alebo mliečny cukor, ako i polyetylénglykoly s vysokou relatívnou molekulovou hmotnosťou, apod.Dosages in solid form for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable, ex-&quot;, &quot; e &quot; • A excipient or carrier, e.g. sodium citrate or dicalcium phosphate and / or (a) fillers or extenders, Reg. starch, lactose, sucrose, glucose, mannitol and orthosilicic acid, b) binders, e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gelatin; c) wetting agents, e.g. d) disintegrating agents, e.g. agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and calcium carbonate, e) solution inhibitors, e.g. (f) absorption accelerators, e.g. quaternary ammonium compounds, g) detergents, e.g. cetyl alcohol and glycerol monostearate; h) adsorbents, e.g. kaolin and bentonite kaolin; and (i) lubricants, e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent. Solid compositions of a similar type may also be employed as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

Dávky v pevnej forme, napr. tablety, dražé, kapsule, pilulky a granule môžu byť pripravené s povlakmi a púzdrami, napr. enterické a s inými povlakmi dobre známymi v odbore farmaceutických príprav liekov. Dávky v pevnej forme môžu prípadne obsahovať zakalenú látku a môžu tiež obsahovať prípravky, ktoré uvoľňujú len alebo prednostne aktívne zložky v určitej časti intestinálneho traktu, prípadne do istej miery zadržované. Príklady zaliatych prípravkov, ktoré môžu byť používané, zahŕňajú polymérne látky a vosky.Dosages in solid form, e.g. tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, e.g. enteric and other coatings well known in the pharmaceutical pharmaceutical art. Dosages in solid form may optionally contain a cloudy substance and may also contain formulations which release only or preferably the active ingredients in a certain part of the intestinal tract, possibly retained to some extent. Examples of embedding compositions that can be used include polymeric substances and waxes.

Pevné prípravky podobného typu môžu byť tiež upotrebené ako plnidlá v ľahko naplnených a husto naplnených želatínových kapsulách použitím takých excipientov ako laktóza alebo mliečny cukor, ako aj polyetylénglykoly s vysokou relatívnou molekulovou hmotnosťou, apod.Solid formulations of a similar type may also be employed as fillers in lightly filled and densely filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

Aktívne zlúčeniny môžu byť tiež v mikrozapúzdrenej forme s jedným alebo viacerými hore uvedenými excipientami. Dávky v pevnej forme, napr. tabletky, dražé, kapsule, pilulky a granule môžu byť pripravené s povlakmi a púzdrami, napr. enterické povlaky, povlaky kontrolujúce uvoľňovanie a s inými povlakmi dobre známymi v odbore farmaceutických preparátov. V takýchtoThe active compounds may also be in microencapsulated form with one or more of the above-mentioned excipients. Dosages in solid form, e.g. tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, e.g. enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulations art. In such

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dávkovacích formách môže byť aktívna zlúčenina primiešaná s aspoň jedným inertným riediacim roztokom, napr. škrobom, laktózou alebo sacharózou. Rovnako dávkovacie formy môžu tiež obsahovať, čo je normálna prax, ďalšie látky iné než inertné riediace roztoky, napr. tabletujúce lubrikanty a iné pomôcky na tabletovanie, napr. stearát horečnatý a mikrokryštalická celulóza. V prípade kapsúl, tabliet a piluliek môžu tiež dávkovacie formy obsahovať pufrujúce činidlo. Prípadne môžu obsahovať zakalujúcu látku a môžu obsahovať prípravky, ktoré uvoľňujú len alebo prednostne aktívne zložky v určitej časti intestinálneho traktu, prípadne do istej miery oneskorené. Príklady prípravkov na inkorporáciu, ktoré môžu byť používané, zahŕňajú polymérne látky a vosky.In dosage forms, the active compound may be admixed with at least one inert diluent, e.g. starch, lactose or sucrose. Likewise, the dosage forms may also contain, as is normal practice, other substances other than inert diluents, e.g. tableting lubricants and other tabletting aids, e.g. magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain a buffering agent. Alternatively, they may contain a opacifying agent and may contain formulations which release only or preferably the active ingredients in a certain part of the intestinal tract, possibly to some extent delayed. Examples of incorporation preparations that may be used include polymeric substances and waxes.

Dávky vo forme na miestne alebo transdermálne aplikácie zlúčeniny tohto vynálezu zahŕňajú masti, pasty, krémy, tekuté formy na vonkajšie použitie, gély, zásypy, roztoky, spreje, inhalačné prostriedky alebo náplasti. Účinná zložka je primiešaná za sterilných podmienok s farmaceutický prijateľným nosičom a s akýmkoľvek potrebným ochranným prostriedkom alebo pufrom podľa potreby. Oftalmické formulácie, ušné kvapky, očné masti, zásypy a roztoky patria do rozsahu predloženého vynálezu.Dosages in topical or transdermal application form of a compound of this invention include ointments, pastes, creams, liquid forms for external use, gels, dusting powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or buffer as desired. Ophthalmic formulations, ear drops, eye ointments, dusting powders and solutions are within the scope of the present invention.

Masti, pasty, krémy a gély môžu obsahovať, okrem aktívnej zlúčeniny tohto vynálezu, excipienty, napr. zvieracie a rastlinné tuky, oleje, vosky, parafíny, škroby, traganth, deriváty celulózy, polyetylénglykoly, silikóny, bentonity, kyselinu ortokremičitú, mastenec, oxid zinočnatý alebo ich zmesi.Ointments, pastes, creams and gels may contain, in addition to the active compound of the invention, excipients, e.g. animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, orthosilicic acid, talc, zinc oxide or mixtures thereof.

Zásypy a spreje môžu obsahovať, okrem aktívnej zlúčeniny tohto vynálezu, excipienty napr. laktózu, mastenec, kyselinu ortokremičitú, hydroxid hlinitý, silikát vápenatý a polyamidový prášok alebo zmesi týchto látok. Spreje môžu ďalej obsahovať obvyklé propelenty napr. chlórfluóruhľovodíky.Powders and sprays may contain, in addition to the active compound of the invention, excipients e.g. lactose, talc, orthosilicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures thereof. Sprays may further contain conventional propellants e.g. chlorofluorocarbons.

Transdermálne náplasti majú navyše výhodu v tom, že poskytujú presné dodanie zlúčeniny do tela. Rovnako dávkovacie formy môžu byť vytvorené rozpúšťaním alebo dispergovaním zlúčeniny vo vhodnom médiu. Prostriedky na zvýšenie absorpcie môžu byť používané na zvýšenie prechodu zlúčeniny cez pokožku. Miera zvýšenia môže byť regulovaná buď riadením preechodu cez membránu alebo dispergovaním zlúčeniny v polymérnej matrici alebo v géli.In addition, transdermal patches have the advantage of providing accurate delivery of the compound to the body. Similarly, dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may be used to increase the passage of the compound through the skin. The rate of increase can be controlled by either controlling membrane passage or dispersing the compound in a polymer matrix or gel.

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9 99 9

999 · 99999 · 99

9 99 9 9 99 9 9 9 9

9 9 · ·9 9 · ·

9 9 9 99

999 99 9998 99 9

Terapeutické aplikácieTherapeutic applications

Podľa spôsobov ošetrenia predloženého vynálezu sú poruchy spôsobené nežiaducou angiogenézou ošetrované alebo je im predchádzané u pacientov, napr. ľudí alebo nižších cicavcov, aplikáciou terapeuticky účinného množstva zlúčeniny vynálezu pacientovi v takých množstvách a v takom období, ktoré sú nevyhnutne nutné na dosiahnutie požadovaného výsledku. Termínom „terapeuticky účinné množstvo“ zlúčeniny vynálezu sa mieni dostačujúce množstvo zlúčeniny vynálezu na inhibovanie angiogenézy v rozumnom pomere prospešnosť/riziko použiteľné na akékoľvek lekárske ošetrenie. Bezpochyby je jasné, že celkové denné použitie zlúčenín a prípravkov predloženého vynálezu záleží na posúdení ošetrujúceho lekára po rozumnom lekárskom úsudku. Špecifická, terapeuticky účinná hladina dávky pre akéhokoľvek jednotlivého pacienta bude záležať na rôznych faktoroch zahŕňajúcich ochorenie, ktoré je ošetrované a silu tohto ochorenia; aktivite používanej špecifickej zlúčeniny; používaného špecifického prípravku; veku, telesnej váhy, celkového zdravia, pohlavia a životospráve pacienta; dobe aplikácie, spôsobu aplikácie a miere exkrécie používanej špecifickej zlúčeniny; dobe trvania ošetrenia; liekov používaných v kombinácii alebo v zhode s používanou špecifickou zlúčeninou; a podobných faktoroch dobre známych v lekárskej praxi. Nič menej dobre známa technika používaná lekármi je založená na „upravení miery dávky“ podľa jednotlivého pacienta, tzn. že sa začína s dávkou nižšou ako je požadovaná na dosiahnutie požadovaného účinku a postupne sa zvyšuje pokiaľ sa nedosiahne potrebný terapeutický účinok.According to the methods of treatment of the present invention, disorders caused by unwanted angiogenesis are treated or prevented in patients, e.g. of humans or lower mammals, 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 "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to inhibit angiogenesis in a reasonable benefit / risk ratio applicable to any medical treatment. Undoubtedly, it is clear that the total daily use of the compounds and compositions of the present invention depends on the judgment of the attending physician after reasonable medical judgment. The specific, therapeutically effective dose level for any individual patient will depend on various factors including the disease being treated and the severity of the disease; the activity of the specific compound used; the specific formulation used; the age, body weight, general health, sex and lifestyle of the patient; the time of administration, the method of administration and the rate of excretion of the specific compound used; duration of treatment; drugs used in combination or in accordance with the specific compound used; and similar factors well known in medical practice. The less well known technique used by physicians is based on "adjusting the dose rate" according to the individual patient; starting from a dose lower than that required to achieve the desired effect and gradually increasing until the desired therapeutic effect is achieved.

Celková denná dávka zlúčenín tohto vynálezu aplikovaná ľuďom alebo iným cicavcom v jedinej dávke alebo v delených dávkach môže byť v množstve napr. od 0,01 do 50 mg/kg telesnej váhy alebo lepšie od 0,11 do 25 mg/kg telesnej váhy. Jednotlivé dávky prípravkov môžu obsahovať také množstvo alebo ich alikvotných častí na vytvorenie dennej dávky. Všeobecne zahŕňajú režimy ošetrenia podľa predloženého vynálezu aplikáciu, pri potrebe takého ošetrenia, pacientovi od asi 1 mg do asi 500 mg zlúčenín(y) predloženého vynálezu denne v jedinej alebo mnohonásobných dávkach.The total daily dose of the compounds of the invention administered to a human or other mammal in a single dose or in divided doses may be in an amount of e.g. from 0.01 to 50 mg / kg body weight or preferably from 0.11 to 25 mg / kg body weight. Single doses of the compositions may contain such amounts or aliquots thereof to form a daily dose. In general, the treatment regimens of the present invention comprise administering to a patient in need of such treatment from about 1 mg to about 500 mg of the compounds (s) of the present invention daily in single or multiple doses.

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Všeobecné spôsoby syntézyGeneral synthesis methods

Podľa reakčnej schémy 1 sa 3-amino-2-hydroxy-karboxylové kyseliny, použité ako východiskové látky na syntézu zlúčenín predloženého vynálezu, pripravia z príslušne substituovaných α-aminokyselín konverziou na odpovedajúci aminoaldehyd, vytvorením odpovedajúceho kyanohydrínu a hydrolýzou. Požadované zlúčeniny sa pripravia chránením voľnej amino skupiny, napr. zavedením ŕerc-butylkarbamátovej chrániacej skupiny, väzbou s príslušným amínom, derivátom aminokyseliny alebo alkoholom a odobratím chrániacej skupiny. Jednotlivé väzobné látky môžu byť zakúpené od komerčných zdrojov alebo pripravené použitím známych chemických transformácií. Následná premena 3amino-2-hydroxy zlúčenín na zlúčeniny predloženého vynálezu sa vykoná štandardnými spôsobmi známymi z doterajšieho stavu techniky, ktoré sú znázornené príkladmi uvedenými nižšie.According to Reaction Scheme 1, the 3-amino-2-hydroxy-carboxylic acids used as starting materials for the synthesis of the compounds of the present invention are prepared from appropriately substituted α-amino acids by conversion to the corresponding aminoaldehyde, formation of the corresponding cyanohydrin and hydrolysis. The desired compounds are prepared by protecting a free amino group, e.g. introduction of a tert-butyl carbamate protecting group, coupling with an appropriate amine, amino acid derivative or alcohol and removal of the protecting group. Individual binders may be purchased from commercial sources or prepared using known chemical transformations. Subsequent conversion of the 3 amino-2-hydroxy compounds to the compounds of the present invention is accomplished by standard methods known in the art, as illustrated by the examples below.

Schéma 1Scheme 1

BoeBoe

NHRNHR

IHIH

ÔH? H

B··· ·· ···B ··· ·· ···

Zlúčeniny a spôsoby predloženého vynálezu budú lepšie pochopené v spojitosti s nasledujúcimi príkladmi, ktoré sú tu uvedené pre názornosť a nemajú nijako obmedzovať rozsah vynálezu.The compounds and methods of the present invention will be better understood in conjunction with the following examples, which are provided by way of illustration and are not intended to limit the scope of the invention in any way.

Príklady uskutočneniaEXAMPLES

Príklad 1Example 1

Hydrochlorid (2RS,3S,l’S)-7V-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamidu(2RS, 3S, 1'S) -7H - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-5 (methylthio) pentanamide hydrochloride

Príklad IAExample IA

Roztok JV-(/erc-butoxykarbonyl)-L-metionínu (12,47 g, 50 mmol) a REDAL (50 mmol) v suchom toluéne (125 ml) sa mieša pri teplote 0 °C po dobu 30 minút, potom pri izbovej teplote po dobu 1 hodiny. Zmes sa nechá reagovať s vodnou Rochellovou soľou a extrahuje sa etyléterom. Extrakt sa postupne premyje soľankou a vodným NaHCOa, suší sa (MgSO^t) a koncentruje sa, čím sa získa bezfarebný sirup (9,05 g).A solution of N - (tert -butoxycarbonyl) -L-methionine (12.47 g, 50 mmol) and REDAL (50 mmol) in dry toluene (125 mL) was stirred at 0 ° C for 30 min, then at room temperature. 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 NaHCO 3, dried (MgSO 4), and concentrated to give a colorless syrup (9.05 g).

Príklad IBExample IB

Roztok produktu z príkladu IA (9,05 g, 38,5 mmol), komplex oxidu sírového a pyridínu (30,64 g, 192,5 mmol) a trietylamínu (26,8 ml, 192,5 mmol) v DMSO (30 ml) sa mieša pri izbovej teplote po dobu 30 minút, ochladí sa na teplotu 0 °C, potom sa nechá postupne reagovať s vodou (20 ml) a s nasýteným vodným KHSO4 (120 ml) a extrahuje etylacetátom. Extrakt sa postupne premyje nasýteným vodným KHSO4 a soľankou, suší sa (MgSO4) a koncentruje sa, čím sa získa bezfarebný sirup (9,00 g).A solution of the product of Example IA (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). ml) was stirred at room temperature for 30 minutes, cooled to 0 ° C, then treated successively with water (20 ml) and saturated aqueous KHSO 4 (120 ml) and extracted with ethyl acetate. The extract was washed sequentially with saturated aqueous KHSO 4 and brine, dried (MgSO 4) and concentrated to give a colorless syrup (9.00 g).

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Príklad 1CExample 1C

Roztok produktu z príkladu IB (9,00 g, 38,5 mmol) a bisulfid sodný (3,80 g, 36,6 mmol) vo vode (200 ml) sa mieša pri teplote 5 °C po dobu 72 hodín, zahreje sa na izbovú teplotu, potom sa nechá reagovať s kyanidom draselným (2,51 g, 38,6 mmol) v etylacetáte (250 ml) po dobu 4 hodín. Separovaná etylacetátová vrstva sa postupne premyje vodou a soľankou, suší sa (MgSOí) a koncentruje sa, čím sa získa bezfarebný sirup, ktorý sa rozpustí v dioxáne (75 ml) a 12 N HCI (75 ml), potom sa zahrieva pri refluxe po dobu 16 hodín. Zmes sa koncentruje vo vákuu a opäť sa rozpustí vo vode (8 ml) a v acetóne (300 ml), pH sa upraví na 5,5 pomocou 1 N NaOH a výsledná pevná látka sa spojí filtráciou a suší sa, čím sa získa 5,81 g pevnej látky.A solution of the product of Example IB (9.00 g, 38.5 mmol) and sodium bisulfide (3.80 g, 36.6 mmol) in water (200 mL) was stirred at 5 ° C for 72 h, warmed. to room 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 successively with water and brine, dried (MgSO 4) and concentrated to give a colorless syrup which was dissolved in dioxane (75 mL) and 12 N HCl (75 mL), then heated at reflux for 16 hours. The mixture was concentrated in vacuo and redissolved in water (8 mL) and acetone (300 mL), adjusted to pH 5.5 with 1 N NaOH, and the resulting solid was collected by filtration and dried to give 5.81 g of solid.

MS (ESI+Q1MS) m/e 180: (M+H)+, 202 (M+ Na)+; (ESI-Q1MS) m/e: 178 (ΜΗ);MS (ESI + Q1MS) mlz 180: (M + H) + , 202 (M + Na) + ; (ESI-Q1MS) m / e: 178 (M);

*H 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).1 H NMR (300 MHz, D 2 O) δ 4.25 (d, 0.5H), 4.14 (d, 0.5H), 3.78 (m, 0.5H), 3.66 (m 0.55), 2.65 (m, 2H), 2.13 (s, 1.5H), 2.09 (s, 1.5H), 1.93 (m, 2H).

Príklad IDExample ID

Roztok produktu z príkladu 1C (5,81 g, 32,4 mmol), BOC-ON (9,58 g,A solution of the product of Example 1C (5.81 g, 32.4 mmol), BOC-ON (9.58 g,

38,9 mmol) a trietylamín (6,77 ml, 48,6 mmol) vo vode (70 ml) a dioxáne (70 ml) sa miešajú pri teplote 45 °C po dobu 5 hodín, zriedia sa etylacetátom a 10% vodným KHSO4, potom sa extrahuje etylacetátom. Extrakt sa postupne premyje vodou a soľankou, suší sa (MgSO4) a koncentruje sa, čím sa získa (2RS,3S)-3-(/erc-butoxykarbonylamino)-2-hydroxy-5-(metyltio)pentánová kyselina (4,05 g).38.9 mmol) and triethylamine (6.77 mL, 48.6 mmol) in water (70 mL) and dioxane (70 mL) were stirred at 45 ° C for 5 hours, diluted with ethyl acetate and 10% aqueous KHSO 4. , then extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (MgSO 4), 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)+; (ESIQ1MS) m/e 278: (M-H)‘.MS (ESI + Q1MS) mlz 280: (M + H) + , 302 (M + Na) + , 581 (2M + Na) + ; (ESI-MS) m / e 278: (MH) -.

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Príklad ΙΕExample ΙΕ

Roztok z príkladu ID (2,79 g, 10 mmol), hydrochlorid L-alanínetylesteru (1,84 g, 12 mmol), EDCI (2,30 g, 12 mmol), HOBT (1,84 g, 12 mmol) a NMM (1,32 ml, 12 mmol) v CH2CI2 (35 ml) sa miešajú pri izbovej teplote po dobu 16 hodín, potom sa odparí do sucha, znovu sa rozpustí v etylacetáte, potom sa postupne premyje vodným NaHCO3, soľankou, 10% vodným KHSO4 a soľankou, suší sa (MgSO4) a koncentruje sa. Zvyšok sa čistí zrýchlenou („flash“) chromatografiou na stĺpci silikagélu 50 % etylacetát/toluén, čím sa získa požadovaná zlúčenina (2,74g).Solution of Example ID (2.79 g, 10 mmol), L-alanine ethyl ester hydrochloride (1.84 g, 12 mmol), EDCI (2.30 g, 12 mmol), HOBT (1.84 g, 12 mmol) and The NMM (1.32 mL, 12 mmol) in CH 2 Cl 2 (35 mL) was stirred at room temperature for 16 hours, then evaporated to dryness, redissolved in ethyl acetate, then washed sequentially with aqueous NaHCO 3, brine, 10% aqueous KHSO4 and brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel with 50% ethyl acetate / toluene to give the title compound (2.74g).

MS (ESI+Q1MS) m/e 379 (M+H)+, 396 (M+Na)+, 279 (M+H-BOC)+.MS (ESI + Q1MS) m / e 379 (M + H) &lt; + &gt;, 396 (M + Na) &lt; + &gt;, 279 (M + H-BOC) &lt; + &gt;.

Príklad 1FExample 1F

Roztok produktu z príkladu 1E (0,40 g, 1,1 mmol) v chlorovodíku nasýteným dioxánom (8 mi) sa mieša pri izbovej teplote po dobu 1 hodiny, odparuje sa do sucha, suspenduje sa v etyléteri, potom sa koncentruje a suší sa vo vákuu, čím sa získa požadovaná zlúčenina (0,24 g).A solution of the product of Example 1E (0.40 g, 1.1 mmol) in hydrogen chloride saturated with dioxane (8 mL) was stirred at room temperature for 1 hour, evaporated to dryness, suspended in ethyl ether, then concentrated and dried under vacuum to give the title compound (0.24 g).

MS (ESI+Q1MS) m/e 279 (M+H)+, 557 (2M+H)+;MS (ESI + Q1MS) mlz 279 (M + H) + , 557 (2M + H) + ;

’H NMR (300 MHz, DMSO-d6) δ 8,46 (d, 0,6H), 8,43 (d, 0,4H), 8,14 (br, 1H),1 H NMR (300 MHz, DMSO-d 6 ) 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).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, O, 6H), 1.33 (d, 1.2H), 1.17-1.23 (dt, 1.8H).

Príklad 2Example 2

Hydrochlorid (2RS,3S, 1 ’S)-/V-((l-etylkarboxamido)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamidu(2RS, 3S, 1'S) - N - ((1-ethylcarboxamido) ethyl) -3-amino-2-hydroxy-5 (methylthio) pentanamide hydrochloride

Produkt z príkladu ID a alanínetylamid sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 1D and alanine methylamide were processed according to the methods of Examples 1E and 1F to give the title compound.

···* · ··· * · • · • • · • • · • · ·· • · • · · · • · • · • • • • ·· · · ·· · · • · · • · · ·· · · ··· · · · ·· · ·

MS (ESI+Q1MS) m/e 278 (M+H)+, 300 (M+Na)+;MS (ESI + Q1MS) m / e 278 (M + H) &lt; + &gt;, 300 (M + Na) &lt; + &gt;;

’H 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 H NMR (300 MHz, D 2 O) 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).1.11 (t, 1.5H), 1.10 (t, 1.5H).

Príklad 3Example 3

Hydrochlorid (2RS,3R, 1 ’ S)-7V-((l-Etylkarboxamido)etyl)-3-amino-2-hydroxy5-(metyItio)pentánamidu(2RS, 3R, 1'S) -7H - ((1-Ethylcarboxamido) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide hydrochloride

Príklad 3AExample 3A

N-(/erc-butoxykarbonyl)-D-metionín sa spracováva podľa spôsobov z príkladov 1A až ID, čím sa získa (2RS,3R)-3-(/erc-butoxykarbonylamino)-2-hydroxy-5(metyltio) pentánová kyselina.N - (tert -butoxycarbonyl) -D-methionine was processed according to the methods of Examples 1A to 1D to give (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-5 (methylthio) pentanoic acid .

Príklad 3BExample 3B

Produkt z príkladu 3A a L-alanínetylamid sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and L-alanine methylamide were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 278 (M+H)+, 300 (M+Na)+;MS (ESI + Q1MS) m / e 278 (M + H) &lt; + &gt;, 300 (M + Na) &lt; + &gt;;

JH NMR (300 MHz, D2O) 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). LH NMR (300 MHz, D 2 O) δ 4.27 to 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).

Príklad 4Example 4

Hydrochlorid (2RS,3R,l’S)-JV-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-5(metyltio)pentánamidu · ·· · ·· ··· · ··· · ·· ·· ··· ·· ··· ·· ···(2RS, 3R, 1'S) -N - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-5 (methylthio) pentanamide hydrochloride · ··· ··· · ··· · ··· · ··· ·· ··· ·· ···

Produkt z príkladu 3A a hydrochlorid L-alanínetylesteru sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and L-alanine ethyl ester hydrochloride were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 279 (M+H)+, 301 (M+Na)+;MS (ESI + Q1MS) m / e 279 (M + H) &lt; + &gt;, 301 (M + Na) &lt; + &gt;;

'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).1 H NMR (300 MHz, D 2 O) 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).

Príklad 5Example 5

Hydrochlorid (2RS,3R)-JV-((2-fenyletyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidu(2RS, 3R) -N - ((2-Phenylethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide hydrochloride)

Produkt z príkladu 3A a l-amino-2-fenyletán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-2-phenylethane were processed according to the method of Example 2 to give the title compound.

MS (APCI+) m/e 283 (M+H)+;MS (APCI +) m / e 283 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,20 (m, 1H), 7,80 (m, 2H), 7,30 (m, 2H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.20 (m, 1H), 7.80 (m, 2H), 7.30 (m, 2H),

7,21 (m, 3H), 6,50 (m, 1H), 4,09 (m, 1H), 3,40 (m, 3H), 2,79 (m, 2H), 2,53 (m, 2H), 2,04 (s, 3H), 1,68 (m, 2H).7.21 (m, 3H), 6.50 (m, 1H), 4.09 (m, 1H), 3.40 (m, 3H), 2.79 (m, 2H), 2.53 (m 2H, 2.04 (s, 3H), 1.68 (m, 2H).

Príklad 6Example 6

Hydrochlorid (2RS,3R)-7V-((3-fenylpropyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidu(2RS, 3R) - N - ((3-Phenylpropyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide hydrochloride)

Produkt z príkladu 3A a l-amino-3-fenylpropán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-3-phenylpropane were treated according to the method of Example 2 to give the title compound.

MS (APCI+) m/e 297 (M+H)+;MS (APCI +) m / e 297 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, DMSO-d6) δ 8,20 (m, 1H), 7,82 (m, 2H), 7,28 (m, 5H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.20 (m, 1H), 7.82 (m, 2H), 7.28 (m, 5H),

6,54 (d, 0,6H), 6,47 (d, 0,4H), 4,09 (m, 1H), 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).6.54 (d, 0.6H), 6.47 (d, 0.4H), 4.09 (m, 1H), 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).

·· • · • · *··· · ·· • · · · · · • · · · ·· ··· ·· ··· ·· ············································

Príklad 7Example 7

Hydrochlorid (2RS,3R)-/V-(4-fenylbutyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidu(2RS, 3R) - N - (4-Phenylbutyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide hydrochloride

Produkt z príkladu 3A a l-amino-4-fenylbutan sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-4-phenylbutane were treated according to the method of Example 2 to give the title compound.

MS (APCI+) m/e 311 (M+H)+;MS (APCI &lt; + &gt;) m / e 311 (M + H) &lt; + &gt;;

*H NMR (300 MHz, DMS0-d6) δ 8,18 (m, 1H), 7,82 (m, 2H), 7,22 (m, 5H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.18 (m, 1H), 7.82 (m, 2H), 7.22 (m, 5H),

6,45 (m, 1H), 4,09 (m, 1H), 3,39 (m, 1H), 3,15 (m, 2H), 2,56 (m, 4H), 2,03 (s, 3H), 1,80 (m, 2H), 1,51 (m, 4H).6.45 (m, 1H); 4.09 (m, 1H); 3.39 (m, 1H); 3.15 (m, 2H); 2.56 (m, 4H); 2.03 (s) 3H), 1.80 (m, 2H), 1.51 (m, 4H).

Príklad 8Example 8

Hydrochlorid (2RS,3R)-TV-(2-(4-metoxyfenyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidu(2RS, 3R) - N - (2- (4-Methoxyphenyl) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide hydrochloride

Produkt z príkladu 3A a l-amino-2-(4-metoxyfenyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-2- (4-methoxyphenyl) ethane were processed according to the method of Example 2 to give the title compound.

MS (APCI+) m/e 313 (M+H)+;MS (APCI +) m / e 313 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,17 (m, 1H), 7,87 (bds, 2H), 7,12 (s, 2H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.17 (m, 1H), 7.87 (bds, 2H), 7.12 (s, 2H),

6,86 (d, 2H), 6,5(m, 1H), 4,1 (m, 1H), 3,72 (s, 3H), 3,30 (m, 2H), 2,70 (m, 2H),6.86 (d, 2H), 6.5 (m, 1H), 4.1 (m, 1H), 3.72 (s, 3H), 3.30 (m, 2H), 2.70 (m , 2H),

2,54 (m, 2H), 2,05(s, 3H), 1,78 (m, 2H).2.54 (m, 2H), 2.05 (s, 3H), 1.78 (m, 2H).

Príklad 9Example 9

Hydrochlorid (2RS,3R)-/V-(2-(4-sulfonamidofenyl)etyl)-3-amino-2-hydroxy-5 (metyltio)pentánamidu(2RS, 3R) - N - (2- (4-Sulfonamidophenyl) ethyl) -3-amino-2-hydroxy-5 (methylthio) pentanamide hydrochloride

Produkt z príkladu 3A a l-amino-2-(4-sulfonamidofenyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-2- (4-sulfonamidophenyl) ethane were processed according to the method of Example 2 to give the title compound.

Φ··· · ·· · ·· • ·· · · ·· · • · · · · · · • ···· ···· ·· ··· ·· ··· ·· ·Φ ··· · ·················································

MS (APCI+) m/e 362 (M+H)+;MS (APCI +) m / e 362 (M + H) &lt; + &gt;;

*H NMR (300 MHz, DMSO-d6) δ 8,24 (m, 1H), 7,84 (m, 2H), 7,75(d, 2H), 7,42 (d, 2H), 7,32 (s, 2H), 6,52 (d, 1H), 4,09 (m, 1H), 3,70 (m, 1H), 3,45(m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.24 (m, 1H), 7.84 (m, 2H), 7.75 (d, 2H), 7.42 (d, 2H), 7 32 (s, 2H), 6.52 (d, 1H), 4.09 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H),

2,86 (m, 2H), 2,58 (m, 2H), 2,04 (s, 3H), 1,67 (m, 2H).2.86 (m, 2H), 2.58 (m, 2H), 2.04 (s, 3H), 1.67 (m, 2H).

Príklad 10Example 10

Dihydrochlorid (2RS,3R)-JV-(2-(2-pyridyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidu(2RS, 3R) -N- (2- (2-Pyridyl) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide dihydrochloride

Produkt z príkladu 3A a l-amino-2-(2-pyridyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-2- (2-pyridyl) ethane were processed according to the method of Example 2 to give the title compound.

MS (APCI+) m/e 284 (M+H)+;MS (APCI +) m / e 284 (M + H) &lt; + &gt;;

*H NMR (300 MHz, DMSO-d6) δ 8,74 (m, 1H), 8,38 (m, 2H), 8,10 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.74 (m, 1H), 8.38 (m, 2H), 8.10 (m, 1H),

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, 1H), 2,04 (s, 3H), 1,80 (m, 2H).7.90 (m, 2H), 7.78 (m, 2H), 4.09 (m, 1H), 3.70 (m, 2H), 3.57 (m, 2H), 3.49 (m 2H, 2.57 (m, 1H), 2.04 (s, 3H), 1.80 (m, 2H).

Príklad 11Example 11

Hydrochlorid (2RS, 3 R)-7V-(2-(4-fenoxy fény l)etyl)-3-amino-2-hydroxy-5-(mety ltio)pentánamidu(2RS, 3R) -N- (2- (4-Phenoxyphenyl) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide hydrochloride

Produkt z príkladu 3A a l-amino-2-(4-fenoxyfenyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-2- (4-phenoxyphenyl) ethane were processed according to the method of Example 2 to give the title compound.

MS (APCI+) m/e 375(M+H)+;MS (APCI +) m / e 375 (M + H) &lt; + &gt;;

*H NMR (300 MHz, DMSO-d6) δ 8,17 (m, 1H), 7,69 (m, 2H), 7,39 (m, 2H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.17 (m, 1H), 7.69 (m, 2H), 7.39 (m, 2H),

7,23 (m, 2H), 7,13 (m, 1H), 6,98 (m, 4H), 6,50 (m, 1H), 4,09 (m, 1H), 3,38 (m, 3H), 2,75(m, 2H), 2,56 (m, 2H), 2,04 (s, 3H), 1,74 (m, 2H).7.23 (m, 2H), 7.13 (m, 1H), 6.98 (m, 4H), 6.50 (m, 1H), 4.09 (m, 1H), 3.38 (m 3H), 2.75 (m, 2H), 2.56 (m, 2H), 2.04 (s, 3H), 1.74 (m, 2H).

·· • · · • · ···· • · ·· · • ·· ··· ·· ·······························

Príklad 12Example 12

Hydrochlorid (2RS.3R, l’S)-Y-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-5(etyltio)pentánamidu(2RS, 3R, 1'S) -Y - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-5 (ethylthio) pentanamide hydrochloride

Príklad 12AExample 12A

N-(/erc-butoxykarbonyl)-D-etionín sa spracováva podľa spôsobov z príkladov 1A až ID, čím sa získa (2RS,3R)-3-(/e/'c-butoxykarbonylamino)-2hydroxy-5-(etyltio)pentánová kyselina.N - (tert -butoxycarbonyl) -D-etionine was processed according to the methods of Examples 1A to 1D to give (2RS, 3R) -3 - (tert -butoxycarbonylamino) -2-hydroxy-5- (ethylthio) pentanoic acid.

Príklad 12BExample 12B

Produkt z príkladu 12A a hydrochlorid etylesteru L-alanínu sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina,The product of Example 12A and L-alanine ethyl ester hydrochloride were processed according to the method of Example 2 to give the title compound, m.p.

MS (ESI+Q1MS) m/e 293 (M+H)+, 585 (2M+H)+;MS (ESI + Q1MS) mlz 293 (M + H) + , 585 (2M + H) + ;

’H NMR (300 MHz, D2O) 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).1 H NMR (300 MHz, D 2 O) 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).

Príklad 13Example 13

Hydrochlorid (2RS,3R)-Y-((4-fenyl)butyl)-3-amino-2-hydroxy-5-(etyltio)pentánamid(2RS, 3R) -Y - ((4-Phenyl) butyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a l-amino-4-fenylbután sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 12A and 1-amino-4-phenylbutane were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 325 (M+H)+, 347 (M+Na)+, 649 (2M+H)+, 671 (2M+Na)+;MS (ESI + Q1MS) mlz 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···· • · • · ·· · ·· ··· ·· • · · • e ·· ···1 H NMR (300 MHz, DMSO-d 6 ) δ 7.16-7.31 (m, 5H), 6.77 (br, 1H), 5.22 (br, d, 0.6H), 5, Δ (br, d, 0.4H), 4.23 (d, 0.4H), 4.12 (d, 0.6H), 3.94 (br, m, 1H), 3.24 ··· · · · · · · · E · e · e · e ·

3,36 (m, 2H), 2,46-2,68 (m, 6H), 1,94-2,16 (m, 2H), 1,47-1,62 (m, 4H), 1,191,28 (m, 3H).3.36 (m, 2H), 2.46-2.68 (m, 6H), 1.94-2.16 (m, 2H), 1.47-1.62 (m, 4H), 1.191, 28 (m, 3 H).

Príklad 14Example 14

Hydrochlorid (2RS,3R)-/V-(3-(karboetoxy)etyl)-3-amino-2-hydroxy-5-(etyltio)pentánamidu(2RS, 3R) - N - (3- (Carboethoxy) ethyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a etyl-3-amino-propionát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 12A and ethyl 3-amino-propionate are processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 293 (M+H)+; 315(M+Na)+;MS (ESI + Q1MS) m / e 293 (M + H) &lt; + &gt;; 315 (M + Na) &lt; + &gt;;

’H NMR (300 MHz, D2O) δ 4,45 (d, 0,4H), 4,31 (d, 0,6H), 4,17 (q, 2H), 3,813,87 (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).1 H NMR (300 MHz, D 2 O) δ 4.45 (d, 0.4H), 4.31 (d, 0.6H), 4.17 (q, 2H), 3.813.87 (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).

Príklad 15Example 15

Hydrochlorid (2RS,3R)-jV-(2-(karbobenzyloxy)etyl)-3-amino-2-hydroxy-5(etyltio)pentánamidu(2RS, 3R) -N- (2- (Carbobenzyloxy) ethyl) -3-amino-2-hydroxy-5 (ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a benzyl-3-amino-propionát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 12A and benzyl 3-amino-propionate are processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 355 (M+H)+, 377 (M+Na)+;MS (ESI + Q1MS) m / e 355 (M + H) &lt; + &gt;, 377 (M + Na) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 7,45 (br, m, 5H), 5,18 (s, 2H), 4,41 (d, 0,4H),1 H NMR (300 MHz, DMSO-d 6 ) 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), 1,161,26 (m, 3H).4.21 (d, 0.6H), 3.46-3.87 (m, 3H), 2.43-2.72 (m, 6H), 1.70-2.03 (m, 2H), 1,161.26 (m, 3H).

Príklad 16Example 16

Hydrochlorid (2RS,3R)-JV-(3-(karboetoxy)propyl)-3-amino-2-hydroxy-5-(etyltio)pentánamidu ·· • · · • e ···· • · ·· ··· ·· ··· ·· ···(2RS, 3R) -N- (3- (carboethoxy) propyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride ··· ·········· ·· ··· ·· ···

Produkt z príkladu 12A a etyl-4-amino-butyrát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 12A and ethyl 4-amino-butyrate were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 307 (M+H)+, 325 (M+Na)+;MS (ESI + Q1MS) mlz 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).1 H NMR (300 MHz, DMSO-d 6 ) 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).

Príklad 17Example 17

Hydrochlorid (2RS,3R, l’S)-A/-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-heptánamidu(2RS, 3R, 1'S) - N - ((1-Ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-heptanamide hydrochloride

Príklad 17AExample 17A

N-(/erc-butoxykarbonyl)-D-norleucín sa spracováva podľa spôsobov z príkladov 1A až ID, čím sa získa (2RS,3R)-3-(/erc-butoxykarbonylamino)-2hydroxy-heptanová kyselina.N - (tert -butoxycarbonyl) -D-norleucine was treated according to the methods of Examples 1A to 1D to give (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-heptanoic acid.

Príklad 17BExample 17B

Produkt z príkladu 17A a hydrochlorid L-alanínetylesteru sa spracovávajú podľa spôsobu z príkladu 1E, čím sa získa požadovaná zlúčenina.The product of Example 17A and L-alanine ethyl ester hydrochloride were processed according to the method of Example 1E to give the title compound.

MS (APCI) m/e 295(M+H)+;MS (APCI) m / e 295 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, DMSO-d6) δ 8,39 (m, 1H), 7,89 (m, 1H), 7,74 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.39 (m, 1H), 7.89 (m, 1H), 7.74 (m, 1H),

6,48 (m, 1H), 4,13 (m, 1H), 4,08 (m, 3H), 3,60 (m, 1H), 1,34 (m, 9H), 1,19 (m, 3H), 0,88 (m, 3H).6.48 (m, 1H); 4.13 (m, 1H); 4.08 (m, 3H); 3.60 (m, 1H); 1.34 (m, 9H); 1.19 (m) 3H), 0.88 (m, 3H).

···· · ·· · ·· • ·· · · ·· · · « • · · · · · · • ···· ···· ·· ··· ·· ··· ·· ······· · ··········································································· ·

Príklad 18 (2RS,3R)-3-amino-2-hydroxy-5-(metyltio) pentánová kyselinaExample 18 (2RS, 3R) -3-Amino-2-hydroxy-5- (methylthio) pentanoic acid

N-(/erc-butoxykarbonyl)-D-metionín sa spracováva podľa spôsobov z príkladov 1A až 1C, čím sa získa (2RS,3R)-3-amino-2-hydroxy-5(metyltio)pentánová kyselina.N - (tert -butoxycarbonyl) -D-methionine was processed according to the methods of Examples 1A to 1C to give (2RS, 3R) -3-amino-2-hydroxy-5 (methylthio) pentanoic acid.

MS (APCI) m/e 180 (M+H)+;MS (APCI) m / e 180 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, DMSO-d6) δ 7,52 (bs, 2H), 3,64 (d, 1H), 3,50 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 7.52 (bs, 2H), 3.64 (d, 1H), 3.50 (m, 1H),

3,30 (m, 2H), 2,58 (m, 2H), 2,03 (s, 3H).3.30 (m, 2H), 2.58 (m, 2H), 2.03 (s, 3H).

