SI21098A1 - Propanoic acid derivatives that inhibit the binding of integrins to their receptors - Google Patents

Abstract

A method for the inhibition of the binding of alfa 4 beta 1 integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-1) and fibronectin; compounds that inhibit this binding; pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of diseases states in which alfa 4 beta 1 is involved.

Description

TEXAS BIOTECHNOLOGY CORPORATIONTEXAS BIOTECHNOLOGY CORPORATION

Derivati propanojske kisline, ki inhibirajo vezavo integrinov na njihove receptorjePropanoic acid derivatives that inhibit the binding of integrins to their receptors

Ta prijava je delno nadaljevanje US patentne prijave serijska št. 09/706,996, vloženeThis application is, in part, a continuation of US patent application serial no. 09 / 706,996, filed

6. novembra 2000, ki je delno nadaljevanje US patentne prijave serijska št. 09/565,507, vložene 5. maja 2000, s prednostjo US provizorične patentne prijave s serijsko št. 60/132,967, vložene 7. maja 1999, in s serijsko št. 60/170,441, vložene 10. decembra 1999.November 6, 2000, which is, in part, a continuation of US patent application serial no. No. 09 / 565,507, filed May 5, 2000, with priority of U.S. provisional patent application Serial No. 60 / 132,967, filed May 7, 1999, and Serial No. 60 / 170,441, filed December 10, 1999.

Predloženi izum je na splošno usmerjen na inhibicijo vezave (x^i-integrina na njegove receptorje, npr. VCAM-1 (vaskulama celična adhezijska molekula-1) in fibronektin. Izum se nanaša tudi na spojine, ki inhibirajo to vezavo, na farmacevtsko aktivne sestavke, ki obsegajo take spojine, in na uporabo takih spojin, kot so bodisi navedene zgoraj ali v formulacijah, za kontrolo ali preprečevanje bolezenskih stanj, v katere je vključen α₄β].The present invention is generally directed to inhibit the binding of (x ^ i-integrin to its receptors, e.g., VCAM-1 (vascular cell adhesion molecule-1) and fibronectin. The invention also relates to compounds that inhibit this binding to pharmaceutically active compositions comprising such compounds, and for the use of such compounds as are either listed above or in the formulations, for the control or prevention of conditions involving α ₄ β].

Kadar tkivo napade mikroorganizem ali je bilo poškodovano, imajo bele krvne celice, imenovane tudi levkociti, glavno vlogo pri vnetnem odzivu. Eden od najbolj pomembnih vidikov vnetnega odziva vključuje dogodek celične adhezije. Na splošno je za bele krvne celice ugotovljeno, da krožijo po krvnem obtoku. Vendar pa, kadar je tkivo inficirano ali postane poškodovano, bele krvne celice prepoznajo napadeno ali poškodovano tkivo, se vežejo na steno kapilare in migrirajo skozi kapilaro v poškodovano tkivo. Te dogodke posreduje družina proteinov, imenovanih celične adhezijske molekule.When tissue is invaded or damaged by a microorganism, white blood cells, also called leukocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. In general, white blood cells are found to circulate through the bloodstream. However, when the tissue is infected or becomes damaged, the white blood cells recognize the affected or damaged tissue, bind to the capillary wall and migrate through the capillary to the damaged tissue. These events are mediated by a family of proteins called cell adhesion molecules.

Obstajajo trije glavni tipi belih krvnih celic: granulociti, monociti in limfociti. Integrin α₄β, (imenovan tudi VLA-4 za zelo pozen antigen-4) je heterodimemi protein, izraženThere are three main types of white blood cells: granulocytes, monocytes, and lymphocytes. Integrin α ₄ β (also called VLA-4 for very late antigen-4) is a heterodimeric protein expressed

-2na površini monocitov, limfocitov in dveh podrazredov granulocitov: eozinofilcev in bazofilcev. Ta protein ima ključno vlogo pri celični adheziji, zaradi njegove sposobnosti, da prepozna in veže VCAM-1 in fibronektin, proteina, povezana z endotelijskimi celicami, ki oblagajo notranjo steno kapilar.-2 on the surface of monocytes, lymphocytes and two subclasses of granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion because of its ability to recognize and bind VCAM-1 and fibronectin, a protein associated with endothelial cells lining the inner wall of the capillaries.

Po infekciji ali poškodbi tkiva, ki obdaja kapilaro, endotelijske celice izrazijo vrsto adhezijskih molekul, vključno VCAM-1, ki so kritične za vezavo belih krvnih celic, ki so potrebne za boj z infekcijo. Pred vezavo na VCAM-1 ali fibronektin se bele krvne celice na začetku vežejo na določene adhezijske molekule, da upočasnijo njihov pretok in da pustijo celicam, da se kotalijo vzdolž aktiviranega endotelija. Monociti, limfociti, bazofilci in eozinofilci so nato sposobni, da se trdno vežejo na VCAM-1 ali fibronektin na steni žile preko a₄Pi-integrina. Dokazano je, da so take interakcije vključene tako v transmigracijo teh belih krvnih celic v poškodvano tkivo kot tudi v sam začetni dogodek kotaljenja.Following infection or damage to the tissue surrounding the capillary, endothelial cells express a variety of adhesion molecules, including VCAM-1, that are critical for the binding of white blood cells that are required to fight infection. Prior to binding to VCAM-1 or fibronectin, white blood cells initially bind to specific adhesion molecules to slow their flow and allow the cells to roll along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to bind tightly to VCAM-1 or fibronectin on the vessel wall via a ₄ Pi integrin. Such interactions have been shown to be involved in both the transmigration of these white blood cells into the damaged tissue and in the initial onset of the rolling.