Príklad 19 (2RS,3R)-N-(2-(4-pyridyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidExample 19 (2RS, 3R) -N- (2- (4-Pyridyl) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide

Produkt z príkladu 3A a l-amino-2-(4-pyridyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina,The product of Example 3A and 1-amino-2- (4-pyridyl) ethane were treated according to the method of Example 2 to give the title compound, m.p.

MS (APCI) m/e 284 (M+H)+;MS (APCI) m / e 284 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,78 (m, 2H), 8,32 (m, 1H), 8,10 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.78 (m, 2H), 8.32 (m, 1H), 8.10 (m, 1H),

7,90 (m, 1H), 7,84 (m, 2H), 4,22 (m, 1H), 4,08 (m, 1H), 3,49 (m, 2H), 3,04 (m, 2H), 2,55(m, 2H), 2,04 (s, 3H), l,75(m, 2H).7.90 (m, 1H), 7.84 (m, 2H), 4.22 (m, 1H), 4.08 (m, 1H), 3.49 (m, 2H), 3.04 (m 2H, 2.55 (m, 2H), 2.04 (s, 3H), 1.75 (m, 2H).

Príklad 20Example 20

Hydrochlorid (2RS,3R)-/V-(2-(karboetoxy)etyl)-3-amino-2-hydroxy-4-fenyl-butánamidu(2RS, 3R) - N - (2- (Carboethoxy) ethyl) -3-amino-2-hydroxy-4-phenylbutanamide hydrochloride

···· · ···· · ·· • · • · · · • · • · • ·· • • · · • ·· • · • · · · • · • · ·· · · • • • • ·· • · · • • · • · • · · • · · ·· · · • 9 · • 9 · ·· · · ·· · ·

Príklad 20AExample 20A

N-(/erc-butoxykarbonyl)-D-fenylalanín sa spracováva podľa spôsobov z príkladov 1A až ID, čím sa získa (2RS,3R)-3-(íerc-butoxykarbonylamino)-2hydroxy-4-fenyl-butanová kyselina.N - (tert -butoxycarbonyl) -D-phenylalanine was processed according to the methods of Examples 1A to 1D to give (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-4-phenyl-butanoic acid.

Príklad 20BExample 20B

Produkt z príkladu 20A a etyl-3-amino-propionát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 20A and ethyl 3-amino-propionate were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 295(M+H)+, 317 (M+Na)+;MS (ESI + Q1MS) mlz 295 (M + H) + , 317 (M + Na) + ;

‘H NMR (300 MHz, MeOH-d4) a 1,19-1,26 (m, 3H), 2,49-2,58 (m, 2H), 2,803,10 (m, 2H), 3,41-3,53 (m, 2H), 3,78-3,85(m, 1H), 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, 1H), 4,02 (d, 1H),1 H NMR (300 MHz, MeOH-d 4 ) and 1.19-1.26 (m, 3H), 2.49-2.58 (m, 2H), 2.803.10 (m, 2H), 3, 41-3.53 (m, 2H), 3.78-3.85 (m, 1H), 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, 1 H), 4.02 (d, 1 H),

4,29 (m, 1H), 7,10-7,27 (m, 5H).4.29 (m, 1H); 7.10-7.27 (m, 5H).

Príklad 21Example 21

Hydrochlorid (2RS,3R)-JV-(3-(karboetoxy)propyl)-3-amino-2-hydroxy-4-fenyIbutánamidu(2RS, 3R) -N- (3- (Carboethoxy) propyl) -3-amino-2-hydroxy-4-phenylbutanamide hydrochloride

Produkt z príkladu 20A a etyl-4-amino-butyrát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 20A and ethyl 4-amino-butyrate were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 309 (M+H)+, 325(M+NH4)+;MS (ESI + Q1MS) mlz 309 (M + H) + , 325 (M + NH 4 ) + ;

’H 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, 1H), 4,05-4,15 (m, 3H), 4,28 (d, 0,3H), 7,25-7,40 (m, 5H).1 H NMR (300 MHz, MeOH-d 4 ) 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, 1H), 4.05-4.15 (m, 3H), 4.28 (d, 0.3H), 7.25- 7.40 (m, 5H).

Príklad 22Example 22

Hydrochlorid (2RS,3R)-7V-(4-fenylbutyl)-3-amino-2-hydroxy-4-fenyl-butánamid ···· · ·· · ·· • ·· · · ·· · · · • · · · · · · »· ··· ·· ··· ·· ·(2RS, 3R) -N- (4-Phenylbutyl) -3-amino-2-hydroxy-4-phenylbutanamide hydrochloride ··· · ··· · · · · · · · · · · · · · · · · · · · ·

Produkt z príkladu 20A a 4-fenylbutylamin sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 20A and 4-phenylbutylamine were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 327 (M+H)+, 653 (2M+H)+;MS (ESI + Q1MS) mlz 327 (M + H) + , 653 (2M + H) + ;

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, 1H), 4,03 (d, 0,7H), 4,29 (d, 0,3H), 7,08-7,39 (m, 10H).NMR (300 MHz, MeOH-d 4 ) δ 1.47-1.69 (m, 4H), 2.65 (t, 2H), 2.80-3.39 (m), 3.75-3, 84 (m, 1H), 4.03 (d, 0.7H), 4.29 (d, 0.3H), 7.08-7.39 (m, 10H).

Príklad 23Example 23

Hydrochlorid (2RS,3R, l’S)-y-((l-etoxykarbonyl)etyl)-3-amino-2-hydroxy-4cyklohexyl-butánamidu(2RS, 3R, 1'S) -y - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-4-cyclohexyl-butanamide hydrochloride

Príklad 23AExample 23A

N-(/erc-Butoxykarbonyl)-D-cyklohexylalanín sa spracováva podľa spôsobov z príkladov 1A až ID, čím sa získa (2RS,3R)-3-(/erc-butoxykarbonylamino)-2hydroxy-4-cyklohexyl-butánová kyselina.N - (tert -Butoxycarbonyl) -D-cyclohexylalanine was processed according to the methods of Examples 1A to 1D to give (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-4-cyclohexyl-butanoic acid.

Príklad 23BExample 23B

Produkt z príkladu 23A a hydrochlorid etylesteru L-alanínu sa spracovávajú podľa spôsobu z príkladu IE, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-alanine ethyl ester hydrochloride were processed according to the method of Example IE to give the title compound.

MS (ESI+Q1MS) m/e 301 (M+H)+, 601 (2M+H)+;MS (ESI + Q1MS) m / e 301 (M + H) &lt; + &gt;, 601 (2M + H) &lt; + &gt;;

*H NMR (300 MHz, MeOH-d4) δ 0,90-1,82 (m, 19H, zahŕňa 1,27, t, 3H; 1,45, d, 3H) 3,57-3,65(m, 3H), 4,15-4,23 (m, 3H), 4,45(q, 2H);1 H NMR (300 MHz, MeOH-d 4 ) 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);

Príklad 24Example 24

Hydrochlorid (2RS,3R)-AT-(2-(karboetoxy)etyl)-3-amino-2-hydroxy-4-cyklohexyl-butánamidu ···· • · ·· ··· ·· ··· ·· ·· ·(2RS, 3R) -AT- (2- (Carboethoxy) ethyl) -3-amino-2-hydroxy-4-cyclohexylbutanamide hydrochloride ············· · ·

Produkt z príkladu 23A a etyl-3-amino-propionát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 23A and ethyl 3-amino-propionate were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 301 (M+H)+, 323 (M+Na)+;MS (ESI + Q1MS) mlz 301 (M + H) + , 323 (M + Na) + ;

’H NMR (300 MHz, MeOH-d4) δ 0,93-1,84 (m, 16H, zahŕňa 1,26, t, 3H) 2,552,61 (m, 2H), 3,47-3,54 (m, 2H), 4,11-4,24 (m, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 0.93-1.84 (m, 16H, includes 1.26, t, 3H) 2,552.61 (m, 2H), 3.47-3.54 (m, 2H), 4.11-4.24 (m, 3H).

Príklad 25Example 25

Hydrochlorid (2RS,3R)-/\T-(3-(karboetoxy)propyl)-3-amino-2-hydroxy-4-cyklohexyl-butánamidu(2RS, 3R) - N - (3- (Carboethoxy) propyl) -3-amino-2-hydroxy-4-cyclohexylbutanamide hydrochloride

Produkt z príkladu 23A a etyl-4-amino-butyrát sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 23A and ethyl 4-amino-butyrate were processed according to the method of Example 2 to give the title compound.

MS (ESI+Q1MS) m/e 335(M+Na-H)+;MS (ESI + Q1MS) mlz 335 (M + Na-H) + ;

*H NMR (300 MHz, MeOH-d4) δ 0,82-1,88 (m, 18H, zahŕňa 1,25, t, 3H), 2,342,39 (m, 2H), 3,18-3,38 (m, zatienené píkom s MeOH), 3,57-3,67 (m, 2H), 4,08-4,25(m, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 0.82-1.88 (m, 18H, includes 1.25, t, 3H), 2,342.39 (m, 2H), 3.18-3, 38 (m, shadowed with MeOH peak), 3.57-3.67 (m, 2H), 4.08-4.25 (m, 3H).

Príklad 26Example 26

Hydrochlorid (2RS,3R, ľ S)-JV-((1 -etoxykarbonyl)etyl)-3-amino-2-hydroxy-4fenyl-butánamidu(2RS, 3R, 1'S) -N - ((1-ethoxycarbonyl) ethyl) -3-amino-2-hydroxy-4-phenylbutanamide hydrochloride

Produkt z príkladu 20A a hydrochlorid etylesteru L-alanínu sa spracovávajú podľa spôsobu z príkladu 1E, čím sa získa požadovaná zlúčenina.The product of Example 20A and L-alanine ethyl ester hydrochloride were processed according to the method of Example 1E to give the title compound.

MS (ESI+Q1MS) m/e 295 (M+ H)+;MS (ESI + Q1MS) mlz 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, 1H), 4,08-4,21 (m, 3H), 4,35-4,47 (m, 1H), 7,25-7,40 (m, 5H).1 H NMR (300 MHz, MeOH-d 4 ) δ 1.25 (dt, 3H), 1.44 (d, 3H), 2.83-3.17 (m, 2H), 3.76-3, 83 (m, 1H), 4.08-4.21 (m, 3H), 4.35-4.47 (m, 1H), 7.25-7.40 (m, 5H).

·· ··· ·· ··· ·· ····· ··· ·· ··· ·· ···

Príklad 27Example 27

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-/V-(4-metoxyfenetyl)-5-(metylsuIfanyl)pentánamidu(2RS, 3R) -3-Amino-2-hydroxy- N - (4-methoxyphenethyl) -5- (methylsulfanyl) pentanamide hydrochloride

Produkt z príkladu 23A a l-amino-2-(4-metoxyfenyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-amino-2- (4-methoxyphenyl) ethane were processed according to the method of Example 2 to give the title compound.

MS (APCI) m/e 313 (M+H)+;MS (APCI) m / e 313 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,24 (m, 1H), 7,82 (m, 2H), 7,12 (d, 2H), 6,86 (d, 2H), 6,53 (d, 1H), 4,08 (m, 1H), 3,72 (s, 3H), 3,38 (m, 2H), 2,70 (m, 2H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.24 (m, 1H), 7.82 (m, 2H), 7.12 (d, 2H), 6.86 (d, 2H), 6 53 (d, 1H), 4.08 (m, 1H), 3.72 (s, 3H), 3.38 (m, 2H), 2.70 (m, 2H),

2,54 (m, 2H), 2,04 (s, 3H), 1,75 (m, 2H).2.54 (m, 2H), 2.04 (s, 3H), 1.75 (m, 2H).

Príklad 28 (2RS,3R)-/V-((2-fenylbutyl)-3-/erc-butoxykarbonylamino-2hydroxy(etyltio)pentánamiduExample 28 (2RS, 3R) - N - ((2-Phenylbutyl) -3- tert -butoxycarbonylamino-2-hydroxy (ethylthio) pentanamide)

Produktu z príkladu 12A a 4-fenylbutylamin sa spracovávajú podľa spôsobu z príkladu 1E, čím sa získa požadovaná zlúčenina.The product of Example 12A and 4-phenylbutylamine were treated according to the method of Example 1E to give the title compound.

MS (APCI-Q1MS) m/e 459 (M+2NH4-H)+;MS (APCI-Q1MS) m / e 459 (M + 2 H 4 -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, 1H), 3,99 (brd, 0,6H), 4,09 (brd, 0,4H), 7,10-7,27 (m, 5H);1 H NMR (300 MHz, MeOH-d 4 ) 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, 1H), 3.99 (brd, 0.6H), 4, 09 (brd, 0.4H), 7.10-7.27 (m, 5H);

Príklad 29 (2RS,3R)-JV-((2-fenylbutyl)-3-acetylamino-2-hydroxy-5-(etyltio)pentánamidExample 29 (2RS, 3R) -N - ((2-Phenylbutyl) -3-acetylamino-2-hydroxy-5- (ethylthio) pentanamide)

Produkt z príkladu 13 a anhydrid kyseliny octovej sa nechajú reagovať v metylénchloride v prítomnosti trietylamínu a čistia sa chromatografiou na stĺp64 ···· · • ·· ·· • · · ·· ··· ·· ··· ·· ··· ci silikagélu mobilnou fázou 1 % metanolom v chloroforme, čím sa získa požadovaná zlúčenina.The product of Example 13 and acetic anhydride are reacted in methylene chloride in the presence of triethylamine and purified by column chromatography 64. or silica gel eluting with 1% methanol in chloroform to give the title compound.

MS (ESI+Q1MS) m/e 367 (M+H)+, 389 (M+Na)+, 733 (2M+H)+, 755(2M+Na)+;MS (ESI + Q1MS) mlz 367 (M + H) + , 389 (M + Na) + , 733 (2M + H) + , 755 (2M + Na) + ;

*H NMR (300 MHz, MeOH-d4) δ 1,23 (t, 3H), 1,48-1,68 (m, 4H), 1,73-1,93 (m, 5H, zahŕňa, 1,87, s, 3H), 2,49-2,57 (m, 4H), 2,63 (t, 2H), 3,10-3,19 (m, 1H), 4,02 (d, 1H), 4,29 (m, 1H), 7,10-7,27 (m, 5H);1 H NMR (300 MHz, MeOH-d 4 ) 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, 1H), 4.02 (d, 1H) 4.29 (m, 1H); 7.10-7.27 (m, 5H);

Príklad 30Example 30

Hydrochlorid (2RS,3R)-/V-((fenylbutyryl)-3-amino-2-hydroxy-4-cyklohexyl)butánamidu(2RS, 3R) - N - ((Phenylbutyryl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-fenylbutylamín sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-phenylbutylamine were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 333 (M+ H)+, 665(2M+ H)+;MS (ESI + Q1MS) mlz 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, 1H), 3,22-3,36 (m, 2H),1 H NMR (300 MHz, CDCl 3 ) 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, 1H), 3.22-3.36 (m, 2H),

2,63 (t, 2H), 0,80-1,83 (m, 19H).2.63 (t, 2H); 0.80-1.83 (m, 19H).

Príklad 31Example 31

Hydrochlorid (2RS, 3 R)-/V-((fenylbutyryl)-3-metoxy karbonylami no-2-hydroxy4-etyltio)pentánamidu(2RS, 3R) - N - ((Phenylbutyryl) -3-methoxycarbonylamino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 13 a metylchlórformiát sa nechajú reagovať v tetrahydrofuráne za prítomnosti trietylamínu a čistenie sa prevádza chromatografiou na stĺpci silikagélu mobilnou fázou 0,5-0,75 % metanolu v chloroforme, čím sa získa požadovaná zlúčenina.The product of Example 13 and methyl chloroformate are reacted in tetrahydrofuran in the presence of triethylamine and purification is performed by silica gel column chromatography eluting with 0.5-0.75% methanol in chloroform to give the title compound.

MS (ESI+Q1MS) m/e 383 (M+ H)+, 400 (M+ NH4)+;MS (ESI + Q1MS) m / e 383 (M + H) +, 400 (M + NH4) +;

···· · ·· · ·· r ·· · · ·· · · · ·· ··· ·· ··· ·· ··· lH NMR (300 MHz, CDC13) δ 7,16-7,30 (m, 5H), 6,73 (br, d, 1H), 5,18 a 5,35 (oba br, d, celkove 1H), 4,25 (br, d, 0,3H), 4,14 (d, 0,7H), 3,97-4,07 (m, 1H), 3,59 a 3,67 (oba s, celkom 3H), 3,23-3,37 (m, 2H), 2,45-2,68 (m, 6H), 1,902,12 (m, 2H), 1,52-1,71 (m, 6H), l,25(dt, 3H).· 1 H NMR (300 MHz, CDCl 3 ) δ 7.16- 7.30 (m, 5H), 6.73 (br, d, 1H), 5.18 and 5.35 (both br, d, total 1H), 4.25 (br, d, 0.3H), 4.14 (d, 0.7H), 3.97-4.07 (m, 1H), 3.59 and 3.67 (both s, total 3H), 3.23-3.37 (m, 2H) 1.49-2.68 (m, 6H), 1.902.12 (m, 2H), 1.52-1.71 (m, 6H), 1.25 (dt, 3H).

Príklad 32 (2RS,3R)-A/-(2-(3-pyridyl)etyl)-3-amino-2-hydroxy-5-(metyltio)pentánamidExample 32 (2RS, 3R) -N- (2- (3-pyridyl) ethyl) -3-amino-2-hydroxy-5- (methylthio) pentanamide

Produkt z príkladu 3A a l-amino-2-(3-pyridyl)etán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1-amino-2- (3-pyridyl) ethane were processed according to the method of Example 2 to give the title compound.

MS (APCI) m/e 284 (M+H)+;MS (APCI) m / e 284 (M + H) &lt; + &gt;;

NMR (300 MHz, DMSO-d6) δ 8,74 (m, 1H), 8,38 (m, 2H), 8,10 (m, 1H),NMR (300 MHz, DMSO-d6) δ 8.74 (m, 1H), 8.38 (m, 2H), 8.10 (m, 1 H);

7,90 (m, 2H), 7,78 (m, 2H), 4,09 (m, 1H), 3,70 (m, 2H), 3,57 (m, 2H), 3,49 (m, 2H), 2,57 (m, 1H), 2,04 (s, 3H), 1,80 (m, 2H).7.90 (m, 2H), 7.78 (m, 2H), 4.09 (m, 1H), 3.70 (m, 2H), 3.57 (m, 2H), 3.49 (m 2H, 2.57 (m, 1H), 2.04 (s, 3H), 1.80 (m, 2H).

Príklad 33Example 33

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-/^-metyl-5-(metylsulfanyl)-/V-fenetylpentánamidu(2RS, 3R) -3-Amino-2-hydroxy- N -methyl-5- (methylsulfanyl) - N -phenethylpentanamide hydrochloride

Produkt z príkladu 3A a l-(N-metylamino)-2-fenyletán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of Example 3A and 1- (N-methylamino) -2-phenylethane were processed according to the method of Example 2 to give the title compound.

MS (APCI) m/e 297 (M+H)+; *H NMR (300 MHz, DMSO-d6) δ 7,88 (m, 1H),MS (APCI) m / e 297 (M + H) &lt; + &gt;; 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.88 (m, 1H),

7,76 (m, 2H), 7,37 (m, 5H), 6,38 (m, 1H), 4,42 (m, 1H), 4,23 (s, 3H), 3,70 (m, 4H), 3,49 (m, 3H), 3,05 (m, 1H), 2,92 (m, 1H), 2,04 (m, 3H).7.76 (m, 2H), 7.37 (m, 5H), 6.38 (m, 1H), 4.42 (m, 1H), 4.23 (s, 3H), 3.70 (m 4H), 3.49 (m, 3H), 3.05 (m, 1H), 2.92 (m, 1H), 2.04 (m, 3H).

···· · ·· · ·· • ·· · · ·· · · · ·· ··· ·· ··· ·· ····· · ·································

Príklad 34Example 34

Hydrochlorid (2RS,3R, l’S)-Y-((2-karboxyetyl)-3-amino-2-hydroxy-4-etyltio)pentánamidu(2RS, 3R, 1'S) -Y - ((2-Carboxyethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Spracovaním podľa spôsobu z príkladu 12B sa získa medziprodukt derivát íerc-butoxykarbonylu. Ten sa zmydelní 1Y-Iítium hydroxidom v roztoku metanolu a vody, čím sa získa Y-chránený derivát karboxylové kyseliny, ktorý sa potom nechá reagovať spôsobom uvedeným v príklade 1F, čím sa získa požadovaná zlúčenina.Workup according to the method of Example 12B yields the intermediate tert-butoxycarbonyl derivative. This was saponified with 1Y-lithium hydroxide in methanol / water to give the Y-protected carboxylic acid derivative which was then reacted as in Example 1F to give the title compound.

MS (ESI+Q1MS) m/e 265(M+ H)+, 287 (M+ Na)+, 529 (2M+ H)+, 551 (2M+Na)+;MS (ESI + Q1MS) mlz 265 (M + H) + , 287 (M + Na) + , 529 (2M + H) + , 551 (2M + Na) + ;

’H NMR (300 MHz, D2O) Ô 2,75-2,50 (m, 4H), 2,12-1,90 (m, 2H), 1,40 (d, 3H),1 H NMR (300 MHz, D 2 O) δ 2.75-2.50 (m, 4H), 2.12-1.90 (m, 2H), 1.40 (d, 3H),

1,24 (dt, 3H);1.24 (dt, 3H);

Príklad 35Example 35

Hydrochlorid (2RS,3R)-Y-((l-metyl-l-etoxykarboxyetyl)-3-amino-2-hydroxy4-etyltio)pentánamidu(2RS, 3R) -Y - ((1-Methyl-1-ethoxycarboxyethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a hydrochlorid etylesteru a-aminoizobutyrovej kyseliny sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 12A and α-aminoisobutyric acid ethyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 307 (M+ H)+;MS (ESI + Q1MS) mlz 307 (M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 4,26-4,14 (m, 3H), 3,77-3,53 (m, 4H), 2,772,55 (m, 4H), 2,14-1,84 (m, 2H), 1,54-1,51 (m, 6H), 1,29-1,22 (m, 6H);1 H NMR (300 MHz, MeOH-d 4 ) δ 4.26-4.14 (m, 3H), 3.77-3.53 (m, 4H), 2.772.55 (m, 4H), 2, 14-1.84 (m, 2H), 1.54-1.51 (m, 6H), 1.29-1.22 (m, 6H);

Príklad 36Example 36

Hydrochlorid (2RS.3R, l'S)-Y-((l-(2-hydroxy)-l-etoxykarboxyetyl)-3-amino-2hydroxy-4-etyltio)pentánamidu(2RS, 3R, 1'S) -Y - ((1- (2-Hydroxy) -1-ethoxycarboxyethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a hydrochlorid L-serínetylesteru sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 12A and L-serine ethyl ester hydrochloride were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 309 (M+ H)+;MS (ESI + Q1MS) mlz 309 (M + H) + ;

’H NMR (300 MHz, D2O) δ 4,67-4,63 (m, 1H), 4,57 (d, 0,3H), 4,44 (d, 0,7H), 4,24-4,15(m, 2H), 4,06-3,87 (3H), 3,76-3,84 (m, 1H), 2,52-2,83 (m, 4H), 2,181,93 (m, 2H), 1,32 - 1,20 (m, 6H);1 H NMR (300 MHz, D 2 O) δ 4.67-4.63 (m, 1H), 4.57 (d, 0.3H), 4.44 (d, 0.7H), 4.24 -4.15 (m, 2H), 4.06-3.87 (3H), 3.76-3.84 (m, 1H), 2.52-2.83 (m, 4H), 2,181.93 (m, 2H), 1.32-1.20 (m, 6H);

Príklad 37 (2RS,3R)-/V-((fenylbutyryl)-3-ferc-butoxykarbonylamino-2-hydroxy-4 etyltio)pentánamidExample 37 (2RS, 3R) -N - ((Phenylbutyryl) -3-tert-butoxycarbonylamino-2-hydroxy-4-ethylthio) pentanamide

Produkt z príkladu 12A a 4-fenylbutylamín sa spracovávajú podľa spôsobu z príkladu 1E, čím sa získa požadovaná zlúčenina.The product of Example 12A and 4-phenylbutylamine were processed according to the method of Example 1E to give the title compound.

MS (ESI+Q1MS) m/e 439 (M+ H)+;MS (ESI + Q1MS) mlz 439 (M + H) + ;

’H NMR (300 MHz, CDC13) δ 7,30-7,15 (m, 5H), 7,03 (t, 1H), 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).1 H NMR (300 MHz, CDCl 3 ) δ 7.30-7.15 (m, 5H), 7.03 (t, 1H), 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, 3 H).

Príklad 38 (2RS,3R)-JV-((fenylbutyryl)-3-formylamino-2-hydroxy-4-etyltio)pentánamidExample 38 (2RS, 3R) -N - ((Phenylbutyryl) -3-formylamino-2-hydroxy-4-ethylthio) pentanamide

Produkt z príkladu 13 a anhydrid kyselín mravčej a octovej v metylénchloride v prítomnosti trietylamínu sa spracovávajú podľa spôsobu z príkladu 1E a čistia sa chromatografiou na stĺpci silikagélu mobilnou fázou 2% metanol v chloroforme, čím sa získa požadovaná zlúčenina.The product of Example 13 and formic and acetic anhydride in methylene chloride in the presence of triethylamine were worked up according to the method of Example 1E and purified by silica gel column chromatography eluting with 2% methanol in chloroform to give the title compound.

MS (ESI+Q1MS) m/e 353 (M+ H)+, 375(M+ Na)+, 727 (2M+ Na)+;MS (ESI + Q1MS) m / e 353 (M + H) &lt; + &gt;, 375 (M + Na) & lt ; + &gt;, 727 (2M + Na) + ;

’H NMR (300 MHz, MeOH-d4) δ 7,26-7,11 (m, 5H), 4,44-4,38 (m, 1H), 4,05 (d,1 H NMR (300 MHz, MeOH-d 4 ) δ 7.26-7.11 (m, 5H), 4.44-4.38 (m, 1H), 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,0.7H), 4.00 (d, 0.3H), 3.27-3.12 (m, 2H), 2.63-2.49 (m, 4H), 1.93-1.30 (m) m.

8H), 1,26-1,20 (m, 3H).8H), 1.26-1.20 (m, 3H).

Príklad 39Example 39

Hydrochlorid (2RS,3R)-/V-Metyl-/V-((etoxykarbonylmetyl)-3-amino-2-hydroxy4-etyltio)pentánamidu(2RS, 3R) - N-Methyl- N - ((ethoxycarbonylmethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a hydrochlorid etylesteru /V-metylglycínu sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 12A and N-methylglycine ethyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 293 (M+ H)+;MS (ESI + Q1MS) m / e 293 (M + H) &lt; + &gt;;

’H NMR (300 MHz, D2O) δ 4,22-4,27 (m, 1H), 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).1 H NMR (300 MHz, D 2 O) δ 4.22-4.27 (m, 1H), 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).

Príklad 40Example 40

Hydrochlorid (2RS, 3 R)-JV-((Fenylbutyryl)-3-hydroxy mety lkarbonylamino-2hydroxy-4-etyltio)pentánamidu(2RS, 3R) -N - ((Phenylbutyryl) -3-hydroxymethylcarbonylamino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 13 a giykolová kyselina sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 13 and the glycolic acid were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 383 (M+ H)+, 405(M+ Na)+, 787 (2M+ Na)+;MS (ESI + Q1MS) m / e 383 (M + H) &lt; + &gt;, 405 (M + Na) & lt ; + &gt;, 787 (2M + Na) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 8,01 (br, t, 1H), 7,68 (d, 1H), 7,26-7,13 (m,1 H NMR (300 MHz, MeOH-d 4 ) δ 8.01 (br, t, 1H), 7.68 (d, 1H), 7.26-7.13 (m,

5H), 4,43-4,32 (m, 1H), 3,94-3,85 (m, 1H), 3,78-3,65 (m, 1H), 3,26-3,15 (m,5H), 4.43-4.32 (m, 1H), 3.94-3.85 (m, 1H), 3.78-3.65 (m, 1H), 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).2H), 3.24-2.98 (m, 2H), 2.64-2.48 (m, 6H), 1.97-1.49 (m, 6H), 1.22 (t, 3H) .

·· • · · • · ·· ······ · · · ···

Príklad 41Example 41

Hydrochlorid (2RS,3RS, l'R)-/V-((l -etoxykarbonyletyl)-3-amino-2-hydroxy-4etyltio)pentánamidu(2RS, 3RS, 1'R) - N - ((1-Ethoxycarbonylethyl) -3-amino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 12A a hydrochlorid D-alanínetylesteru sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 12A and D-alanine ethyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 293 (M+ H)+;MS (ESI + Q1MS) m / e 293 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 4,55-4,15 (m, 4H), 3,76-3,67 (m, 2H), 2,752,51 (m, 4H), 2,05-2,17 (m, 1H), 1,97-1,85 (m, 1H), 1,45 (t, 3H), 1,31-1,22 (m, 6H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.55-4.15 (m, 4H), 3.76-3.67 (m, 2H), 2,752.51 (m, 4H), 2, 05-2.17 (m, 1H), 1.97-1.85 (m, 1H), 1.45 (t, 3H), 1.31-1.22 (m, 6H).

Príklad 42Example 42

Hydrochlorid (2RS,3R, l'R)-W-((l-etoxykarbonyletyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R, 1'R) - N - ((1-Ethoxycarbonylethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23A a hydrochlorid D-alanínetylesteru sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and D-alanine ethyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 301 (M+ H)+;MS (ESI + Q1MS) mlz 301 (M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 4,54-4,42 (m, 1H), 4,28-4,16 (m, 2H), 3,763,57 (m, 2H), 1,82-0,83 (m, 19H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.54-4.42 (m, 1H), 4.28-4.16 (m, 2H), 3.763.57 (m, 2H), 1, 82-0.83 (m, 19H).

Príklad 43Example 43

Hydrochlorid (2RS,3R)-JV-((l-metyl-l-etoxykarbonyletyl)-3-amino-2-hydroxy4-cyklohexyl)butánamidu(2RS, 3R) -N - ((1-Methyl-1-ethoxycarbonylethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23A a hydrochlorid etylesteru alfa-aminoizobutyrovej kyseliny sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and alpha-aminoisobutyric acid ethyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

·· · · ·· • · · »· ··· ·· ···································

MS (ESI+Q1MS) m/e 315 (M+ H)+, 629 (2M+ H)+;MS (ESI + Q1MS) mlz 315 (M + H) + , 629 (2M + H) + ;

lH NMR (300 MHz, MeOH-d4) δ 4,23-4,09 (m, 3H), 3,76-3,57 (m, 1H), 1,820,82 (m, 22H). 1 H NMR (300 MHz, MeOH-d 4 ) δ 4.23-4.09 (m, 3H), 3.76-3.57 (m, 1H), 1.820.82 (m, 22H).

Príklad 44Example 44

Hydrochlorid (2RS,3R)-/V-((Fenylbutyryl)-3-metoxykarbonylmetylamino-2hydroxy-4-etyltio)pentánamidu(2RS, 3R) - N - ((Phenylbutyryl) -3-methoxycarbonylmethylamino-2-hydroxy-4-ethylthio) pentanamide hydrochloride

Produkt z príkladu 13 a metylbrómacetát sa nechajú reagovať v dimetylsulfoxide v prítomnosti hydridu sodného a spracovávajú podľa spôsobu z príkladu IE, čím sa získa požadovaná zlúčenina.The product of Example 13 and methyl bromoacetate are reacted in dimethylsulfoxide in the presence of sodium hydride and treated according to the method of Example IE to give the title compound.

MS (ESI+Q1MS) m/e 397 (M+ H)+, 419 (M+ Na)+;MS (ESI + Q1MS) mlz 397 (M + H) + , 419 (M + Na) + ;

lH NMR (300 MHz, CDC13) δ 8,01 (s, 1H), 7,31-7,16 (m, 5H), 6,53 (br, 1H), 4,35-4,25(m, 1H), 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). 1 H NMR (300 MHz, CDCl 3 ) δ 8.01 (s, 1H), 7.31-7.16 (m, 5H), 6.53 (br, 1H), 4.35-4.25 ( m, 1H), 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).

Príklad 45Example 45

Hydrochlorid (2RS,3R,l’S)-/Y-((l-etoxykarbonyletyl)-3-amino-2-hydroxy-4benzyltio)butánamidu(2RS, 3R, 1'S) - / Y - ((1-Ethoxycarbonylethyl) -3-amino-2-hydroxy-4-benzylthio) butanamide hydrochloride

Príklad 45AExample 45A

N-(/erc-Butoxykarbonyl)-S-benzyl-D-cysteín sa spracováva podľa spôsobu z príkladu 1A až 1B, čím sa pripraví A/-(/erc-butoxykarbonyl)-S-benzyl-Dcysteinal.N - (tert -Butoxycarbonyl) -S-benzyl-D-cysteine was processed according to the method of Examples 1A to 1B to prepare N - (tert -butoxycarbonyl) -S-benzyl-Dcysteinal.

···· · ·· · ·· • · · · ··· · ·· • · · · · · · ··· ··· ··· ·· ··· ·· ··· ·· ······· · ····································································· ·

Príklad 45BExample 45B

Produkt z príkladu 286491, IA (3,56g, 12,1 mmol) sa suspenduje v ľadovej vode (70 ml) a pridá sa bisulfid sodný (l,26g, 12,1 mmol) a mieša sa pri teplote 0 °C po dobu 1,5 hodiny, potom sa nechá v chladiacom boxe cez noc. Pridá sa etylacetát (70 ml) a kyanid draselný (0,79g, 12,1 mmol) a intenzívne sa mieša po dobu 4 hodiny. Separovaná etylacetátová vrstva sa premyje postupne vodou a soľankou, suší sa (MgSO4) a koncentruje sa, čím sa získa bezfarebný sirup poskytujúci 3,40 g pevné látky.The product of Example 286491, IA (3.56g, 12.1 mmol) was suspended in ice water (70 mL) and sodium bisulfide (1.26g, 12.1 mmol) was added and stirred at 0 ° C for 1.5 hours, then left in the refrigerator overnight. Ethyl acetate (70 mL) and potassium cyanide (0.79g, 12.1 mmol) were added and stirred vigorously for 4 hours. The separated ethyl acetate layer was washed sequentially with water and brine, dried (MgSO 4 ) and concentrated to give a colorless syrup giving 3.40 g of solid.

Príklad 45CExample 45C

Produkt z príkladu 45B (3,40 g) sa rozpustí v 50 ml metanole v ľadovom kúpeli a plynný chlorovodík sa nechá reakčnou zmesou prebublávať do tej doby, pokiaľ nie je nasýtená. Potom sa mieša pri teplote 0 °C po dobu 3 hodín a pri izbovej teplote cez noc. Rozpúšťadlo sa odparí do sucha a do zvyšku sa pridá 20 ml vody. Do zmesi sa pridá 10 % kyslý uhličitan, na upravenie pH nad 9, olej sa extrahuje etylacetátom (50 ml x 2). Spojená etylacetátová vrstva sa premyje 10 % kyslým uhličitanom sodným (2 x), soľankou (3 x), rýchlo sa suší nad bezvodým sulfátom sodným. Etylacetát sa odstráni odparením, čím sa získa l,77g tmavého hnedého oleja.The product of Example 45B (3.40 g) was dissolved in 50 mL of methanol in an ice bath and hydrogen chloride gas was bubbled through the reaction mixture until saturated. Then stir at 0 ° C for 3 hours and at room temperature overnight. The solvent is evaporated to dryness and 20 ml of water are added to the residue. To the mixture was added 10% acid carbonate, to adjust the pH above 9, the oil was extracted with ethyl acetate (50 mL x 2). The combined ethyl acetate layer was washed with 10% sodium bicarbonate (2 x), brine (3 x), dried rapidly over anhydrous sodium sulfate. The ethyl acetate was removed by evaporation to give 1.77g of a dark brown oil.

Potom sa spracováva podľa spôsobu z príkladu 1D a čistí sa chromatot grafiou na stĺpci silikagélu mobilnou fázou 12,5 % acetónu v hexáne, čím sa získa 0,12 g metylesteru (2RS,3R)-3-(/erc-butoxykarbonylamino)-2-hydroxy-4benzyltio-butánovej kyseliny.It was then treated according to the method of Example 1D and purified by chromatography on a silica gel column using 12.5% acetone in hexane as eluent to give 0.12 g of (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-methyl ester. -hydroxy-4-benzylthi-butanoic acid.

Príklad 45DExample 45D

Produkt z príkladu 45C sa nechá reagovať s ΙΎ-lítium hydroxidom v roztoku metanolu a vody, čím sa získajú jej voľné deriváty karboxylové kyseliny, potom sa vykoná väzbou s etylesterom L-alanínu podľa postupuThe product of Example 45C is reacted with ΙΎ-lithium hydroxide in a solution of methanol and water to give its free carboxylic acid derivatives, followed by coupling with L-alanine ethyl ester according to the procedure

···· • ···· • • ·· • · · ·· • · · · • · • ·· • · · ·· • · · · • · • • ·· · · ··· · · · ·· · · ··· · · · ·· · · • •

z príkladu IE sa vykoná sa odstránenie chrániacej skupiny podľa spôsobu opísaného v príklade 1F, čím sa získa požadovaná zlúčenina.from Example IE, deprotection according to the method described in Example 1F to give the title compound.

MS (ESI+Q1MS) m/e 341 (M+H)+, 363 (M+Na)+, 681 (2M+H)+;MS (ESI + Q1MS) m / e 341 (M + H) &lt; + &gt;, 363 (M + Na) &lt; + &gt;, 681 (2M + H) &lt; + &gt;;

NMR (300 MHz, MeOH-d4) δ 7,38-7,22 (m, 5H), 4,51-4,38 (m, 2H), 4,234,05 (m, 2H), 3,76-3,56 (m, 4H), 2,86-2,77 (m, 1H), 2,72-2,61 (m, 1H), 1,461,38 (m, 3H), 1,321,16 (m, 3H).NMR (300 MHz, MeOH-d 4 ) δ 7.38-7.22 (m, 5H), 4.51-4.38 (m, 2H), 4.234.05 (m, 2H), 3.76- 3.56 (m, 4H), 2.86-2.77 (m, 1H), 2.72-2.61 (m, 1H), 1.461.38 (m, 3H), 1.321.16 (m, 3H).

Príklad 46Example 46

Hydrochlorid (2RS,3R, l’S)-Á/-((2-hydroxy-l-etoxykarbonyletyl)-3-amino-2hydroxy-4-cyklohexyl)butánamidu(2RS, 3R, 1'S) - N - ((2-Hydroxy-1-ethoxycarbonylethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23 A a hydrochlorid etylesteru L-serínu sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-serine ethyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 317 (M+H)+, 633 (2M+H)+;MS (ESI + Q1MS) mlz 317 (M + H) + , 633 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 4,45-4,55 (m, 1H), 4,26-4,18 (m, 3H), 4,003,87 (m, 2H), 3,69-3,63 (m, 1H), 0,94-1,83 (m, 16H, zahŕňa 1,29 t, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.45-4.55 (m, 1H), 4.26-4.18 (m, 3H), 4.003.87 (m, 2H), 3, 69-3.63 (m, 1H), 0.94-1.83 (m, 16H, includes 1.29 t, 3H).

Príklad 47Example 47

Hydrochlorid (2RS,3R, l’S)-JV-((2-acetoxypropyl)-3-amino-2-hydroxy-4-cyklohexyl)butánamidu(2RS, 3R, 1'S) - N - ((2-Acetoxypropyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Príklad 47AExample 47A

N-(/erc-Butoxykarbonyl)-L-alaninol (438 mg, 2,5 mmol) sa rozpustí v 5 ml metylénchloride v ľadovom kúpeli a v acetylchloride (0,294 ml, 3,75 mmol), potom sa pridá trietylamín (0,7 ml, 5 mmol) a nechá sa reagovať pri teplote 0 °C po dobu 1 hodiny a pri izbovej teplote po dobu 2 dní. Zmes saN - (tert -Butoxycarbonyl) -L-alaninol (438 mg, 2.5 mmol) was dissolved in 5 mL of methylene chloride in an ice bath and in acetyl chloride (0.294 mL, 3.75 mmol) then triethylamine (0.7 mL) was added. ml, 5 mmol) and allowed to react at 0 ° C for 1 hour and at room temperature for 2 days. Mix

···· • • ···· • • • ·· • • · · • • · • · • · • · • · • · • ·· · • ·· · ·· • · · • • · ·· • · · • · ·· • · · ·· · · ··· · · · ·· · · ··· · · · ·· ·· ·· ··

zriedi 25 ml etylacetátu a organická vrstva sa premyje 10 % kyslým uhličitanom sodným (3x), soľankou (2x), suší sa nad bezvodým síranom horečnatým a potom odparuje do sucha, čím sa získa 380 mg N-(ŕerc-butoxykarbonyl)-Oacetyl-L-alaninolu.Dilute with 25 mL ethyl acetate and wash the organic layer with 10% sodium bicarbonate (3x), brine (2x), dry over anhydrous magnesium sulfate and then evaporate to dryness to give 380 mg of N- (tert-butoxycarbonyl) -Oacetyl- L-alaninol.