Čeprav migracija belih krvnih celic na mesto poškodbe pomaga v boju z infekcijo in uničuje tuji material, pa lahko v mnogih primerih ta migracija postane nekontrolirana z belimi krvnimi celicami, ki navalijo na sceno in povzročijo obsežno poškodbo tkiva. Spojine, sposobne da blokirajo ta proces, so zato lahko koristne kot terapevtska sredstva. Zato bi bilo koristno, da bi razvili inhibitorje, ki bi preprečili vezavo belih krvnih celic na VCAM-1 in fibronektin.Although the migration of white blood cells to the site of injury helps fight infection and destroy foreign material, in many cases this migration can become uncontrolled with white blood cells that invade the scene and cause extensive tissue damage. Compounds capable of blocking this process may therefore be useful as therapeutic agents. Therefore, it would be useful to develop inhibitors that prevent the binding of white blood cells to VCAM-1 and fibronectin.

Nekatere bolezni, ki bi jih lahko zdravili z inhibicijo α₄βι-vezave, vključujejo, vendar neomejujoče, aterosklerozo, revmatoidni artritis, astmo, alergijo, multiplo sklerozo, lupus, vnetne bolezni črevesja, zavračanje presadkov, kontaktno hipersenzitivnost in diabetes tip 1. Poleg tega, da so α₄β! našli v nekaterih belih krvnih celicah, pa so ga našli tudi v različnih rakavih celicah, ki vključujejo levkemij ske, melanomske, limfomske in sarkomske celice. Zato se domneva, da je lahko celična adhezija, ki vključuje α₄β_ΐ5 vključena v metastazo določenih rakov. Inhibitorji α₄βι-vezave so zato koristni tudi pri zdravljenju nekaterih oblik raka.Some of the diseases that could be treated with inhibition of α ₄ βι-binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity and type 1 diabetes. that α ₄ β! found in some white blood cells, but was also found in various cancer cells that include leukemia, melanoma, lymphoma and sarcoma cells. Therefore, it is believed that cell adhesion involving α ₄ β _{ΐ5 may be} involved in the metastasis of certain cancers. Α ₄ βι-binding inhibitors are therefore also useful in the treatment of some cancers.

Izolacija in čiščenje peptida, ki inhibira vezavo α₄βι na protein, je opisana v US patentu št. 5,510,332. Peptidi, ki inhibirajo vezavo, so prikazani v WO 95/15973, EP 0 341 915, EP 0 422 938 Al, US patentu št. 5,192,746 in WO 96/06108. Nove spojine, ki so uporabne za inhibicijo in preprečevanje celične adhezije in patologij, posredovanih s celično adhezijo, so prikazne v WO 96/22966, WO 98/04247 in WO 98/04913.Isolation and purification of a peptide that inhibits α ₄ βι binding to a protein is described in U.S. Pat. No. 5,510,332. Binding inhibitory peptides are shown in WO 95/15973, EP 0 341 915, EP 0 422 938 Al, US Pat. No. 5,192,746 and WO 96/06108. Novel compounds useful for inhibiting and preventing cell adhesion and cell adhesion-mediated pathologies are shown in WO 96/22966, WO 98/04247 and WO 98/04913.

Zato je predmet predloženega izuma, da zagotovimo nove spojine, ki so inhibitorji α₄βι-vezave, in farmacevtske sestavke, ki vključujejo take nove spojine.Therefore, it is an object of the present invention to provide novel compounds that are inhibitors of α ₄ βι-binding and pharmaceutical compositions that include such novel compounds.

Predloženi izum je usmerjen na nove spojine z naslednjo formulo I:The present invention is directed to novel compounds of the following Formula I:

formula Iformula I

JJ

kje krog Q pomeni enega ali več obročev, q je celo število od 0 do 6where the circle Q means one or more rings, q is an integer from 0 to 6

M je izbran iz skupine, ki jo sestavljajo -C(R⁹)(R¹⁰)- in -(CH₂)_U-, kjer je u celo število od 0 do 3M is selected from the group consisting of -C (R ⁹ ) (R ¹⁰ ) - and - (CH ₂ ) _U -, where u is an integer from 0 to 3

J je izbran iz skupine, ki jo sestavljajo -O-, -S- in -NR T je izbran iz skupine, ki jo sestavljata -C(O)- in -(CH₂)_b, kjer je b celo število od 0 do 3J is selected from the group consisting of -O-, -S- and -NR T is selected from the group consisting of -C (O) - and - (CH ₂ ) _b , where b is an integer from 0 to 3

L je izbran iz skupine, ki jo sestavljajo -O-, -NR¹³-, -S- in -(CH₂)_V, kjer je v celo število 0 ali 1L is selected from the group consisting of -O-, -NR ¹³ -, -S- and - (CH ₂ ) _V , where v is 0 or 1

X je izbran iz skupine, ki jo sestavljajo -CO₂B, -PO₃H₂, -SO₃H, -SO₂NH₂,X is selected from the group consisting of -CO ₂ B, -PO ₃ H ₂ , -SO ₃ H, -SO ₂ NH ₂ ,

-SO₂NHCOR¹⁴, -OPO3H2, -C(O)NHC(O)R¹⁵, -C(O)NHSO2R¹⁶, tetrazolil, oksazolil in hidroksil-SO ₂ NHCOR ¹⁴ , -OPO3H2, -C (O) NHC (O) R ¹⁵ , -C (O) NHSO2R ¹⁶ , tetrazolyl, oxazolyl and hydroxyl

R¹¹, R¹² in R¹³ so vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkinilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inR ¹¹ , R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, carboxamide, carboxamide. cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carboxyalkyl, and carbamyl group

B, R¹, R⁴, R⁶, R⁸, R⁹, R¹⁰, R¹⁴, R¹⁵ in R¹⁶ so pri vsakem pojavljanju neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkilna, alifatska acilna,B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁴ , R ¹⁵ and R ¹⁶ are independently selected at each occurrence from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl,

-CF₃, -CO₂H, -SH, -CN, -NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(C₁-C₃alkil)-C(O)(C₁-C₃alkilna), -NHC(O)N(C_r CjalkiljCCOj-NHCCj-Caalkilna), -NHC(O)NH(C_rC₆alkilna), -NHSO₂(C,C₃alkilna), -NHSO₂(arilna), alkoksialkilna, alkilamino, alkenilamino, di(CiC₃)amino, -C(O)O-(C,-C₃)alkilna, -C(O)NH-(C_rC₃)alkilna, -C(O)N(C_r C₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(Ci-C₃alkilna), -SO₃(C!-C₃alkilna), sulfonamido, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, kjer so B, R¹, R⁴, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ in R¹⁶ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone, pri čemer, kadar je L -NR¹³-, lahko R⁴ in R¹³, vzeta skupaj, tvorita obroč in kjer R⁶ in R⁸, vzeta skupaj, lahko tvorita obroč in pri čemer, kadar je M -C(R⁹)(R¹⁰)-, lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč, ali njihovo farmacevtsko sprejemljivo sol.-CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) ( C ₁ -C ₃ alkyl), -NHC (O) N (C _r CjalkiljCCOj-NHCCj-Caalkilna), NHC (O) NH (C _r C ₆ alkyl), -NHSO ₂ (C, C ₃ alkyl), - -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (CIC ₃₎ amino, -C (O) O- (C, -C ₃₎ alkyl, -C (O) NH- (C _r C ₃₎ alkyl, -C (O) N (C _r C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO ₂ - (C 1 -C ₃ alkyl), -SO ₃ (C 1 -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group wherein B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ¹⁶ unsubstituted or substituted by at least one s an electron-donating or electron-withdrawing black where, when L is -NR ¹³ -, R ⁴ and R ¹³ taken together can form a ring and where R ⁶ and R ⁸ taken together can form a ring and wherein when M is -C (R ⁹ ) (R ¹⁰ ) -, R ⁹ and R ¹⁰ taken together may form a ring, or a pharmaceutically acceptable salt thereof.

Za formulo I imajo lahko predložene prednostne spojine krog Q kot arilni, cikloalkilni, biarilni ali heterociklilni obroč.For Formula I, the preferred compounds may have a circle Q as an aryl, cycloalkyl, biaryl or heterocyclyl ring.

Bolj podrobno so lahko spojine v smislu izuma opisane s spodnjo formulo II:In more detail, the compounds of the invention may be described by the formula II below:

R⁴ kjer je Y pri vsakem pojavljanju neodvisno izbran iz skupine, ki jo sestavljajo C(O), N, CR⁷, C(R²)(R³), NR⁵, CH, O in S, m je celo število od 2 do 5R ⁴ wherein Y at each occurrence is independently selected from the group consisting of C (O), N, CR ⁷ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S, m is an integer of 2 to 5

W je izbran iz skupine, ki jo sestavljajo C, N in CRW is selected from the group consisting of C, N and CR

T je izbran iz skupine, ki jo sestavljajo C(O) in (CH₂)b, kjer je b celo število odT is selected from the group consisting of C (O) and (CH ₂ ) b, where b is an integer of

Odo 3 >Odo 3>

L je izbran iz skupine, ki jo sestavljajo O, NR , S in (CH₂)_n, kjer je n celo število Oali 1L is selected from the group consisting of O, NR, S and (CH ₂ ) _n , where n is an integer Oali 1

R⁵, R¹¹ in R¹³ so pri vsakem pojavljanju vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkinilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna,R ⁵ , R ¹¹ and R ¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde , carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl,

-6tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, in-6thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group, and

B, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰ in R²² so vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkilna, alifatska acilna, -CF₃, -CO2H, -SH, -CN, -NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(C₁-C₃alkil)-C(O)(C₁-C₃alkilna), -NHC(O)N(C₁-C₃alkil)C(O)-NH(C₁C₃alkilna), -NHC(O)NH(C_rC₆alkilna), -NHSO₂(C,-C₃alkilna), -NHSO₂(arilna, alkoksialkilna, alkilamino, alkenilamino, di(Cj-C₃)amino, -C(O)O-(C_r C₃)alkilna, -C(O)NH-(C₁-C₃)alkilna, -C(O)N(C_rC₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(C]-C₃alkilna), -SO₃-(C_rC₃alkilna), sulfonamido, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, kjer so B, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³ in R²² nesubstituirani ali substituirani z vsaj eno skupino, ki daje elektrone ali odvzema elektrone, in pri čemer, kadar je L -NR¹³-, lahko R⁴ in R¹³, vzeta skupaj, tvorita obroč, in pri čemer lahko R⁶ in R⁸, vzeta skupaj, tvorita obroč in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč, ali njihovo farmacevtsko sprejemljivo sol.B, R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ²² are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO2H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C ₁ -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) -NH (C ₁ C ₃ alkyl), -NHC (O) NH (C _r C ₆ alkyl), -NHSO ₂ (C, -C ₃ alkyl), -NHSO ₂ (aryl, alkoxyalkyl, alkylamino, alkenylamino, di (Cl-C ₃₎ amino, -C (O) O- ( C _r C ₃ alkyl, -C (O) NH- (C ₁ -C ₃ ) alkyl, -C (O) N (C _r C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , - OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, alkylaryl, alkylaryl, alkylaryl, alkylaryl SO ₂ - (C ] -C ₃ alkyl), -SO ₃ - (C _r C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group, wherein B, R ^2, R ^3, R ^4, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹³ and R ^{22 are} unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, and wherein when L is -NR ¹³ -, R ⁴ and R ¹³ taken together may form a ring, and wherein R ⁶ and R ⁸ together may form a ring, and wherein R ⁹ and R ¹⁰ taken together may form a ring, or a pharmaceutically acceptable salt thereof. sol.

Bolj podrobno lahko spojine v smislu izuma opišemo s spodnjo formulo III:In more detail, the compounds of the invention can be described by the formula III below:

formula III kjer je q celo število od nič do 4,formula III where q is an integer from zero to 4,

T je izbran iz skupine, ki jo sestavljata C(O) in (CH₂)b, kjer je b celo število od 0 do 3T is selected from the group consisting of C (O) and (CH ₂ ) b, where b is an integer from 0 to 3

L je izbran iz skupine, ki jo sestavljajo O, NR¹³, S in (CH₂)_n, kjer je n celo število Oali 1L is selected from the group consisting of O, NR ¹³ , S and (CH ₂ ) _n , where n is an integer Oali 1

R¹¹ in R¹³ sta vsak neodvisno izbrana iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkilnilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, inR ¹¹ and R ¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkylnylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkenyl , cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and -C (benzoyl) aryl (O) -C (benzyloxy) and (C)

B, R¹, R⁴, R⁶, R⁸, R⁹ in R¹⁰ so pri vsakem pojavljanju neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkoksi, alifatska acilna, -CF₃, -CO₂H, -SH, -CN, -NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, N(C₁-C₃alkil)-C(O)(C₁-C₃alkilna), -NHC(O)N(C_rC₃alkil)C(O)NH(Ci-C₃ alkilna), -NHC(O)NH(C_rC₆alkilna), -NHSO₂(C_rC₃alkilna), -NHSO₂(arilna), alkoksialkilna, alkilamino, alkenilamino, di(Ci-C₃)amino, -C(O)O-(C_r C₃)alkilna, -C(O)NH(C_rC₃)alkilna, -C(O)N(C₁-C₃alkilna)₂, -CH=NOH,B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and R ¹⁰ are independently selected at each occurrence from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkoxy , aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, N (C ₁ -C ₃ alkyl) -C ( O) (C ₁ -C ₃ alkyl), -NHC (O) N (C _r C ₃ alkyl) C (O) NH (C 1 -C ₃ alkyl), -NHC (O) NH (C _r C ₆ alkyl) , -NHSO ₂ (C _r C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (Ci-C ₃₎ amino, -C (O) O- (C _r C ₃ alkyl), - C (O) NH (C _r C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH,

-ΡΟ₃Η₂, -ΟΡΟ₃Η₂, haloalkilna, alkoksialkoksi, karboksialdehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(Ci-C₃alkilna), -SO3-(Ci-C₃alkilna), sulfonamido, karbamatna, ariloksialkilna in C(O)NH(benzilna) skupina, kjer so B, R¹, R⁴, R⁶, R⁸, R⁹, R¹⁰, R¹¹ in R¹³ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone in pri čemer, kadar je L -NR¹³-, lahko R⁴ in R¹³, vzeta skupaj, tvorita obroč in pri čemer lahko R in R , vzeta skupaj, tvorita obroč in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč ali njihova farmacevtsko sprejemljiva sol.-ΡΟ ₃ Η ₂ , -ΟΡΟ ₃ Η ₂ , haloalkyl, alkoxyalkyloxy, carboxyldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylarylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylalkyl, arylaryl, alkilheterociklilna, heterocyclylalkyl, sulfonyl, -SO ₂ - (C-C ₃ alkyl), --SO3 @ (Ci-C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group, wherein B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{13 are} unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, and where, when L is -NR ¹³ -, R ⁴ and R ¹³ taken together form a ring and wherein R and R taken together can form a ring and wherein R ⁹ and R ¹⁰ taken together can form a ring or a pharmaceutically acceptable salt thereof.

Predložene prednostne spojine s formulo III imajo q kot ena ali dva, R¹ pri vsakem pojavljanju neodvisno kot aralkil ali alkil, R⁶ kot alkil, B, R⁸, R⁹, R¹⁰ in R¹¹ so vsak neodvisno kot vodik, T kot -(CH₂)_b-, pri čemer je b nič, L kot -(CH₂)_n-, pri čemer je n nič in R⁴ kot aril.The present preferred compounds of formula III have q as one or two, R ¹ at each occurrence independently as aralkyl or alkyl, R ⁶ as alkyl, B, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each independently as hydrogen, T as - (CH ₂ ) _b -, where b is zero, L as - (CH ₂ ) _n -, where n is zero and R ^{4 is} aryl.