Príklad 47BExample 47B

Produkt z príkladu 47A (380 mg) sa spracováva podľa spôsobu z príkladu 1F, čím sa získa 0,26 g jeho odpovedajúcej soli, ktorá (0,26g, 1,69 mmol) sa potom viaže s produktom z príkladu 23A (509mg, 1,69 mmol) podľa spôsobu opísaného v príklade IE a čistí sa chromatografiou na stĺpci silikagélu mobilnou fázou 15 % acetónom v hexáne, čím sa získa 0,35 g derivátu N-(tercbutoxykarbonyl). Získaný produkt (0, 35 g) sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaný produkt (290mg).The product of Example 47A (380 mg) was treated according to the method of Example 1F to give 0.26 g of its corresponding salt, which (0.26g, 1.69 mmol) was then coupled with the product of Example 23A (509mg, 1M). , 69 mmol) according to the method described in Example IE and purified by silica gel column chromatography eluting with 15% acetone in hexane to give 0.35 g of the N- (tert-butoxycarbonyl) derivative. The obtained product (0.35 g) was treated according to the method of Example 1F to give the desired product (290mg).

MS (ESI+Q1MS) m/e 301 (M+ H)+, 601 (2M+ H)+;MS (ESI + Q1MS) m / e 301 (M + H) &lt; + &gt;, 601 (2M + H) &lt; + &gt;;

’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, majoritný, 2,03 s, minoritný, celkovo 3H), 1,83-0,94 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) 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).

Príklad 48Example 48

Hydrochlorid (2RS,3R,2’S)-2V-((2-propionyioxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R, 2'S) -2V - ((2-Propionyioxypropyl) -3-amino-2-hydroxy-4cyclohexyl) butanamide hydrochloride

Podľa spôsobu z príkladu 47A, ale nahradením acetylchloridu za propionylchlorid, sa pripraví A-(/erc-butoxykarbonyl)-(9-propionyl-L-alaninol, ktorý sa spracováva podľa spôsobu z príkladu 47B, čím sa získa požadovaná zlúčenina.According to the method of Example 47A, but substituting acetyl chloride for propionyl chloride, N - (tert -butoxycarbonyl) - (9-propionyl-L-alaninol) was prepared, which was processed according to the method of Example 47B to give the title compound.

MS (ESI+Q1MS) m/e 315(M+ H)+, 629 (2M+ H)+;MS (ESI + Q1MS) mlz 315 (M + H) + , 629 (2M + H) + ;

···· • · ·· • · · ·· • · · ·· ··· ·· ··· ’H NMR (300 MHz, MeOH-d4) δ 4,25-3,97 (m, 4H), 3,74-3,56 (m, 2H), 2,402,32 (m, 2H), 1,83-0,94 (m, 19H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.25-3.97 (m, 4H) ), 3.74-3.56 (m, 2H), 2.402.32 (m, 2H), 1.83-0.94 (m, 19H).

Príklad 49Example 49

Hydrochlorid (2RS,3R,2’S)-y-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R, 2'S) -Y - ((2-Benzoyloxypropyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Podľa spôsobu z príkladu 47A, ale nahradením acetylchloridu za benzoylchlorid, sa pripraví AT-(/erc-butoxykarbonyl)-O-benzoyl-L-alaninoI, ktorý sa spracováva podľa spôsobu z príkladu 47B, čím sa získa požadovaná zlúčenina.According to the method of Example 47A but substituting acetyl chloride for benzoyl chloride, N - (tert -butoxycarbonyl) -O-benzoyl-L-alaninyl was prepared, which was processed according to the method of Example 47B, to give the title compound.

MS (ESI+Q1MS) m/e 363 (M+ H)+, 725(2M+ H)+, 747 (2M+ Na)+;MS (ESI + Q1MS) mlz 363 (M + H) + , 725 (2M + H) + , 747 (2M + Na) + ;

’H NMR (300 MHz, MeOH-d4) δ 8,07-8,02 (m, 2H), 7,65-7,58 (m, 1H), 7,527,45 (m, 2H), 4,44-4,07 (m, 4H), 3,60-3,54 (m, 1H), 1,78-0,82 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.07-8.02 (m, 2H), 7.65-7.58 (m, 1H), 7.527.45 (m, 2H), 4, 44-4.07 (m, 4H), 3.60-3.54 (m, 1H), 1.78-0.82 (m, 16H).

Príklad 50Example 50

Hydrochlorid (2RS,3R,2’R)-/V-((2-benzoyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R, 2'R) - N - ((2-Benzoyloxypropyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Podľa spôsobu z príkladu 47A, ale nahradením JV-(ferc-butoxykarbonyl)L-alaninolu za JV-(/erc-butoxykarbonyl)-D-alaninol a acetylchloridu za benzoylchlorid, sa pripraví 7V-(/erc-butoxykarbonyl)-O-benzoyl-D-alaninol, ktorý sa spracováva podľa spôsobu z príkladu 47B, čím sa získa požadovaná zlúčenina.According to the method of Example 47A, but substituting N - (tert -butoxycarbonyl) L-alaninol for N - (tert -butoxycarbonyl) -D-alaninol and acetyl chloride for benzoyl chloride, N - (tert -butoxycarbonyl) -O-benzoyl was prepared. -D-alaninol, which was processed according to the method for EXAMPLE 47B to give the title compound.

MS (ESI+Q1MS) m/e 363 (M+ H)+, 725 (2M+ H)+;MS (ESI + Q1MS) mlz 363 (M + H) + , 725 (2M + H) + ;

‘H NMR (300 MHz, MeOH-d4) δ 8,07-8,02 (m, 2H), 7,65-7,58 (m, 1H), 7,537,44 (m, 2H), 4,43-4,12 (m, 4H), 3,62-3,48 (m, 1H), 1,74-0,82 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.07-8.02 (m, 2H), 7.65-7.58 (m, 1H), 7.537.44 (m, 2H), 4, 43-4.12 (m, 4H), 3.62-3.48 (m, 1H), 1.74-0.82 (m, 16H).

···· · ·· · ·· • ·· · ·· · · · ·· ··· ·· ··· ·· ······· ···························································

Príklad 51Example 51

Hydrochlorid (2RS,3R,2’R)-jV-((2-propionyloxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R, 2'R) - N - ((2-Propionyloxypropyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Podľa spôsobu z príkladu 47A, ale nahradením /V-(íerc-butoxykarbonyl)L-alaninolu za W-(/erc-butoxykarbonyl)-D-alaninol a acetylchloridu za propionylchlorid, sa pripraví N-(ŕerc-butoxykarbonyl)-O-propionyl-D-alaninol, ktorý sa spracováva podľa spôsobu z príkladu 47B, čím sa získa požadovaná zlúčenina.According to the method of Example 47A, but substituting N - (tert -butoxycarbonyl) L-alaninol for N - (tert -butoxycarbonyl) -D-alaninol and acetyl chloride for propionyl chloride, N- (tert-butoxycarbonyl) -O-propionyl was prepared. -D-alaninol, which was processed according to the method for EXAMPLE 47B to give the title compound.

MS (ESI+Q1MS) m/e 315(M+ H)+, 629 (2M+ H)+; *H NMR (300 MHz, MeOHd4) δ 4,23-4,00 (m, 4H), 3,62-3,53 (m, 1H), 2,43-2,32 (m, 2H), 1,82-0,94 (m, 19H).MS (ESI + Q1MS) mlz 315 (M + H) + , 629 (2M + H) + ; 1 H NMR (300 MHz, MeOH 4 ) δ 4.23-4.00 (m, 4H), 3.62-3.53 (m, 1H), 2.43-2.32 (m, 2H), 1.82-0.94 (m, 19H).

Príklad 52Example 52

Hydrochlorid (2RS,3R,2’R)-jV-((2-acetoxypropyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R, 2'R) - N - ((2-Acetoxypropyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Podľa spôsobu z príkladu 47A, ale nahradením W-(terc-butoxykarbonyl)L-alaninolu za JV-(/erc-butoxykarbonyl)-D-alaninol sa pripraví N-(tercbutoxykarbonyl)-0-acetyl-D-alaninol, ktorý sa spracováva podľa spôsobu z príkladu 47B, čím sa získa požadovaná zlúčenina.According to the method of Example 47A, but substituting N - (tert -butoxycarbonyl) L-alaninol for N - (tert -butoxycarbonyl) -D-alaninol, N- (tert-butoxycarbonyl) -O-acetyl-D-alaninol is prepared which is treated according to the method of Example 47B to give the title compound.

MS (ESI+Q1MS) m/e 301 (M+ H)+, 601 (2M+ H)+;MS (ESI + Q1MS) m / e 301 (M + H) &lt; + &gt;, 601 (2M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) Ô 4,25-3,99 (m, 4H), 3,74-3,54 (m, 2H), 2,06, 2,04 (2,04, s, majoritný, 2,06 s, minoritný, celkove 3H), 1,83-0,82 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 )? 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).

·*·· · • ·· • · • · • · · ·· ··· ·· • · · • · • · · • · ·· · ·· • · · • · • t · • ·· * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 53Example 53

Hydrochlorid (2RS,3R, l'S)-7V-((l-benzyloxykarbonyletyl)-3-amino-2-hydroxy4-cyklohexyl)butánamidu(2RS, 3R, 1'S) - N - ((1-Benzyloxycarbonylethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23A a hydrochlorid benzylesteru L-alanínu sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-alanine benzyl ester hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 363 (M+ H)+, 725(2M+ H)+;MS (ESI + Q1MS) mlz 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), 4,574,48 (m, 1H), 4,27-4,15 (m, 1H), 3,63-3,56 (m, 1H), 1,82-0,87 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.38-7.32 (m, 5H), 5.21-5.17 (m, 2H), 4.574.48 (m, 1H), 4, 27-4.15 (m, 1H); 3.63-3.56 (m, 1H); 1.82-0.87 (m, 16H).

Príklad 54Example 54

Hydrochlorid (2RS,3R,l’S)-/V-(4-etoxykarbonyl-2-(ľ-aminoetyl)tiazol)-3-amino-2-hydroxy-4-cyklohexyl)butánamidu(2RS, 3R, 1'S) - N - (4-Ethoxycarbonyl-2- (1'-aminoethyl) thiazole) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Príklad 54AExample 54A

Amid JV-(terc-butoxykarbonyl)-L-alanínu (3,76 g, 20 mmol) sa suspenduje v 70 ml metylénchloride v ľadovom kúpeli a pridá sa hexafluórfosfbrečnan trietyloxónia (4,97g, 20 mmol). Mieša sa pri teplote 0 °C po dobu 30 minút a pri izbovej teplote cez noc. Metylénchloridová vrstva sa premyje vodou (2x), 10 % kyslým uhličitanom sodným (2x), vodou (2x), suší sa nad bezvodým síranom horečnatým. Potom sa odparuje do sucha, suší sa vo vákuu, čím sa získaN - (tert-butoxycarbonyl) -L-alanine amide (3.76 g, 20 mmol) was suspended in 70 mL methylene chloride in an ice bath and triethyloxonium hexafluorophosphate (4.97 g, 20 mmol) was added. Stir at 0 ° C for 30 minutes and at room temperature overnight. The methylene chloride layer was washed with water (2x), 10% sodium bicarbonate (2x), water (2x), dried over anhydrous magnesium sulfate. It is then evaporated to dryness, dried under vacuum to yield

2,72 g iminoéteru.2.72 g of imino ether.

MS (ESI+Q1MS) m/e 217 (M+H)+ , 433 (2M+ H)+, 455 (2M+Na)+.MS (ESI + Q1MS) m / e 217 (M + H) &lt; + &gt;, 433 (2M + H) + , 455 (2M + Na) + .

·· · · • • • · • · • · • · • · • · • · • · • · • · • • • • • • • · • · • · • · • • • • • · · • · · • • • • • • • · • · • · • · • · • · ··· · · · ·· · · ·· · ·

Príklad 54BExample 54B

Produkt z príkladu 54A (2,72g, 12,6 mmol) sa rozpustí v 40 ml etanolu a pridá sa hydrochlorid etylesteru L-cysteínu (2,57g, 13,86 mmol). Mieša sa pri izbovej teplote po dobu 2 dní. Etanol sa odparí a zvyšok sa čistí priamo chromatografiou na stĺpci silikagélu mobilnou fázou 30 % etylacetátom v hexáne, čím sa získa 2,91 g čistého analóga tiazolínu. MS (ESI+Q1MS) m/e 303 (M+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. Stir at room temperature for 2 days. The ethanol was evaporated and the residue was purified directly by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give 2.91 g of the pure thiazoline analog. MS (ESI + Q1MS) m / e 303 (M &lt; + &gt;)

H)+ , 325 (M+ Na)+.H) + , 325 (M + Na) &lt; + &gt;.

Príklad 54CExample 54C

Do produktu z príkladu 54B (604mg, 2 mmol) v 50 ml banke s guľatým dnom sa pridá bromid med’ný (316 mg, 1,1 mmol) a bezvodý octan med’ný (0,40g, 2,2 mmol). Banka sa opakovane evakuuje argónom a pomocou injekčnej ihly sa pridá 15 ml benzénu. Za stáleho miešania pri teplote 60 °C sa počas 15 minút opatrne pridá Zerc-butylperbenzoát a opatrne sa refluxuje po dobu 4 hodín. Surový produkt sa čistí priamo chromatografiou na stĺpci silikagélu mobilnou fázou 30 % etylacetátu v hexánoch, čím sa získa 390 mg čistého derivátu tiazolu. Získaný produkt (320 mg) sa nechá reagovať podľa spôsobu opísaného v príklade 1F a kopuluje s produktom z príkladu 23A podľa spôsobu opísaného v príklade IE, čím sa získa derivát Y-(ŕerc-butoxykarbonyl) požadovanej zlúčeniny (220 mg).To the product of Example 54B (604mg, 2 mmol) in a 50 mL round bottom flask was added copper bromide (316 mg, 1.1 mmol) and anhydrous copper acetate (0.40g, 2.2 mmol). The flask was repeatedly evacuated with argon and 15 ml benzene was added via a syringe. While stirring at 60 ° C, tert-butyl perbenzoate is carefully added over 15 minutes and refluxed carefully for 4 hours. The crude product was purified directly by silica gel column chromatography eluting with 30% ethyl acetate in hexanes to give 390 mg of pure thiazole derivative. The obtained product (320 mg) was reacted according to the method described in Example 1F and coupled with the product of Example 23A according to the method described in Example IE to give the Y- (tert-butoxycarbonyl) derivative of the title compound (220 mg).

Príklad 54DExample 54D

Produkt z príkladu 54C (60 mg) sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaná zlúčenina.The product of Example 54C (60 mg) was treated according to the method of Example 1F to give the title compound.

MS (ESI+Q1MS) m/e 384 (M+ H)+, 767 (2M+ H)+;MS (ESI + Q1MS) mlz 384 (M + H) + , 767 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 8,38, 8,34 (8,34, s, majoritný, 8,38, s, minoritní oba 1H), 5,51-5,27 (m, 1H), 4,43-4,23 (m, 4H), 3,71-3,57 (m, 1H), 1,70, (d, 3H), 1,86-0,88 (m, 19H, zahŕňa 1,37 t, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.38, 8.34 (8.34, s, major, 8.38, s, minor both 1H), 5.51-5.27 (m, 1H), 4.43-4.23 (m, 4H), 3.71-3.57 (m, 1H), 1.70, (d, 3H), 1.86-0.88 (m, 19H) , includes 1.37 t, 3H).

··· ·

Príklad 55Example 55

Dihydrochlorid (2RS,3R)-N-(monodansylkadaveno)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R) -N- (Monodansylcadaveno) -3-amino-2-hydroxy-4-cyclohexyl) butanamide dihydrochloride

Produkt z príkladu 23A a monodansylkadaverín sa spracovávajú podľa spôsobov z príkladov IE a IF, čím sa získa požadovaná zlúčenina.The product of Example 23A and monodansylcadaverine were processed according to the methods of Examples IE and IF to give the title compound.

MS (ESI+Q1MS) m/e 519 (M+ H)+;MS (ESI + Q1MS) mlz 519 (M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 8,90 (d, 1H), 8,58 (d, 1H), 8,36 (d, 1H), 8,06 (d, 1H), 7,87 (q, 2H), 4,23 (d, 0,3H), 4,12 (d, 0,7H), 3,72-3,44 (m, 8H), 3,232,97 (m, 2H), 2,87 (t, 2H), 1,81-0,77 (m, 19H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.90 (d, 1H), 8.58 (d, 1H), 8.36 (d, 1H), 8.06 (d, 1H), 7 87 (q, 2H), 4.23 (d, 0.3H), 4.12 (d, 0.7H), 3.72-3.44 (m, 8H), 3.232.97 (m, 2H) 1.87 (t, 2H), 1.81-0.77 (m, 19H).

Príklad 56Example 56

Dihydrochlorid (2RS,3R)-JV-(2-metyI-5-nitro-imidazol-etyl)-3-amino-2-hydroxy-4-cyklohexyl)butánamidu(2RS, 3R) -N- (2-Methyl-5-nitro-imidazol-ethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide dihydrochloride

Produkt z príkladu 23A a l-(2-aminoetyl)-2-metyl-5-nitro imidazol sa spracovávajú podľa spôsobov z príkladov IE a IF, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1- (2-aminoethyl) -2-methyl-5-nitro imidazole were processed according to the methods of Examples IE and IF to give the title compound.

MS (ESI+Q1MS) m/e 354 (M+ H)+, 707 (2M+ H)+;MS (ESI + Q1MS) mlz 354 (M + H) + , 707 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 8,63 (mn, 1H), 8,52,8,50 (oba s, celkove 1H), 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).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.63 (mn, 1H), 8.52.8.50 (both s, total 1H), 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).

Príklad 57Example 57

Dihydrochlorid (2RS,3R)-/V-(5-nitropyridyl-2-aminoetyl)-3-amino-2-hydroxy4-cyklohexyl)butánamidu • *··(2RS, 3R) - N - (5-Nitropyridyl-2-aminoethyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide dihydrochloride • * ··

Produkt z príkladu 23A a 2-(2-aminoetylamino)-5-nitro-pyridin sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2- (2-aminoethylamino) -5-nitro-pyridine were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 366 (M+ H)+, 731 (2M+ H)+;MS (ESI + Q1MS) mlz 366 (M + H) + , 731 (2M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 8,94 (br, d, 1H), 8,41 (br, 1H), 7,90 (d, 1H),1 H NMR (300 MHz, MeOH-d 4 ) δ 8.94 (br, d, 1H), 8.41 (br, 1H), 7.90 (d, 1H),

7,77 (d, 1H), 7,61-7,49 (m, 2H), 6,98 (br, 1H), 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).7.77 (d, 1H), 7.61-7.49 (m, 2H), 6.98 (br, 1H), 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) .

Príklad 58Example 58

Dihydrochlorid (2RS,3R)-/V-(5-metoxy-tryptaminyl)-3-amino-2-hydroxy-4cyklohexyl)butánamidu(2RS, 3R) -N- (5-Methoxy-tryptaminyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide dihydrochloride

Produkt z príkladu 23A a 5-metoxytryptamín sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and 5-methoxytryptamine were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 374 (M+ H)+, 747 (2M+ H)+;MS (ESI + Q1MS) mlz 374 (M + H) + , 747 (2M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 7,91 (m, 1H), 7,78 (d, 1H), 7,63-7,52 (m, 2H), 7,25-7,06 (m, 1H), 4,24 (d, 0,3H), 4,13 (d, 0,7H), 3,93-3,82 (m, 4H, zahŕňa 3,84, s, 3H), 3,75-3,44 (m, 4H), 3,00-2,87 (m, 2H), 1,76-0,66 (m, 13H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.91 (m, 1H), 7.78 (d, 1H), 7.63-7.52 (m, 2H), 7.25-7, 06 (m, 1H), 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).

Príklad 59Example 59

Hydrochlorid (2RS,3R)-/V-(3-0-metyl-dopaminyl)-3-amino-2-hydroxy-4-cyklohexyl)butánamidu(2RS, 3R) - N - (3-O-Methyl-dopaminyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23A a hydrochlorid 3-0-metyldopamínu sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-O-methyldopamine hydrochloride were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 351 (M+ H)+, 701 (2M+ H)+;MS (ESI + Q1MS) mlz 351 (M + H) + , 701 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 7,90-7,74 (m, 1H), 7,60-7,46 (m, 1H), 6,846,65(m, 3H), 4,21 (d, 0,3H), 4,10 (d, 0,7H), 3,85 (s, 3H), 3,62-3,34 (m, 4H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.90-7.74 (m, 1H), 7.60-7.46 (m, 1H), 6.846.65 (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).2.75 (t, 2H); 1.82-0.76 (m, 13H).

Príklad 60Example 60

Hydrochlorid (2RS,3R)-A/-(2-aminometylbenzimidazolyl)-3-amino-2-hydroxy4-cyklohexyl)butánamidu(2RS, 3R) -N- (2-Aminomethylbenzimidazolyl) -3-amino-2-hydroxy-4-cyclohexyl) butanamide hydrochloride

Produkt z príkladu 23A a dihydrochlorid monohydrátu 2-(aminometyl)benzimidazolu sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2- (aminomethyl) benzimidazole monohydrate were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 331 (M+H)+, 661 (2M+H)+;MS (ESI + Q1MS) mlz 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).1 H NMR (300 MHz, MeOH-d 4 ) 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).

Príklad 61Example 61

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(2-metyl-5-nitroimidazolyl-etyl)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (2-methyl-5-nitroimidazolyl-ethyl) -amide hydrochloride

Príklad 61AExample 61A

Produkt z príkladu 23A a hydrochlorid benzylesteru L-alanínu sa spracovávajú podľa spôsobu z príkladu IE, čím sa získa derivát N-(Jerc-butoxykarbonylu) (3,80 g), ktorý sa po dobu 3,5 hodín hydrogenuje v 50 ml etanolu v prítomnosti 0,3 g 10% paládia na aktívnom uhlí ako katalyzátora. Zmes sa nechá prechádzať celitom 545 a odparí sa do sucha, Čím sa získa (2RS,3R)-/V[(3-/erc-butoxykarbonylamino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanín (3,16 g)· ····The product of Example 23A and L-alanine benzyl ester hydrochloride were treated according to the method of Example IE to give the N- (tert-butoxycarbonyl) derivative (3.80 g), which was hydrogenated in 50 mL of ethanol in 50 mL for 3.5 hours. in the presence of 0.3 g of 10% palladium on activated carbon catalyst. The mixture was passed through Celite 545 and evaporated to dryness to give (2RS, 3R) - N - [(3- tert -butoxycarbonylamino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine (3.16 g) ) · ····

Príklad 61BExample 61B

Produkt z príkladu 61A a l-(2-aminoetyl)-2-metyl-5-nitroimidazol sa spracovávajú podľa spôsobov z príkladov 1E a IF, čím sa získa požadovaná zlúčenina.The product of Example 61A and 1- (2-aminoethyl) -2-methyl-5-nitroimidazole were processed according to the methods of Examples 1E and IF to give the title compound.

MS (ESI+Q1MS) m/e 425(M+ H)+, 849 (2M+ H)+;MS (ESI + Q1MS) mlz 425 (M + H) + , 849 (2M + H) + ;

‘H NMR (300 MHz, MeOH-d4) δ 8,58, 8,56 (oba s, celkove 1H), 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 zahŕňa 1,34, d).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.58, 8.56 (both s, total 1H), 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).

Príklad 62Example 62

Dihydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(5-nitropyridylaminoetyl)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (5-nitropyridylaminoethyl) amide dihydrochloride

Produkt z príkladu 61A a 2-(2-aminoetylamino)-5-nitro-pyridin sa spracovávajú podľa spôsobov z príkladov 1E a IF, čím sa získa požadovaná zlúčenina.The product of Example 61A and 2- (2-aminoethylamino) -5-nitro-pyridine were processed according to the methods of Examples 1E and IF to give the title compound.

MS (ESI+Q1MS) m/e 437 (M+ H)+, 873 (2M+ H)+;MS (ESI + Q1MS) mlz 437 (M + H) + , 873 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 8,94-8,37 (br, m, 1H), 7,92-7,75 (m, 1H), 7,62-7,50 (m, 1H), 4,37-4,17 (m, 3H), 3,78-3,50 (m, 5H), 1,85-0,80 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.94-8.37 (br, m, 1H), 7.92-7.75 (m, 1H), 7.62-7.50 (m 1H, 4.37-4.17 (m, 3H), 3.78-3.50 (m, 5H), 1.85-0.80 (m, 16H).

Príklad 63Example 63

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(etylizonipekotát)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (ethyl-isonipecotate) amide hydrochloride

Produkt z príkladu 61A a etylizonipekotát sa spracovávajú podľa spôsobov z príkladov 1E a IF, čím sa získa požadovaná zlúčenina.The product of Example 61A and ethyl isonipecotate are processed according to the methods of Examples 1E and IF to give the title compound.

MS (ESI+Q1MS) m/e 412 (M+ H)+, 823 (2M+ H)+;MS (ESI + Q1MS) mlz 412 (M + H) + , 823 (2M + H) + ;

········

·· · · • • ·· · · • · • · • • • · • · ·· · · • • • • • • • · • · • · • · • • • • • · · • · · • • • • • • • · • · • · • · • · • · ··· · · · ·· · · • · • ·

’H NMR (300 MHz, MeOH-d4) δ 4,41-3,93 (m, 4H), 3,76-3,57 (m, 3H), 3,002,82 (m, IH), 2,72-2,53 (m, IH), 2,08-1,92 (m, 2H), 1,85-0,80 (m, 23H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.41-3.93 (m, 4H), 3.76-3.57 (m, 3H), 3.002.82 (m, 1H), 2, 72-2.53 (m, 1H), 2.08-1.92 (m, 2H), 1.85-0.80 (m, 23H).

Príklad 64Example 64

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(2-pyrolidinopropyl)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (2-pyrrolidinopropyl) amide hydrochloride

Produkt z príkladu 61A a l-(3-aminopropyl)-2-pyrolidón sa spracovávajú podľa spôsobov z príkladov IE a 1F, Čím sa získa požadovaná zlúčenina.The product of Example 61A and 1- (3-aminopropyl) -2-pyrrolidone were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 397 (M+ H)+, 793 (2M+ H)+;MS (ESI + Q1MS) mlz 397 (M + H) + , 793 (2M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 4,38-4,24 (m, 2H), 3,74-3,56 (m, 2H), 3,523,43 (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 zahŕňa 1,42, d, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.38-4.24 (m, 2H), 3.74-3.56 (m, 2H), 3.523.43 (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).

Príklad 65Example 65

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(5-metoxytryptamín)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (5-methoxytryptamine) amide hydrochloride

Produkt z príkladu 61A a 5-metoxytryptamín sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 5-methoxytryptamine were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 455 (M+ H)+, 889 (2M+ H)+;MS (ESI + Q1MS) mlz 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), 3,523,43 (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 zahŕňa 1,42, d, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.38-4.24 (m, 2H), 3.74-3.56 (m, 2H), 3.523.43 (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).

········

• ·· · • ·· · ·· • · • · • · · • · · · • · • · • · · • · ·· · · • · • · • · · • · • · • · • · · • · • · • · ·· · · • · • · ··· · · · ·· · · ·· · ·

Príklad 66Example 66

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(3-0-metoxydopamín) amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (3-O-methoxydopamine) amide hydrochloride

Produkt z príkladu 61A a hydrochlorid 3-0-metoxydopamínu sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 3-O-methoxydopamine hydrochloride were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 422 (M+ H)+, 843 (2M+ H)+;MS (ESI + Q1MS) mlz 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, 1H), 3,44-3,35 (m, 2H), 2,72 (t, 2H), 1,85-0,82 (m, 16H zahŕňa 1,34, d, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 6.80-6.63 (m, 4H), 4.38-4.16 (m, 2H), 3.84 (s, 3H), 3, 67-3.56 (m, 1H), 3.44-3.35 (m, 2H), 2.72 (t, 2H), 1.85-0.82 (m, 16H includes 1.34, d , 3H).

Príklad 67Example 67

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(2-benzimidazolmety l)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (2-benzimidazolomethyl) amide hydrochloride

Produkt z príkladu 61A a dihydrochlorid monohydrátu 2-(aminometyl)benzimidazolu sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 2- (aminomethyl) benzimidazole monohydrate were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 402 (M+ H)+, 803 (2M+ H)+;MS (ESI + Q1MS) mlz 402 (M + H) + , 803 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 7,90-7,46 (m, 5H), 4,54-4,44 (m, 1H), 4,24 (d, 0,7H), 3,75-3,48 (m, 2H), 1,80-0,83 (m, 16H zahŕňa 1,50, d, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.90-7.46 (m, 5H), 4.54-4.44 (m, 1H), 4.24 (d, 0.7H), 3.75-3.48 (m, 2H), 1.80-0.83 (m, 16H includes 1.50, d, 3H).

Príklad 68Example 68

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(5-fenyl-pyrazol-3)amidu ····(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (5-phenyl-pyrazol-3) amide hydrochloride ····

Produkt z príkladu 61 A a 3-amino-5-fenylpyrazol sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 3-amino-5-phenylpyrazole were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 414 (M+ H)+, 827 (2M+ H)+;MS (ESI + Q1MS) m / e 414 (M + H) &lt; + &gt;, 827 (2M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,92-7,46 (m, 5H), 6,80 (br, 1H), 4,64-4,56 (m, 1H), 4,33 (d, 0,3H), 4,24 (d, 0,7H), 3,75-3,56 (m, 2H), 1,84-0,93 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.92-7.46 (m, 5H), 6.80 (br, 1H), 4.64-4.56 (m, 1H), 4, 33 (d, 0.3H), 4.24 (d, 0.7H), 3.75-3.56 (m, 2H), 1.84-0.93 (m, 16H).

Príklad 69Example 69

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(2-hydroxy-5-nitro-l)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (2-hydroxy-5-nitro-1) amide hydrochloride

Produkt z príkladu 61A a 2-amino-4-nitrofenol sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 2-amino-4-nitrophenol were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 409 (M+ H)+, 817 (2M+ H)+, ’H NMR (300 MHz, MeOH-d4) δ 9,03-8,96 (m, 1H), 7,98-7,77 (m, 2H), 7,477,60 (m, 1H), 4,55-4,65 (m, 1H), 4,33 (d, 0,3H), 4,23 (d, 0,7H), 3,75-3,55 (m, 2H), 1,84-0,69 (m, 16H).MS (ESI + Q1MS) mlz 409 (M + H) + , 817 (2M + H) + , 1 H NMR (300 MHz, MeOH-d 4 ) δ 9.03-8.96 (m, 1H), 7 98-7.77 (m, 2H), 7.477.60 (m, 1H), 4.55-4.65 (m, 1H), 4.33 (d, 0.3H), 4.23 (d 0.75), 3.75-3.55 (m, 2H), 1.84-0.69 (m, 16H).

Príklad 70Example 70

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(5-brómtiazol-2)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (5-bromothiazol-2) amide hydrochloride

Produkt z príkladu 61A a hydrobromid 2-amino-5-brómtiazol sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 2-amino-5-bromothiazole hydrobromide were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 433 (M+ H)+, 867 (2M+ H)+;MS (ESI + Q1MS) mlz 433 (M + H) + , 867 (2M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 7,42 (s, 1H), 4,65-4,57 (m, 1H), 4,31 (d, 0,3H), 4,20 (d, 0,7H), 3,76-3,49 (m, 2H), 1,84-0,76 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.42 (s, 1H), 4.65-4.57 (m, 1H), 4.31 (d, 0.3H), 4.20 (s) d, 0.7H), 3.76-3.49 (m, 2H), 1.84-0.76 (m, 16H).

··· ··*· • ·· • · • · • · · ·· ··· ·· • · • · • · • · • ···· ······································

Príklad 71Example 71

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(4-nitro-2-hydroxyfenyl-l)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (4-nitro-2-hydroxyphenyl-1) amide hydrochloride

Produkt z príkladu 61A a 2-amino-5-nitrofenol sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 2-amino-5-nitrophenol were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 409 (M+ H)+, 817 (2M+ H)+;MS (ESI + Q1MS) mlz 409 (M + H) + , 817 (2M + H) + ;

*H NMR (300 MHz, D2O) δ 8,08-7,98 (m, 1H), 7,85-7,68 (m, 2H), 4,68-4,57 (m, 1H), 3,76-3,49 (m, 2H), 1,88-0,80 (m, 16H).1 H NMR (300 MHz, D 2 O) δ 8.08-7.98 (m, 1H), 7.85-7.68 (m, 2H), 4.68-4.57 (m, 1H) 3.76-3.49 (m, 2H); 1.88-0.80 (m, 16H).

Príklad 72Example 72

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanyl(l-etylpyrazol)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanyl (1-ethylpyrazole) amide hydrochloride

Produkt z príkladu 61A a 5-amino-l-etylpyrazol sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A and 5-amino-1-ethylpyrazole were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 366 (M+ H)+, *H NMR (300 MHz, D2O) δ 7,74-7,70 (br, 1H), 7,55 (br, 1H), 4,52-3,98 (m, 4H), 3,71-3,62 (m, 1H), 1,76-0,86 (m, 19H).MS (ESI + Q1MS) m / e 366 (M + H) + , 1 H NMR (300 MHz, D 2 O) δ 7.74-7.70 (br, 1H), 7.55 (br, 1H), 4.52-3.98 (m, 4H), 3.71-3.62 (m, 1H), 1.76-0.86 (m, 19H).

Príklad 73Example 73

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(etylizonipekotát)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl (ethyl isonipecotate) amide hydrochloride

Produkt z príkladu 23A a etylizonipekotát sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and ethyl isonipecotate were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 341 (M+ H)+;MS (ESI + Q1MS) mlz 341 (M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 4,14 (q, 2H), 3,73-3,48 (m, 2H), 0,83-1,93 (m, 20H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.14 (q, 2H), 3.73-3.48 (m, 2H), 0.83-1.93 (m, 20H).

Príklad 74Example 74

Dihydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(3-imidazolyl propyl)amidu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (3-imidazolyl-propyl) -amide dihydrochloride

Produkt z príkladu 23A a l-(3-aminopropyl)imidazol sa spracovávajú podľa spôsobov z príkladov 1E a IF, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1- (3-aminopropyl) imidazole were processed according to the methods of Examples 1E and IF to give the title compound.

MS (ESI+Q1MS) m/e 309 (M+ H)+, 617 (2M+ H)+;MS (ESI + Q1MS) mlz 309 (M + H) + , 617 (2M + H) + ;

*H NMR (300 MHz, MeOH-d4) δ 9,04 (s, 1H), 7,73 (s, 1H), 7,60 (s, 1H), 4,354,21 (m, 3H), 3,42-3,16 (m, 2H), 2,18-2,07 (m, 2H), 0,82-1,83 (m, 15H).1 H NMR (300 MHz, MeOH-d 4 ) δ 9.04 (s, 1H), 7.73 (s, 1H), 7.60 (s, 1H), 4,354.21 (m, 3H), 3 42-3.16 (m, 2H); 2.18-2.07 (m, 2H); 0.82-1.83 (m, 15H).

Príklad 75Example 75

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-karboxyl-2-(l-amino)etyltiazolu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (4-carboxyl-2- (1-amino) ethylthiazole hydrochloride)

Produkt z príkladu 54C (0,2g, 0,414 mmol) sa nechá reagovať s 1/Vlítium hydroxidom (0,5 ml, 0,5 mmol) v metanole po dobu 3 hodín, do zmesi sa pridá 8 ml vody a metanol sa odparí. Vodná vrstva sa premyje etylacetátom a okyslí sa pridaním 10 % hydrogénsíranu draselného. Produkt sa extrahuje etylacetátom (15 ml x 2) a etylacetátová vrstva sa premyje soľankou (2x), suší sa nad bezvodým síranom horečnatým. Odparenie rozpúšťadla poskytne 160 mg, ktoré sa spracovávajú podľa spôsobu z príkladu IF, čím sa získa požadovaná zlúčenina (120 mg).The product of Example 54C (0.2g, 0.414 mmol) was treated with 1 / lithium hydroxide (0.5 mL, 0.5 mmol) in methanol for 3 hours, 8 mL of water was added to the mixture and the methanol was evaporated. The aqueous layer was washed with ethyl acetate and acidified by the addition of 10% potassium bisulfate. The product was extracted with ethyl acetate (15 mL x 2) and the ethyl acetate layer was washed with brine (2x), dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 160 mg, which was processed according to the method of Example IF to give the title compound (120 mg).

MS (ESI+Q1MS) m/e 356 (M+ H)+, 378 (M+ Na)+, 711 (2M+ H)+, 733 (2M+ Na)+;MS (ESI + Q1MS) mlz 356 (M + H) + , 378 (M + Na) + , 711 (2M + H) + , 733 (2M + Na) + ;

···· · ·· • ·· · · • · · · « · · · · • « · · · ·· • · · *H NMR (300 MHz, D2O) δ 8,20 (s, 1H), 5,40-5,29 (m, 1H), 4,34 (d, 0,3H),1 H NMR (300 MHz, D 2 O) δ 8.20 (s, 1H) · H NMR (300 MHz, D 2 O) δ 8.20 (s, 1H) 5.40-5.29 (m, 1H), 4.34 (d, 0.3H),

4,27 (d, 0,7H), 3,69-3,53 (m, 2H), 1,72-0,73 (m, 16H).4.27 (d, 0.7H), 3.69-3.53 (m, 2H), 1.72-0.73 (m, 16H).

Príklad 76Example 76

Etyl-(2RS,3R,2'S)-2-((-3-(acetylamino)-4-cyklohexyl-2hydroxybutanoyl)amino) propanoátEthyl (2RS, 3R, 2'S) -2 - ((- 3- (acetylamino) -4-cyclohexyl-2-hydroxybutanoyl) amino) propanoate

Produkt z príkladu 23 (0,050g, 0,15 mmol), diizopropyletylamín (0,055 ml, 0,31 mmol) a acetylchlorid (0,012 ml, 0,16 mmol) v dichlórmetáne sa mieša pri teplote 0°C po dobu 2 hodín, roztok sa postupne premyje s vodným hydrogénuhličitanom sodným, vodou a soľankou, suší sa (MgSO4) a koncentruje sa, čím sa získa požadovaná zlúčenina.Example 23 (0.050g, 0.15 mmol), diisopropylethylamine (0.055 mL, 0.31 mmol) and acetyl chloride (0.012 mL, 0.16 mmol) in dichloromethane were stirred at 0 ° C for 2 h, solution was sequentially washed with aqueous sodium bicarbonate, water, and brine, dried (MgSO 4 ), and concentrated to give the title compound.

MS (APCI) m/e 343 (M+ H)+;MS (APCI) m / e 343 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 7,81 (m, 1H), 7,32 (m, 2H), 5,92 (d, 1H), 4,30 (m, 1H), 4,11 (m, 4H), 3,95 (m, 1H), 3,73 (m, 2H), 3,38 (m, 1H), 1,78 (s, 3H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.81 (m, 1H), 7.32 (m, 2H), 5.92 (d, 1H), 4.30 (m, 1H), 4 11 (m, 4H), 3.95 (m, 1H), 3.73 (m, 2H), 3.38 (m, 1H), 1.78 (s, 3H),

1,63 (6H), 1,32 (m, 2H), 1,23 (m, 9H), 0,89 (m, 1H).1.63 (6H), 1.32 (m, 2H), 1.23 (m, 9H), 0.89 (m, 1H).

Príklad 77Example 77

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-benzyloxykarbonylamino)butylamidu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (4-benzyloxycarbonylamino) butylamide hydrochloride

Produkt z príkladu 23A a hydrochlorid /V-benzyloxykarbonyl-l,4-diaminobutánu sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and N-benzyloxycarbonyl-1,4-diaminobutane hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 406 (M+H)+, 428 (M+Na)+, 811 (2M+ H)+;MS (ESI + Q1MS) mlz 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).1 H NMR (300 MHz, MeOH-d 4 ) 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).