Bolj podrobno lahko spojine v smislu izuma opišemo s spodnjo formulo IV:In more detail, the compounds of the invention can be described by the formula IV below:

formula IV kjer je s celo število od nič do pet,formula IV where s is an integer from zero to five,

R²¹ je izbran iz skupine, ki jo sestavljajo aril, alkilheterociklil, heterociklilalkil, heterocikloil, aralkil, alkilaril, alkil, aroil, ariloksi, cikloalkil, cikloalkenil, cikloalkinil, biaril, arilamino, tioaril in diarilaminoR ²¹ is selected from the group consisting of aryl, alkylheterocyclyl, heterocyclylalkyl, heterocycloyl, aralkyl, alkylaryl, alkyl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, biaryl, arylamino, thioaryl and diarylamino

B, R⁶, R⁸, R⁹, R¹⁰, R¹⁷, R¹⁸, R¹⁹ in R²⁰ so pri vsakem pojavljanju vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkilnoksi, tioalkoksi, hidroksialkoksi, alifatska acilna, -CF₃, -CO₂H, -SH, -CN, NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(Ci-C₃-alkil)-C(O)(Ci-C₃alkilna), -NHC(O)N(Cr C₃alkil)C(O)NH(Ci-C₃alkilna), -NHC(O)NH(Ci-C₆alkilna), -NHSO₂(C_r C₃alkilna), -NHSO₂(arilna, alkoksialkilna, alkilamino, alkenilamino, di(C_r C₃)amino, -C(O)O-(C_rC₃)alkilna, -C(O)NH(C_rC₃)alkilna, -C(O)N(C_r C₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksialdehidna, karboksiamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(Ci-C₃alkilna), -SO₃(C_rC₃alkilna), sulfonamido, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, inB, R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyloxy, thioalkoxy, hydroxyalkoxy, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (Ci-C ₃ alkyl) -C (O) (Ci-C ₃ alkyl), -NHC (O) N (Ci-C ₃ alkyl) C (O) NH (Ci-C ₃ alkyl), -NHC (O) NH (C -C ₆ alkyl), -NHSO ₂ (C _r C ₃ alkyl), -NHSO ₂ (aryl, alkoxyalkyl, alkylamino, alkenylamino, di (C _r C ₃ ) amino, -C (O) O- (C _r C ₃ ) alkyl, -C (O) NH (C _r C ₃ ) alkyl, -C (O) N (C _r C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl , alkoxyalkoxy, carboxyaldehyde, carboxyamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, aralkyl, aralkyl, aralkyl sulphanilic, -SO ₂ - (C-C ₃ alkyl), -SO ₃ (C _r C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group, and

R¹¹ je izbran iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkilnilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, kjer so B, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹⁷, R¹⁸, R¹⁹, R²⁰ in R²¹ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone in kjer R⁶ in R⁸, vzeta skupaj, lahko tvorita obroč in kjer R⁹ in R¹⁰, vzeta skupaj, lahko tvorita obroč in kjer R¹⁸ in R¹⁹, vzeta skupaj, lahko tvorita obroč in kjer R¹⁹ in R²⁰, vzeta skupaj, lahko tvorita obročR ¹¹ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkylnylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkilheterociklilna, heterocyclylalkyl, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group, wherein B, R ^6, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ unsubstituted or substituted by at least one electron-donating or electron-withdrawing group and where R ⁶ and R ⁸ taken together may form a ring and where R ⁹ and R ¹⁰ taken together can form a ring and where R ¹⁸ and R ¹⁹ taken together can form a ring and where R ¹⁹ and R ²⁰ taken together can form a ring

-1010 ali njihova farmacevtsko sprejemljiva sol.-1010 or a pharmaceutically acceptable salt thereof.

Predložene prednostne spojine s formulo IV imajo B, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸ in R²⁰ vsakega neodvisno kot vodik, R⁶ in R¹⁹ vsakega neodvisno kot alkil, s kot celo število od nič do tri, R¹⁷ pri vsakem pojavljanju neodvisno kot halogen, alkil, haloalkil, -CF₃, alkoksi ali -OH, in R²¹ kot aril. Predložena najbolj prednostna spojina s formulo IV ima s kot nič, R⁶ kot butil, B, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸ in R²⁰ vsakega neodvisno kot vodik, in R kot l,3-benzodioksol-5-il.The present preferred compounds of formula IV have B, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ and R ²⁰ each independently as hydrogen, R ⁶ and R ¹⁹ each independently as alkyl, with an integer from zero to three, R ¹⁷ at each occurrence is independently as halogen, alkyl, haloalkyl, -CF ₃ , alkoxy or -OH, and R ²¹ as aryl. The most preferred compound of formula IV presented is having zero, R ⁶ as butyl, B, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ and R ²⁰ each independently as hydrogen, and R as 1,3-benzodioxole- 5-il.