·· · ·· * ·» ···· · · · • · · · · · · • ···* ···· «·· · · · · · ·· ··· ·· ··· ·· * ···························································· · * ····

Príklad 78Example 78

Hydrochlorid benzyl esteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-beta-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-beta-alanine benzyl ester hydrochloride

Produkt z príkladu 23A a hydrochlorid benzyl-/V-(2-aminoetyl)karbamátu sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and benzyl N- (2-aminoethyl) carbamate hydrochloride were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 378 (M+ H)+, 400 (M+ Na)+;MS (ESI + Q1MS) m / e 378 (M + H) &lt; + &gt;, 400 (M + Na) &lt; + &gt;;

’H 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 zatienené píkom s MeOH), 1,84-0,91 (m, 13H),1 H NMR (300 MHz, MeOH-d 4 ) 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 peaked with MeOH peak), 1.84-0.91 (m, 13H),

Príklad 79Example 79

Dihydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-monodansylkadaverínamidu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl monodansyl-cadaverinamide dihydrochloride

Produkt z príkladu 12A a monodansylkadaverín sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 12A and monodansylcadaverine were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 511 (M+ H)+, 533 (M+ Na)+;MS (ESI + Q1MS) mlz 511 (M + H) + , 533 (M + Na) + ;

’H NMR (300 MHz, MeOH-d4) δ 8,87 (d, 1H), 8,55 (d, 1H), 8,35 (d, 1H), 8,02 (d, 1H), 7,88-7,82 (m, 2H), 4,26 (d, 0,4H), 4,18 (d, 0,6H), 3,70-3,56 (m, 2H),1 H NMR (300 MHz, MeOH-d 4 ) δ 8.87 (d, 1H), 8.55 (d, 1H), 8.35 (d, 1H), 8.02 (d, 1H), 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).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).

Príklad 80Example 80

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-(4-toluénsulfonyl)aminobutyl)amidu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (4- (4-toluenesulfonyl) aminobutyl) amide hydrochloride

···· • • ···· • • • ·· • • · · • ·· • · • · · · • · • · ·· • · · • ·· • · • · · · • · • · • · • · • · · • · · ·· · · ··· · · · ·· · ·

Príklad 80AExample 80A

Podľa spôsobu z príkladu 77 sa produkt z príkladu 23A a hydrochlorid Nbenzyloxykarbonyl-l,4-diaminobutánu viažu ako v príklade IE, čím sa získa chránená zlúčenina. Produkt (260 mg) sa hydrogenuje v 10 ml etanolu v prítomnosti 30 mg 10 % paládia na aktívnom uhlí po dobu 3 hodín. Potom sa nechá reagovať podľa spôsobu opísaného v príklade 61 A, čím sa získa 200 mg. MS (ESI+Q1MS) m/e 372 (M+ H)+.According to the method of Example 77, the product of Example 23A and N-benzyloxycarbonyl-1,4-diaminobutane hydrochloride were coupled as in Example IE to give the 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 then reacted according to the method described in Example 61 A to give 200 mg. MS (ESI + Q1MS) mlz 372 (M + H) + .

Príklad 80BExample 80B

Produkt z príkladu 80A (92,8 mg, 0,25 mmol) sa rozpustí v 5 ml metylénchloridu v ľadovom kúpeli a pridá sa diizopropyletylamín (0,048 ml, 0,275 mmol) a p-toluénsulfonylchlorid (47,7 mg, 0,25 mmol). Potom sa nechá reakcia bežať pri teplote 0 °C po dobu 3 hodín a pri izbovej teplote cez noc. Odstráni sa metylénchlorid a zvyšok sa čistí chromatografiou na stĺpci silikagélu mobilnou fázou 15 - 30 % acetónu v hexánoch. Získaný produkt sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaná zlúčenina (70 mg).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. . The reaction was then allowed to run at 0 ° C for 3 hours and at room temperature overnight. The methylene chloride was removed and the residue was purified by silica gel column chromatography eluting with 15-30% acetone in hexanes. The product was worked up according to the method of Example 1F to give the title compound (70 mg).

MS (ESI+Q1MS) m/e 426 (M+ H)+, 448 (M+Na)+, 533 (M+ Na)+;MS (ESI + Q1MS) m / e 426 (M + H) &lt; + &gt;, 448 (M + Na) &lt; + &gt;, 533 (M + Na) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 7,73 (d, 2H), 7,37 (d, 2H), 4,22 (d, 0,4H),1 H NMR (300 MHz, MeOH-d 4 ) 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, 1H), 2,84 (t, 2H), 2,43 (s, 3H), 1,84-0,81 (m, 17H).4.13 (d, 0.6H), 3.74-3.56 (m, 2H), 3.25-3.07 (m, 1H), 2.84 (t, 2H), 2.43 ( s, 3H), 1.84-0.81 (m, 17H).

Príklad 81Example 81

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(2-4-toluénsulfonylaminoetyl)amidu • ΦΦΦ · ·· · • ·· ♦ · ·· ·· φφφ φ φ φφφ φ · · ·· ·ΦΦ φ· φφφ(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (2-4-toluenesulfonylaminoethyl) amide hydrochloride · ·· · ΦΦ φ · φφφ

Príklad 81ΑExample 81Α

Podľa spôsobu z príkladu 77 sa produkt z príkladu 23A a hydrochlorid benzyl-7V-(2-aminoetyl)karbamát viažu ako v príklade IE, čím sa získa chránená zlúčenina. Produkt (220 mg) sa hydrogenuje v 10 ml etanolu v prítomnosti 20 mg 10 % paládia na aktívnom uhlí po dobu 3 hodín. Potom sa nechá reagovať podľa spôsobu z príkladu 61A, čím sa získa 130 mg požadovanej zlúčeniny. MS (ESI+Q1MS) m/e 344 (M+ H)+.Following the method of Example 77, the product of Example 23A and benzyl N - (2-aminoethyl) carbamate hydrochloride were coupled as in Example IE to give 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 then reacted according to the method of Example 61A to give 130 mg of the desired compound. MS (ESI + Q1MS) mlz 344 (M + H) + .

Príklad 81BExample 81B

Produkt z príkladu 81A (42,8 mg, 0,125 mmol) a p-toluénsulfonylchlorid (23,8 mg, 0,125 mmol) sa spracovávajú podľa spôsobu z príkladu 80B, čím sa získa požadovaná zlúčenina (20 mg).The product of Example 81A (42.8 mg, 0.125 mmol) and p-toluenesulfonyl chloride (23.8 mg, 0.125 mmol) were treated according to the method of Example 80B to give the title compound (20 mg).

MS (ESI+Q1MS) m/e 426 (M+ H)+, 448 (M+Na)+, 533 (M+ Na)+ ;MS (ESI + Q1MS) m / e 426 (M + H) &lt; + &gt;, 448 (M + Na) &lt; + &gt;, 533 (M + Na) &lt; + &gt;;

*H NMR (300 MHz, MeOH-d4) Ô 7,73 (d, 2H), 7,38 (d, 2H), 4,23 (d, 0,4H),1 H NMR (300 MHz, MeOH-d 4 )? 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, 1H), 3,02-2,93 (m, 2H), 2,84 (t, 2H), 2,43 (s, 3H), 1,84-0,92 (m, 13H).4.15 (d, 0.6H), 3.76-3.56 (m, 2H), 3.25-3.07 (m, 1H), 3.02-2.93 (m, 2H), 2.84 (t, 2H), 2.43 (s, 3H), 1.84-0.92 (m, 13H).

Príklad 82Example 82

Dihydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(4-aminobutyl)amidu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (4-aminobutyl) amide dihydrochloride

Produkt z príkladu 80A (100 mg) sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaná zlúčenina (70 mg).The product of Example 80A (100 mg) was treated according to the method of Example 1F to give the title compound (70 mg).

MS (ESI+Q1MS) m/e 272 (M+ H)+;MS (ESI + Q1MS) mlz 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 zatienená píkom s MeOH), 2,96 (t, 2H), 1,84-0,80 (m, 17H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.28 (d, 0.4H), 4.16 (d, 0.6H), 3.77-3.56 (m, 2H), 3, 46-3.14 (m, 2H shielded with MeOH peak), 2.96 (t, 2H), 1.84-0.80 (m, 17H).

Príklad 83Example 83

Dihydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-(2-aminoetyl)amidu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl- (2-aminoethyl) amide dihydrochloride

Produkt z príkladu 81 A (60 mg) sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaná zlúčenina (45 mg).The product of Example 81A (60 mg) was treated according to the method of Example 1F to give the title compound (45 mg).

MS (ESI+Q1MS) m/e 244 (M+ H)+;MS (ESI + Q1MS) m / e 244 (M + H) &lt; + &gt;;

’H 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, 1H), 3,18-3,03 (m, 2H), 1,84-0,92 (m, 13H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.33 (d, 0.2H), 4.24 (d, 0.8H), 3.75-3.56 (m, 3H), 3, 48-3.38 (m, 1H), 3.18-3.03 (m, 2H), 1.84-0.92 (m, 13H).

Príklad 84Example 84

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-.W-(4-(((3-(trifluórmetyl)fenyl)sulfonyl)amino)butyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4 - (((3- (trifluoromethyl) phenyl) sulfonyl) amino) butyl) butanamide hydrochloride

Produkt z príkladu 81 A a m-(trifluórmetyl)benzénesulfonylchlorid sa spracovávajú podľa spôsobu z príkladu 80B, čím sa získa požadovaná zlúčenina.The product of Example 81A and m- (trifluoromethyl) benzenesulfonyl chloride were processed according to the method of Example 80B to give the title compound.

MS (APCI) m/e 480 (M+H)+;MS (APCI) m / e 480 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,08 (m, 4H), 7,86 (m, 2H), 7,73 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.08 (m, 4H), 7.86 (m, 2H), 7.73 (m, 1H),

6,41 (d, 1H), 3,99 (m, 1H), 3,70 (m, 2H), 3,49 (m, 1H), 3,06 (m, 2H), 2,76 (m, 2H), l,65(m, 4H), 1,40 (m, 5H), 1,15 (m, 3H), 0,84 (m, 3H).6.41 (d, 1H); 3.99 (m, 1H); 3.70 (m, 2H); 3.49 (m, 1H); 3.06 (m, 2H); 2.76 (m) 2H, 1.65 (m, 4H), 1.40 (m, 5H), 1.15 (m, 3H), 0.84 (m, 3H).

Príklad 85Example 85

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-N-4-(((3,4-dimetoxyfenyl)sulfonyl)amino)butyl)-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N-4 - (((3,4-dimethoxyphenyl) sulfonyl) amino) butyl) hydroxybutanamide hydrochloride

Produkt z príkladu 81A a 3,4-dimetoxybenzénesulfonylchlorid sa spracovávajú podľa spôsobu z príkladu 80B, čím sa získa požadovaná zlúčenina.The product of Example 81A and 3,4-dimethoxybenzenesulfonyl chloride were processed according to the method of Example 80B to give the title compound.

• · · · ··· ··· ··· • a ··· ·· ··· ·· ···• · · · ··· ··· ··· · a ··· ·· ··· ·· ···

MS (APCI) m/e 472 (M+ H)+;’H NMR (300 MHz, DMSO-d6) δ 8,10 (m, 1H), 7,92 (m, 1H), 7,73 (m, 1H), 7,44 (m, 1H), 7,42 (m, 1H), 7,12 (m, 1H), 6,42 (m, 1H), 3,98 (m, 1H), 3,84 (s, 3H), 3,81 (s, 3H), 3,70 (m, 2H), 3,49 (m, 1H), 3,08 (m, 2H), 2,67 (m, 2H), 1,65 (m, 4H), 1,40 (m, 5H), 1,18 (m, 3H), 0,84 (m, 3H).MS (APCI) m / e 472 (M + H) + 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.10 (m, 1H), 7.92 (m, 1H), 7.73 (m 1 H, 7.44 (m, 1 H), 7.42 (m, 1 H), 7.12 (m, 1 H), 6.42 (m, 1 H), 3.98 (m, 1 H), 3 84 (s, 3H), 3.81 (s, 3H), 3.70 (m, 2H), 3.49 (m, 1H), 3.08 (m, 2H), 2.67 (m, 2H), 1.65 (m, 4H), 1.40 (m, 5H), 1.18 (m, 3H), 0.84 (m, 3H).

Príklad 86Example 86

Hydrochlorid (2RS,3R)-/V-(4-(((4-(acetylamino)fenyl)sulfonyl)amino)butyl)-3amino-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) - N - (4 - (((4- (acetylamino) phenyl) sulfonyl) amino) butyl) -3-amino-4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 81 A a 4-acetamidobenzénesulfonylchlorid sa spracovávajú podľa spôsobu z príkladu 80B, čím sa získa požadovaná zlúčenina.The product of Example 81A and 4-acetamidobenzenesulfonyl chloride were treated according to the method of Example 80B to give the title compound.

MS (APCI) m/e 469 (M+ H)+;MS (APCI) m / e 469 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 7,72 (m, 4H), 7,41 (m, 1H), 5,93 (d, 1H), 3,79 (m, 3H), 3,04 (m, 2H), 2,73 (s, 3H), 2,68 (m, 1H), 2,09 (s, 3H), 1,60 (m, 2H),1 H NMR (300 MHz, DMSO-d 6 ) δ 7.72 (m, 4H), 7.41 (m, 1H), 5.93 (d, 1H), 3.79 (m, 3H), 3 0.04 (m, 2H), 2.73 (s, 3H), 2.68 (m, 1H), 2.09 (s, 3H), 1.60 (m, 2H),

1,24 (m, 4H), 1,13 (m, 5H), 0,85 (m, 3H).1.24 (m, 4H), 1.13 (m, 5H), 0.85 (m, 3H).

Príklad 87Example 87

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(4-((2-naftylsulfonyl)amino)butyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4 - ((2-naphthylsulfonyl) amino) butyl) butanamide hydrochloride

Produkt z príkladu 81A a 2-naftylsulfonylchlorid sa spracovávajú podľa spôsobu z príkladu 80B, čím sa získa požadovaná zlúčenina.The product of Example 81A and 2-naphthylsulfonyl chloride were processed according to the method of Example 80B to give the title compound.

MS (APCI) m/e 462 (M+ H)+;MS (APCI) m / e 462 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMS0-d6) δ 8,61 (s, 1H), 8,15 (m, 2H), 8,04 (m, 2H), 7,82 (m, 1H), 7,70 (m, 4H), 6,41 (m, 1H), 3,99 (m, 1H), 3,69 (m, 2H), 3,50 (m, 1H), 3,04 (m, 2H), 2,77 (m, 2H), 1,64 (m, 4H), 1,42 (5H), 1,14 (m, 3H), 0,85 (m, 3H).1 H NMR (300 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.15 (m, 2H), 8.04 (m, 2H), 7.82 (m, 1H), 7 70 (m, 4H), 6.41 (m, 1H), 3.99 (m, 1H), 3.69 (m, 2H), 3.50 (m, 1H), 3.04 (m, 1H) 2H), 2.77 (m, 2H), 1.64 (m, 4H), 1.42 (5H), 1.14 (m, 3H), 0.85 (m, 3H).

·» • · • · • · · • a a · · • · · • · · ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

I · · ··· ·· ·I · · ··· ·· ·

Príklad 88Example 88

Hydrochlorid 4-sulfonamidbenzylesteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine 4-sulfonamide-benzyl ester hydrochloride

Produkt z príkladu 23A a 4-(2-aminoetyl)benzénesulfonamid sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4- (2-aminoethyl) benzenesulfonamide were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 384 (M+ H)+ ;MS (ESI + Q1MS) m / e 384 (M + H) &lt; + &gt;;

’H 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).1 H NMR (300 MHz, MeOH-d 4 ) 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).

Príklad 89Example 89

Hydrochlorid benzylesteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine benzyl ester hydrochloride

Produkt z príkladu 23A a benzylester aminoizobutyrovej kyseliny sa spracovávajú podľa spôsobov z príkladov 1E a 1F, čím sa získa požadovaná zlúčenina.The product of Example 23A and aminoisobutyric acid benzyl ester were processed according to the methods of Examples 1E and 1F to give the title compound.

MS (ESI+Q1MS) m/e 377 (M+ H)+, 753 (2M+H)+;MS (ESI + Q1MS) m / e 377 (M + H) &lt; + &gt;, 753 (2M + H) &lt; + &gt;;

*H 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).1 H NMR (300 MHz, MeOH-d 4 ) 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).

Príklad 90Example 90

Hydrochlorid cyklohexylesteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu ·· · ·· • ·· · · ·· · · · · · · • · · · · · · · · • · · · · · · ·· ··· ·· ··· ·· * ····(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) -butanoyl-L-alanine hydrochloride cyclohexyl ester ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · *

Príklad 90AExample 90A

N-(íerc-Butoxykarbonyl)-L-alanín (0,945 g, 5 mmol) sa rozpustí v 10 ml metanolu a pridajú sa 2 ml vody a pH sa upraví na 7,0 pridávaním 20 % uhličitanu cézneho. Zmes sa odparí do sucha, znovu odparí (2 x) z 5 ml N,Ndimetylformamidu a suspenduje do 10 ml N,/\/-dimetylformamidu.N- (tert -Butoxycarbonyl) -L-alanine (0.945 g, 5 mmol) was dissolved in 10 mL of methanol and 2 mL of water was added and the pH was adjusted to 7.0 by adding 20% cesium carbonate. The mixture was evaporated to dryness, re-evaporated (2 x) from 5 ml of N, N-dimethylformamide and suspended in 10 ml of N, N -dimethylformamide.

Pridá sa cyklohexylbromid (0,677 ml, 5,5 mmol) a mieša sa pri izbovej teplote cez noc. Zmes sa zriedi 40 ml etylacetátom, organická vrstva sa premyje soľankou (2 x), 10 % kyslým uhličitanom sodným (2 x), soľankou (2x), suší sa nad bezvodým síranom horečnatým. Potom sa odparuje do sucha, čím sa získa 0,97 g cyklohexylester W-(ferc-butoxykarbonyl)-L-alanínu. Všetko sa spracováva podľa spôsobu z príkladu IF k získaniu hydrochloridu cyklohexylesteru L-alanínu (0,68 g).Add cyclohexyl bromide (0.677 mL, 5.5 mmol) and stir at room temperature overnight. Dilute the mixture with 40 mL ethyl acetate, wash the organic layer with brine (2x), 10% sodium bicarbonate (2x), brine (2x), dry over anhydrous magnesium sulfate. It is then evaporated to dryness to give 0.97 g of N - (tert-butoxycarbonyl) -L-alanine cyclohexyl ester. All was worked up according to the method of Example IF to give L-alanine cyclohexyl ester hydrochloride (0.68 g).

Príklad 90BExample 90B

Produkt z príkladu 23 A a produkt z príkladu 90A sa spracovávajú podľa spôsobov z príkladov 1E a IF, čím sa získa požadovaná zlúčenina.The product of Example 23A and the product of Example 90A were processed according to the methods of Examples 1E and IF to give the title compound.

MS (ESI+Q1MS) m/e 3 55 (M+ H)+, 709 (2M+H)+;MS (ESI + Q1MS) mle 355 (M + H) + , 709 (2M + H) + ;

‘H NMR (300 MHz, MeOH-d4) δ 4,46-4,35 (m, 1H), 4,28 (d, 0,3H), 4,17 (d, 0,7H), 3,78-3,56 (m, 2H), 0,74-1,81 (m, 27H zahŕňa 1,45 d, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.46-4.35 (m, 1H), 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).

Príklad 91Example 91

Hydrochlorid 2-((fenylsulfonyl)metyl)benzylesteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine, 2 - ((phenylsulfonyl) methyl) benzyl ester hydrochloride

Podľa spôsobu z príkladu 90A, ale nahradením cyklohexylbromidu za 1brómmetyl-2-[(fenylsulfonyl)metyl]benzén, potom postupom podľa spôsobu z príkladu IF sa získa požadovaná zlúčenina.Following the procedure of Example 90A but substituting cyclohexyl bromide for 1-bromomethyl-2 - [(phenylsulfonyl) methyl] benzene, then following the procedure of Example IF, the title compound was obtained.

e e · · · · · · • · · · · · · ··· ·· ·e e · · · · · · · · · ··· ···

MS (ESI+Q1MS) m/e 517 (M+ H)+, 539 (M+Na)+, 1033 (2M+H)+;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), 7,467,32 (m, 2H), 7,27-7,18 (m, 1H), 7,06-6,98 (m, 1H), 5,22-5,18 (m, 2H), 4,694,66 (m, 2H), 4,54 - 4,44 (m, 1H), 4,27 (d, 0,3H), 4,16 (d, 0,7H), 3,76-3,54 (m, 2H), 1,83-0,74 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.75-7.68 (m, 3H), 7.62-7.53 (m, 2H), 7.467.32 (m, 2H), 7, 27-7.18 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.18 (m, 2H), 4,694.66 (m, 2H), 4.54- 4.44 (m, 1H), 4.27 (d, 0.3H), 4.16 (d, 0.7H), 3.76-3.54 (m, 2H), 1.83-0, 74 (m, 16H).

Príklad 92Example 92

Hydrochlorid cyklopropylesteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine cyclopropyl ester hydrochloride

Podľa spôsobu z príkladu 90A, ale nahradením cyklohexylbromidu za cyklopropylbromid, potom postupom podľa spôsobu z príkladu 1F sa získa požadovaná zlúčenina.Following the procedure of Example 90A, but substituting cyclohexyl bromide for cyclopropyl bromide, then following the procedure of Example 1F, the title compound was obtained.

MS (ESI+Q1MS) m/e 315(M+ H)+, 629 (2M+H)+;MS (ESI + Q1MS) mlz 315 (M + H) + , 629 (2M + H) + ;

JH NMR (300 MHz, MeOH-d4) δ 5,06-4,97 (m, 1H), 4,45-4,36 (m, 1H), 4,17 (d, 0,7H), 3,63-3,57 (m, 1H), 1,84-0,90 (m, 20H). LH NMR (300 MHz, MeOH-d4) δ 5.06 to 4.97 (m, 1H), 4.45-4.36 (m, 1H), 4.17 (d, 0.7H), 3.63-3.57 (m, 1H); 1.84-0.90 (m, 20H).

Príklad 93Example 93

Hydrochlorid 4-/erc-butylbenzyl esteru (2RS,3R)-3-amino-2-hydroxy-4cyklohe-xyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine 4- tert -butylbenzyl ester hydrochloride

Podľa spôsobu z príkladu 90A, ale nahradením cyklohexylbromidu za 4íerc-butylbenzylbromid, potom postupom podľa spôsobu z príkladu 1F sa získa požadovaná zlúčenina.Following the procedure of Example 90A but substituting cyclohexyl bromide for 4-tert-butylbenzyl bromide, then following the procedure of Example 1F, the title compound was obtained.

MS (ESI+Q1MS) m/e 419 (M+ H)+, 837 (2M+H)+;MS (ESI + Q1MS) mlz 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, 1H), 4,28 (d, 0,3H), 4,16 (d, 0,7H), 3,74-3,55 (m, 2H), 1,84-0,90 (m, 25H zahŕňa 1,32 s, 9H a 1,45 d, 3H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.42-7.28 (m, 4H), 5.15 (s, 2H), 4.56-4.47 (m, 1H), 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).

···· ·· • · · • 9 · · • * ·· ·························· · 9

Príklad 94Example 94

Hydrochlorid 4-metoxykarbonylbenzylesteru (2RS,3R)-3-amino-2-hydroxy-4cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine 4-methoxycarbonylbenzyl ester hydrochloride

Podľa spôsobu z príkladu 90A, ale nahradením cyklohexylbromidu za 4metoxy-karbonylbenzylbromid, potom postupom podľa spôsobu z príkladu 1F sa získa požadovaná zlúčenina.Following the procedure of Example 90A but substituting cyclohexyl bromide for 4-methoxycarbonylbenzyl bromide, then following the procedure of Example 1F, the title compound was obtained.

MS (ESI+Q1MS) m/e 421 (M+ H)+, 841 (2M+H)+;MS (ESI + Q1MS) mlz 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, 1H), 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).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.04-7.46 (m, 4H), 5.26 (s, 2H), 4.62-4.51 (m, 1H), 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).

Príklad 95Example 95

Hydrochlorid 4-trifluórmety lbenzylesteru ((2RS,3R)-3-amino-2-hydroxy-4cyklohexyl)butanoyl-L-alanínu((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) -butanoyl-L-alanine 4-trifluoromethylbenzyl ester hydrochloride

Podľa spôsobu z príkladu 90A, ale nahradením cyklohexylbromidu za 4trifluór-metylbenzylbromid, potom postupom podľa spôsobu z príkladu 1F sa získa požadovaná zlúčenina.Following the procedure of Example 90A, but substituting cyclohexyl bromide for 4-trifluoromethylbenzyl bromide, then following the procedure of Example 1F, the title compound was obtained.

MS (ESI+Q1MS) m/e 431 (M+ H)+, 861 (2M+H)+ ;MS (ESI + Q1MS) mlz 431 (M + H) + , 861 (2M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 7,70-7,56 (m, 4H), 5,27 (s, 2H), 4,62-4,52 (m, 1H), 4,31 (d, 0,3H), 4,16 (d, 0,7H), 3,76-3,56 (m, 2H), 1,81-0,66 (m, 16H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.70-7.56 (m, 4H), 5.27 (s, 2H), 4.62-4.52 (m, 1H), 4, 31 (d, 0.3H), 4.16 (d, 0.7H), 3.76-3.56 (m, 2H), 1.81-0.66 (m, 16H).

Príklad 96Example 96

Hydrochlorid ((2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanín(fenacylester 4-(metyl)fenyloctovej kyseliny)((2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine hydrochloride (4- (methyl) phenylacetic acid phenacylate) hydrochloride

Podľa spôsobu z príkladu 90A, ale nahradením cyklohexylbromidu za fenacylester 4-metoxy(4-brómmetyl)fenyloctovej kyseliny, potom postupom podľa spôsobu z príkladu IF sa získa požadovaná zlúčenina.Following the procedure of Example 90A, but substituting cyclohexyl bromide for the 4-methoxy (4-bromomethyl) phenylacetic acid phenacylate, then following the procedure of Example IF, the title compound was obtained.

MS (ESI+Q1MS) m/e 539 (M+ H)+;MS (ESI + Q1MS) mlz 539 (M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 7,96-7,32 (m, 9H), 5,46-5,17 (m, 4H), 4,594,48 (m, 1H), 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).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.96-7.32 (m, 9H), 5.46-5.17 (m, 4H), 4.594.48 (m, 1H), 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).

Príklad 97Example 97

Hydrochlorid ((2RS,3R)-3-amino-4-cyklohexyl-AT-(2,4-dichlórbenzyl)-2-hydroxybutánamidu((2RS, 3R) -3-Amino-4-cyclohexyl-N - (2,4-dichlorobenzyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2,4-dichlórbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,4-dichlorobenzylamine were treated according to the method of Example 101 to give the title compound.

MS (ESI+Q1MS) m/e 359 (M+H)+ ’H NMR (300MHz, MeOH-d4) δ 7,47 (d, 1H), 7,39 (d, 1H), 7,30 (dd, 1H), 4,54 (q, 2H), 4,13 (d, 1H), 3,49 (m, 1H), 3,0 (br s, 1H), 0,82-1,80 (m, 13H).MS (ESI + Q1MS) m / e 359 (M + H) + 1 H NMR (300MHz, MeOH-d 4 ) δ 7.47 (d, 1H), 7.39 (d, 1H), 7.30 ( dd, 1H), 4.54 (q, 2H), 4.13 (d, 1H), 3.49 (m, 1H), 3.0 (br s, 1H), 0.82-1.80 ( m, 13H).

Príklad 98Example 98

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-jV-(3-metoxy fenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-methoxyphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-metoxyanilin sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (ESI+Q1MS) m/e 307 (M+H)+, 329 (M+Na)+;MS (ESI + Q1MS) mlz 307 (M + H) + , 329 (M + Na) + ;

'H NMR (300MHz, MeOH-d4) δ 7,37 (t, 1H), 7,23 (dd, 1H), 7,16 (m, 1H), 6,72 (m, 1H), 4,24 (d, 1H), 3,79 (s, 3H), 3,66 (m, 1H), 0,80-1,85 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.37 (t, 1H), 7.23 (dd, 1H), 7.16 (m, 1H), 6.72 (m, 1H), 4, 24 (d, 1H), 3.79 (s, 3H), 3.66 (m, 1H), 0.80-1.85 (m, 13H).

···· · ···· · ·· • · • · · · • · • · • ·· • • · · • ·· • · · • · · · • · · • · • • • • • a • • a • « · «· • • • · • · • • • · • · • · • · ··· · · · ·· · · ··· · · · aa · aa ·

Príklad 99Example 99

Hydrochlorid metyl-(2RS,3R,2’R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-4-metylpentanoátuMethyl (2RS, 3R, 2'R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -4-methylpentanoate hydrochloride

Produkt z príkladu 23A a metylester L-leucínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-leucine methyl ester were processed according to the method of Example 101 to give the title compound.

MS (ESI+Q1MS) m/e 329 (M+H)+, 351 (M+Na)+;MS (ESI + Q1MS) mlz 329 (M + H) + , 351 (M + Na) + ;

’H 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).1 H NMR (300MHz, MeOH-d 4 ) δ 4.50 (m, 1H), 4.10 (d, 1H), 3.73 (s, 3H), 3.39 (m, 1H), 1, 2-1.81 (m, 13H), 0.9-1.0 (m, 9H).

Príklad 100Example 100

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-Y-(2-furylmetyl)-2-hydroxybutánamid(2RS, 3R) -3-Amino-4-cyclohexyl-Y- (2-furylmethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a furfurylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and furfurylamine were processed according to the method of Example 101 to give the title compound.

MS (ES1+Q1MS) m/e 281 (M+H)+, 303 (M+Na)+;MS (ESI + Q1MS) m / e 281 (M + H) &lt; + &gt;, 303 (M + Na) &lt; + &gt;;

’H 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).1 H NMR (300MHz, MeOH-d 4 ) δ 7.42 (m, 1H), 6.35 (m, 1H), 6.28 (d, 1H), 4.47 (q, 2H), 4, 13 (d, 1H), 3.51 (m, 1H), 0.90-1.80 (m, 13H).

Príklad 101Example 101

Hydrochlorid (2RS,3R, l’RS)-3-amino-4-cyklohexyl-2-hydroxy-Y-(l-(l-naftyl)etyl)butánamidu(2RS, 3R, 1'RS) -3-Amino-4-cyclohexyl-2-hydroxy-Y- (1- (1-naphthyl) ethyl) butanamide hydrochloride

Produkt z príkladu 23A (2,4 g, 8,64 mmol) sa rozpustí v N,Ndimetylacetamidu, čím sa získa 48 ml (roztok A). l-Hydroxy-7-azabenzotriazol (HOAT- l,92g, 13,2mmol), hexafluórfosfát O-(7-azabenzotriazol-l-yl)-l,1,3,3tetrametyluronia (HATU-4,8 g, 13,4mmol) a diizopropyletylamín (2,4 ml, 13,4 • ·· · · ·· · · · • · · · · · · • ···· · · · · ··· ··· · · ·· ·· ·· ··· ·· · mmol) sa rozpustia v /V,Af-dimetylacetamide na vytvorenie 48 ml (roztok B). Roztok A sa rovnomerne rozdelí do 48 individuálnych reaktorov. Potom sa do týchto reaktorov pridá v rovnaných podieloch roztok B. Reaktory sa trepú 10 minút pri izbovej teplote. Do jedného z týchto reaktorov sa pridá l-(l-naftyl)etylamín (0, 04 ml, 0,275 mmol) a zmes sa trepfe zhruba 75 hodín. Do reakcie sa pridá dichlórmetán (5ml) a voda (5ml) a trepe sa. Vodná vrstva sa odstráni a reaktor sa umiestni na extraktor kvapalnej fázy na premytie (2 x) IN kyselinou chlorovodíkovou, vodou (1 x) a nakoniec uhličitanom sodným (2x). Zvyšná voda sa odstráni a rozpúšťadlo sa odparí tak, aby vzorka bola suchá. Zvyšok sa rozpustí v dichlórmetáne (1 ml) a umiestni sa na extraktor pevnej fázy na eluovanie na 1 g silikagélovej cartridge mobilnej fázy 13 % etylacetát v hexánoch. Príslušné frakcie sa spoja a vysušia. Zvyšok sa rozpustí v 4M kyseline chlorovodíkovej v dioxáne (1 ml) na odštiepenie chrániacej skupiny. Po jednej hodine sa rozpúšťadlo úplne odparí a 48 amínov sa naraz spracováva v dávkach. Na základe čistoty stanovenej pomocou HPLC sa látka buď spracováva tak ako je, alebo sa vykoná preparatívne HPLC čistenie pred tým, než sa spracováva.The product of Example 23A (2.4 g, 8.64 mmol) was dissolved in N, N-dimethylacetamide to give 48 mL (solution A). 1-Hydroxy-7-azabenzotriazole (HOAT-1, 92g, 13.2mmol), hexafluorophosphate O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU-4.8 g, 13.4mmol) ) and diisopropylethylamine (2.4 ml, 13.4). Dissolve in N, N-dimethylacetamide to make 48 ml (solution B). Solution A is evenly distributed to 48 individual reactors. Solution B is then added in equal portions to the reactors. The reactors are shaken for 10 minutes at room temperature. 1- (1-Naphthyl) ethylamine (0.04 ml, 0.275 mmol) was added to one of these reactors and the mixture was shaken for about 75 hours. Dichloromethane (5ml) and water (5ml) were added to the reaction and shaken. The aqueous layer was removed and the reactor was placed on a liquid phase extractor to wash (2X) with 1N hydrochloric acid, water (1X) and finally sodium carbonate (2X). The residual water was removed and the solvent was evaporated until the sample was dry. The residue was dissolved in dichloromethane (1 mL) and placed on a solid phase extractor to elute on 1 g mobile phase silica gel cartridge 13% ethyl acetate in hexanes. The appropriate fractions were combined and dried. The residue was dissolved in 4M hydrochloric acid in dioxane (1 mL) to remove the protecting group. After one hour, the solvent was completely evaporated and 48 amines were run in batches at once. On the basis of the purity determined by HPLC, the substance is either treated as is or a preparative HPLC purification is performed before it is treated.

MS (ESI+Q1MS) m/e 355 (M+H)+, 377 (M+Na)+;MS (ESI + Q1MS) m / e 355 (M + H) &lt; + &gt;, 377 (M + Na) &lt; + &gt;;

[H NMR (300MHz, MeOH-d4) δ 8,16 (m, IH), 7,89 (d, IH), 7,81 (d, IH), 7,447,63 (m, 4H), 5,90 (q, IH), 4,08 (dd, IH), 3,48 (m, IH), 2,98 (br s, IH), 0,851,91 (m, 17H). 1 H NMR (300MHz, MeOH-d 4 ) δ 8.16 (m, 1H), 7.89 (d, 1H), 7.81 (d, 1H), 7.447.63 (m, 4H), 5, 90 (q, 1H), 4.08 (dd, 1H), 3.48 (m, 1H), 2.98 (br s, 1H), 0.851.91 (m, 17H).

Príklad 102Example 102

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3-(2-oxo-l-pyrolidinyl) propyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (3- (2-oxo-1-pyrrolidinyl) propyl) butanamide hydrochloride

Produkt z príkladu 23A a l-(3-aminopropyl)-2-pyrolidón sa spracovávajú podľa spôsobov z príkladov 1E a IF, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1- (3-aminopropyl) -2-pyrrolidone were processed according to the methods of Examples 1E and IF to give the title compound.

MS (ESI+Q1MS) m/e 326 (M+ H)+, 651 (2M+ H)+;MS (ESI + Q1MS) mlz 326 (M + H) + , 651 (2M + H) + ;

100 ···· • · « · ·· · ·· • · · • · • · · ·· ··· ·· ·· · *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).100 • ···· · '· · · · · · · · • • • · · · · · · · · · · · · · H NMR (300 MHz, MeOH-d4) δ 4.24 (d 0.44), 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).

Príklad 103Example 103

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(l,2-dimetylpropyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (1,2-dimethylpropyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 1,2-dimetylpropylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1,2-dimethylpropylamine were treated according to the method of Example 101 to give the title compound.

MS (ESI+Q1MS) m/e 271 (M+H)+, 293 (M+Na)+;MS (ESI + Q1MS) m / e 271 (M + H) &lt; + &gt;, 293 (M + Na) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 4,28 (d, 1H), 3,74 (m, 1H), 1,05-1,80 (m, 13H), 0,88 - 0,94 (m, 1H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.28 (d, 1H), 3.74 (m, 1H), 1.05-1.80 (m, 13H), 0.88 - 0.94 (m, 1 H).

Príklad 104Example 104

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine hydrochloride

Produkt z príkladu 61 A sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaná zlúčenina.The product of Example 61A was processed according to the method of Example 1F to give the title compound.

MS (ESI-Q1MS) m/e 271 (M-H)+, 307 (M+Na-H)+, 543 (2M-H)+, 565 (2M+NaH)+;MS (ESI-QMS) m / e 271 (MH) + , 307 (M + Na-H) + , 543 (2M-H) + , 565 (2M + NaH) + ;

’H NMR (300 MHz, D2O) δ 4, 28-4,47 (m, 2H), 3,86-3,62 (m, 2H), 1,75-0,78 (m, 16H).1 H NMR (300 MHz, D 2 O) δ 4, 28-4.47 (m, 2H), 3.86-3.62 (m, 2H), 1.75-0.78 (m, 16H) .

Príklad 105Example 105

Hydrochlorid benzylesteru (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine benzyl ester hydrochloride

101101

• • • • • ·· • • · · • ·· • · • · · · • · • · • ·· • • · · • ·· • • · · • • • · • • · • • • • • • · • · • • • • • • ··· · · · ·· · · ··· · · · ·· · · • •

Produkt z príkladu 20A a benzylester L-alanínu sa spracovávajú podľa spôsobov z príkladov IE a IF, čím sa získa požadovaná zlúčenina.The product of Example 20A and L-alanine benzyl ester were processed according to the methods of Examples IE and IF to give the title compound.

MS (ESI+Q1MS) m/e 357 (M+H)+, 713 (2M+H)+;MS (ESI + Q1MS) mlz 357 (M + H) + , 713 (2M + H) + ;

‘H NMR (300 MHz, D2O) δ 7,39-7,17 (m, 10H), 5,16 (s, 2H), 4,53-4,43 (m, 1H), 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).1 H NMR (300 MHz, D 2 O) δ 7.39-7.17 (m, 10H), 5.16 (s, 2H), 4.53-4.43 (m, 1H), 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).

Príklad 106Example 106

Hydrochlorid (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl)butanoyl-L-aIanínu(2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl-L-alanine hydrochloride

Príklad 106AExample 106A

Produkt z príkladu 20A a benzylester L-alanínu sa spracovávajú podľa spôsobov z príkladov IE, čím sa získa benzylester (2RS,3R)-3-(íerc-butoxykarbonylamino)-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu, 0,5g vyššie uvedeného produktu sa hydrogenuje v 20 ml izopropylalkoholu v prítomnosti 20 mg 10 % paládia na aktívnom uhlí, čím sa získa (2RS,3R)-3-(/erc-butoxykarbonylamino)-2-hydroxy-4-cyklohexyl)butanoyl-L-alanínu (0,4g).The product of Example 20A and L-alanine benzyl ester were processed according to the methods of Examples IE to give (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-4-cyclohexyl) butanoyl-L-alanine benzyl ester. 5 g of the above product is hydrogenated in 20 ml of isopropanol in the presence of 20 mg of 10% palladium on charcoal to give (2RS, 3R) -3- (tert-butoxycarbonylamino) -2-hydroxy-4-cyclohexyl) butanoyl- L-alanine (0.4g).

Príklad 106BExample 106B

Produkt z príkladu 106,1 A sa spracováva podľa spôsobu z príkladu IF, čím sa získa požadovaná zlúčenina.The product of Example 106.1 A was processed according to the method of Example IF to give the title compound.

MS (ESI+Q1MS) m/e 267 (M+H)+, 289 (M+Na)+, 533 (2M+H)+, 555 (2M+Na)+;MS (ESI + Q1MS) m / e 267 (M + H) &lt; + &gt;, 289 (M + Na) &lt; + &gt;, 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).1 H NMR (300 MHz, D 2 O) 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).

·· ··· ·

102 ··· • · ·· • · · • · • · · ·· ··· • · · • · ···102 · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 107Example 107

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-fenylbutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N -phenylbutanamide hydrochloride

Produkt z príkladu 23A a anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and aniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 277 (M+H)+;MS (APCI) m / e 277 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 7,64 (m, 2H), 7,35 (m, 2H), 7,14 (m, 1H), 4,22 (d, 1H), 3,61 (m, 1H), 0,91-1,85 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.64 (m, 2H), 7.35 (m, 2H), 7.14 (m, 1H), 4.22 (d, 1H), 3, 61 (m, 1H), 0.91-1.85 (m, 13H).

Príklad 108Example 108

Hydrochlorid (2RS,3R)-3-amino-Ar-(2-chlórfenetyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-amino-N - (2-chlorophenethyl) -4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a 2-(2-chlorfenyl)etylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2- (2-chlorophenyl) ethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 339 (M+H)+;MS (APCI) m / e 339 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 7,2-7,4 (m, 4H), 4,04 (d, 1H), 3,00 (m, 1H), 0,9-1,81 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.2-7.4 (m, 4H), 4.04 (d, 1H), 3.00 (m, 1H), 0.9-1.81 (m, 13H).

Príklad 109Example 109

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-N-(3-fenylpropyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-phenylpropyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-fenyl-l-propylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-phenyl-1-propylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 319 (M+H)+;MS (APCI) m / e 319 (M + H) &lt; + &gt;;

·· · ·· · · • ·· · · ·· · · • · · · · · ···· · · · · · · · · · · · · · · · · · · · · · · · ·

103 ··· ·· ··· ·· ’H NMR (300MHz, MeOH-d4) δ 7,12-7,3 (m, 5H), 4,1 (d, 1H), 3,25 (m, 1H), 2,65 (m, 6H), 0,90-1,90 (m, 13H).103 1 H NMR (300MHz, MeOH-d 4 ) δ 7.12-7.3 (m, 5H), 4.1 (d, 1H), 3.25 (m 1 H, 2.65 (m, 6H), 0.90-1.90 (m, 13H).

Príklad 110Example 110

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-N-(l,2,3,4-tetrahydro-l-naftalenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (1,2,3,4-tetrahydro-1-naphthalenyl) butanamide hydrochloride

Produkt z príkladu 23A a 1,2,3,4-tetrahydro-l-naftylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1,2,3,4-tetrahydro-1-naphthylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 3661 (2M+H)+;MS (APCI) mlz 3661 (2M + H) + ;

’H NMR (300MHz, MeOH-d4) δ 7,15 (m, 4H), 5,12 (m, 1H), 4,14 (m, 1H), 3,58 (m, 1H), 2,81 (m, 2H), 2,05 (m, 1H), 0,90-1,90 (m, 16H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.15 (m, 4H), 5.12 (m, 1H), 4.14 (m, 1H), 3.58 (m, 1H), 2, 81 (m, 2H), 2.05 (m, 1H), 0.90-1.90 (m, 16H).

Príklad 111Example 111

Hydrochlorid (2RS,3R)-3-amino-/V-(4-(íerc-butyl)cyklohexyl)-4-cyklohexyl-2hydroxybutánamidu(2RS, 3R) -3-Amino- N - (4- (tert-butyl) cyclohexyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a l-amino-4-(l,l-dimetyletyl)cyklohexán sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-amino-4- (1,1-dimethylethyl) cyclohexane were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 339 (M+H)+, 677,3 (2M+H)+;MS (APCI) m / e 339 (M + H) &lt; + &gt;, 677.3 (2M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 4,03 (d, 1H), 3,62 (m, 1H), 3,49 (m, 1H), 0,902,00 (m, 22H), 0,89 (m, 9H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.03 (d, 1H), 3.62 (m, 1H), 3.49 (m, 1H), 0.902.00 (m, 22H), 0, 89 (m, 9 H).

·· · ·· • · ·· · · · • · · · ··· · ·· · · · · · · · · · · · ·

104 ···· • · • · · ·· ··· • · · · · ·· ··· ·· ·104 ····················

Príklad 112Example 112

Hydrochlorid (2RS, 3 R)-3-amino-4-cyklohexy 1-//-(3,5-dichlórfeny l)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-1H - (3,5-dichlorophenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3,4-dichlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4-dichloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 345 (M+H)+;MS (APCI) m / e 345 (M + H) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 7,74 (d, 2H), 7,20 (t, 1H), 4,23 (d, 1H), 3,58 (m, 1H), 0,92-1,85 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.74 (d, 2H), 7.20 (t, 1H), 4.23 (d, 1H), 3.58 (m, 1H), O, 92-1.85 (m, 13H).

Príklad 113Example 113

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-//-(2-etylhexyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2-ethylhexyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2-etylhexylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-ethylhexylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 313 (M+H)+;MS (APCI) m / e 313 (M + H) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 4,03 (dd, 1H), 3,13 (m, 1H), 0,89-1,85 (m, 29H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.03 (dd, 1H), 3.13 (m, 1H), 0.89-1.85 (m, 29H).

Príklad 114Example 114

Hydrochlorid butyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)acetátuButyl (2RS, 3R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) acetate hydrochloride

Produkt z príkladu 23A a n-butylester glycínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and n-butyl glycine ester were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 315(M+H)+;MS (APCI) m / e 315 (M + H) &lt; + &gt;;

105 ···· · ·· • ·· · · • · · · • ·· ·· · · · • · · ·· ·· ·· ··· ·· ··· *H NMR (300MHz, MeOH-d4) δ 4,16 (m, 2H), 4,02 (m, 1H), 3,50 (m, 1H), 0,90-1,85 (m, 19H), 0,95 (t, 3H).105 @ 1 H NMR (300MHz, MeOH-). d 4 ) δ 4.16 (m, 2H), 4.02 (m, 1H), 3.50 (m, 1H), 0.90-1.85 (m, 19H), 0.95 (t, 3H).

Príklad 115Example 115

Hydrochlorid (2RS,3R)-3-amino-.W-(l,3-benzodioxol-5-ylmetyl)-4-cyklohexyl2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (1,3-benzodioxol-5-ylmethyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a piperonylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and piperonylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 33 5 (M+H)+, (669 (2M+H)+;MS (APCI) mle 335 (M + H) + , (669 (2M + H) + ;

’H NMR (300MHz, MeOH-d4) δ 6,80 (m, 2H), 5,92 (s, 1H), 4,32 (q, 2H), 4,11 (d, 1H), 3,50 (m, 1H), 0,85-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 6.80 (m, 2H), 5.92 (s, 1H), 4.32 (q, 2H), 4.11 (d, 1H), 3, 50 (m, 1H); 0.85-1.80 (m, 13H).

Príklad 116Example 116

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(2, 4-dimetoxyfenyl)-2hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl- N - (2,4-dimethoxyphenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2,4-dimetoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,4-dimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 673 (2M+H)+;MS (APCI) m / e 673 (2M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,09 (d, 1H), 6,63 (d, 1H), 6,51 (dd, 1H), 4,27 (d, 1H), 3,89 (s, 3H), 3,79 (s, 3H), 3,67 (m, 1H), 0,95-1,87 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.09 (d, 1H), 6.63 (d, 1H), 6.51 (dd, 1H), 4.27 (d, 1H), 3, 89 (s, 3H), 3.79 (s, 3H), 3.67 (m, 1H), 0.95-1.87 (m, 13H).

Príklad 117Example 117

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Af-(3-metoxy-5(trifluórmetyl)fenyl)butánamidu ···· · ·· · ·· • ·· · · ·· · • · · · · · ·(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-methoxy-5- (trifluoromethyl) phenyl) butanamide hydrochloride ··· · ··· · ··· · · · · · · · · · ·

106 • · · · · ·· ··· ·· ··· ·· ·106 • · · · ·············

Produkt z príkladu 23A a 3-metoxy-5-(trifluórmetyl)anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methoxy-5- (trifluoromethyl) aniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 375(M+H)+, 748 (2M+H)+;MS (APCI) m / e 375 (M + H) &lt; + &gt;, 748 (2M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,55 (m, 1H), 7,47 (t, 1H), 6,85 (m, 1H), 4,10 (d, 1H), 3,45 (m, 1H), 0,80-1,75 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.55 (m, 1H), 7.47 (t, 1H), 6.85 (m, 1H), 4.10 (d, 1H), 3, 45 (m, 1H); 0.80-1.75 (m, 13H).

Príklad 118Example 118

Hydrochlorid (2RS,3R)-3-amino-4-cykIohexyl-Ä/-decyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N-decyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a undecylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and undecylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 681 (2M+H)+;MS (APCI) mle 681 (2M + H) + ;

’H NMR (300MHz, MeOH-d4) δ 3,85 (d, 1H), 3,22 (m, 2H), 3,13 (m, 1H), 0,851,85 (m, 32H).1 H NMR (300MHz, MeOH-d 4 ) δ 3.85 (d, 1H), 3.22 (m, 2H), 3.13 (m, 1H), 0.851.85 (m, 32H).

Príklad 119 (2RS,3R)-3-amino-/V-(lR,4S)bicyklo(2,2,l)hept-2-yl)-4-cyklohexyl-2hydroxybutánamidExample 119 (2RS, 3R) -3-Amino- N - (1R, 4S) bicyclo (2.2.1) hept-2-yl) -4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a 2-aminonorbornán sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-aminonorbornane were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 295(M+H)+, 589 (2M+H)+;MS (APCI) m / e 295 (M + H) &lt; + &gt;, 589 (2M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 4,05 (t, 1H), 3,66 (m, 1H), 3,51 (m, 1H), 2,30 (br s, 1H), 2,22 (m, 1H), 0,90-1,80 (m, 21H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.05 (t, 1H), 3.66 (m, 1H), 3.51 (m, 1H), 2.30 (br s, 1H), 2 22 (m, 1H); 0.90-1.80 (m, 21H).

107 ···· · · • ·· · · · • · · · ·· ··· ·· ···107 ···· · · · · · · · · · · · · · ·

Príklad 120Example 120

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-TV-(2-fluórbenzyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2-fluorobenzyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2-fluórbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-fluorobenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 309 (M+H)+, 616 (2M+H)+;MS (APCI) m / e 309 (M + H) &lt; + &gt;, 616 (2M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,32 (m, 2H), 7,11 (m, 2H), 4,5 (q, 2H), 4,14 (d, 1H), 3,52 (m, 1H), 0,87-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.32 (m, 2H), 7.11 (m, 2H), 4.5 (q, 2H), 4.14 (d, 1H), 3, 52 (m, 1H), 0.87-1.80 (m, 13H).

Príklad 121Example 121

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-JV-(4-fluór-3-(trifluórmetyl)benzyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (4-fluoro-3- (trifluoromethyl) benzyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-(trifluórmetyl)-4-fluórbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3- (trifluoromethyl) -4-fluorobenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 377 (M+H)+;MS (APCI) m / e 377 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,64 (m, 2H), 7,29 (t, 1H), 4,45 (q, 2H), 4,12 (d, 1H), 3,49 (m, 1H), 0,80-1,80 (me, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.64 (m, 2H), 7.29 (t, 1H), 4.45 (q, 2H), 4.12 (d, 1H), 3, 49 (m, 1H); 0.80-1.80 (me, 13H).

Príklad 122Example 122

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-W-(l-(4-fluórfenyl)etyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (1- (4-fluorophenyl) ethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 4-fluór-a-metylbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčeninaThe product of Example 23A and 4-fluoro-α-methylbenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 645(2M+H)+;MS (APCI) m / e 645 (2M + H) &lt; + &gt;;

108 • ·· · · ·· • · · · · • · · · · · • · · · · · ·· ··· ·· ··* ·· • · · • · ’H NMR (300MHz, MeOH-d4) δ 7,36 (m, 2H), 7,04 (t, 2H), 5,06 (m, 1H), 4,05 (d, 1H), 3,47 (tn, 1H), 0,80-l,85(m, 17H).108 NMR H NMR (300MHz, MeOH-) NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR NMR d 4 ) δ 7.36 (m, 2H), 7.04 (t, 2H), 5.06 (m, 1H), 4.05 (d, 1H), 3.47 (tn, 1H), 0 80-1.85 (m, 17H).

Príklad 123Example 123

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(tetrahydro-2-furanyl metyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (tetrahydro-2-furanyl methyl) butanamide hydrochloride

Produkt z príkladu 23A a tetrahydrofurfurylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and tetrahydrofurfurylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 285 (M+H)+;MS (APCI) m / e 285 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 4,07 (m, 1H), 3,88 (m, 1H), 3,75 (m, 1H), 3,48 (m, 1H), 1,92 (m, 1H), 0,90-1,85 (m, 19H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.07 (m, 1H), 3.88 (m, 1H), 3.75 (m, 1H), 3.48 (m, 1H), 1, 92 (m, 1H); 0.90-1.85 (m, 19H).

Príklad 124Example 124

Hydrochlorid etyl-(2RS,3R)-(4-((-3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-1 -piperidinekarboxylátuEthyl (2RS, 3R) - (4 - ((- 3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -1-piperidinecarboxylate hydrochloride

Produkt z príkladu 23A a etyl-4-amino-l-piperidinekarboxylát sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and ethyl 4-amino-1-piperidinecarboxylate were treated according to the method of Example 101 to give the title compound.

MS (APCI) m/e 356 (M+H)+;MS (APCI) m / e 356 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 4,1 (q, 2H), 4,05 (t, 1H), 3,91 (m, 1H), 3,48 (m, 1H), 2,94 (m, 2H), 1,26-1,90 (m, 17H), 1,25 (t, 3H), 0,95 (m, 2H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.1 (q, 2H), 4.05 (t, 1H), 3.91 (m, 1H), 3.48 (m, 1H), 2, 94 (m, 2H), 1.26-1.90 (m, 17H), 1.25 (t, 3H), 0.95 (m, 2H).

Príklad 125Example 125

Hydrochlorid (2RS,3R)-3-amino-W-(l,3-benzodioxol-5-yl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (1,3-benzodioxol-5-yl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

109109

Produkt z príkladu 23A a 3,4-metyléndioxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4-methylenedioxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 321 (M+H)+, 640 (2M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;, 640 (2M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,32 (d, 1H), 7,00 (dd, 1H), 6,77 (dd, 1H),1 H NMR (300MHz, MeOH-d 4 ) δ 7.32 (d, 1H), 7.00 (dd, 1H), 6.77 (dd, 1H),

5,94 (s, 2H), 4,25 (d, 1H), 3,68 (m, 1H), 0,90-1,85 (m, 13H).5.94 (s, 2H), 4.25 (d, 1H), 3.68 (m, 1H), 0.90-1.85 (m, 13H).

Príklad 126Example 126

Hydrochlorid Zerc-butyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)acetátuTert-Butyl (2RS, 3R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) acetate hydrochloride

Produkt z príkladu 23A a Zerc-butylester glycínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and tert-butyl glycine ester were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 315 (M+H)+;MS (APCI) m / e 315 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 4,10 (d, 1H), 3,91 (q, 2H), 3,45(m, 1H), 1,48 (s, 9H), 0,90-1,85 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.10 (d, 1H), 3.91 (q, 2H), 3.45 (m, 1H), 1.48 (s, 9H), 0, 90-1.85 (m, 13H).

Príklad 127Example 127

Hydrochlorid metyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-fenylpropanoátuMethyl (2RS, 3R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-phenylpropanoate hydrochloride

Produkt z príkladu 23A a metylester fenylalanínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and phenylalanine methyl ester were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 363 (M+H)+;MS (APCI) m / e 363 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 7,23 (m, 5H), 4,74 (m, 1H), 4,17 (d, 1H), 3,73 (s, 3H), 3,47 (m, 1H), 3,01-3,25 (m, 2H), 0,70-1,78 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.23 (m, 5H), 4.74 (m, 1H), 4.17 (d, 1H), 3.73 (s, 3H), 3, 47 (m, 1H), 3.01-3.25 (m, 2H), 0.70-1.78 (m, 13H).

110 ···· • a • a • · a · · • · • ·· aa a a a • · · a a a a a a a ••a aa ·110 ···· a a a a a a a a a a a a a a a a a a

Príklad 128Example 128

Hydrochlorid metyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-metylpentanoátMethyl (2RS, 3R, 2´S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-methylpentanoate hydrochloride

Produkt z príkladu 23A a metylester L-izoleucínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-isoleucine methyl ester were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 657 (2M+H)+;MS (APCI) mlz 657 (2M + H) + ;

’H NMR (300MHz, MeOH-d4) δ 4,41 (m, 2H), 4,33 (d, 1H), 4,17 (m, 1H), 3,95 (s, 3H), 3,73 (d, 2H), 0,90-1,78 (m, 22H).1 H NMR (300MHz, MeOH-d 4 ) δ 4.41 (m, 2H), 4.33 (d, 1H), 4.17 (m, 1H), 3.95 (s, 3H), 3, 73 (d, 2H), 0.90-1.78 (m, 22H).

Príklad 129Example 129

Hydrochlorid metyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)hexanoátuMethyl (2RS, 3R, 2'S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) hexanoate hydrochloride

Produkt z príkladu 23A a metylester L-norleucínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-norleucine methyl ester were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 657 (2M+H); ’H NMR (300MHz, MeOH-d4) δ 4,44 (m, 1H), 4,13 (d, 1H), 3,74 (s, 3H), 3,45(m, 1H), 0,90-1,82 (m, 22H).MS (APCI) mlz 657 (2M + H) ; 1 H NMR (300MHz, MeOH-d 4 ) δ 4.44 (m, 1H), 4.13 (d, 1H), 3.74 (s, 3H), 3.45 (m, 1H), O, 90-1.82 (m, 22H).

Príklad 130Example 130

Hydrochlorid metyl-(2RS,3R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-metylbutanoátuMethyl (2RS, 3R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-methylbutanoate hydrochloride

Produkt z príkladu 23 A a metylester L-valínu sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and L-valine methyl ester were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 315(M+H)+;MS (APCI) m / e 315 (M + H) &lt; + &gt;;

111111

NMR (300MHz, MeOH-d4) δ 4,36 (d, 2H), 4,05 (d, 1H), 3,72 (s, 3H), 2,20 (m, 2H), 0,98 (s, 3H), 0,96 (s, 3H), 0,87-1,84 (m, 13H).NMR (300MHz, MeOH-d 4 ) δ 4.36 (d, 2H), 4.05 (d, 1H), 3.72 (s, 3H), 2.20 (m, 2H), 0.98 ( s, 3H), 0.96 (s, 3H), 0.87-1.84 (m, 13H).

Príklad 131 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-((lS)-l-(2-naftyl)etyl)butánamidExample 131 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - ((1S) -1- (2-naphthyl) ethyl) butanamide

Produkt z príkladu 23A a (S)-l-amino-l-(2-naftyl)etán sa spracovávajú podľa spôsobu z príkladu 24, čím sa získa požadovaná zlúčenina.The product of Example 23A and (S) -1-amino-1- (2-naphthyl) ethane were processed according to the method of Example 24 to give the title compound.

MS (ESI) m/e 355 (M+H)+;MS (ESI) mlz 355 (M + H) + ;

’H NMR (300 MHz, DMSO-d6) δ 8,63 (d, 1H), 7,88 (m, 2H), 7,78 (m, 3H), 7,54 (dd, 1H), 7,48 (m, 2H), 6,46 (d, 1H), 5,13 (m, 1H), 4,02 (m, 1H), 3,28 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.63 (d, 1H), 7.88 (m, 2H), 7.78 (m, 3H), 7.54 (dd, 1H), 7 48 (m, 2H); 6.46 (d, 1H); 5.13 (m, 1H); 4.02 (m, 1H); 3.28 (m, 1H);

1,58 (m, 2H), 1,52 (d, 3H), 1,38-1,06 (m, 9H), 0,77 (m, 1H), 0,63 (m, 1H); Analyticky vypočítané pre C22H3oN202S»HCl: C, 67,59; H, 7,99; N, 7,17, Zistené. C, 67,42; H, 8,03; N, 7,08.1.58 (m, 2H), 1.52 (d, 3H), 1.38-1.06 (m, 9H), 0.77 (m, 1H), 0.63 (m, 1H); C 22 H calcd for 3 oN 2 02S »HCl: C, 67.59; H, 7.99; N, 7.17. Found. C, 67.42; H, 8.03; N, 7.08.

Príklad 132Example 132

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/ý-((lR)-l-(2-naftyl)etyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-1H - ((1R) -1- (2-naphthyl) ethyl) butanamide hydrochloride

Produkt z príkladu 23A a (R)-l-amino-l-(2-naftyl)etán sa spracovávajú podľa spôsobu z príkladu 24, čím sa získa požadovaná zlúčenina.The product of Example 23A and (R) -1-amino-1- (2-naphthyl) ethane were processed according to the method of Example 24 to give the title compound.

MS (ESI) m/e 355(M+H)+;MS (ESI) mlz 355 (M + H) + ;

*H NMR (300 MHz, DMSO-d6) δ 8,67 (d, 1H), 7,83 (m, 5H), 7,56 (dd, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.67 (d, 1H), 7.83 (m, 5H), 7.56 (dd, 1H),

7,48 (m, 2H), 6,49 (d, 1H), 5,13 (m, 1H), 4,09 (t, 1H), 3,28 (m, 1H), 1,58 (m, 2H), 1,50 (d, 3H), 1,38-1,06 (m, 9H), 0,77 (m, 1H), 0,63 (m, 1H).7.48 (m, 2H), 6.49 (d, 1H), 5.13 (m, 1H), 4.09 (t, 1H), 3.28 (m, 1H), 1.58 (m 2 H, 1.50 (d, 3H), 1.38-1.06 (m, 9H), 0.77 (m, 1H), 0.63 (m, 1H).

112112

Príklad 133Example 133

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-V-((l S)-l-(l-naftyl)etyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N - ((1S) -1- (1-naphthyl) ethyl) butanamide hydrochloride

Produkt z príkladu 23A a (S)-l-amino-l-(l-naftyl)etán sa spracovávajú podľa spôsobu z príkladu 24, čím sa získa požadovaná zlúčenina.The product of Example 23A and (S) -1-amino-1- (1-naphthyl) ethane were processed according to the method of Example 24 to give the title compound.

MS (ESI) m/e 355(M+H)+;MS (ESI) mlz 355 (M + H) + ;

’H NMR (300 MHz, DMSO-d6) δ 8,69 (d, 1H), 8,13 (d, 1H), 7,94 (dd, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.69 (d, 1H), 8.13 (d, 1H), 7.94 (dd, 1H),

7,81 (m, 3H), 7,60 (d, 1H), 7,52 (m, 2H), 6,47 (d, 1H), 5,77 (m, 1H), 3,99 (t, 1H), 3,23 (m, 1H), 1,61 (m, 2H), 1,57 (d, 3H), (m, 9H), 0,78-0,60 (m, 2H); Analyticky vypočítané pre C22H3oN202S-HCl: C, 67,59; H, 7,99; N, 7,17, Zistené: C, 67,25; H, 7,92; N, 6,96.7.81 (m, 3H), 7.60 (d, 1H), 7.52 (m, 2H), 6.47 (d, 1H), 5.77 (m, 1H), 3.99 (t 1H, 3.23 (m, 1H), 1.61 (m, 2H), 1.57 (d, 3H), (m, 9H), 0.78-0.60 (m, 2H); Calculated for C 22 H 3 oN 2 0 2 S-HCl: C, 67.59; H, 7.99; N, 7.17. Found: C, 67.25; H, 7.92; N, 6.96.

Príklad 134Example 134

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-((l R)-1-(1 -nafty l)etyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - ((1 R) -1- (1-naphthyl) ethyl) butanamide hydrochloride

Produkt z príkladu 23A a (R)-l-amino-l-(l-naftyl)etán sa spracovávajú podľa spôsobu z príkladu 24, čím sa získa požadovaná zlúčenina.The product of Example 23A and (R) -1-amino-1- (1-naphthyl) ethane were processed according to the method of Example 24 to give the title compound.

MS (ESI) m/e 355(M+H)+;MS (ESI) mlz 355 (M + H) + ;

’H NMR (300 MHz, DMSO-d6) δ 8,71 (d, 1H), 8,14 (d, 1H), 7,94 (dd, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.71 (d, 1H), 8.14 (d, 1H), 7.94 (dd, 1H),

7,82 (d, 1H), 7,79 (bds, 2H), 7,60 (d, 1H), 7,52 (m, 2H), 6,43 (d, 1H), 5,76 (m, 1H), 4,11 (t, 1H, J=5 Hz), 3,23 (m, 1H), 1,61 (m, 2H), 1,53 (d, 3H), 1,38-1,11 (m, 9H), 0,81 (m, 1H), 0,63 (m, 1H);7.82 (d, 1H), 7.79 (bds, 2H), 7.60 (d, 1H), 7.52 (m, 2H), 6.43 (d, 1H), 5.76 (m 1 H, 4.11 (t, 1H, J = 5 Hz), 3.23 (m, 1H), 1.61 (m, 2H), 1.53 (d, 3H), 1.38-1 11 (m, 9H); 0.81 (m, 1H); 0.63 (m, 1H);

Analyticky vypočítané pre C22H3oN202S»HCI»0,33 H2O: C, 66,58; H, 8,04; N, 7,06, Zistené: C, 66,46; H, 8,07; N, 6,81Calculated for C 22 H 3 oN 2 0 2 S »HCl» 0.33 H2O: C, 66.58; H, 8.04; N, 7.06. Found: C, 66.46; H, 8.07; N, 6.81

113 ···· • · *»· • ·· · ·· · · ·· · • · · · · ·· ·113 ···············

Príklad 135Example 135

Trifluóracetát etyl-(2RS,3R,2’R)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-fluórpropanoátuEthyl (2RS, 3R, 2'R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-fluoropropanoate trifluoroacetate

Príklad 135A ľ/B-fluór-DL-alanín sa spracováva podľa spôsobu z príkladu ID, čím sa získa požadovaná zlúčenina.Example 135A 1'-B-fluoro-DL-alanine was processed according to the method of Example 1D to give the title compound.

MS (APCI+) m/e 208 (M+H)+,MS (APCI +) m / e 208 (M + H) &lt; + &gt;

Príklad 135BExample 135B

Produkt z príkladu 135A sa spracováva podľa spôsobu z príkladu 137A, čím sa získa požadovaná zlúčenina.The product of Example 135A was processed according to the method of Example 137A to give the title compound.

MS (APCI+) m/e 236 (M+H)+.MS (APCI +) m / e 236 (M + H) &lt; + &gt;.

Príklad 135CExample 135C

Produkt z príkladu 135B sa spracováva podľa spôsobu z príkladu 1F, čím sa získa požadovaná zlúčenina.The product of Example 135B was processed according to the method of Example 1F to give the title compound.

MS (APCI+) m/e 136 (M+H)+.MS (APCI +) m / e 136 (M + H) &lt; + &gt;.

Príklad 135DExample 135D

Produkt z príkladu 23A a produkt z príkladu 135C sa spracovávajú podľa spôsobu z príkladu IE, čím sa získa požadovaná zlúčenina.The product of Example 23A and the product of Example 135C were processed according to the method of Example IE to give the title compound.

MS (APCI+) m/e 419 (M+H)+.MS (APCI +) m / e 419 (M + H) &lt; + &gt;.

114114

Príklad 135EExample 135E

Roztok z príkladu 135D (0,27 g, 0,62 mmol) v dichlórmetáne (3 ml) obsahujúci trifluóroctová kyselinu (2 ml) sa mieša pri izbovej teplote po dobu 3 hodiny, odparuje sa do sucha, suspenduje sa v etyléteri, potom sa koncentruje a suší vo vákuu, čím sa získa požadovaná zlúčenina (0,24 g).A solution of Example 135D (0.27 g, 0.62 mmol) in dichloromethane (3 mL) containing trifluoroacetic acid (2 mL) was stirred at room temperature for 3 hours, evaporated to dryness, suspended in ethyl ether, then concentrated in vacuo. concentrated and dried in vacuo to give the title compound (0.24 g).

MS (APCI) m/e 336 (M+H)+;MS (APCI) m / e 336 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, DMSO-d6) δ 7,75 (m, 2H), 6,43 (m, 1H), 6,18 (m, 2H),1 H NMR (300 MHz, DMSO-d 6 ) δ 7.75 (m, 2H), 6.43 (m, 1H), 6.18 (m, 2H),

5,84 (m, 1H), 4,26 (m, 1H), 4,13 (m, 3H), 3,38 (m, 1H), 1,67 (m, 8H), 1,28 (m, 1H), 1,19 (m, 3H), 1,10 (m, 2H).5.84 (m, 1H), 4.26 (m, 1H), 4.13 (m, 3H), 3.38 (m, 1H), 1.67 (m, 8H), 1.28 (m 1 H, 1.19 (m, 3H), 1.10 (m, 2H).

Príklad 136Example 136

Trifluóracetát (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-hydroxy-l-(hydroxy metyl)etyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2-hydroxy-1- (hydroxymethyl) ethyl) butanamide trifluoroacetate

Príklad 136AExample 136A

JV-(Benzyloxykarbonyl)-O-(t-butyl)-L-serín sa spracováva podľa spôsobu z príkladu 1A, čím sa získa požadovaná zlúčenina.N - (Benzyloxycarbonyl) -O- (t-butyl) -L-serine was processed according to the method of Example 1A to give the title compound.

MS (ESI+Q1MS) m/e 282 (M+H)+.MS (ESI + Q1MS) mlz 282 (M + H) + .

Príklad 136BExample 136B

Produkt z príkladu 136A sa spracováva podľa spôsobu z príkladu 106,1 A, čím sa získa požadovaná zlúčenina.The product of Example 136A was processed according to the method of Example 106.1 A to give the title compound.

MS (APCI+) m/e 311 (M+H)+.MS (APCI +) m / e 311 (M + H) &lt; + &gt;.

115 ·· · • · ·· • · · • t · • · · ·· ···115 ·· · t · t · t ·

Príklad 136CExample 136C

Produkt z príkladu 23A a produkt z príkladu 136B sa spracovávajú podľa spôsobov z príkladov IE a 135B, čím sa získa požadovaná zlúčenina.The product of Example 23A and the product of Example 136B were processed according to the methods of Examples IE and 135B to give the title compound.

MS (APCI) m/e 275(M+H)+;MS (APCI) m / e 275 (M + H) &lt; + &gt;;

*H NMR (300 MHz, D2O) δ 7,64 (m, 2H), 6,49 (m, 1H), 4,70 (m, 1H), 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 H NMR (300 MHz, D 2 O) δ 7.64 (m, 2H), 6.49 (m, 1H), 4.70 (m, 1H), 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, 1H).1.22 (m, 3H); 0.89 (m, 1H).

Príklad 137Example 137

Trifluóracetát 4-(/erc-butyl)benzyl(2RS,3R,2'R)-2-((3-amino-4-cyklohexyl-2hydroxybutanoyl)amino)-3 hydroxypropanoátu4- (tert-Butyl) benzyl (2RS, 3R, 2'R) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate trifluoroacetate

Príklad 137AExample 137A

Roztok A/-(t-butyloxykarbonyl)-(?-(t-butyl)-L-serínu (0,54 g, 2,1 mmol) a DCC (0,47 g, 2,2 mmol) v CH2CI2 (5 ml) sa mieša pri teplote 0 °C po dobu 15 minút, nechá sa reagovať s para-t-butylbenzylalkoholom (0,33 g, 2,0 mmol) a katalytickým DMAP a mieša po dobu 16 hodín. Roztok sa odparuje do sucha a zvyšok sa čistí zrýchlenou („flash“) chromatografiou na stĺpci silikagélu 5 % etylacetát/toluénom, čím sa získa požadovaná zlúčenina (0,49 g).A solution of N - (t-butyloxycarbonyl) - (R - (t-butyl) -L-serine (0.54 g, 2.1 mmol) and DCC (0.47 g, 2.2 mmol) in CH 2 Cl 2 (5 mL) was stirred at 0 ° C for 15 min, treated with para-t-butylbenzyl alcohol (0.33 g, 2.0 mmol) and catalytic DMAP, and stirred for 16 h. The residue was purified by flash column chromatography on silica gel with 5% ethyl acetate / toluene to give the title compound (0.49 g).

MS (APCI+) m/e 311 (M+H)+.MS (APCI +) m / e 311 (M + H) &lt; + &gt;.

Príklad 137BExample 137B

Produkt z príkladu 137A sa spracováva podľa spôsobov z príkladov 1F, IE a 135B, čím sa získa požadovaná zlúčenina.The product of Example 137A was processed according to the methods of Examples 1F, IE and 135B to give the title compound.

MS (APCI) m/e 435(M+H)+;MS (APCI) m / e 435 (M + H) &lt; + &gt;;

116116

• · ’H NMR (300 MHz, D2O) δ 7,72 (m, 2H), 7,41 (m, 3H), 7,28 (m, 1H), 5,40 (s, 2H), 5,14 (m, 2H), 4,89 (m, 1H), 4,70 (m, 2H), 4,12 (m, 1H), 3,76 (m, 1H),1 H NMR (300 MHz, D 2 O) δ 7.72 (m, 2H), 7.41 (m, 3H), 7.28 (m, 1H), 5.40 (s, 2H), 5.14 (m, 2H), 4.89 (m, 1H), 4.70 (m, 2H), 4.12 (m, 1H), 3.76 (m, 1H),

1,64 (m, 6H), 1,42 (m, 2H), 1,28 (s, 9H), 1,14 (m, 1H), 0,84 (m, 2H).1.64 (m, 6H), 1.42 (m, 2H), 1.28 (s, 9H), 1.14 (m, 1H), 0.84 (m, 2H).

Príklad 138Example 138

Trifluóracetát 4-nitrobenzyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoátu4-Nitrobenzyl- (2RS, 3R, 2´S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate trifluoroacetate

Príklad 138A /V-BOC-O-(t-Butyl)-L-Serín a 4-nitro-benzylalkohol sa spracovávajú podľa spôsobu z príkladu 137A, čím sa získa požadovaná zlúčenina.Example 138A N-BOC-O- (t-Butyl) -L-Serine and 4-nitro-benzyl alcohol were processed according to the method of Example 137A to give the title compound.

Príklad 138BExample 138B

Produkt z príkladu 23A a produkt z príkladu 138 sa spracovávajú podľa spôsobu z príkladu 138B, čím sa získa požadovaná zlúčenina.The product of Example 23A and the product of Example 138 were processed according to the method of Example 138B to give the title compound.

MS (APCI) m/e 424 (M+H)+;MS (APCI) m / e 424 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,86 (m, 1H), 8,23 (d, 2H), 7,67 (m, 1H), 7,63 (d, 2H), 5,32 (s, 2H), 4,93 (m, 1H), 4,76 (m, 2H), 4,48 (m, 1H), 4,13 (m, 1H),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.86 (m, 1H), 8.23 (d, 2H), 7.67 (m, 1H), 7.63 (d, 2H), δ 32 (s, 2H), 4.93 (m, 1H), 4.76 (m, 2H), 4.48 (m, 1H), 4.13 (m, 1H),

3,78 (m, 2H), 1,62 (m, 6H), 1,40 (m, 2H), 1,18 (m, 3H).3.78 (m, 2H), 1.62 (m, 6H), 1.40 (m, 2H), 1.18 (m, 3H).

Príklad 139Example 139

Trifluóracetát 3-nitrobenzyl-(2RS,3R,2’S)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoátu3-Nitrobenzyl- (2RS, 3R, 2´S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate trifluoroacetate

N-BOC-O-(t-Butyl)-L-Serín a 3-nitro-benzylalkohol sa spracovávajú podľa spôsobov z príkladov 137A a 137B, čím sa získa požadovaná zlúčenina.N-BOC-O- (t-Butyl) -L-Serine and 3-nitro-benzyl alcohol were processed according to the methods of Examples 137A and 137B to give the title compound.

·· ·· • ·· · · ·· · · · • · · · · · • ···· «··· • · · · · · · ··· ·· ··· ·· · 117· 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117 117

MS (APCI) m/e 424 (M+H)+;MS (APCI) m / e 424 (M + H) &lt; + &gt;;

*H 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), l,15(m, 2H) 0,80 (m, IH).1 H NMR (300 MHz, DMSO-d 6 ) δ 8.80 (m, 1H), 8.24 (m, 1H), 7.86 (m, 1H), 7.70 (m, 2H), δ 32 (m, 2H), 4.91 (m, 1H), 4.74 (m, 2H), 4.13 (m, 1H), 3.32 (m, 2H), 1.63 (m, 2H) 6H), 1.40 (m, 2H), 1.15 (m, 2H) 0.80 (m, 1H).

Príklad 140Example 140

Trifluóracetát 4-(trifluórmetyl)benzyl-(2RS,3R,2'S)-2-((3-amino-4-cyklohexyl2-hydroxybutanoyl)amino)-3-hydroxypropanoátu4- (Trifluoromethyl) benzyl (2RS, 3R, 2'S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate trifluoroacetate

N-BOC-č?-(t-Butyl)-L-Serín a 4-(trifluórmetyl)benzylalkohol sa spracovávajú podľa spôsobov z príkladov 137A a 137B, čím sa získa požadovaná zlúčenina.N-BOC-N - (t-Butyl) -L-Serine and 4- (trifluoromethyl) benzyl alcohol were processed according to the methods of Examples 137A and 137B to give the title compound.

MS (APCI) m/e 447 (M+H)+;MS (APCI) m / e 447 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,82 (m, IH), 7,74 (m, 3H), 7,58 (m, IH),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.82 (m, 1H), 7.74 (m, 3H), 7.58 (m, 1H),

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).5.28 (s, 2H), 4.91 (m, 1H), 4.48 (m, 1H), 4.23 (m, 2H), 4.21 (m, 1H), 3.83 (m 2H, 1.65 (m, 6H), 1.40 (m, 2H), 1.18 (m, 2H), 0.79 (m, 1H).

Príklad 141Example 141

Trifluóracetát 3-(trifluórmetoxy)benzyl-(2RS,3R,2'S)-2-((3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-hydroxypropanoátu3- (Trifluoromethoxy) benzyl- (2RS, 3R, 2'S) -2 - ((3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-hydroxypropanoate trifluoroacetate

N-BOC-O-(t-Butyl)-L-Serín a 3-(trifluórmetoxy)benzylalkohol sa spracovávajú podľa spôsobov z príkladov 137A a 137B, čím sa získa požadovaná zlúčenina.N-BOC-O- (t-Butyl) -L-Serine and 3- (trifluoromethoxy) benzyl alcohol were processed according to the methods of Examples 137A and 137B to give the title compound.

MS (APCI) m/e 463 (M+H)+;MS (APCI) m / e 463 (M + H) &lt; + &gt;;

*H NMR (300 MHz, DMSO-d6) δ 8,78 (m, IH), 7,73 (m, 2H), 7,50 (m, IH),1 H NMR (300 MHz, DMSO-d 6 ) δ 8.78 (m, 1H), 7.73 (m, 2H), 7.50 (m, 1H),

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), l,15(m, 2H), 0,82 (m, IH).7.37 (m, 3H), 5.24 (m, 2H), 4.90 (m, 1H), 4.83 (m, 2H), 4.11 (m, 1H), 4.05 (m) 1H, 3.99 (m, 2H), 1.62 (m, 6H), 1.40 (m, 2H), 1.15 (m, 2H), 0.82 (m, 1H).

·· • · · • ··· · · · · ·

118 ·· ···118 ·· ···

Príklad 142Example 142

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/\/-(4-fluórfenetyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (4-fluorophenethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23 A a 4-fluórfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-fluorophenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 323 (M+H)+;MS (APCI) m / e 323 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,25 (m, 2H), 7,00 (m, 2H), 4,10 (d, 1H), 3,60 (m, 2H), 3,40 (m, 2H), 2,85 (t, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.25 (m, 2H), 7.00 (m, 2H), 4.10 (d, 1H), 3.60 (m, 2H), 3 40 (m, 2H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 143 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(4-metylfenyl)butánamidExample 143 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4-methylphenyl) butanamide

Produkt z príkladu 23A a p-toluidín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and p-toluidine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 291 (M+H)+;MS (APCI) m / e 291 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,52 (d, 2H), 7,16 (d, 2H), 4,28 (d, 1H), 3,65 (m, 1H), 2,31 (s, 3H), 0,92-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.52 (d, 2H), 7.16 (d, 2H), 4.28 (d, 1H), 3.65 (m, 1H), 2, 31 (s, 3H), 0.92-1.86 (m, 13H).

Príklad 144 (2RS,3R)-3-amino-4-cyklohexyl-/V-(4-fluórfenyl)-2-hydroxybutánamidExample 144 (2RS, 3R) -3-Amino-4-cyclohexyl-N- (4-fluorophenyl) -2-hydroxybutanamide

Produkt z príkladu 23A a 4-fluoranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-fluoroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 295(M+H)+;MS (APCI) m / e 295 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,65 (q, 2H), 7,07 (t, 2H), 4,29 (d, 1H), 3,74 (m, 1H), 0,92-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.65 (q, 2H), 7.07 (t, 2H), 4.29 (d, 1H), 3.74 (m, 1H), O, 92-1.88 (m, 13H).