Spojine v smislu predloženega izuma lahko opišemo tudi s formulo V, prikazano spodaj:The compounds of the present invention can also be described by the formula V shown below:

kjer je krog Q obroč, ki je izbran iz skupine, ki jo sestavljajowhere the circle Q is a ring selected from the group consisting of it

q je celo število od nič do štiriq is an integer from zero to four

B, R¹, R⁶, R⁸, R⁹ in R¹⁰ so vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik,B, R ¹ , R ⁶ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen,

-1111 halogen, alkil, alkenil, alkinil, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkil, alifatski acil, -CF₃, -CO₂H, -SH, -CN, NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonil, heterocikloil, karboksi, -N(Ci-C₃alkil)-C(O)(CiC₃alkil), -NHC(O)NH(Ci-C₃alkil),-NHC(O)N(Ci-C₃alkil)C(O)NH(Ci-C₃alkil), -NHSO₂(Ci-C₃alkil), -NHSO₂(aril), alkoksialkil, -C_rC₃alkilamino, alkenilamino, alkinilamino, di(Ci-C₃alkil)amino, -C(O)O-(Ci-C₃alkil), C(O)NH-(C_rC₃alkil), -CH=NOH, -PO₃H₂, -OPO₃H₂, -C(O)N(C,-C₃alkil)₂, haloalkil, alkoksialkoksi, karboksaldehid, karboksamid, cikloalkil, cikloalkenil, cikloalkinil, cikloalkilalkil, aril, aroil, ariloksi, arilamino, biaril, tioaril, diarilamino, heterociklil, alkilaril, aralkenil, aralkil, alkilheterociklil, heterociklilalkil, sulfonil, -SO₂-(Ci-C₃alkil), -SO₃-(Ci-C₃alkil), sulfonamido, ariloksialkil, karboksil, karbamat in -C(O)NH(benzil)-1111 halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C 1 -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) NH (C 1 -C ₃ alkyl), - NHC (O) N (C 1 -C) ₃ alkyl) C (O) NH (C 1 -C ₃ alkyl), -NHSO ₂ (C 1 -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, -C _r C ₃ alkylamino, alkenylamino, alkynylamino, di (Ci -C ₃ alkyl) amino, -C (O) O- (Ci-C ₃ alkyl), C (O) NH- (C _r C ₃ alkyl), -CH = NOH, -PO ₃ H _2, -OPO ₃ H ₂ , -C (O) N (C 1 -C ₃ alkyl) ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylarylamino; , alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO ₂ - (C 1 -C ₃ alkyl), -SO ₃ - (C 1 -C ₃ alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate and -C (O) NH (benzyl)

R⁵ in R¹¹ sta vsak neodvisno izbrana iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkinilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inR ⁵ and R ¹¹ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxylalkyl, cycloalkylalkyl, cycloalkylamide, , cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and (C) aryl (benzyloxy) and (C) aryloxyalkyl and (C)

R je izbran iz skupine, ki jo sestavljajo aril, alkilheterociklil, heterociklilalkil, heterocikloil, aralkil, alkilaril, alkil, aroil, ariloksi, cikloalkil, cikloalkenil, cikloalkinil, biaril, arilamino, tioaril in diarilamino, kjer so B, R¹, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹ in R²¹ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone, r o pri čemer lahko R in R , vzeta skupaj, tvorita obroč in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč ali njihova farmacevtsko sprejemljiva sol.R is selected from the group consisting of aryl, alkylheterocyclyl, heterocyclylalkyl, heterocycloyl, aralkyl, alkylaryl, alkyl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, biaryl, arylamino, thioaryl and diarylamino, wherein B, R ^1, R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ²¹ unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, wherein R and R taken together may form a ring and wherein R ⁹ and R ¹⁰ taken together form a ring or a pharmaceutically acceptable salt thereof.

-1212-1212

Predložene prednostne spojine s formulo V imajo B, R⁶, R⁸, R⁹, R¹⁰ in R¹¹ vsakega neodvisno kot vodik in alkil, R¹ in R⁵ pri vsakem pojavljanju neodvisno kot vodik, 2tienilmetil, benzil ali metil in R²¹ kot aril.The present preferred compounds of formula V have B, R ⁶ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each independently as hydrogen and alkyl, R ¹ and R ⁵ at each occurrence independently as hydrogen, 2-thienylmethyl, benzyl or methyl, and R ²¹ like aryl.