119119

···· ···· • • ·· · · • • • · • · • • • e • e • • • • ·· · ·· · • • • • • • • • • • • · • · • • • ·» • · » • · ··· • · · · · • • • ·· • · · • · · ··· • · · · · · • ·· • · ·

Príklad 145 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-N-(4-metoxyfenyl)butánamidExample 145 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4-methoxyphenyl) butanamide

Produkt z príkladu 23A a p-anizidín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and p-anisidine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 307 (M+H)+;MS (APCI) m / e 307 (M + H) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 7,54 (d, 2H), 6,90 (d, 2H), 4,29 (d, 1H), 3,80 (s, 3H), 3,67 (m, 1H), 0,92-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.54 (d, 2H), 6.90 (d, 2H), 4.29 (d, 1H), 3.80 (s, 3H), 3, 67 (m, 1H); 0.92-1.88 (m, 13H).

Príklad 146 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-metoxyfenyl)butánamidExample 146 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2-methoxyphenyl) butanamide

Produkt z príkladu 23A a o-anizidín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and o-anisidine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 307 (M+H)+;MS (APCI) m / e 307 (M + H) &lt; + &gt;;

lH NMR (300MHz, MeOH-d4) δ 8,28 (dd, 1H), 7,03-7,15 (m, 2H), 6,94 (td, 1H), 4,34 (d, 1H), 3,91 (s, 3H), 3,77 (m, 1H), 0,96-1,89 (m, 13H). 1 H NMR (300MHz, MeOH-d 4 ) δ 8.28 (dd, 1H), 7.03-7.15 (m, 2H), 6.94 (td, 1H), 4.34 (d, 1H) 1.91 (s, 3H), 3.77 (m, 1H), 0.96-1.89 (m, 13H).

Príklad 147 (2RS,3R)-3-amino-/V-(4-chlórfenyl)-4-cyklohexyl-2-hydroxybutánamidExample 147 (2RS, 3R) -3-Amino- N - (4-chlorophenyl) -4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a 4-chlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-chloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 311 (M+H)+;MS (APCI) m / e 311 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,67 (d, 2H), 7,33 (d, 2H), 4,30 (d, 2H), 3,74 (m, 1H), 0,92-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.67 (d, 2H), 7.33 (d, 2H), 4.30 (d, 2H), 3.74 (m, 1H), O, 92-1.86 (m, 13H).

·· • · · • · • · ·· ··· · · · · · · · ·

120 ···· · • ·· • · • · • · · ·· ··· ·· • · · • · • · · ·· ···120 ····················

Príklad 148 (2RS,3R)-3-amino-7\/-(3-chlórfenyl)-4-cy klohexy 1-2-hydroxybutánami dExample 148 (2RS, 3R) -3-Amino-7H- (3-chlorophenyl) -4-cyclohexyl-2-hydroxybutanes d

Produkt z príkladu 23A a 3-chlóranilin sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-chloroaniline were treated according to the method of Example 101 to give the title compound.

MS (APCI) m/e 311 (M+H)+;MS (APCI) m / e 311 (M + H) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 7,87 (t, 1H), 7,15 (qd, 1H), 7,32 (t, 1H), 7,14 (qd, 1H), 4,31 (d, 1H), 3,73 (m, 1H), 0,93-1,87 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.87 (t, 1H), 7.15 (qd, 1H), 7.32 (t, 1H), 7.14 (qd, 1H), 4, 31 (d, 1H), 3.73 (m, 1H), 0.93-1.87 (m, 13H).

Príklad 149 (2RS,3R)-3-amino-y-(2-chlórfenyl)-4-cyklohexyl-2-hydroxybutánamidExample 149 (2RS, 3R) -3-Amino-y- (2-chloro-phenyl) -4-cyclohexyl-2-hydroxy-butanamide

Produkt z príkladu 23A a 2-chlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-chloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 311 (M+H)+;MS (APCI) m / e 311 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,33 (dd, 1H), 7,48 (dd, 1H), 7,34 (dt, 1H),1 H NMR (300MHz, MeOH-d 4 ) δ 8.33 (dd, 1H), 7.48 (dd, 1H), 7.34 (dt, 1H),

7,16 (dt, 1H), 4,40 (d, 1H), 3,80 (m, 1H), 2,69 (s, 1H), 0,96-1,88 (m, 13H).7.16 (dt, 1H), 4.40 (d, 1H), 3.80 (m, 1H), 2.69 (s, 1H), 0.96-1.88 (m, 13H).

Príklad ISO (2RS,3R)-3-amino-A/-(4-(/erc-butyl)fenyl)-4-cyklohexyl-2-hydroxybutánamidExample ISO (2RS, 3R) -3-Amino-N- (4- (tert-butyl) phenyl) -4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a 4-/erc-butylanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4- tert -butylaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 333 (M+H)+;MS (APCI) m / e 333 (M + H) &lt; + &gt;;

JH NMR (300MHz, MeOH-d4) δ 7,57 (d, 2H), 7,54 (d, 2H), 4,28 (d, 1H), 3,72 (m, 1H), 1,33 (s, 9H), 0,92-1,88 (m, 13H). LH NMR (300 MHz, MeOH-d4) δ 7.57 (d, 2H), 7.54 (d, 2H), 4.28 (d, 1H), 3.72 (m, 1 H), 1, 33 (s, 9H), 0.92-1.88 (m, 13H).

• ·· · ·· ·· · · ·· · • · · · ·• · · · · · · · · · · · · · · · · ·

121 ···· • · · ·· ··· • · · · · ·· ··· ·· ·121 ··················

Príklad 1S1 (2RS,3R)-3-Amino-4-cyklohexyl-2-hydroxy-/^-(3(trifluórmetyl)fenyl)butánamidExample 1S1 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3 (trifluoromethyl) phenyl) butanamide

Produkt z príkladu 23A a 3-(trifluórmetyl)anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3- (trifluoromethyl) aniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 345(M+H)+;MS (APCI) m / e 345 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,16 (s, 1H), 7,86 (d, 1H), 7,54 (t, 1H), 7,43 (d, 1H), 4,33 (d, 1H), 3,77 (m, 1H), 0,93-1,87 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.16 (s, 1H), 7.86 (d, 1H), 7.54 (t, 1H), 7.43 (d, 1H), 4, 33 (d, 1H), 3.77 (m, 1H), 0.93-1.87 (m, 13H).

Príklad 152 (2RS,3R)-3-Amino-4-cyklohexyl-2-hydroxy-/V-(4(trifluórmetyl)fenyl)butánamidExample 152 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4 (trifluoromethyl) phenyl) butanamide

Produkt z príkladu 23A a 4-(trifluórmetyl)anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4- (trifluoromethyl) aniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 345 (M+H)+;MS (APCI) m / e 345 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,89 (d, 2H), 7,64 (d, 2H), 4,34 (d, 1H), 3,74 (m, 1H), 0,95-1,87 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.89 (d, 2H), 7.64 (d, 2H), 4.34 (d, 1H), 3.74 (m, 1H), O, 95-1.87 (m, 13H).

Príklad 153 (2RS,3R)-3-amino-4-cyklohexyl-/V-(3,4-dichlórfenyl)-2-hydroxybutánamidExample 153 (2RS, 3R) -3-Amino-4-cyclohexyl-N- (3,4-dichlorophenyl) -2-hydroxybutanamide

Produkt z príkladu 23A a 3,4-dichlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4-dichloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 345 (M)+;MS (APCI) m / e 345 (M) &lt; + &gt;;

·· • · · • ··· · · · · ·

122 ···· · • ·· • · • · • · · ·· ··· ·· • · · • · • · · ·· ··· • · ·· · ’H NMR (300MHz, MeOH-d4) δ 8,04 (d, IH), 7,55 (dd, 1H), 7,47 (d, 1H), 4,32 (d, 1H), 3,75 (m, 1H), 0,92-1,83 (m, 13H).122 1 H NMR (300MHz, MeOH-d) _______________________________________ NMR NMR NMR 1 H NMR (300MHz, MeOH-d) 4 ) δ 8.04 (d, 1H), 7.55 (dd, 1H), 7.47 (d, 1H), 4.32 (d, 1H), 3.75 (m, 1H), 0, 92-1.83 (m, 13H).

Príklad 154 (2RS,3R)-3-amino-4-cyklohexyl-7V-(2,4-dichlórfenyl)-2-hydroxybutánamidExample 154 (2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,4-dichloro-phenyl) -2-hydroxy-butanamide

Produkt z príkladu 23A a 2,4-dichlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,4-dichloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 345 (M)+;MS (APCI) m / e 345 (M) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 8,32 (d, 1H), 7,55 (d, 1H), 7,37 (dd, 1H), 4,40 (d, 1H), 3,66 (m, 1H), 0,95-1,87 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.32 (d, 1H), 7.55 (d, 1H), 7.37 (dd, 1H), 4.40 (d, 1H), 3, 66 (m, 1H); 0.95-1.87 (m, 13H).

Príklad 155 (2RS,3R)-3-amino-.N-(4-brómfenyl)-4-cyklohexyl-2-hydroxybutánamidExample 155 (2RS, 3R) -3-Amino-N- (4-bromophenyl) -4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a 4-brómanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-bromoaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 356 (M+H)+;MS (APCI) m / e 356 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,62 (d, 2H), 7,47 (d, 2H), 4,30 (d, 1H), 3,73 (m, 1H), 0,92-1,85 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.62 (d, 2H), 7.47 (d, 2H), 4.30 (d, 1H), 3.73 (m, 1H), O, 92-1.85 (m, 13H).

Príklad 156 (2RS,3R)-3-amino-7\/-(4-(Zerc-butyl)benzyl)-4-cyklohexyl-2-hydroxybutánamidExample 156 (2RS, 3R) -3-Amino-N- (4- (tert-butyl) benzyl) -4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a 4-/erc-butylbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4- tert -butylbenzylamine were processed according to the method of Example 101 to give the title compound.

123 ···· • ·· • · « · • · · ·· ··· • · ·· · · • · · · · • · · · · · • · · · · ·· ··· ··123 ···························

MS (APCI) m/e 347 (M+H)+;MS (APCI) m / e 347 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,35(d, 2H), 7,24 (d, 2H), 4,39 (q, 2H), 4,16 (d, 1H), 3,58 (m, 1H), 1,39 (s, 9H), 0,87-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.35 (d, 2H), 7.24 (d, 2H), 4.39 (q, 2H), 4.16 (d, 1H), 3, 58 (m, 1H), 1.39 (s, 9H), 0.87-1.80 (m, 13H).

Príklad 157 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3(trifluórmetyl)benzyl)butánamidExample 157 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (3 (trifluoromethyl) benzyl) butanamide

Produkt z príkladu 23A a 3-(trifluórmetyl)benzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3- (trifluoromethyl) benzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 359 (M+H)+;MS (APCI) m / e 359 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,64 (s, 1H), 7,57 (m, 3H), 4,50 (q, 2H), 4,20 (d, 1H), 3,58 (m, 1H), 0,82-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.64 (s, 1H), 7.57 (m, 3H), 4.50 (q, 2H), 4.20 (d, 1H), 3, 58 (m, 1H), 0.82-1.80 (m, 13H).

Príklad 158 (2RS,3R)-3-Amino-4-cyklohexyl-2-hydroxy-/V-(4(trifluórmetyl)benzyl)butánamidExample 158 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (4 (trifluoromethyl) benzyl) butanamide

Produkt z príkladu 23A a 4-(trifluórmetyl)benzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4- (trifluoromethyl) benzylamine were processed according to the method of Example 101 to give 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, 1H), 3,62 (m, 1H), 0,86-1,80 (m, 13H).MS (APCI) m / e 359 (M + H) + ; 1 H NMR (300MHz, MeOH-d 4 ) δ 7.63 (d, 2H), 7.51 (d, 2H), 4.50 ( q, 2H), 4.20 (d, 1H), 3.62 (m, 1H), 0.86-1.80 (m, 13H).

Príklad 159 (2RS,3R)-3-amino-/V-(2-chlórbenzyl)-4-cyklohexyl-2-hydroxybutánamidExample 159 (2RS, 3R) -3-Amino- N - (2-chlorobenzyl) -4-cyclohexyl-2-hydroxybutanamide

124 ·· · ·· • ·· · · ·· · • i a · · · · • ···· · · · · ··· a·· · · ·· ··· ·· ··· ·· ·124 · i a a a a a a a a a 124

Produkt z príkladu 23A a 3-chlórbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-chlorobenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 325(M+H)+;MS (APCI) m / e 325 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,40 (m, 2H), 7,27 (m, 2H), 4,55 (q, 2H), 4,22 (d, 1H), 3,61 (m, 1H), 0,88-1,81 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.40 (m, 2H), 7.27 (m, 2H), 4.55 (q, 2H), 4.22 (d, 1H), 3, 61 (m, 1H), 0.88-1.81 (m, 13H).

Príklad 160Example 160

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-2V-(2-metoxy-5-nitrofenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-2H- (2-methoxy-5-nitrophenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metoxy-5-nitroanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxy-5-nitroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 352 (M+H)+;MS (APCI) m / e 352 (M + H) &lt; + &gt;;

!H NMR (300 MHz, MeOH-d4) δ 9,30 (d, 0,5H), 8,10 (m, 1H), 7,25 (d, 1H), ! 1 H NMR (300 MHz, MeOH-d 4 ) δ 9.30 (d, 0.5H), 8.10 (m, 1H), 7.25 (d, 1H),

4,40 (d, 1H), 4,08 (s, 3H), 3,82 (m, 1H), 3,75 (m, 1H), 3,65 (m, 1H), 3,58 (m, 1H), l,75(m, 5H), 1,40 (m, 6H), l,05(m, 2H).4.40 (d, 1H); 4.08 (s, 3H); 3.82 (m, 1H); 3.75 (m, 1H); 3.65 (m, 1H); 3.58 (m) 1 H, 1.75 (m, 5H), 1.40 (m, 6H), 1.05 (m, 2H).

Príklad 161Example 161

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyI-N-(3,5-dimetoxyfenyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (3,5-dimethoxyphenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3,5-dimetoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,5-dimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 337 (M+H)+;MS (APCI) m / e 337 (M + H) &lt; + &gt;;

*H NMR (300 MHz, MeOH-d4) δ 6,92 (d, 2H), 6,60 (t, 1H), 4,28 (d, 1H), 3,78 (s, 6H), 3,73 (m, 1H), 3,65 (m, 1H), 3,58 (m, 1H), 1,75 (m, 5H), 1,40 (m, 6H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 6.92 (d, 2H), 6.60 (t, 1H), 4.28 (d, 1H), 3.78 (s, 6H), 3 73 (m, 1H), 3.65 (m, 1H), 3.58 (m, 1H), 1.75 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).

125 ···· · ·· • ·· a · a · · · a ·· aa aaa • · · a · · · a a a aaa aa a • a a « · aa ··· ··125 ···· · ·· · a · a · a · aa aaa · a · a · a a aaa aa a · a a «· aa ··· ··

Príklad 162Example 162

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(3-fenoxyfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N - (3-phenoxyphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-fenoxyanilin sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-phenoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 369 (M+H)+;MS (APCI) m / e 369 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,40 (m, 5H), 7,10 (m, 4H), 6,75 (m, IH),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.40 (m, 5H), 7.10 (m, 4H), 6.75 (m, 1H),

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).4.28 (d, 1H), 3.72 (m, 1H), 3.66 (m, 2H), 3.58 (m, 1H), 1.75 (m, 5H), 1.50 (m) 2H, 1.30 (m, 4H), 1.00 (m, 2H).

Príklad 163Example 163

Hydrochlorid (((2RS,3R)-3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)(2,5-dimetoxybenzyl)chloronia(((2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxybutanoyl) amino) (2,5-dimethoxybenzyl) chloronium hydrochloride

Produkt z príkladu 23A a 2,5-dimetoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,5-dimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 365(M+H)+;MS (APCI) m / e 365 (M + H) &lt; + &gt;;

’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 (m, 2H), 3,40 (m, IH), 2,78 (t, 2H), 1,75 (m, 5H),1 H NMR (300 MHz, MeOH-d 4 ) δ 6.42 (d, 2H), 6.35 (t, 1H), 4.11 (d, 1H), 3.75 (s, 6H), 3 65 (m, 1H), 3.55 (m, 2H), 3.40 (m, 1H), 2.78 (t, 2H), 1.75 (m, 5H),

1,40 (m, 6H), 0,90 (m, 2H).1.40 (m, 6H); 0.90 (m, 2H).

Príklad 164Example 164

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-Y-(2, 4-dichlórfenetyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-Y- (2,4-dichloro-phenethyl) -2-hydroxy-butanamide hydrochloride

Produkt z príkladu 23A a 2,4-dichlórfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,4-dichlorophenethylamine were processed according to the method of Example 101 to give the title compound.

···· · ·· · ·· • ·· · · ·· · · · • · · · · · ····· · ·· · ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

126 ·· ··· ·· ··· ·· ···126 ·· ··· ·· ··· ·· ···

MS (APCI) m/e 373 (M+H)+;MS (APCI) m / e 373 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,45 (d, 1H), 7,30 (m, 2H), 4,00 (d, 1H), 3,60 (m, 2H), 3,45 (m, 2H), 3,00 (m, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.45 (d, 1H), 7.30 (m, 2H), 4.00 (d, 1H), 3.60 (m, 2H), 3 45 (m, 2H), 3.00 (m, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 165Example 165

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(2, 6-dichlórfenetyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl- N - (2,6-dichlorophenethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2,6-dichlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,6-dichloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 373 (M+H)+, ’H NMR (300 MHz, MeOH-d4) δ 7,38 (d, 2H), 7,20 (t, 1H), 4,10 (d, 1H), 3,60 (m, 3H), 3,40 (m, 1H), 3,25(m, 2H), l,75(m, 7H), 1,45 (m, 2H), 1,30 (m, 2H), 1,00 (m, 2H).MS (APCI) m / e 373 (M + H) + , 1 H NMR (300 MHz, MeOH-d 4 ) δ 7.38 (d, 2H), 7.20 (t, 1H), 4.10 ( d, 1H), 3.60 (m, 3H), 3.40 (m, 1H), 3.25 (m, 2H), 1.75 (m, 7H), 1.45 (m, 2H), 1.30 (m, 2H); 1.00 (m, 2H).

Príklad 166Example 166

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(3-fluórfenetyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl- N - (3-fluorophenethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-fluórfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-fluorophenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 323 (M+H)+;MS (APCI) m / e 323 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,30 (m, 1H), 7,00 (m, 3H), 4,10 (d, 1H), 3,65 (m, 1H), 3,58 (m, 2H), 3,40 (m, 1H), 2,85 (t, 2H), 1,75 (m, 5H), 1,60 (m, 2H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.30 (m, 1H), 7.00 (m, 3H), 4.10 (d, 1H), 3.65 (m, 1H), 3 58 (m, 2H); 3.40 (m, 1H); 2.85 (t, 2H); 1.75 (m, 5H); 1.60 (m, 2H);

1,45 (m, 2H), 1,28 (m, 2H), 0,95 (m, 2H).1.45 (m, 2H), 1.28 (m, 2H), 0.95 (m, 2H).

127 • · · ·· · · · • φ · ··· ·· ··· ·· ·127 · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 167Example 167

Hydrochlorid (2RS,3R)-3-amino-W-(3,4-bis(benzyloxy)fenetyl)-4-cyklohexyl-2hydroxybutánamidu(2RS, 3R) -3-Amino- N - (3,4-bis (benzyloxy) phenethyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3,4-dibenzyloxyfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4-dibenzyloxyphenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 517 (M+H)+;MS (APCI) m / e 517 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,45 (t, 5H), 7,35 (m, 5H), 6,95 (m, 2H), 8,78 (d, 1H), 5,10 (d, 4H), 4,10 (d, 1H), 3,65 (m, 1H), 3,55 (m, 2H), 3,40 (m, 1H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.45 (t, 5H), 7.35 (m, 5H), 6.95 (m, 2H), 8.78 (d, 1H), δ 10 (d, 4H), 4.10 (d, 1 H), 3.65 (m, 1 H), 3.55 (m, 2 H), 3.40 (m, 1 H),

2,75 (m, 2H), 1,75 (m, 5H), 1,60 (m, 2H), 1,40 (m, 4H), 0,90 (m, 2H).2.75 (m, 2H), 1.75 (m, 5H), 1.60 (m, 2H), 1.40 (m, 4H), 0.90 (m, 2H).

Príklad 168Example 168

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-A/-(4-fenoxyfenetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4-phenoxyphenethyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-fenoxyfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-phenoxyphenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 397 (M+H)+;MS (APCI) m / e 397 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,35 (t, 2H), 7,25 (d, 2H), 7,08 (t, 1H), 6,95 (t, 4H), 4,12 (d, 1H), 3,65 (m, 4H), 2,85 (m, 2H), 1,75 (m, 5H), 1,50 (m, 6H), 0,95 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.35 (t, 2H), 7.25 (d, 2H), 7.08 (t, 1H), 6.95 (t, 4H), 4 12 (d, 1H); 3.65 (m, 4H); 2.85 (m, 2H); 1.75 (m, 5H); 1.50 (m, 6H); 0.95 (m, 2H).

Príklad 169Example 169

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-(trifluórmetoxy)fenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2- (trifluoromethoxy) phenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-(trifluórmetoxy)anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2- (trifluoromethoxy) aniline were processed according to the method of Example 101 to give the title compound.

128 ···· · ·· · · • ·· · · ·· · · · • · · · · · · • · · · · · · · • · · ··· ·· ·· ··· ·· ··· ·128 ···· ······················· ··· ·

MS (APCI) m/e 361 (M+H)+;MS (APCI) m / e 361 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,34 (dd, 1H), 7,38 (dt, 2H), 7,26 (dt, 1H), 4,39 (d, 1H), 3,78 (m, 1H), 0,94-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.34 (dd, 1H), 7.38 (dt, 2H), 7.26 (dt, 1H), 4.39 (d, 1H), 3, 78 (m, 1H), 0.94-1.86 (m, 13H).

Príklad 170Example 170

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(3-(trifluórmetoxy)fenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3- (trifluoromethoxy) phenyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-(trifluórmetoxy)anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3- (trifluoromethoxy) aniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 361 (M+H)+;MS (APCI) m / e 361 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,85(s, 1H), 7,57 (qd, 1H), 7,43 (t, 1H), 7,05(td, 1H), 4,33 (d, 1H), 3,76 (m, 1H), 0,91-1,87 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.85 (s, 1H), 7.57 (qd, 1H), 7.43 (t, 1H), 7.05 (td, 1H), 4, 33 (d, 1H), 3.76 (m, 1H), 0.91-1.87 (m, 13H).

Príklad 171Example 171

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(2-metylfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (2-methylphenyl) butanamide hydrochloride

Produkt z príkladu 23A a o-anizidín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and o-anisidine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 291 (M+H)+;MS (APCI) m / e 291 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,68 (dd, 1H), 7,22 (dq, 2H), 7,13 (dq, 1H), 4, (d, 1H), 3,74 (m, 1H), 2,30 (s, 3H), 0,94-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.68 (dd, 1H), 7.22 (dq, 2H), 7.13 (dq, 1H), 4, (d, 1H), 3.74 (m, 1H), 2.30 (s, 3H), 0.94-1.88 (m, 13H).

129 ···· · • ·· • · • · • · · ·· ··· ·· · ·· • · ·· · • · · · · • · · · · ·· ··· ··129 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 172Example 172

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(2,6-dimetylfenyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,6-dimethyl-phenyl) -2-hydroxy-butanamide hydrochloride

Produkt z príkladu 23A a 2,6-dimetylanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,6-dimethylaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 3O5(M+H)+;MS (APCI) m / e 30 (M + H) &lt; + &gt;;

'H NMR (300MHz, MeOH-d4) δ 7,14 (s, 3H), 4,38 (d, 1H), 3,61 (m, 1H), 2,24 (s, 6H), 0,89-1,89 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.14 (s, 3H), 4.38 (d, 1H), 3.61 (m, 1H), 2.24 (s, 6H), 0, 89-1.89 (m, 13H).

Príklad 173Example 173

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-V-(4-jód-2-metylfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4-iodo-2-methylphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metyl-4-jódanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methyl-4-iodoaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 416 (M)+;MS (APCI) m / e 416 (M) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,16 (d, 1H), 7,47 (dd, 1H), 7,03 (d, 1H), 4,38 (d, 1H), 3,74 (m, 1H), 2,25 (s, 3H), 0,91-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.16 (d, 1H), 7.47 (dd, 1H), 7.03 (d, 1H), 4.38 (d, 1H), 3, 74 (m, 1H); 2.25 (s, 3H); 0.91-1.86 (m, 13H).

Príklad 174Example 174

Hydrochlorid (2RS,3R)-3-amino-/V-(4-anilíno-2-metoxyfenyl)-4-cyklohexyl-2hydroxybutánamidu(2RS, 3R) -3-Amino- N - (4-anilino-2-methoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a l-amino-2-metoxy-4-(JV-fenylamino)benzén sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-amino-2-methoxy-4- (N-phenylamino) benzene were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 398 (M+H)+;MS (APCI) m / e 398 (M + H) &lt; + &gt;;

130 'H NMR (3ΟΟΜΗζ, MeOH-d4) δ 8,05 (d, 1H), 7,24 (t, 2H), 7,10 (d, 2H), 6,88 (m, 1H), 6,78 (d, 1H), 6,70 (dd, 1H), 4,32 (d, 1H), 3,76 (s, 3H), 3,74 (m, 1H),130 1 H NMR (3 H, MeOH-d 4 ) δ 8.05 (d, 1H), 7.24 (t, 2H), 7.10 (d, 2H), 6.88 (m, 1H), 6 78 (d, 1H), 6.70 (dd, 1H), 4.32 (d, 1H), 3.76 (s, 3H), 3.74 (m, 1H),

0,85-1,89 (m, 13H).0.85-1.89 (m, 13H).

···· · ·· • ·· · · ····· · ·· · ·· ·

Príklad 175Example 175

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-A-(2-etoxyfenyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2-ethoxyphenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2-etyoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-ethyoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 321 (M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 8,30 (dd, 1H), 7,09 (dt, 1H), 7,03 (t, 1H), 6,93 (dt, 1H), 4,34 (d, 1H), 4,14 (q, 2H), 3,79 (m, 1H), 1,45 (t, 3H), 0,92-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.30 (dd, 1H), 7.09 (dt, 1H), 7.03 (t, 1H), 6.93 (dt, 1H), 4, 34 (d, 1H), 4.14 (q, 2H), 3.79 (m, 1H), 1.45 (t, 3H), 0.92-1.88 (m, 13H).

Príklad 176Example 176

Hydrochlorid (2RS,3R)-3-amino-7V-(4-chlór-2-metoxy-5-metylfenyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (4-chloro-2-methoxy-5-methylphenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2-metoxy-4-chlór-5-toluidín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxy-4-chloro-5-toluidine were treated according to the method of Example 101 to give the title compound.

MS (APCI) m/e 355 (M+H)+;MS (APCI) m / e 355 (M + H) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 8,24 (s, 1H), 7,05 (s, 1H), 4,34 (d, 1H), 3,89 (s, 3H), 3,78 (m, 1H), 2,30 (s, 3H), 0,94-1,89 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.24 (s, 1H), 7.05 (s, 1H), 4.34 (d, 1H), 3.89 (s, 3H), 3, 78 (m, 1H), 2.30 (s, 3H), 0.94-1.89 (m, 13H).

131131

Príklad 177Example 177

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-Aľ-(2,5-dimetoxyfenyl)-2-hydroxybutánamidu(2RS, 3R) -3-amino-4-cyclohexyl-I '- (2,5-dimethoxyphenyl) -2-hydroxybutanamide

Produkt z príkladu 23A a 2,5-dimetoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,5-dimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 337 (M+H)+;MS (APCI) m / e 337 (M + H) &lt; + &gt;;

'H NMR (300MHz, MeOH-d4) δ 8,00 (d, 1H), 6,95 (d, 1H), 6,67 (dd, 1H), 4,34 (d, 1H), 3,86 (s, 3H), 3,79 (m, 1H), 3,75 (s, 3H), 0,94-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.00 (d, 1H), 6.95 (d, 1H), 6.67 (dd, 1H), 4.34 (d, 1H), 3, 86 (s, 3H), 3.79 (m, 1H), 3.75 (s, 3H), 0.94-1.86 (m, 13H).

Príklad 178Example 178

Hydrochlorid (2RS,3R)-/V-(5-(acetylamino)-2-metoxyfenyl)-3-amino-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) - N - (5- (Acetylamino) -2-methoxyphenyl) -3-amino-4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a l-amino-2-metoxy-4-(JV-acetylamino)benzén sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-amino-2-methoxy-4- (N-acetylamino) benzene were processed according to the method of Example 101 to give the title compound.

’H NMR (300MHz, MeOH-d4) δ 8,00 (d, 1H), 7,54 (d, 1H), 7,44 (dt, 1H), 7,42 (td, 1H), 4,48 (d, 1H), 4,41 (d, 1H), 4,06 (s, 3H), 3,83 (m, 1H), 3,15 (s, 3H), 0,89-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.00 (d, 1H), 7.54 (d, 1H), 7.44 (dt, 1H), 7.42 (td, 1H), 4, 48 (d, 1H), 4.41 (d, 1H), 4.06 (s, 3H), 3.83 (m, 1H), 3.15 (s, 3H), 0.89-1.88 (m, 13H).

Príklad 179Example 179

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-A-(2-metoxydibenzo(b,d)furan-3-yl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (2-methoxydibenzo (b, d) furan-3-yl) butanamide hydrochloride

Produkt z príkladu 23A a 3-amino-2-metoxydibenzofurán sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-amino-2-methoxydibenzofuran were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 397 (M+H)+;MS (APCI) m / e 397 (M + H) &lt; + &gt;;

········

132 ’H NMR (300MHz, MeOH-d4) δ 8,67 (s, 1H), 7,98 (qd, 1H), 7,69 (s, 1H), 7,54 (q, 1H), 7,43 (qd, 1H), 7,43 (dt, 1H), 4,41 (d, 1H), 4,06 (s, 3H), 3,84 (m, 1H),132 1 H NMR (300MHz, MeOH-d 4 ) δ 8.67 (s, 1H), 7.98 (qd, 1H), 7.69 (s, 1H), 7.54 (q, 1H), 7 43 (qd, 1H), 7.43 (dt, 1H), 4.41 (d, 1H), 4.06 (s, 3H), 3.84 (m, 1H),

0,98-1,90 (m, 13H).0.98-1.90 (m, 13H).

• ·· ·· · · • · · • · · ·· · · · • · · • · · ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 180Example 180

Hydrochlorid (2RS,3R)-3-amino-/V-(5-chlór-2,4-dimetoxyfenyl)-4-cyklohexyl2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (5-chloro-2,4-dimethoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2,4-dimetoxy-5-chlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,4-dimethoxy-5-chloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 371 (M+H)+;MS (APCI) m / e 371 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,29 (s, 1H), 6,80 (s, 1H), 4,33 (d, 1H), 3,95 (s, 3H), 3,90 (s, 3H), 3,74 (m, 1H), 0,82-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.29 (s, 1H), 6.80 (s, 1H), 4.33 (d, 1H), 3.95 (s, 3H), 3, 90 (s, 3H), 3.74 (m, 1H), 0.82-1.88 (m, 13H).

Príklad 181Example 181

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyi-/V-(2,5-dietoxyfenyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,5-diethoxy-phenyl) -2-hydroxy-butanamide hydrochloride

Produkt z príkladu 23A a 2,5-dietoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,5-diethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 365 (M+H)+;MS (APCI) m / e 365 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,00 (d, 1H), 6,92 (d, 1H), 6,63 (dd, 1H), 4,34 (d, 1H), 4,09 (q, 2H), 4,01 (q, 2H), 3,81 (m, 1H), 1,42 (t, 3H), 1,36 (t, 3H),1 H NMR (300MHz, MeOH-d 4 ) δ 8.00 (d, 1H), 6.92 (d, 1H), 6.63 (dd, 1H), 4.34 (d, 1H), 4, 09 (q, 2H), 4.01 (q, 2H), 3.81 (m, 1H), 1.42 (t, 3H), 1.36 (t, 3H),

0,93-1,89 (m, 13H).0.93-1.89 (m, 13H).

········

133 • ·· · · · • · · · • · · · · • · · · ·· ··· ·· · • · ·· ·133 · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 182Example 182

Hydrochlorid (2RS,3R)-3-amino-JV-(5-(/erc-butyl)-2-metoxyfenyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (5- (tert -butyl) -2-methoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 32-metoxy-5-ŕerc-butylanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 32-methoxy-5-tert-butylaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 363 (M+H)+;MS (APCI) m / e 363 (M + H) &lt; + &gt;;

'H NMR (300MHz, MeOH-d4) δ 8,42 (d, 1H), 7,15 (dd, 1H), 6,95 (d, 1H), 4,34 (d, 1H), 3,89 (s, 3H), 3,76 (m, 1H), 1,30 (s, 9H), 0,93-1,89 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.42 (d, 1H), 7.15 (dd, 1H), 6.95 (d, 1H), 4.34 (d, 1H), 3, 89 (s, 3H), 3.76 (m, 1H), 1.30 (s, 9H), 0.93-1.89 (m, 13H).

Príklad 183Example 183

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-fenoxyfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2-phenoxyphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-fenoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-phenoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 369 (M+H)+;MS (APCI) m / e 369 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 8,35 (dd, 1H), 7,37 (m, 2H), 7,14 (m, 3H), 7,02 (m, 2H), 6,92 (d, 1H), 4,31 (d, 1H), 3,71 (m, 1H), 0,89-1,81 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.35 (dd, 1H), 7.37 (m, 2H), 7.14 (m, 3H), 7.02 (m, 2H), 6, 92 (d, 1H), 4.31 (d, 1H), 3.71 (m, 1H), 0.89-1.81 (m, 13H).

Príklad 184Example 184

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-metyl-5-nitrofenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2-methyl-5-nitrophenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metyl-5-nitroanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methyl-5-nitroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 336 (M+H)+;MS (APCI) m / e 336 (M + H) &lt; + &gt;;

·· · ·· • · ·· · · · • · · · · ····························

134 'H NMR (300MHz, MeOH-d4) δ 8,77 (d, 1H), 8,00 (dd, 1H), 7,50 (d, 1H), 4,44 (d, 1H), 3,79 (m, 1H), 3,19 (d, 1H), 3,06 (d, 1H), 2,42 (s, 3H), 0,82-1,88 (m,134 1 H NMR (300MHz, MeOH-d 4 ) δ 8.77 (d, 1H), 8.00 (dd, 1H), 7.50 (d, 1H), 4.44 (d, 1H), 3 79 (m, 1H), 3.19 (d, 1H), 3.06 (d, 1H), 2.42 (s, 3H), 0.82-1.88 (m,

13H).13H).

• · · · · • ·· ··· ·· *• · · · · ·

Príklad 185Example 185

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(4-fenoxyfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (4-phenoxyphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-fenoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-phenoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 369 (M+H)+;MS (APCI) m / e 369 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,63 (d, 2H), 7,34 (t, 2H), 7,09 (t, 1H), 6,96 (d, 3H), 4,20 (d, 1H), 3,58 (m, 1H), 0,93-1,91 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.63 (d, 2H), 7.34 (t, 2H), 7.09 (t, 1H), 6.96 (d, 3H), 4, 20 (d, 1H), 3.58 (m, 1H), 0.93-1.91 (m, 13H).

Príklad 186Example 186

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-N-(4-metoxybenzyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (4-methoxybenzyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-metoxybenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-methoxybenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 321 (M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) Ô 7,25 (d, 2H), 6,87 (d, 2H), 4,35 (q, 2H), 4,15 (d, 1H), 3,77 (s, 3H), 3,57 (m, 1H), 0,85-1,78 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.25 (d, 2H), 6.87 (d, 2H), 4.35 (q, 2H), 4.15 (d, 1H), 3, 77 (s, 3H), 3.57 (m, 1H), 0.85-1.78 (m, 13H).

Príklad 187Example 187

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7\/-(4-metylbenzyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-7H- (4-methylbenzyl) butanamide hydrochloride

135 ··«· • · • · • · • · · ·· ··· ·· • · ·· ·· • · · • · • · • · ·· ·135 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Produkt z príkladu 23A a 4-metylbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-methylbenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 305 (M+H)+;MS (APCI) m / e 305 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,20 (d, 2H), 7,12 (d, 2H), 4,38 (q, 2H), 4,11 (d, 1H), 3,53 (m, 1H), 2,30 (s, 3H), 0,86-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.20 (d, 2H), 7.12 (d, 2H), 4.38 (q, 2H), 4.11 (d, 1H), 3, 53 (m, 1H), 2.30 (s, 3H), 0.86-1.80 (m, 13H).

Príklad 188Example 188

Hydrochlorid (2RS,3R)-3-amino-/V-(3-chlórbenzyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (3-chlorobenzyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-chlórbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-chlorobenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 325 (M+H)+;MS (APCI) m / e 325 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,34 (s, 1H), 7,26 (m, 3H), 4,41 (q, 2H), 4,17 (d, 1H), 3,55 (m, 1H), 0,87-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.34 (s, 1H), 7.26 (m, 3H), 4.41 (q, 2H), 4.17 (d, 1H), 3, 55 (m, 1H); 0.87-1.80 (m, 13H).

Príklad 189Example 189

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-A/-(3-metoxybenzy l)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-methoxybenzyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-metoxybenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methoxybenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 321 (M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,22 (t, 1H), 6,88 (m, 2H), 6,80 (m, 1H), 4,38 (q, 2H), 3,99 (d, 1H), 3,77 (s, 3H), 0,82-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.22 (t, 1H), 6.88 (m, 2H), 6.80 (m, 1H), 4.38 (q, 2H), 3, 99 (d, 1H), 3.77 (s, 3H), 0.82-1.80 (m, 13H).

136136

···· • • ···· • • • • · • • • · • ·· • · • · · · • · • · • ·· • • · · • ·· • • · · • • • · • • · • • · ·· • · ·· • ··· • · · · • · ·· • · ·· • ··· • · · · • ·· • · · • • • •

Príklad 190Example 190

Hydrochlorid (2RS,3R)-3-amino-7\/-(4-brómbenzyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino-N- (4-bromobenzyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 4-brómbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-bromobenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 371 (M+H)+;MS (APCI) m / e 371 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,40 (d, 2H), 7,25 (d, 2H), 4,45 (d, 1H), 4,37 (d, 1H), 4,02 (d, 1H), 3,35(m, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.40 (d, 2H), 7.25 (d, 2H), 4.45 (d, 1H), 4.37 (d, 1H), 4 0.02 (d, 1H), 3.35 (m, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 191Example 191

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3-metylbenzyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (3-methylbenzyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-metylbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methylbenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 305 (M+H)+;MS (APCI) m / e 305 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,25(m, 4H), 4,90 (d, 1H), 4,30 (d, 1H), 4,12 (d, 1H), 3,55 (m, 2H), 2,35 (s, 3H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.25 (m, 4H), 4.90 (d, 1H), 4.30 (d, 1H), 4.12 (d, 1H), 3 55 (m, 2H), 2.35 (s, 3H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 192Example 192

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-fenetylbutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N-phenethylbutanamide hydrochloride

Produkt z príkladu 23A a fenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and phenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 3O5(M+H)+;MS (APCI) m / e 30 (M + H) &lt; + &gt;;

137 ···· · ·· • ·· · · · • · · · ·· • · · • · · ··· ·· ··· ·· ··· ’H NMR (300 MHz, MeOH-d4) δ 7,25(m, 5H), 4,00 (d, 1H), 3,50 (m, 4H), 2,85 (t, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).137 1 H NMR (300 MHz, MeOH-d 4) ______________________________________ NMR NMR NMR NMR 1 H NMR (300 MHz, MeOH-d 4) δ 7.25 (m, 5H), 4.00 (d, 1H), 3.50 (m, 4H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 193Example 193

Hydrochlorid (2RS,3R)-3-amino-A/-(4-chlórbenzyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (4-chlorobenzyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 4-chlórbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-chlorobenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 325(M+H)+;MS (APCI) m / e 325 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,32 (s, 4H), 4,40 (q, 2H), 4,18 (d, 1H), 3,59 (m, 1H), 0,87-1,80 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.32 (s, 4H), 4.40 (q, 2H), 4.18 (d, 1H), 3.59 (m, 1H), O, 87-1.80 (m, 13H).

Príklad 194Example 194

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(4-metylfenetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (4-methylphenethyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-metylfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methylphenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 319 (M+H)+;MS (APCI) m / e 319 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,10 (s, 4H), 4,05 (d, 1H), 3,50 (m, 4H), 2,80 (t, 2H), 2,30 (s, 3H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.10 (s, 4H), 4.05 (d, 1H), 3.50 (m, 4H), 2.80 (t, 2H), 2 30 (s, 3H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 195Example 195

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(4-metoxy-fenetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-Y- (4-methoxy-phenethyl) butanamide hydrochloride

138 ··*· · ·· • ·· · · • · · · ·· · · · • · · • · · · · ·· ··· ·· • · · · ··· ·· ···138 · · 138 · ·

Produkt z príkladu 23A a 4-metoxyfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-methoxyphenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 335(M+H), 669 (2M+H)+;MS (APCI) m / e 335 (M + H), 669 (2M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,15 (d, 2H), 6,80 (d, 2H), 4,05 (d, 1H), 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).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.15 (d, 2H), 6.80 (d, 2H), 4.05 (d, 1H), 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).

Príklad 196Example 196

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/\/-(3-metoxyfenetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-methoxyphenethyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-metoxy fenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methoxy-phenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 335(M+H)+;MS (APCI) m / e 335 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,15 (d, 2H), 6,85 (d, 2H), 4,05 (d, 1H), 3,75 (d, 3H), 3,45 (m, 4H), 2,78 (t, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.15 (d, 2H), 6.85 (d, 2H), 4.05 (d, 1H), 3.75 (d, 3H), 3 45 (m, 4H), 2.78 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 197Example 197

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-?/-(2-metoxyfenetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (2-methoxyphenethyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metoxyfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxyphenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 335(M+H)+;MS (APCI) m / e 335 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,19 (m, 2H), 6,90 (m, 2H), 4,05 (d, 1H), 3,85 (s, 3H), 3,45 (m, 4H), 2,85 (t, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.19 (m, 2H), 6.90 (m, 2H), 4.05 (d, 1H), 3.85 (s, 3H), 3 45 (m, 4H), 2.85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

········

139 • ·· · · ·· • · · · · • · · · · · • · · · · · ·· ··· ·· ··· ·· • · · • · • · ·· ·139 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 198Example 198

Hydrochlorid (2RS,3R)-3-amino-A/-(4-chlórfenetyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (4-chlorophenethyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 4-chlórfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-chlorophenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 339 (M+H)+;MS (APCI) m / e 339 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 7,25 (m, 4H), 3,92 (d, 1H), 3,48 (m, 4H), 2,82 (t, 2H), 1,71 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.25 (m, 4H), 3.92 (d, 1H), 3.48 (m, 4H), 2.82 (t, 2H), 1 71 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 199Example 199

Hydrochlorid (2RS,3R)-3-amino-/V-(3-chlórfenetyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (3-chlorophenethyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-chlórfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-chlorophenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 339 (M+H)+;MS (APCI) m / e 339 (M + H) &lt; + &gt;;

*H NMR (300 MHz, MeOH-d4) δ 7,25 (m, 4H), 4,05 (d, 1H), 3,55 (m, 2H), 3,45 (m, 2H), 2,85 (t, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.25 (m, 4H), 4.05 (d, 1H), 3.55 (m, 2H), 3.45 (m, 2H), 2 85 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 200Example 200

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3-(trifluórmetyl) fenetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (3- (trifluoromethyl) phenethyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-trifluórmetylfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-trifluoromethylphenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 373 (M+H)+;MS (APCI) m / e 373 (M + H) &lt; + &gt;;

···· ·· ····· ·· ·

140 • · · ·· ·· ·· • · • · ·· · *Η 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).140 Η NMR (300 MHz, MeOH-d 4 ) δ 7.55 (m, 4H), 4.05 (d, 1H), 3, Δ (m, 2H), 3.45 (m, 2H), 2.95 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H) ).

Príklad 201Example 201

Hydrochlorid (2RS,3R)-3-amino-AÍ-(4-bromfenetyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino-N- (4-bromophenethyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 4-brómfenetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-bromophenethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 385(M+H)+;MS (APCI) m / e 385 (M + H) &lt; + &gt;;

’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).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.41 (d, 2H), 7.16 (d, 2H), 3.90 (d, 1H), 3.50 (m, 4H), 2 80 (t, 2H), 1.70 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 202Example 202

Hydrochlorid (2RS,3R)-/V-(l-adamantyl)-3-amino-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) - N - (1-Adamantyl) -3-amino-4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 1 -adamantanamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina,The product of Example 23A and 1-adamantanamine were processed according to the method of Example 101 to give the title compound, m.p.

MS (APCI) m/e 335(M+H)+;MS (APCI) m / e 335 (M + H) &lt; + &gt;;

’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).1 H NMR (300 MHz, MeOH-d 4) δ 3.95 (d, 1H), 3.45 (m, 2H), 2.09 (s, 10H), 1.75 (s, 10H), 1, 40 (m, 6H), 0.90 (m, 2H).

Príklad 203Example 203

Hydrochlorid (2RS,3R)-/V-(2-adamantyl)-3-amino-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) - N - (2-Adamantyl) -3-amino-4-cyclohexyl-2-hydroxybutanamide hydrochloride

141 ··«· • ·140 ·· «· • ·

Produkt z príkladu 23A a 2-adamantamin sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-adamantamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 335(M+H)+;MS (APCI) m / e 335 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 4,15 (d, 1H), 4,00 (s, 1H), 3,55 (m, 2H), 1,80 (m, 19H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.15 (d, 1H), 4.00 (s, 1H), 3.55 (m, 2H), 1.80 (m, 19H), 1 40 (m, 6H), 0.90 (m, 2H).

Príklad 204Example 204

Hydrochlorid (2RS, 3 R)-3-amino-/V-cy kloheptyl-4-cy klohexy 1-2-hy droxybutánamidu(2RS, 3R) -3-Amino- N -cycloheptyl-4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a cykloheptylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and cycloheptylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 297 (M+H)+;MS (APCI) m / e 297 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 4,00 (d, 1H), 3,90 (m, 1H), 3,41 (m, 2H), 1,50 (m, 23H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.00 (d, 1H), 3.90 (m, 1H), 3.41 (m, 2H), 1.50 (m, 23H), 0 90 (m, 2H).

Príklad 205Example 205

Hydrochlorid (2RS, 3 R)-3-am ino-4-cy klohexy l-/V-(cyklohexy 1 mety l)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (cyclohexylmethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a cyklohexylmetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and cyclohexylmethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 297 (M+H)+;MS (APCI) m / e 297 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 4,02 (d, 1H), 3,40 (m, 2H), 3,15 (m, 1H), 3,00 (m, 1H), 1,50 (m, 24H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.02 (d, 1H), 3.40 (m, 2H), 3.15 (m, 1H), 3.00 (m, 1H), 1 50 (m, 24H).

········

142 ·· • ·· · · • · · !142 ·· · ·· ·!

• · · · · • · · · ·· ··· ·· ·» · · • · · • · · · • · · ··· ·· • · ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 206Example 206

Hydrochlorid (2RS,3R)-3-amino-N,4-dicyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino-N, 4-dicyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a cyklohexylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and cyclohexylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 283 (M+H)+;MS (APCI) m / e 283 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 4,05 (d, 1H), 3,70 (m, 1H), 3,45 (m, 2H), 1,50 (m, 21H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.05 (d, 1H), 3.70 (m, 1H), 3.45 (m, 2H), 1.50 (m, 21H), 0 90 (m, 2H).

Príklad 207Example 207

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-AT-cyklopentyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N-cyclopentyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a cyklopentylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and cyclopentylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 269 (M+H)+;MS (APCI) m / e 269 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 4,15 (m, 1H), 3,95 (d, 1H), 3,35 (m, 2H), 1,50 (m, 19H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.15 (m, 1H), 3.95 (d, 1H), 3.35 (m, 2H), 1.50 (m, 19H), 0 90 (m, 2H).

Príklad 208Example 208

Hydrochlorid (2RS,3R)-3-amino-/\/-cyklobutyl-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N -cyclobutyl-4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a cyklobutylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and cyclobutylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 255(M+H)+;MS (APCI) m / e 255 (M + H) &lt; + &gt;;

···· • · · · · :::···· · · · ·

• ···· · · · · j• ···· · · · · j

*..* ··· *··* ··· ·· ···* .. * ··· * ·· * ··· ·· ···

143 ’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).143 1 H NMR (300 MHz, MeOH-d 4 ) δ 4.35 (m, 1H), 4.00 (d, 1H), 3.45 (m, 1H), 2.30 (m, 2H), 2.05 (m, 2H), 1.75 (m, 7H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 209Example 209

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(l-metyl-3-fenylpropyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-Y- (1-methyl-3-phenylpropyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-fenyl-2-aminopropán sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-phenyl-2-aminopropane were treated according to the method of Example 101 to give the title compound.

MS (ESI) m/e 333 (M+H)+;MS (ESI) mlz 333 (M + H) + ;

’H 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 H NMR (300 MHz, MeOH-d 4 ) δ 7.40 (m, 5H), 4.10 (d, 1H), 3.90 (m, 1H), 3.75 (m, 1H), 3 68 (m, 1H), 3.55 (m, 2H), 2.65 (m, 2H), 1.75 (m, 7H), 1.45 (m, 2H),

1,20 (m, 5H), 0,90 (m, 2H).1.20 (m, 5H), 0.90 (m, 2H).

Príklad 210Example 210

Hydrochlorid (2RS, 3 R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(l-mety 1-2-(3(trifluórmetyl)fenyl)etyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-Y- (1-methyl-2- (3 (trifluoromethyl) phenyl) ethyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-(3-trifluórmetylfenyl)-2-aminopropán sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3- (3-trifluoromethylphenyl) -2-aminopropane were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 387 (M+H)+;MS (APCI) m / e 387 (M + H) &lt; + &gt;;

’H 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), l,75(m, 5H), 1,30 (m, 9H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.50 (m, 4H), 4.25 (m, 2H), 4.10 (d, 1H), 4.00 (d, 1H), 3 50 (m, 2H), 3.00 (m, 1H), 2.90 (m, 2H), 1.75 (m, 5H), 1.30 (m, 9H), 0.90 (m, 2H) 2H).

········

144144

Príklad 211Example 211

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-JV-(l,5-dimetylhexyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (1,5-dimethylhexyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 1,5-dimetylhexylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1,5-dimethylhexylamine were treated according to the method of Example 101 to give the title compound.

MS (ESI) m/e 313 (M+H)+;MS (ESI) mlz 313 (M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 4,10 (m, 1H), 3,95 (m, 1H), 3,55 (m, 2H),1 H NMR (300 MHz, MeOH-d 4 ) δ 4.10 (m, 1H), 3.95 (m, 1H), 3.55 (m, 2H),

1,75 (m, 7H), 1,25 (m, 7H), 1,00 (m, 2H), 0,80 (m, 6H).1.75 (m, 7H), 1.25 (m, 7H), 1.00 (m, 2H), 0.80 (m, 6H).

Príklad 212Example 212

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(l-metylhexyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (1-methylhexyl) butanamide hydrochloride

Produkt z príkladu 23A a 1-metylhexylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-methylhexylamine were treated according to the method of Example 101 to give the title compound.

MS (ESI) m/e 299 (M+H)+;MS (ESI) mlz 299 (M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 4,10 (d, 1H), 3,95 (m, 1H), 3,55 (m, 2H), 1,75 (m, 8H), 1,45 (m, 2H), 1,35 (m, 8H), 1,15 (m, 4H), 0,80 (m, 5H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.10 (d, 1H), 3.95 (m, 1H), 3.55 (m, 2H), 1.75 (m, 8H), 1 45 (m, 2H), 1.35 (m, 8H), 1.15 (m, 4H), 0.80 (m, 5H).

Príklad 213Example 213

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(3-izopropoxypropyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-isopropoxypropyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-izopropoxypropylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-isopropoxypropylamine were processed according to the method of Example 101 to give the title compound.

MS (ESI) m/e 301 (M+H)+;MS (ESI) mlz 301 (M + H) + ;

145 ’H NMR (300 MHz, MeOH-d4) δ 4,15 (d, 1H), 3,60 (m, 2H), 3,55 (m, 4H), 1,75 (m, 6H), 1,40 (m, 8H), 1,15 (d, 6H), 1,00 (m, 2H).145 1 H NMR (300 MHz, MeOH-d 4 ) δ 4.15 (d, 1H), 3.60 (m, 2H), 3.55 (m, 4H), 1.75 (m, 6H), 1.40 (m, 8H), 1.15 (d, 6H), 1.00 (m, 2H).

Príklad 214Example 214

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3-izobutoxypropyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (3-isobutoxypropyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-izobutoxypropylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-isobutoxypropylamine were processed according to the method of Example 101 to give the title compound.

MS (ESI) m/e 315(M+H)+;MS (ESI) mlz 315 (M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 4,15 (d, 1H), 3,62 (m, 1H), 3,50 (t, 2H), 3,40 (m, 1H), 3,20 (d, 2H), 1,80 (m, 9H), 1,45 (m, 2H), 1,30 (m, 3H), 0,90 (m, 10H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.15 (d, 1H), 3.62 (m, 1H), 3.50 (t, 2H), 3.40 (m, 1H), 3 20 (d, 2H), 1.80 (m, 9H), 1.45 (m, 2H), 1.30 (m, 3H), 0.90 (m, 10H).

Príklad 215Example 215

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-N-(4-(4-morfolinyl)fenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4- (4-morpholinyl) phenyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-morfolínanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-morpholinaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 362 (M+H)+;MS (APCI) m / e 362 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,85 (d, 2H), 7,60 (d, 2H), 4,32 (d, 1H), 4,05 (t, 4H), 3,75 (m, 2H), 3,65 (m, 2H), 3,58 (m, 4H), 1,50 (m, 11H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.85 (d, 2H), 7.60 (d, 2H), 4.32 (d, 1H), 4.05 (t, 4H), 3 75 (m, 2H), 3.65 (m, 2H), 3.58 (m, 4H), 1.50 (m, 11H), 1.00 (m, 2H).

Príklad 216Example 216

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(3,3-difenylpropyl)-2-hydroxybutánamidu ····(2RS, 3R) -3-Amino-4-cyclohexyl- N - (3,3-diphenylpropyl) -2-hydroxybutanamide hydrochloride ····

146146

Produkt z príkladu 23A a 3,3-difenylpropylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,3-diphenylpropylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 395(M+H)+;MS (APCI) m / e 395 (M + H) &lt; + &gt;;

'H NMR (300 MHz, MeOH-d4) δ 7,30 (m, 8H), 7,15 (m, 2H), 4,10 (d, 1H), 4,00 (t, 1H), 3,55 (m, 2H), 3,25 (m, 1H), 3,15 (m, 1H), 2,30 (q, 2H), 1,75 (m, 7H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.30 (m, 8H), 7.15 (m, 2H), 4.10 (d, 1H), 4.00 (t, 1H), 3 55 (m, 2H); 3.25 (m, 1H); 3.15 (m, 1H); 2.30 (q, 2H); 1.75 (m, 7H);

1,45 (m, 2H), 1,25 (m, 2H), 0,90 (m, 2H).1.45 (m, 2H), 1.25 (m, 2H), 0.90 (m, 2H).

Príklad 217Example 217

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(l,4-dimetylpentyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (1,4-dimethylpentyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 1,4-dimetylpentylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1,4-dimethylpentylamine were processed according to the method of Example 101 to give the title compound.

MS (ESI) m/e 299 (M+H)+;MS (ESI) mlz 299 (M + H) + ;

’H NMR (300 MHz, MeOH-d4) δ 4,10 (m, 1H), 3,80 (m, 1H), 3,55 (m, 1H),1 H NMR (300 MHz, MeOH-d 4 ) δ 4.10 (m, 1H), 3.80 (m, 1H), 3.55 (m, 1H),

1,75 (m, 6H), 1,50 (m, 5H), 1,20 (m, 8H), 0,90 (m, 8H).1.75 (m, 6H), 1.50 (m, 5H), 1.20 (m, 8H), 0.90 (m, 8H).

Príklad 218Example 218

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Á/-metyl-Á/-(l-nafty 1metyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N-methyl-N - (1-naphthylmethyl) butanamide hydrochloride

Produkt z príkladu 23A a /V-metyl-A/-(l-naftyl)metylamín sa spracovávajú podľa spôsobu z príkladu 24, čím sa získa požadovaná zlúčenina.The product of Example 23A and N-methyl-N- (1-naphthyl) methylamine were processed according to the method of Example 24 to give the title compound.

MS (ESI) m/e 355(M+H)+;MS (ESI) mlz 355 (M + H) + ;

’H NMR (300 MHz, DMSO-d6) ô 7,90 (m, 3H), 7,68 (d, 1H), 7,52 (m, 3H), 6,51 (m, 1H), 5,08 (dd, 1,2H), 4,96 (dd, 0,8H), 4,45 (m, 0,6H), 4,20 (m, 0,4H), 3,03 ····1 H NMR (300 MHz, DMSO-d 6 ) δ 7.90 (m, 3H), 7.68 (d, 1H), 7.52 (m, 3H), 6.51 (m, 1H), δ Δ 08 (dd, 1.2H), 4.96 (dd, 0.8H), 4.45 (m, 0.6H), 4.20 (m, 0.4H), 3.03 ····

147 (s, 1,8H), 2,98 (s, 1,2H), 1,80 (m, 1H), 1,63 (m, 3H), 1,43 (m, 2H), 1,31 (m, 2H), 1,17 (m, 4H), 0,81 (m, 2H);147 (s, 1.8H), 2.98 (s, 1.2H), 1.80 (m, 1H), 1.63 (m, 3H), 1.43 (m, 2H), 1.31 (m, 2H), 1.17 (m, 4H), 0.81 (m, 2H);

Analyticky vypočítané pre C22H3oN202S«HCl«0,5C2H80: C, 66,27; H, 8,11; N, 6,44. Zistené: C, 65,96; H, 7,82; N, 6,31.Anal. Calcd for C 22 H 30 N 2 O 2 S · HCl · 0.5C 2 H 8 O: C, 66.27; H, 8.11; N, 6.44. Found: C, 65.96; H, 7.82; N, 6.31.

Príklad 219Example 219

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Aľ-metyl-/V-((lS)-l(1 -naftyl)etyl)butánamidu(2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxy-N- methyl / V - ((S) -l (1-naphthyl) ethyl) butanamide

Produkt z príkladu 23A a (S)-N-metyl-Y-((lS)-l-(l-naftyl)etylamín sa spracovávajú podľa spôsobu z príkladu 24, čím sa získa požadovaná zlúčenina.The product of Example 23A and (S) -N-methyl-Y - ((1S) -1- (1-naphthyl) ethylamine) were processed according to the method of Example 24 to give the title compound.

MS (ESI) m/e 369 (M+H)+;MS (ESI) mlz 369 (M + H) + ;

’H NMR (300 MHz, DMSO-d6) δ 7,90 (m, 3H), 7,68 (d, 1H), 7,52 (m, 3H), 6,43 (m, 1H), 4,20 (t, 1H), 2,59 (s, 3H), 1,80 (m, 1H), 1,63 (m, 3H), 1,53 (d, 3H),1 H NMR (300 MHz, DMSO-d 6 ) δ 7.90 (m, 3H), 7.68 (d, 1H), 7.52 (m, 3H), 6.43 (m, 1H), 4 20 (t, 1H), 2.59 (s, 3H), 1.80 (m, 1H), 1.63 (m, 3H), 1.53 (d, 3H),

1,43 (m, 2H), 1,31 (m, 2H), 1,17 (m, 4H), 0,81 (m, 2H);1.43 (m, 2H), 1.31 (m, 2H), 1.17 (m, 4H), 0.81 (m, 2H);

Analyticky vypočítané pre C23H32N2O2S*HCl»0,75H2O: C, 66,01; H, 8,31; N, 6,69. Zistené: C, 66,25; H, 8,09; N, 6,31.Calcd for C2 3H3 2 N 2 O 2 S * HCl »0.75H 2 O: C, 66.01; H, 8.31; N, 6.69. Found: C, 66.25; H, 8.09; N, 6.31.

Príklad 220Example 220

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(2-metoxy-5trifluórmetyl)fenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-Y- (2-methoxy-5-trifluoromethyl) phenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metoxy-5-(trifluórmetoxy)anilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxy-5- (trifluoromethoxy) aniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 375 (M+H)+;MS (APCI) m / e 375 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,70 (d, 1H), 7,44 (dd, 1H), 7,20 (d, 1H), 4,35 (d, 1H), 4,00 (s, 3H), 3,72 (m, 1H), 0,92-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.70 (d, 1H), 7.44 (dd, 1H), 7.20 (d, 1H), 4.35 (d, 1H), 4, Δ O (s, 3H), 3.72 (m, 1H), 0.92-1.86 (m, 13H).

········

148148

Príklad 221Example 221

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Aľ-(4-metoxy (1,1 bifenyl)-3-yl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N ' - (4-methoxy (1,1-biphenyl) -3-yl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metoxy-5-fenylanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxy-5-phenylaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 383 (M+H)+;MS (APCI) m / e 383 (M + H) &lt; + &gt;;

*H NMR (300 MHz, MeOH-d4) δ 7,60 (d, 2H), 7,40 (t, 4H), 7,15 (m, 1H), 7,05 (d, 1H), 4,25 (d, 1H), 3,95 (s, 3H), 3,55 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.60 (d, 2H), 7.40 (t, 4H), 7.15 (m, 1H), 7.05 (d, 1H), 4 25 (d, 1H), 3.95 (s, 3H), 3.55 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.90 (m, 2H).

Príklad 222Example 222

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-JV-(23-dihydro-l,4-benzodioxin6-yl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (23-dihydro-1,4-benzodioxin-6-yl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3,4-etylénedioxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4-ethylenedioxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 335(M+H)+;MS (APCI) m / e 335 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,25 (s, 1H), 7,00 (d, 1H), 6,80 (d, 1H), 4,25 (m, 5H), 3,70 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.25 (s, 1H), 7.00 (d, 1H), 6.80 (d, 1H), 4.25 (m, 5H), 3 70 (m, 2H); 1.75 (m, 5H); 1.40 (m, 6H); 1.00 (m, 2H).

Príklad 223Example 223

Hydrochlorid (2RS,3R)-3-amino-A/-(3-(benzyloxy)fenyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (3- (benzyloxy) phenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-benzyloxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-benzyloxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 383 (M+H)+;MS (APCI) m / e 383 (M + H) &lt; + &gt;;

149 ’H NMR (300 MHz, MeOH-d4) δ 7,20 (m, 6H), 6,90 (d, 1H), 6,40 (m, 2H), 5,05 (d, 2H), 4,30 (d, 1H), 3,70 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), 1,00 (m, 2H).149 1 H NMR (300 MHz, MeOH-d 4 ) δ 7.20 (m, 6H), 6.90 (d, 1H), 6.40 (m, 2H), 5.05 (d, 2H), 4.30 (d, 1H), 3.70 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).

Príklad 224Example 224

Hydrochlorid (2RS, 3 R)-3-amino-4-cyklohexyl-/V-(3-etoxy fény l)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (3-ethoxyphenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-etoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-ethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 321 (M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,40 (d, 1H), 7,20 (m, 2H), 6,70 (d, 1H), 4,25 (d, 1H), 4,00 (q, 2H), 3,70 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), l,05(m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.40 (d, 1H), 7.20 (m, 2H), 6.70 (d, 1H), 4.25 (d, 1H), 4 1.00 (q, 2H), 3.70 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 1.05 (m, 2H).

Príklad 225Example 225

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(3,4,5-trimetoxyfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (3,4,5-trimethoxyphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 3,4,5-trimetoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4,5-trimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 367 (M+H)+;MS (APCI) m / e 367 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,10 (s, 2H), 4,30 (d, 1H), 3,80 (m, 11H), 1,80 (m, 5H), 1,50 (m, 2H), 1,30 (m, 4H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.10 (s, 2H), 4.30 (d, 1H), 3.80 (m, 11H), 1.80 (m, 5H), 1 50 (m, 2H); 1.30 (m, 4H); 1.00 (m, 2H).

Príklad 226Example 226

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-7V-(2-(2-fluórfenyl)-l-metyletyl)-2-hydroxybutánamidu ···· ·· · ·· · • · ·· · · ·· • · · · · · • · · · · · · • · · · · · ·· ··· ·· ··(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2- (2-fluorophenyl) -1-methylethyl) -2-hydroxybutanamide, hydrochloride ··· ··· ·······························

150150

Produkt z príkladu 23A a 3-(2-fluórfenyl)-2-aminopropán sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3- (2-fluorophenyl) -2-aminopropane were treated according to the method of Example 101 to give the title compound.

MS (APCI) m/e 337 (M+H)+;MS (APCI) m / e 337 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO) δ 7,60 (m, 1H), 7,30 (m, 2H), 7,10 (m, 1H), 4,10 (m, 1H), 2,80 (m, 2H), 1,80 (m, 6H), 1,40 (m, 1H), 1,10 (m, 8H), 0,80 (m, 2H).1 H NMR (300 MHz, DMSO) δ 7.60 (m, 1H), 7.30 (m, 2H), 7.10 (m, 1H), 4.10 (m, 1H), 2.80 (m, 1H) m, 2H), 1.80 (m, 6H), 1.40 (m, 1H), 1.10 (m, 8H), 0.80 (m, 2H).

Príklad 227Example 227

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(2-(4-fluórfenyl)-l,l-dimetyletyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2- (4-fluorophenyl) -1,1-dimethylethyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2-(4-fluórfenyl)-l, 1-dimetyletylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2- (4-fluorophenyl) -1,1-dimethylethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 351 (M+H)+;MS (APCI) m / e 351 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO) δ 7,20 (m, 2H), 7,05 (m, 2H), 3,60 (d, 1H), 3,00 (s, 2H), 1,65 (m, 5H), 1,40 (m, 2H), 1,20 (m, 10H), 0,80 (m, 2H).1 H NMR (300 MHz, DMSO) δ 7.20 (m, 2H), 7.05 (m, 2H), 3.60 (d, 1H), 3.00 (s, 2H), 1.65 ( m, 5H), 1.40 (m, 2H), 1.20 (m, 10H), 0.80 (m, 2H).

Príklad 228Example 228

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(2,3-dihydro-lH-indén-l-yl)2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,3-dihydro-1H-inden-1-yl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 1-aminoindan sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-aminoindan were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 317 (M+H)+;MS (APCI) m / e 317 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, DMSO) δ 7,95(m, 1H), 7,20 (m, 3H), 5,30 (m, 1H), 3,75 (d, 1H), 3,00 (m, 2H), 2,80 (m, 2H), 2,38 (m, 1H), 1,95 (m, 1H), 1,70 (m, 5H),1 H NMR (300 MHz, DMSO) δ 7.95 (m, 1H), 7.20 (m, 3H), 5.30 (m, 1H), 3.75 (d, 1H), 3.00 ( m, 2H), 2.80 (m, 2H), 2.38 (m, 1H), 1.95 (m, 1H), 1.70 (m, 5H),

1,20 (m, 6H), 0,90 (m, 2H).1.20 (m, 6H), 0.90 (m, 2H).

········

151 • · ·· ·151 • · ·· ·

Príklad 229Example 229

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-((l S,2R)-2-fenylcyklopropyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - ((1S, 2R) -2-phenylcyclopropyl) butanamide hydrochloride

Produkt z príkladu 23A a trans-2-fenylcyklopropylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and trans-2-phenylcyclopropylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 317 (M+H)+;MS (APCI) m / e 317 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,25 (t, 2H), 7,15 (m, 3H), 4,12 (d, 1H), 3,55 (m, 2H), 2,95 (m, 1H), 2,15 (m, 1H), 1,75 (m, 7H), 1,45 (m, 2H), 1,25 (m, 4H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.25 (t, 2H), 7.15 (m, 3H), 4.12 (d, 1H), 3.55 (m, 2H), 2 95 (m, 1H), 2.15 (m, 1H), 1.75 (m, 7H), 1.45 (m, 2H), 1.25 (m, 4H), 1.00 (m, 2H).

Príklad 230Example 230

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyI-2-hydroxy-/V-(l, 1,3,3-tetrametylbutyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (1,1,3,3-tetramethylbutyl) butanamide hydrochloride

Produkt z príkladu 23A a /erc-octylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and tert-octylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 313 (M+H)+;MS (APCI) m / e 313 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO) δ 3,60 (d, 1H), 2,95(m, 1H), l,75(m, 7H), 1, 35(s, 6H), 1,20 (m, 6H), 0,98 (s, 9H), 0,80 (m, 2H).1 H NMR (300 MHz, DMSO) δ 3.60 (d, 1H), 2.95 (m, 1H), 1.75 (m, 7H), 1.35 (s, 6H), 1.20 (m, 1H) m, 6H), 0.98 (s, 9H), 0.80 (m, 2H).

Príklad 231Example 231

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-/V-(l,3-dimetylbutyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (1,3-dimethylbutyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 1,3-dimetylbutylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1,3-dimethylbutylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 285(M+H)+;MS (APCI) m / e 285 (M + H) &lt; + &gt;;

··· ·

152 ’H NMR (300 MHz, DMSO) δ 3,70 (m, 1H), 2,95 (m, 1H), 1,80 (m, 8H), 1,40 (m, 2H), 1,20 (m, 4H), 1,05 (d, 3H), 0,85 (m, 8H).152 1 H NMR (300 MHz, DMSO) δ 3.70 (m, 1H), 2.95 (m, 1H), 1.80 (m, 8H), 1.40 (m, 2H), 1.20 (m, 4H), 1.05 (d, 3H), 0.85 (m, 8H).

Príklad 232Example 232

Hydrochlorid metyl-4-((2RS,3R)-3-amino-4-cyklohexyl-2-hydroxybutanoyl)amino)-3-tiofenkarboxylátuMethyl 4 - ((2RS, 3R) -3-amino-4-cyclohexyl-2-hydroxybutanoyl) amino) -3-thiophenecarboxylate hydrochloride

Produkt z príkladu 23A a metyl-3-aminotiofén-4-karboxylát sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and methyl 3-aminothiophene-4-carboxylate were treated according to the method of Example 101 to give the title compound.

MS (APCI) m/e 341 (M+H)+;MS (APCI) m / e 341 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 8,40 (s, 1H), 8,10 (s, 1H), 3,95(d, 1H), 3,80 (s, 3H), 3,10 (m, 1H), 1,70 (m, 5H), 1,20 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.40 (s, 1H), 8.10 (s, 1H), 3.95 (d, 1H), 3.80 (s, 3H), 3 10 (m, 1H), 1.70 (m, 5H), 1.20 (m, 6H), 0.90 (m, 2H).

Príklad 233Example 233

Hydrochlorid (2RS,3R)-/V-(l-(l-adamantyl)etyl)-3-amino-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) - N - (1- (1-Adamantyl) ethyl) -3-amino-4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a l-(l-adamantyl)etylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1- (1-adamantyl) ethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 363 (M+H)+;MS (APCI) m / e 363 (M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO) δ 3,75 (d, 1H), 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).1 H NMR (300 MHz, DMSO) δ 3.75 (d, 1H), 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).

Príklad 234 (2RS,3R)-3-amino-2-hydroxy-4-cyklohexyl) butanoyl-((S)-(-)-(l-nafty l)etyl)amidExample 234 (2RS, 3R) -3-Amino-2-hydroxy-4-cyclohexyl) butanoyl - ((S) - (-) - (1-naphthyl) ethyl) amide

153153

Produktu z príkladu 12A a (S)-(-)-(l-naftyl)etylamín sa spracovávajú podľa spôsobov z príkladov IE a 1F, čím sa získa požadovaná zlúčenina.The product of Example 12A and (S) - (-) - (1-naphthyl) ethylamine were processed according to the methods of Examples IE and 1F to give the title compound.

MS (ESI+Q1MS) m/e 347 (M+ H)+, 693 (2M+ H)+;MS (ESI + Q1MS) m / e 347 (M + H) &lt; + &gt;, 693 (2M + H) &lt; + &gt;;

’H NMR (300 MHz, DMSO-d6) δ 8,75-7,47 (m, 7H), 6,55 (br, 1H), 4,82-4,75 (m, 1H), 4,15 (d, 1H), 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).1 H NMR (300 MHz, DMSO-d 6 ) δ 8.75-7.47 (m, 7H), 6.55 (br, 1H), 4.82-4.75 (m, 1H), 4, 15 (d, 1H); 3.60-3.33 (br, m, 3H); 2.68-2.34 (m, 3.6H); 2.18 (q, 0.4H); 87-1.68 (m, 2H), 1.58-1.53 (m, 3H), 1.13 (t, 0.6H), 0.98 (t, 0.4H).

Príklad 235Example 235

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-7V-(l-naftylmetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (1-naphthylmethyl) butanamide hydrochloride

Produkt z príkladu 23A a 1-naftylmetylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1-naphthylmethylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 341 (M+H)+;MS (APCI) m / e 341 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 8,15 (d, 1H), 7,85 (q, 2H), 7,50 (m, 4H), 4,90 (m, 2H), 4,15 (d, 1H), 3,50 (m, 2H), 1,70 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.15 (d, 1H), 7.85 (q, 2H), 7.50 (m, 4H), 4.90 (m, 2H), 4 15 (d, 1H); 3.50 (m, 2H); 1.70 (m, 5H); 1.40 (m, 6H); 0.90 (m, 2H).

Príklad 236Example 236

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-V-(3-(trifluórmetoxy)benzy l)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3- (trifluoromethoxy) benzyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-trifluórmetoxybenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-trifluoromethoxybenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 375 (M+H)+;MS (APCI) m / e 375 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,40 (t, 1H), 7,30 (d, 1H), 7,22 (s, 1H), 7,19 (d, 1H), 4,55 (d, 1H), 4,40 (d, 1H), 4,15 (d, 1H), 3,50 (m, 2H), 1,75 (m, 5H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.40 (t, 1H), 7.30 (d, 1H), 7.22 (s, 1H), 7.19 (d, 1H), 4 55 (d, 1H); 4.40 (d, 1H); 4.15 (d, 1H); 3.50 (m, 2H); 1.75 (m, 5H);

1,40 (m, 6H), 0,95 (m, 2H).1.40 (m, 6H); 0.95 (m, 2H).

········

154 • · ·· • ·· «· · · • · · • · · · • · · ··· ·· • ·· · ·· · · ·· • · · · • · · · · • · · · ··· ·· ···154 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ···

Príklad 237Example 237

Hydrochlorid (2RS,3R)-3-amino- /V-(3,5-bis(trifluórmetyl)benzyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino- N - (3,5-bis (trifluoromethyl) benzyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-metylbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methylbenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 427 (M+H)+;MS (APCI) m / e 427 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,95 (s, 2H), 7,85 (s, 1H), 4,65 (d, 1H), 4,50 (d, 1H), 4,10 (d, 1H), 3,40 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), 0,90 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.95 (s, 2H), 7.85 (s, 1H), 4.65 (d, 1H), 4.50 (d, 1H), 4 10 (d, 1H); 3.40 (m, 2H); 1.75 (m, 5H); 1.40 (m, 6H); 0.90 (m, 2H).

Príklad 238 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2(trifluórmetyl)benzyl)butánamidExample 238 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2 (trifluoromethyl) benzyl) butanamide

Produkt z príkladu 23A a 2-trifluórmetylbenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-trifluoromethylbenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 359 (M+H)+;MS (APCI) m / e 359 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,70 (d, 1H), 7,58 (m, 2H), 7,45 (t, 1H), 4,75 (d, 1H), 4,55 (d, 1H), 4,19 (d, 1H), 3,55 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), 0,95 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.70 (d, 1H), 7.58 (m, 2H), 7.45 (t, 1H), 4.75 (d, 1H), 4 55 (d, 1H), 4.19 (d, 1H), 3.55 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.95 (m, 2H).

Príklad 239Example 239

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-W-(4-(trifluórmetoxy)benzyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (4- (trifluoromethoxy) benzyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-trifluórmetoxybenzylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-trifluoromethoxybenzylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 375 (M+H)+;MS (APCI) m / e 375 (M + H) &lt; + &gt;;

···· • ····· • ·

155 ·· • · ·· · • · • · φ φ • ·155 ·· · · · · · · · · · ·

Φ· 'Η NMR (300 MHz, MeOH-d4) δ 7,45 (d, 2Η), 7,22 (d, 2Η), 4,50 (d, 1Η), 4,38 (d, 1H), 4,10 (d, 1H), 3,45 (m, 2H), 1,75 (m, 5H), 1,40 (m, 6H), 0,95 (m, 2H).Δ · 1 H NMR (300 MHz, MeOH-d 4 ) δ 7.45 (d, 2Η), 7.22 (d, 2Η), 4.50 (d, 1Η), 4.38 (d, 1H) 4.10 (d, 1H), 3.45 (m, 2H), 1.75 (m, 5H), 1.40 (m, 6H), 0.95 (m, 2H).

Príklad 240Example 240

Hydrochlorid (2RS,3R)-3-amino-7V-(6-chlór-3-pyridinyl)-4-cyklohexyl-2-hydroxybutánamidu(2RS, 3R) -3-Amino-N- (6-chloro-3-pyridinyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3-amino-6-chlórpyridín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-amino-6-chloropyridine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 312 (M+H)+;MS (APCI) m / e 312 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 8,70 (s, 1H), 8,20 (d, 1H), 7,40 (d, 1H), 4,30 (d, 1H), 3,80 (m, 2H), 1,80 (m, 6H), 1,50 (m, 2H), 1,30 (m, 3H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 8.70 (s, 1H), 8.20 (d, 1H), 7.40 (d, 1H), 4.30 (d, 1H), 3 80 (m, 2H), 1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 3H), 1.00 (m, 2H).

Príklad 241 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-//-(6-metyl-2-pyridinyl)butánamidu hydrochloridExample 241 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (6-methyl-2-pyridinyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-amino-6-metylpyridin sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-amino-6-methylpyridine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 292 (M+H)+;MS (APCI) m / e 292 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) Ô 8,05 (d, 2H), 7,30 (m, 1H), 4,45 (d, 1H), 3,70 (m, 2H), 2,60 (s, 3H), 1,80 (m, 5H), 1,40 (m, 6H), 1,00 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 )? 8.05 (d, 2H), 7.30 (m, 1H), 4.45 (d, 1H), 3.70 (m, 2H), 2 60 (s, 3H), 1.80 (m, 5H), 1.40 (m, 6H), 1.00 (m, 2H).

Príklad 242Example 242

Hydrochlorid (2RS,3R)-3-amino-A/-(5-chlór-2-metoxyfenyl)-4-cyklohexyl-2hydroxybutánamidu(2RS, 3R) -3-Amino- N - (5-chloro-2-methoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

156 ···· • · ··156 ···· · · ··

• ·· • · · • ·· • · · • ·· ·· · · • ·· ·· · · ·· · · • · • · • · · • · · • · · · • · · · • · · · • · · · • · · • · · • · · • · · ·· ·· ·· ·· ··· ·· ··· ·· ·· · ·

Produkt z príkladu 23A a 2-metoxy-5-chlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxy-5-chloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 341 (M+H)+;MS (APCI) m / e 341 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,39 (d, 1H), 7,11 (dd, 1H), 7,02 (d, 1H), 4,36 (d, 1H), 3,82 (s, 3H), 3,79 (m, 1H), 0,98-1, 88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.39 (d, 1H), 7.11 (dd, 1H), 7.02 (d, 1H), 4.36 (d, 1H), 3, 82 (s, 3H), 3.79 (m, 1H), 0.98-1.88 (m, 13H).

Príklad 243Example 243

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-JV-(2-metoxy-5-metylfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (2-methoxy-5-methylphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-metoxy-5-metylanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-methoxy-5-methylaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 321 (M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,13 (s, 1H), 6,92 (s, 2H), 4,33 (d, 1H), 3,89 (s, 3H), 3,78 (m, 1H), 2,28 (s, 3H), 0,92-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.13 (s, 1H), 6.92 (s, 2H), 4.33 (d, 1H), 3.89 (s, 3H), 3, 78 (m, 1H), 2.28 (s, 3H), 0.92-1.88 (m, 13H).

Príklad 244Example 244

Hydrochlorid (2RS,3R)-3-amino-^/-(4-chlór-2,5-dimetoxyfenyl)-4-cyklohexyl2-hydroxybutánamidu(2RS, 3R) -3-Amino-N- (4-chloro-2,5-dimethoxyphenyl) -4-cyclohexyl-2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2,5-dimetoxy-4-chlóranilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,5-dimethoxy-4-chloroaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 370 (M)+;MS (APCI) m / e 370 (M) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 8,23 (s, 1H), 7,09 (s, 1H), 4,36 (d, 1H), 3,88 (s, 3H), 3,85(s, 3H), 3,79 (m, 1H), 0,97-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.23 (s, 1H), 7.09 (s, 1H), 4.36 (d, 1H), 3.88 (s, 3H), 3, 85 (s, 3H), 3.79 (m, 1H), 0.97-1.88 (m, 13H).