Predložene prednostne spojine vključujejo (3S)-(l,3-benzodioksol-5-il)-3-(((2S)-2-(2okso-3-(2-tienilmetil)tetrahidro-1 (2H)-pirimidinil)heksanoil)amino) propanoj sko kislino, (3 S)-3 -(1,3 -benzodioksol-5 -il)-3 -((2R,S)-2-(3 -benzil- 5 -metil-2-okso-1 (2H)piridinil)heksanoilamino)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3((2R,S)-2-(3-(3-klorobenzil)-5-metil-2-okso-l(2H)piridinil)heksanoilamino)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3-(((2S)2- (2-okso-3-(fenilmetil)-l-(2H)-piridinil)heksanoil)amino)propanoj sko kislino, (3S)3- (l,3-benzodioksol-5-il)-3-((2-(3-klorofenil)metil)-5-metil-2-okso-l(2H)piridinil)heksanoil)amino)propanojsko kislino, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin-1 (2H)-il)heksanoil]amino} -3 -(3,5 -dimetoksifenil)propanoj sko kislino, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-(3fluoro-4-metoksifenil)propanoj sko kislino, (3 S)-3 - {[2-(3 -benzil- 5 -metil-2oksopiridin-l(2H)-il)heksanoil]amino}-3-(3-izopropoksifenil)propanojsko kislino, (3S)-3-({2-[3-(3 -klorobenzil)-5 -metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3 izopropoksifenil)propanojsko kislino, (3S)-3-(3-izopropoksifenil)-3--{2-[3-(2metoksibenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojsko kislino, (3 S)-3 - {[2-(3 -benzil-5 -metil-2-oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(3 -etoksi-4metoksifenil)propanojsko kislino, (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin-1 (2H)il)heksanoil]amino}-3-(4-metoksi-3-metilfenil)propanojsko kislino, (3 S)-3-{[2-(3 benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-fenilpropanojsko kislino, (3S)-3-({2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4metilfenil)propanoj sko kislino, (3 S)-3 -({ 2- [3 -(2-klorobenzil)- 5 -metil-2-oksopiridin1 (2H)-il]heksanoil}amino)-3-(3-izopropoksifenil)propanojsko kislino, (3 S)-3 -({2- [3 (2-klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-fenilpropanojsko kislino, (3 S)-3 -(1 -metil-1 H-indol-6-il)-3 -({ 2- [5 -metil-2-okso-3 -(fenilmetil)-1 (2H)piridiniljheksanoil}amino)propanojsko kislino, (3 S)-3 - {3 - [(1-metiletil)oksi]fenil}-3({2-[5-metil-3-(2-naftalenilmetil)-2-okso-l(2H)-piridnil]heksanoil}amino)Suggested preferred compounds include (3S) - (1,3-benzodioxol-5-yl) -3 - (((2S) -2- (2-oxo-3- (2-thienylmethyl) tetrahydro-1 (2H) -pyrimidinyl) hexanoyl ) amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3-benzyl-5-methyl-2-oxo- 1 (2H) pyridinyl) hexanoylamino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 ((2R, S) -2- (3- (3-chlorobenzyl) -5- methyl-2-oxo-1 (2H) pyridinyl) hexanoylamino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2S) 2- (2-oxo-3 - (phenylmethyl) -1- (2H) -pyridinyl) hexanoyl) amino) propanoic acid, (3S) 3- (1,3-benzodioxol-5-yl) -3 - ((2- (3-chlorophenyl) methyl ) -5-methyl-2-oxo-1 (2H) pyridinyl) hexanoyl) amino) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2oxopyridin-1 ( 2H) -yl) hexanoyl] amino} -3- (3,5-dimethoxyphenyl) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3fluoro-4-methoxyphenyl) propanoic acid, (3S) -3 - {[2- (3-benzyl-5-methyl-2oxopyridin-1 (2H) ) -yl) hexanoyl] amino} -3- (3-yl) zopropoxyphenyl) propanoic acid, (3S) -3 - ({2- [3- (3-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3 isopropoxyphenyl) propanoic acid, (3S) -3- (3-isopropoxyphenyl) -3- {2- [3- (2methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (3-ethoxy-4methoxyphenyl) propanoic acid, (3S ) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin-1 (2H) yl) hexanoyl] amino} -3- (4-methoxy-3-methylphenyl) propanoic acid, (3 S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3-phenylpropanoic acid, (3S) -3 - ({2- [3- ( 2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3 S) -3 - ({2- [3 - (2 -chlorobenzyl) -5-methyl-2-oxopyridin (2H) -yl] hexanoyl} amino) -3- (3-isopropoxyphenyl) propanoic acid, (3 S) -3 - ({2- [3 (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3-phenylpropanoic acid, (3 S) -3- (1-methyl-1H- indol-6-yl) -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) pyridinylhexanoyl} amino) propanoic acid, (3 S) -3 - {3 - [ (1-methylethyl) oxy] phenyl} -3 ({2- [5-methyl-3- (2-naphthalenylmethyl) -2-oxo-1 (2H) pyridyl] hexanoyl} amino)

-1313 propanoj sko kislino, (3 S)-3 -({2- [5 -metil-2-okso-3 -(fenilmetil)-1 (2H)-piridini 1] heksanoil}amino)-3-[3-(2-metilpropil)fenil]propanojsko kislino, (3S)-3-[3(difluorometil)fenil]-3-({2-[5-metil-2-okso-3-(fenilmetil)-l(2H)-piridinil]heksanoil} amino)propanoj sko kislino, (3 S)-3 - {3 - [(1 -metiletil)oksi] fenil} -3 -({2- [5 -metil- 3-[(2metilfenil)metil]-2-okso-l(2H)-piridinil]heksanoil}amino)propanojsko kislino, (3S)-3(3 -fluorofenil)-3 -( { 2- [5 -metil-2-okso-3 -(fenilmetil)-1 (2H)-piridinil]heksanoil} amino) propanoj sko kislino, (3S)-3-({2-[3- [(2-kloro-4-fluorofenil)metil]- 5 -metil-2-okso1 (2H)-piridinil]heksanoil} amino)-3 - {3 - [(1 -metiletil)oksi] fenil }propanoj sko kislino in (3 S)-3 - { 3 - [(1 -metiletil)oksi] fenil }-3-({2- [5 -metil-2-okso-1 -(fenilmetil)-1,2-dihidro-3 piridinil]-2-fenilacetil}amino)propanoj sko kislino, in njene farmacevtsko sprejemljive soli.-1313 propanoic acid, (3 S) -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) -3- [3- (2-methylpropyl) phenyl] propanoic acid, (3S) -3- [3 (difluoromethyl) phenyl] -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl} amino) propanoic acid, (3 S) -3 - {3 - [(1-methylethyl) oxy] phenyl} -3 - ({2- [5-methyl-3 - [(2methylphenyl) methyl] -2-oxo-1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid, (3S) -3 (3-fluorophenyl) -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid, (3S) -3 - ({2- [3- [(2-chloro-4-fluorophenyl) methyl] -5-methyl-2-oxo ( 2H) -pyridinyl] hexanoyl} amino) -3- {3 - [(1-methylethyl) oxy] phenyl} propanoic acid and (3 S) -3- {3 - [(1-methylethyl) oxy] phenyl} - 3 - ({2- [5-methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3 pyridinyl] -2-phenylacetyl} amino) propanoic acid, and its pharmaceutically acceptable salts.