···· • ····· • ·

157 • · · ·· ··· ·· · • · ·· • · · • · · • · · ·· ··· • · • · · • · • · · • · ·· ·157 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 245Example 245

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-A^-(2,3-dimetoxyfenyl)-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,3-dimethoxyphenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 2,3-dimetoxyanilin sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,3-dimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 337 (M+H)+;MS (APCI) m / e 337 (M + H) &lt; + &gt;;

'H NMR (300MHz, MeOH-d4) δ 7,93 (d, 1H), 7,04 (t, 1H), 6,83 (d, 1H), 4,35 (d, 1H), 3,88 (m, 6H), 3,79 (m, 1H), 0,94-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.93 (d, 1H), 7.04 (t, 1H), 6.83 (d, 1H), 4.35 (d, 1H), 3, 88 (m, 6H), 3.79 (m, 1H), 0.94-1.88 (m, 13H).

Príklad 246Example 246

Hydrochlorid (2RS, 3 R)-3-am i no-4-cyklohexy 1-//-(3,4-dimetoxyfenyl )-2-hydroxybutánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-1H - (3,4-dimethoxyphenyl) -2-hydroxybutanamide hydrochloride

Produkt z príkladu 23A a 3,4-dimetoxyanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3,4-dimethoxyaniline were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 337 (M+H)+;MS (APCI) m / e 337 (M + H) &lt; + &gt;;

’H NMR (300MHz, MeOH-d4) δ 7,39 (d, 1H), 7,14 (dd, 1H), 6,91 (d, 1H), 4,27 (d, 1H), 3,83 (s, 3H), 3,81 (s, 3H), 3,72 (m, 1H), 0,95-1,86 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 7.39 (d, 1H), 7.14 (dd, 1H), 6.91 (d, 1H), 4.27 (d, 1H), 3, 83 (s, 3H), 3.81 (s, 3H), 3.72 (m, 1H), 0.95-1.86 (m, 13H).

MS (APCI) m/e 321 (M+H)+;MS (APCI) m / e 321 (M + H) &lt; + &gt;;

Príklad 247Example 247

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/^-(3-metoxy-4-metylfenyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N- (3-methoxy-4-methylphenyl) butanamide hydrochloride

Produkt z príkladu 23A a 3-metoxy-4-metylanilín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 3-methoxy-4-methylaniline were processed according to the method of Example 101 to give the title compound.

··· ···· ·

158 ’H NMR (300MHz, MeOH-d4) Ô 7,35 (s, 1H), 7,06 (d, 2H), 4,28 (d, 1H), 3,82 (s, 3H), 3,72 (m, 1H), 2,14 (s, 3H), 0,91-1,86 (m, 13H).158 1 H NMR (300MHz, MeOH-d 4 )? 7.35 (s, 1H), 7.06 (d, 2H), 4.28 (d, 1H), 3.82 (s, 3H), 3 72 (m, 1H); 2.14 (s, 3H); 0.91-1.86 (m, 13H).

Príklad 248Example 248

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-Y-(4-metoxy-2-naftyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N - (4-methoxy-2-naphthyl) butanamide hydrochloride

Produkt z príkladu 23A a 4-metoxy-2-naftylamín sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-methoxy-2-naphthylamine were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 357 (M+H)+;MS (APCI) m / e 357 (M + H) &lt; + &gt;;

*H NMR (300MHz, MeOH-d4) δ 8,13 (dd, 1H), 7,82 (d, 1H), 7,73 (d, 1H), 7,47 (m, 1H), 7,38 (m, 1H), 7,24 (d, 1H), 4,35 (d, 1H), 4,02 (s, 3H), 3,77 (m, 1H), 0,95-1,88 (m, 13H).1 H NMR (300MHz, MeOH-d 4 ) δ 8.13 (dd, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 7.47 (m, 1H), 38 (m, 1H), 7.24 (d, 1H), 4.35 (d, 1H), 4.02 (s, 3H), 3.77 (m, 1H), 0.95-1.88 (m, 13H).

Príklad 249Example 249

Hydrochlorid (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-/V-(2-tienylmetyl)butánamidu(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy- N - (2-thienylmethyl) butanamide hydrochloride

Produkt z príkladu 23A a 2-(aminometyl) tiofén sa spracovávajú podľa spôsobu z príkladu 101, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2- (aminomethyl) thiophene were processed according to the method of Example 101 to give the title compound.

MS (APCI) m/e 297 (M+H)+;MS (APCI) m / e 297 (M + H) &lt; + &gt;;

‘H NMR (300MHz, MeOH-d4) δ 7,29 (dd, 1H), 7,02 (dd, 1H), 6,95 (dd, 1H),1 H NMR (300MHz, MeOH-d 4 ) δ 7.29 (dd, 1H), 7.02 (dd, 1H), 6.95 (dd, 1H),

4,59 (q, 2H), 4,15 (d, 1H), 3,58 (m, 1H), 0,82-1,80 (m, 13H).4.59 (q, 2H), 4.15 (d, 1H), 3.58 (m, 1H), 0.82-1.80 (m, 13H).

Príklad 250 (2RS, 3R)-3-amino-/V-butyl-4-cyklohexy 1-2-hy droxy-/V-metylbutánamid ··· · • ·Example 250 (2RS, 3R) -3-Amino- N -butyl-4-cyclohexyl-2-hydroxy- N -methylbutanamide

159159

Produkt z príkladu 23A (2,4 g, 8,64 mmol) sa rozpustí v bezvodom dichlórmetáne, čím sa získa 24 ml (roztok A). Hydrát 1-hydroxybenzotriazol (HOBT 0,96 g, 7,78 mmol) a 4-(dimetylamino)-pyridin (DMAP-0,096 g, kat.) sa rozpustia v 2:1 dichlórmetán : /V,/V-dimetylformamid na pripravenie 48ml (roztok B). Hydrochlorid l-[3-(dimetylamino)propyl]-3-etylkarbodiimidu (EDCI-2,30 g, 12,96 mmol) sa rozpustí v bezvodom dichlórmetáne, čím sa získa 48 ml (roztok C). Roztok A sa rovnomerne rozdelí do 48 jednotlivých reaktorov. Do týchto rovnakých reaktorov sa v rovnakých dávkach pridajú roztoky B a C. Reaktory sa trepú 15 minút pri izbovej teplote. Do jedného z týchto reaktorov sa pridá Ύ-metylbutylamín (0,022 ml, 0,27 mmol) a zmes sa trepe zhruba 20 hodín. Do tejto reakčnej zmesi sa pridá dichlórmetán (2,5 ml) a trepe sa. Reaktor sa umiestni na extraktor tekutej fázy na premytie IM hydrogensíranom sodným (2 x), vodou (1 x), a nakoniec 2N hydrogénuhličitanom sodným (2 x). Akákoľvek zvyšná voda sa odstráni a rozpúšťadlo tiež. Zvyšok sa rozpustí v 4M kyseline chlorovodíkovej v dioxánoch (1 ml) na odštiepenie chrániacej skupiny. Po jednej hodine sa rozpúšťadlo úplne odstráni. 48 amínov sa naraz spracováva v dávkach. Na základe čistoty stanovenej pomocou HPLC sa látka buď spracováva tak ako je, alebo sa vykoná preparatívna HPLC, čistenie pred tým, než sa spracováva.The product of Example 23A (2.4 g, 8.64 mmol) was dissolved in anhydrous dichloromethane to give 24 mL (solution A). 1-Hydroxybenzotriazole hydrate (HOBT 0.96 g, 7.78 mmol) and 4- (dimethylamino) -pyridine (DMAP-0.096 g, cat.) Are dissolved in 2: 1 dichloromethane: N, N -dimethylformamide to prepare 48ml (solution B). 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI-2.30 g, 12.96 mmol) was dissolved in anhydrous dichloromethane to give 48 mL (solution C). Solution A is evenly distributed to 48 individual reactors. To these same reactors, solutions B and C were added in equal portions. The reactors were shaken for 15 minutes at room temperature. Jedného-Methylbutylamine (0.022 mL, 0.27 mmol) was added to one of these reactors and the mixture was shaken for about 20 hours. To this reaction mixture was added dichloromethane (2.5 mL) and shaken. The reactor was placed on a liquid phase extractor to wash IM with sodium hydrogen sulphate (2x), water (1x), and finally 2N sodium bicarbonate (2x). Any residual water is removed and the solvent also. The residue was dissolved in 4M hydrochloric acid in dioxanes (1 mL) to remove the protecting group. After one hour, the solvent was completely removed. 48 amines are simultaneously processed in batches. On the basis of the purity determined by HPLC, the substance is either treated as is, or a preparative HPLC is performed, before it is treated.

MS (APCI) m/e 271 (M+H)+;MS (APCI) m / e 271 (M + H) &lt; + &gt;;

*H NMR (300 MHz, MeOH-d4) δ 4,45 (t, 1H), 3,45 (m, 3H), 3,14 (s, 2H), 2,95 (s, 1H),1 H NMR (300 MHz, MeOH-d 4 ) δ 4.45 (t, 1H), 3.45 (m, 3H), 3.14 (s, 2H), 2.95 (s, 1H),

1,7 (m, 5H), 1,4 (m, 4H), 0,95 (m, 6H).1.7 (m, 5H), 1.4 (m, 4H), 0.95 (m, 6H).

Príklad 251 (2RS3R)-3-amino-4-cyklohexy 1-1-(2,6-dimetyl-4-morfolinyl)-2-hydroxy-lbutanónExample 251 (2RS 3 R) -3-Amino-4-cyclohexyl-1- (2,6-dimethyl-4-morpholinyl) -2-hydroxy-1-butanone

Produkt z príkladu 23A a 2,6-dimetyImorfolín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,6-dimethyl-morpholine were treated according to the method of Example 250 to give the title compound.

··· ···· ·

160160

MS (APCI) m/e 299 (M+H)+;MS (APCI) m / e 299 (M + H) &lt; + &gt;;

'H 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).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.4 (m, 2H), 3.95 (m, 1H), 3.55 (m, 3H), 2.85 (m, 1H), 2 4 (m, 1H), 1.7 (m, 5H), 1.5 (m, 3H), 1.2 (m, 9H), 0.95 (m, 2H).

• ·• ·

II • ·II • ·

Príklad 252 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-N,N-bis(metoxymetyl)butánamidExample 252 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-N, N-bis (methoxymethyl) butanamide

Produkt z príkladu 23A a bis(2-metoxyetyl)amín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and bis (2-methoxyethyl) amine were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 317 (M+H)+;MS (APCI) m / e 317 (M + H) &lt; + &gt;;

’H NMR (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).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.65 (d, 1H), 3.9 (m, 1H), 3.55 (m, 9H), 3.35 (m, 6H), 1 7 (m, 5H), 1.4 (m, 6H), 0.95 (m, 2H).

Príklad 253 (2RS,3R)-3-amino-4-cyklohexyl-l-[3,4-dihydro-2(lH)-izochinolinyl]-2hydroxy-l-butanónExample 253 (2RS, 3R) -3-Amino-4-cyclohexyl-1- [3,4-dihydro-2 (1H) -isoquinolinyl] -2-hydroxy-1-butanone

Produkt z príkladu 23A a 1,2,3,4-tetrahydroizochinolín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and 1,2,3,4-tetrahydroisoquinoline were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 317 (M+H)+;MS (APCI) m / e 317 (M + H) &lt; + &gt;;

’H NMR (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).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.2 (m, 4H), 4.7 (m, 2H), 4.55 (d, 1H), 3.8 (m, 2H), 3 5 (m, 1H), 2.95 (m, 2H), 1.7 (m, 5H), 1.4 (m, 6H), 0.95 (m, 2H).

• ·• ·

161161

Príklad 254 (2RS,3R)-3-amino-l-(l-azepanyl)-4-cyklohexyl-2-hydroxy-l-butanónExample 254 (2RS, 3R) -3-Amino-1- (1-azepanyl) -4-cyclohexyl-2-hydroxy-1-butanone

Produkt z príkladu 23A a hexametylénimín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and hexamethylenimine were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 283 (M+H)+;MS (APCI) m / e 283 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 4,45 (d, 1H), 3,65 (m, 2H), 3,55 (m, 3H), 1,61,8 (m, 13H), 0,95-1,5 (m, 8H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.45 (d, 1H), 3.65 (m, 2H), 3.55 (m, 3H), 1.61.8 (m, 13H) 0.95-1.5 (m, 8H).

Príklad 255 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-l-[4-fenyl-3,6-dihydro-l(2//)pyridinyl]-l-butanónExample 255 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-1- [4-phenyl-3,6-dihydro-1 (2H) -pyridinyl] -1-butanone

Produkt z príkladu 23A a hydrochlorid 4-fenyl-l,2,3,6-tetrahydropyridínu sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 343 (M+H)+;MS (APCI) m / e 343 (M + H) &lt; + &gt;;

‘H NMR (300 MHz, MeOH-d4) δ 7,35 (m, 5H), 6,15 (m, 1H), 4,45 (dd, 1H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.35 (m, 5H), 6.15 (m, 1H), 4.45 (dd, 1H),

4,25 (m, 2H), 3,85 (m, 2H), 3,55 (m, 1H), 2,6 (m, 2H), 1,7 (m, 5H), 0,95-1,5 (m, 8H).4.25 (m, 2H), 3.85 (m, 2H), 3.55 (m, 1H), 2.6 (m, 2H), 1.7 (m, 5H), 0.95-1 1.5 (m, 8H).

MS (APCI) m/e 347 (M+H)+;MS (APCI) m / e 347 (M + H) &lt; + &gt;;

Príklad 256 (2RS,3R)-3-amino-/V-benzyl-Ä/-butyl-4-cyklohexyl-2-hydroxybutánamidExample 256 (2RS, 3R) -3-Amino- N -benzyl-N-butyl-4-cyclohexyl-2-hydroxybutanamide

Produkt z príkladu 23A a n-butylbenzylamín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina, »···The product of Example 23A and n-butylbenzylamine are treated according to the method of Example 250 to give the title compound.

162 ’H NMR (300 MHz, MeOH-d4) δ 7,4 (m, 5H), 4,7 (m, 2H), 4,4 (dd, 1H), 3,5 (m, 2H), 3,25 (m, 1H), 2,1-1,7 (m, 15H), 0,92 (m, 5H).162 1 H NMR (300 MHz, MeOH-d 4 ) δ 7.4 (m, 5H), 4.7 (m, 2H), 4.4 (dd, 1H), 3.5 (m, 2H), 3.25 (m, 1H), 2.1-1.7 (m, 15H), 0.92 (m, 5H).

Príklad 257 (2RS,3R)-3-amino-4-cyklohexyl-l-[(2R,6S)-2,6-dimetylmorfolinyl]-2-hydroxy1-butanónExample 257 (2RS, 3R) -3-Amino-4-cyclohexyl-1 - [(2R, 6S) -2,6-dimethylmorpholinyl] -2-hydroxy-1-butanone

Produkt z príkladu 23A a c/s-2,6-dimetylmorfolín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and cis-2,6-dimethylmorpholine were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 299 (M+H)+;MS (APCI) m / e 299 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 4,5 (dd, 1H), 4,35 (m, 1H), 3,95 (m, 1H), 3,55 (m, 1H), 2,9 (m, 1H), 2,4 (m, 1H), 1,5-1,7 (m, 8H), 0,95- 1, 3 (m, 1H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.5 (dd, 1H), 4.35 (m, 1H), 3.95 (m, 1H), 3.55 (m, 1H), 2 9 (m, 1H); 2.4 (m, 1H); 1.5-1.7 (m, 8H); 0.95-1.3 (m, 1H).

Príklad 258 (2RS,3R)-3-Amino-A/-[(2-chlór2,3,5-cyklohexatrien-l-yl)metyl]-4-cyklohexyl2-hydroxy-/V-metylbutánamidExample 258 (2RS, 3R) -3-Amino-N - [(2-chloro-2,3,5-cyclohexatrien-1-yl) methyl] -4-cyclohexyl-2-hydroxy- N -methylbutanamide

Produkt z príkladu 23A a 2-chlór-/V-metylbenzylamín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2-chloro- N -methylbenzylamine were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 339 (M+H)+;MS (APCI) m / e 339 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,35 (m, 4H), 4,75 (m, 2H), 4,4-4,55 (dd, 1H),1 H NMR (300 MHz, MeOH-d 4 ) δ 7.35 (m, 4H), 4.75 (m, 2H), 4.4-4.55 (dd, 1H),

3,5 (m, 1H), 3,14 (s, 2H), 2,99 (s, 1H), 1,7 (m, 5H), 0,95-1,5 (m, 8H).3.5 (m, 1H), 3.14 (s, 2H), 2.99 (s, 1H), 1.7 (m, 5H), 0.95-1.5 (m, 8H).

Príklad 259 (2RS,3R)-3-amino-/V-(l,3-benzodioxol-5-ylmetyl)-4-cyklohexyl-2-hydroxy-/VmetylbutánamidExample 259 (2RS, 3R) -3-Amino- N - (1,3-benzodioxol-5-ylmethyl) -4-cyclohexyl-2-hydroxy- N -methylbutanamide

163 · · ···163 · · ···

Produkt z príkladu 23A a JV-etyl-3,4-(metylénedioxy)anilín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and N-ethyl-3,4- (methylenedioxy) aniline were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 349 (M+H)+;MS (APCI) m / e 349 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 6,9 (d, 1H), 6,83 (d, 1H), 6,78 (dd, 1H), 6,04 (d, 2H), 4,19 (d, 1H), 3,9 (m, 1H), 3,5 (m, 1H), 3,25 (m, 1H), 1,65 (m, 5H), 1,4 (m, 2H), 1,0-1,25 (m, 7H), 0,8 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 6.9 (d, 1H), 6.83 (d, 1H), 6.78 (dd, 1H), 6.04 (d, 2H), 4 19 (d, 1H), 3.9 (m, 1H), 3.5 (m, 1H), 3.25 (m, 1H), 1.65 (m, 5H), 1.4 (m, 2H), 1.0-1.25 (m, 7H), 0.8 (m, 2H).

Príklad 260 (2RS,3R)-3-amino-4-cyklohexyl-JV-(2,4-dichlorbenzyl)-/V-etyl-2hydroxybutánamidExample 260 (2RS, 3R) -3-Amino-4-cyclohexyl-N- (2,4-dichlorobenzyl) -N-ethyl-2-hydroxybutanamide

Produkt z príkladu 23A a 2,4-dichlór-jV-etylbenzylamín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and 2,4-dichloro-N-ethylbenzylamine were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 387 (M+H)+;MS (APCI) m / e 387 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 7,29-7,52 (m, 3H), 4,65 (m, 2H), 4,3-4,5 (dd, 1H), 3,55 (m, 2H), 3,45 (m, 1H), 1,7 (m, 5H), 1,5 (m, 2H), 1,1-1,4 (m, 7H), 0,95 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 7.29-7.52 (m, 3H), 4.65 (m, 2H), 4.3-4.5 (dd, 1H), 3, 55 (m, 2H), 3.45 (m, 1H), 1.7 (m, 5H), 1.5 (m, 2H), 1.1-1.4 (m, 7H), 0.95 (m, 2H).

Príklad 261 ety 1-3-[[(2RS, 3 R)-3-amino-4-cyklohexyl-2-hydroxybutanoyl] (benzyl) aminojpropanoátExample 261 Ethyl 1-3 - [[(2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxybutanoyl] (benzyl) amino] propanoate

Produkt z príkladu 23A a etylester A/-benzyl-3-aminopropiónovej kyseliny sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and N -benzyl-3-aminopropionic acid ethyl ester were processed according to the method of Example 250 to give the title compound.

MS (APCI) m/e 391 (M+H)+;MS (APCI) m / e 391 (M + H) &lt; + &gt;;

164 'H NMR (300 MHz, MeOH-d4) δ 7,3 (m, 5H), 4,7 (m, 3H), 4,1 (m, 2H), 3,4 (m,164 1 H NMR (300 MHz, MeOH-d 4 ) δ 7.3 (m, 5H), 4.7 (m, 3H), 4.1 (m, 2H), 3.4 (m,

1H), 2,6 (m, 2H), 1,7 (m, 5H), 1,15-1,5 (m, 9H), 0,95 (m, 2H).1H), 2.6 (m, 2H), 1.7 (m, 5H), 1.15-1.5 (m, 9H), 0.95 (m, 2H).

Príklad 262 (2RS,3R)-3-amino-4-cyklohexyl-2-hydroxy-l-(l-piperidinyl)-l-butanónExample 262 (2RS, 3R) -3-Amino-4-cyclohexyl-2-hydroxy-1- (1-piperidinyl) -1-butanone

Produkt z príkladu 23A a piperidín sa spracovávajú podľa spôsobu z príkladu 250, čím sa získa požadovaná zlúčenina.The product of Example 23A and piperidine were treated according to the method of Example 250 to give the title compound.

MS (APCI) m/e 269 (M+H)+;MS (APCI) m / e 269 (M + H) &lt; + &gt;;

’H NMR (300 MHz, MeOH-d4) δ 4,45 (d, 1H), 3,7 (m, 2H), 3,5 (m, 3H), 1,7 (m, 9H), 1,5 (m, 4H), 1,3 (m, 4H), 1,0 (m, 2H).1 H NMR (300 MHz, MeOH-d 4 ) δ 4.45 (d, 1H), 3.7 (m, 2H), 3.5 (m, 3H), 1.7 (m, 9H), 1 1.5 (m, 4H), 1.3 (m, 4H), 1.0 (m, 2H).

Príklad 263Example 263

Hydrochlorid (2RS,3R,5'S)-A/-[4-(N-fenylhydantoyl)butyl]-3-amino-2-hydroxy5-(etyltio)pentánanamidu(2RS, 3R, 5'S) - N - [4- (N-Phenylhydantoyl) butyl] -3-amino-2-hydroxy-5- (ethylthio) pentananamide hydrochloride

Krok (a) ľerc-butoxid draselný (112 mg) sa pridá do roztoku hydrochloridu metylesteru N(epsilon)(/erc-butoxykarbonyl)-L-lyzínu (300 mg) a fenylizokyanátu (110 ml) v 5 ml tetrahydroíuránu. Výsledná zmes sa mieša pri izbovej teplote po dobu jedného dňa. Po pridaní približne rovnakého množstva /erc-butoxidu draselného sa výsledná zmes zahrieva pri teplote 65 - 70 °C po dobu 1 hodiny. Rozpúšťadlo sa odstráni a etylacetát sa pridá do zvyšku, ktorý sa premyje postupne soľankou, 10 % KHSO4, soľankou, 10 % NaHC03 a soľankou a suší nad bezvodým síranom horečnatým. Po odstránení rozpúšťadiel vo vákuu sa zvyšok produktu nechá reagovať s 4N chlorovodíkom v dioxánoch po dobu 1 hodiny a znovu sa odparí do sucha.Step (a) Potassium tert-butoxide (112 mg) was added to a solution of N (epsilon) methyl tert -butoxycarbonyl-L-lysine hydrochloride (300 mg) and phenyl isocyanate (110 mL) in 5 mL of tetrahydrofuran. The resulting mixture was stirred at room temperature for one day. After addition of approximately the same amount of potassium tert-butoxide, the resulting mixture was heated at 65-70 ° C for 1 hour. The solvent was removed and ethyl acetate was added to the residue, which was washed sequentially with brine, 10% KHSO 4 , brine, 10% NaHCO 3 and brine, and dried over anhydrous magnesium sulfate. After removal of the solvents in vacuo, the remainder of the product was treated with 4N hydrogen chloride in dioxanes for 1 hour and evaporated again to dryness.

• ·• ·

165 • · ·· ··· ·· • · • · ·· ·165 • · ·········

Krok (b)Step (b)

Produkt z kroku (a) príkladu 12 sa nechá reagovať s produktom z kroku (a) tohoto príkladu použitím spôsobu opísaného v príklade 2, čím sa získa požadovaná zlúčenina.The product of step (a) of Example 12 is reacted with the product of step (a) of this example using the method described in Example 2 to give the title compound.

Príklad 264Example 264

Hydrochlorid (2RS,3R,5'R)-Y-[4-(N-fenylhydantoyl)-butyl]-3-amino-2-hydroxy-5-(etyltío)pentánamid(2RS, 3R, 5'R) -Y- [4- (N-Phenylhydantoyl) butyl] -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Použitím hydrochloridu metylesteru N(epsilon) (íerc-butoxykarbonyl)-Dlyzínu a fenylizokyanátu podľa spôsobu z príkladu 263 sa získa vyššie uvedený stereoizomér.Using N (epsilon) (tert-butoxycarbonyl) -Dlysine methyl ester hydrochloride and phenyl isocyanate according to the method of Example 263, the above stereoisomer is obtained.

Príklad 265Example 265

Hydrochlorid (2RS,3R,4'R)-Y-[4-(N-(2,4-dimetoxyfenyl)hydantoyl)propyl]-3amino-2-hydroxy-5-(etyltio)pentánamidu(2RS, 3R, 4'R) -N- [4- (N- (2,4-Dimethoxyphenyl) hydantoyl) propyl] -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Použitím hydrochloridu metylesteru N(epsilon) (/erc-butoxykarbonyl)-Lornitínu a 2,4-dimetoxyfenylizokyanát podľa spôsobu z príkladu 263 sa získa vyššie uvedená zlúčenina.Using N (epsilon) (tert -butoxycarbonyl) -ornitine-2,4-dimethoxyphenylisocyanate hydrochloride according to the method of Example 263, the above compound is obtained.

Príklad 266Example 266

Hydrochlorid (2RS,3R,5'S)-Y-[4-(N-(4-triflóurometoxyfenyl)hydantoyl)butyl]3-amino-2-hydroxy-5-(etyltio)pentánamidu(2RS, 3R, 5'S) -Y- [4- (N- (4-Trifluoromethoxyphenyl) hydantoyl) butyl] 3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Použitím hydrochlorid metylesteru N(epsilon)(/erc-butoxykarbonyl)-Llyzínu a 4-trifluórmetoxyfenylfenylizokyanátu podľa spôsobu z príkladu 28 sa získa vyššie uvedená zlúčenina.Using N (epsilon) (tert-butoxycarbonyl) -lysine methyl ester hydrochloride and 4-trifluoromethoxyphenylphenylisocyanate according to the method of Example 28, the above compound is obtained.

• · · ·• · · ·

166166

Príklad 267Example 267

Hydrochlorid (2RS,3 R,5'S,8'S)-V-[4-(3-Metyl-2,5-dioxopiperazín-2-yl)butyl]3-amino-2-hydroxy-5-(etyltio)pentánamidu(2RS, 3R, 5'S, 8'S) -N- [4- (3-Methyl-2,5-dioxopiperazin-2-yl) butyl] 3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Krok (a)Step (a)

Hydrochlorid metylesteru L-alanyl-N'-benzyloxykarbonyllyzínu sa syntetizuje štandardným spôsobom peptidovej syntézy, ktorá je dobre známa zo súčasného stavu techniky. Výsledný ester dipeptidu (250 mg) sa rozpustí v toluéne (20 ml), pridá sa trietylamín a zmes sa utesní v rúre a zahrieva sa pri teplote 140 °C po dobu 12 hodín. Rozpúšťadlo sa odstráni a produkt sa rozpustí v etylacetáte (30 ml) a premyje sa postupne soľankou, 10 % KHSO4 a soľankou a suší sa nad bezvodým síranom horečnatým. Rozpúšťadlo sa odstráni vo vákuu a výslednému produktu sa odstráni chrániaca skupina štandardnými technikami, ktoré sú dobre známe v súčasnom stave techniky.L-alanyl-N'-benzyloxycarbonyllysine methyl ester hydrochloride is synthesized by standard peptide synthesis techniques well known in the art. The resulting dipeptide ester (250 mg) was dissolved in toluene (20 mL), triethylamine was added, and the mixture was sealed in an oven and heated at 140 ° C for 12 hours. The solvent was removed and the product was dissolved in ethyl acetate (30 mL) and washed sequentially with brine, 10% KHSO 4 and brine, and dried over anhydrous magnesium sulfate. The solvent is removed in vacuo and the resulting product is deprotected by standard techniques well known in the art.

Krok (b)Step (b)

Produkt z kroku (a) príkladu 12 a produkt z vyššie uvedeného kroku (a) sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of step (a) of Example 12 and the product of step (a) above were processed according to the method of Example 2 to give the title compound.

Použitím spôsobu z príkladu 32 a aminokyselín s veľmi odlišnými postrannými reťazcami môže byť syntetizované množstvo substituovaných diketopiperazínov a doplnené do zlúčenín predloženého vynálezu spôsobmi podrobnejšie opísanými vo vyššie uvedených príkladoch.Using the method of Example 32 and amino acids with very different side chains, a number of substituted diketopiperazines can be synthesized and added to the compounds of the present invention by the methods described in more detail in the above examples.

Príklad 268Example 268

Hydrochlorid (2RS,3R)-V-[4-(ftalimido)butyl]-3-amino-2-hydroxy-5-(etyltio)pentánamidu • · · · • · · • · • · · • · • ·· · • ·· · · · • · · · • · · · · • · · · · ·· ··· ·· ·(2RS, 3R) - N - [4- (Phthalimido) butyl] -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

167167

Krok (a)Step (a)

Mono-2V-(/erc)-butoxykarbonyl-l,4-diaminobután (190 mg) a anhydrid kyseliny ftalovej (150 mg) sa rozpustí v 5 ml toluénu a jemne sa refluxuje v olejovom kúpeli (117 - 120 °C), kým celá východisková látka nezreaguje. Reakčná zmes sa zriedi 15 ml etylacetátom a organická vrstva sa premyje postupne soľankou, 10 % KHSO4, soľankou, 10 % NaHCO3 a soľankou a suší sa nad bezvodým síranom horečnatým Rozpúšťadlo sa odparí, čím sa získa surový produkt, ktorý sa nechá reagovať s 4N chlorovodíkom v dioxánoch po dobu 1 hodiny. Rozpúšťadlo sa odstráni, vychytáva sa v dietyléteri, odparuje sa (2 x) na odstránenie HCI a suší sa.Mono-N - (tert) -butoxycarbonyl-1,4-diaminobutane (190 mg) and phthalic anhydride (150 mg) were dissolved in 5 mL of toluene and gently refluxed in an oil bath (117-120 ° C) until the entire starting material does not react. The reaction mixture was diluted with 15 ml ethyl acetate and the organic layer was washed with brine, 10% KHSO4, brine, 10% NaHCO3, brine, and dried over anhydrous magnesium sulfate, the solvent was evaporated to give the crude product which was treated with 4 N with hydrogen chloride in dioxanes for 1 hour. The solvent was removed, taken up in diethyl ether, evaporated (x2) to remove HCl and dried.

Krok (b)Step (b)

Produkt z kroku (a) príkladu 3 a vyššie uvedený produkt kroku (a) sa spracovávajú spôsobom z príkladu 2, čím sa získa požadovaná zlúčenina.The product of step (a) of Example 3 and the above product of step (a) are treated as in Example 2 to give the title compound.

Použitím spôsobu podrobnejšie opísaného v kroku (a) príkladu 268 môže byť syntetizované veľa ň/-(aminoalkyl)ftalimidov a doplnené do zlúčenín predloženého vynálezu. Príklady takých V-(aminoalkyl)ftalimidov zahŕňajú zlúčeniny, kde q môže byť v rozpätí 1 - 6, vrátane a A môže byť atóm vodíka, halogén, nižší alkyl, nižšia alkoxy skupina, nitro skupina alebo karboxy skupinaUsing the method described in more detail in step (a) of Example 268, many N - (aminoalkyl) phthalimides can be synthesized and added to the compounds of the present invention. Examples of such V- (aminoalkyl) phthalimides include compounds wherein q may be in the range of 1-6 inclusive, and A can be a hydrogen atom, halogen, lower alkyl, lower alkoxy, nitro or carboxy

Príklad 269Example 269

Hydrochlorid (2RS,3R)-7V-(2-tien-2-yletyl)-3-amino-2-hydroxy-5-(etyltio)pentánamidu(2RS, 3R) -N- (2-Thien-2-ylethyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide hydrochloride

Produkt z kroku (a) príkladu 12 a 2-(2-aminoetyl)tiofén sa spracovávajú podľa spôsobu z vyššie uvedeného príkladu 2, čím sa získa požadovaná zlúčenina.The product of step (a) of Example 12 and 2- (2-aminoethyl) thiophene were treated according to the method of Example 2 above to give the title compound.

• · · ·• · · ·

168 • ·· • · • · • · · ·· ··· ·· · · • · • · · · • · · ··· ·· ·168 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Príklad 270Example 270

Hydrochlorid (2RS,3R)-(N-metyl-Aľ-propyl)-3-amino-2-hydroxy-5-(etyltio) pentánamidu(2RS, 3R) - (N-methyl-N- propyl) -3-amino-2-hydroxy-5- (ethylthio) pentanamide

Produkt z kroku (a) príkladu 12 a jV-metyl-A-propylamín sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of step (a) of Example 12 and N-methyl-N-propylamine were treated according to the method of Example 2 to give the title compound.

Rovnakým spôsobom môžu byť alkylamíny a dialkylamíny, v ktorých dve alkylové skupiny sú rovnaké alebo sú rôzne, konvertované na zlúčeniny predloženého vynálezu spôsobom podrobnejšie opísaným v príklade 35.In the same way, alkylamines and dialkylamines in which the two alkyl groups are the same or different may be converted to the compounds of the present invention in the manner described in more detail in Example 35.

Príklad 271 (2RS,3R)-7V-[2-(g-aminobutyrolaktamyl)etyl]-3-amino-2-hydroxy-5(etyltio)pentánamidExample 271 (2RS, 3R) -N- [2- (g-Aminobutyrolactamyl) ethyl] -3-amino-2-hydroxy-5 (ethylthio) pentanamide

Produkt z kroku (a) príkladu 12 a l-amino-2-[g-aminobutyrolaktamyljetán sa spracovávajú podľa spôsobu z príkladu 2, čím sa získa požadovaná zlúčenina.The product of step (a) of Example 12 and 1-amino-2- [g-aminobutyrolactamyl] ethane were processed according to the method of Example 2 to give the title compound.

Rovnakým spôsobom môžu byť aminoalkyllaktámy doplnené do zlúčenín predloženého vynálezu pomocou spôsobov podrobnejšie opísaných vo vyššie uvedených príkladoch.In the same way, aminoalkyl lactams can be added to the compounds of the present invention by methods described in more detail in the above examples.

Príklad 272Example 272

Hydrochlorid (2RS,3S,l’S)-7^-[(l-karboxyl)etyl]3-amino-2-tio-5-(metyltio)pentánamidu(2RS, 3S, 1'S) -7 - [(1-Carboxyl) ethyl] 3-amino-2-thio-5- (methylthio) pentanamide hydrochloride

Zlúčenina z príkladu IE (0,40 g, 1,1 mmol) v 3 ml metylénchloridu obsahujúceho 50 % molárny zvyšok trietylamínu pri teplote 0 °C sa nechá reagovať s metánsulfonylchloridom (0,1 ml, 1,31 mmol). Po dobehnutí reakcie sa zmes premyje soľankou, 10 % KHSO4, suší sa nad MgSO4. Do roztoku mezylátu ····Example IE (0.40 g, 1.1 mmol) in 3 mL of methylene chloride containing a 50 mole residue of triethylamine at 0 ° C was treated with methanesulfonyl chloride (0.1 mL, 1.31 mmol). After completion of the reaction, the mixture was washed with brine, 10% KHSO 4 , dried over MgSO 4 . Into mesylate solution ····

• ·· • ·· · · · • · · · • · · · · • · · · · ·· ··· ·· *• ·······················

169 (0,45 mmol) v 5 ml THF sa pridá roztok p-metoxybenzylmerkaptánu (0,104g, 0,675 mmol) za prítomnosti IN NaOH pri teplote 0 °C pod atmosférou dusíku. Po ďalších 30 minútach pri izbovej teplote za stáleho miešania sa produkt čistí chromatografiou na stĺpci silikagélu mobilnou fázou 10 % etylacetátu v toluéne.169 (0.45 mmol) in 5 mL THF was added a solution of p-methoxybenzyl mercaptan (0.104g, 0.675 mmol) in the presence of 1N NaOH at 0 ° C under nitrogen. After an additional 30 minutes at room temperature with stirring, the product was purified by silica gel column chromatography eluting with 10% ethyl acetate in toluene.

Získaný p-metoxybenzylmerkaptoderivát (0,4 mmol) sa rozpustí v 3 ml metanolu, pridá sa 2N NaOH tak, aby hodnota pH bola okolo 12. Reakcia sa spracováva podľa všeobecného spôsobu a produkt sa nechá reagovať s 4N HCI v dioxánoch po dobu 1,5 hodiny, čím sa získa požadovaná zlúčenina.The obtained p-methoxybenzyl mercaptoderivative (0.4 mmol) is dissolved in 3 ml of methanol, 2N NaOH is added until the pH is about 12. The reaction is worked up according to the general method and the product is reacted with 4N HCl in dioxanes for 1, 5 hours to give the title compound.

Príklad 273Example 273

Hydrochlorid (2RS,3S, l’S)-/V-[(l-etoxykarbonyl)etyl]-3-amino-2-oxo-5-(metyltio)pentánamidu(2RS, 3S, 1'S) - N - [(1-ethoxycarbonyl) ethyl] -3-amino-2-oxo-5- (methylthio) pentanamide hydrochloride

Príklad IE (0,4 g, 1,1 mmol) sa oxiduje pyridínium chlórchrómanom (710 mg, 3,3 mmol) v 5 ml metylénchloridu dokiaľ východisková látka nezreaguje. Získaný diketón sa čistí chromatografiou na stĺpci silikagélu. Výsledný produkt sa spracováva podľa spôsobu opísaného v kroku (f) v príklade 1, čím sa získa požadovaná zlúčenina.Example IE (0.4 g, 1.1 mmol) was oxidized with pyridinium chlorochromate (710 mg, 3.3 mmol) in 5 mL of methylene chloride until the starting material was reacted. The diketone obtained is purified by silica gel column chromatography. The resulting product is worked up according to the method described in step (f) in Example 1 to give the title compound.

Claims (1)

PATEATOVÉ NÁROKY tv tttf-iwo ···: .··. ·· • · ··· ·!!PATH CLAIMS tv tttf-iwo ···:. ··. ·· • · ··· · !! • ···· · · · J JJ J ·..* ·:· *··* ··· ·· ···· .. * ·: · * ·· * ··· ·· ··· 170170 1. Zlúčenina majúca vzorec (I):1. A compound having the formula (I): A2 (M alebo jej farmaceutický prijateľné soli, estery alebo jej prekurzory liečiv, kde malé čísla označujú chirálne centrá v zlúčenine;A 2 (M or pharmaceutically acceptable salts, esters or prodrugs thereof, wherein small numbers denote chiral centers in the compound; index m je 1-3 substituent R1 je vybraný zo skupiny pozostávajúcej z (1) atóm vodíka, (2) alkylu, (3) karboxaldehydu, (4) alkanoylu, kde alkanoyl môže byť prípadne substituovaný hydroxylom, a (5) -(CH2)nCO2R4, kde index n je 0 - 6 a substituent R4 je vybraný zo skupiny pozostávajúcej z (a) atómu vodíka, (b) alkylu, (c) cykloalkylu, (d) (cykloalkyl)alkylu, (e) arylu, a (f) arylalkylu, kde bod (c) a (d) môže byť prípadne substituovaný 1, 2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej z ····m is 1-3 R 1 is selected from the group consisting of (1) a hydrogen atom, (2) alkyl, (3) carboxaldehyde, (4) alkanoyl, wherein alkanoyl may be optionally substituted with hydroxyl, and (5) - ( CH 2 ) n CO 2 R 4 , wherein the index n is 0-6 and R 4 is selected from the group consisting of (a) a hydrogen atom, (b) alkyl, (c) cycloalkyl, (d) (cycloalkyl) alkyl, (e) (a) aryl, and (f) arylalkyl, wherein (c) and (d) may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of 171 • · ·· • ·· ·· · · • · · • · · · • · · ··· ·· ··· ·· • · • · • · ·· · (i) alkylu, (ii) alkoxy skupiny, a171 (i) alkyl, (ii) alkoxy groups, and (iii) arylu, a(iii) aryl, and kde bod (e) a (f) môže byť prípadne substituovaný 1,2 alebo 3 substituentami nezávisle vybranými zo skupiny pozostávajúcej zwherein (e) and (f) may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of
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