Druge predložene prednostne spojine vključujejo:Other preferred compounds provided include:

(3S)-3-{[(2S)-2-(3-benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-(3',4'dimetoksi-1,1 '-bifenil-4-il)propanojsko kislino, 3S)-3-({(2S)-2-[3-(2-klorobenzil)-5metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(3',4'-dimetoksi-l,r-bifenil-4il)propanoj sko kislino, (3 S)- 3 -(1,1 ’-bifenil-4 - i 1) - 3 -({(2 S)-2 - [3 -(2-kloro-6-metilbenzil)5-metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)propanojsko kislino, (3 S)-3- {[(2S)-2(3 -benzil-5-metil-2-oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(1,1 '-bifenil-4il)propanoj sko kislino, (3 S)-3 -(1,1 ’ - b i feni 1-4 - il) - 3 -({(2 S)-2- [3 -(2-klorobenzil)-5 -metil2- oksopiridin-1 (2H)-il]heksanoil} amino)propanoj sko kislino, (3 S)-3- {[(2S)-2-(3 benzil-5 -metil-2-oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(4'-metil-1,1' -bi fenil-4 il)propanoj sko kislino, (3 S)-3 -({(2 S)-2- [3 -(2-klorobenzil)-5-metil-2-oksopiridin1 (2H)-il]heksanoil} amino)-3 -(4'-metil-1,1 '-bifenil-4-il)propanoj sko kislino, (3 S)-3 ({(2S)-2-[3-(2-kloro-6-metilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)3- (4'-metil-1,1 '-bifenil-4-il)propanojsko kislino, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin-l(2H)-il)heksanoil]amino}-3-(2',6'-dimetoksi-l,r-bifenil-4-il)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)-3-(2',6'-dimetoksi-l,r-bifenil-4-il)propanojsko kislino, (3S)-3({(2S)-2- [3 -(2-kloro-6-metilbenzil)- 5 -metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-1414(3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (3 ', 4'dimethoxy-1 , 1'-biphenyl-4-yl) propanoic acid, 3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3 ', 4'-dimethoxy-1,1'-biphenyl-4yl) propanoic acid, (3 S) -3- (1,1'-biphenyl-4 - and 1) -3 - ( {(2S) -2- [3- (2-chloro-6-methylbenzyl) 5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- { [(2S) -2 (3-Benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (1,1'-biphenyl-4yl) propanoic acid, (3 S ) -3 - (1,1 '- bi-phen 1-4-yl) -3 - ({(2 S) -2- [3- (2-chlorobenzyl) -5-methyl2-oxopyridin-1 (2H) - yl] hexanoyl} amino) propanoic acid, (3 S) -3 - {[(2S) -2- (3 benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3 - (4'-methyl-1,1'-bi-phenyl-4-yl) propanoic acid, (3 S) -3 - ({(2 S) -2- [3- (2-chlorobenzyl) -5-methyl -2-oxopyridin (2H) -yl] hexanoyl} amino) -3- (4'-methyl-1,1'-biphenyl-4-yl) propanoic acid, (3 S) -3 ({(2S) - 2- [3- (2-Chloro-6-m ethylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) 3- (4'-methyl-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3- {[(2S) -2- (3-benzyl-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4- yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- ( 2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 ({(2S) -2- [3- (2-chloro-6-methylbenzyl) -5-methyl -2-Oxopyridin-1 (2H) -yl] hexanoyl} amino) -1414

3-(2',6'-dimetoksi-l,r-bifenil-4-il)propanojsko kislino, (3S)-3-{[(2S)-2-(3-benzil-5metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-(l,r-bifenil-3-il)propanojsko kislino, (3 S)-3-( 1,1 '-bifenil-3 -il)-3 -({(2 S)-2- [3 -(2-klorobenzil)-5-metil-2-oksopiridinl(2H)-il]heksanoil}amino)propanojsko kislino, (3S)-3-(l,l'-bifenil-3-il)-3-({(2S)-2[3 -(2-kloro-6-metilbenzil)-5 -metil-2-oksopiridin-1 (2H)il]heksanoil}amino)propanojsko kislino, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin- l(2H)-il)heksanoil]amino}-3-(2'-metoksi-1,1 '-bifenil-3-il)propanojsko kislino, (3 S)-3 -({(2 S)-2-[3 -(2-klorobenzil)-5 -metil-2-oksopiridin-1 (2H)il]heksanoil}amino)-3-(2'-metoksi-l,r-bifenil-3-il)propanojsko kislino, (3S)-3-({(2S)2-[3-(2-kloro-6-metilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(2'metoksi-1,1 '-bifenil-3 -il)propanoj sko kislino, (3 S)-3 -({(2 S)-2- [3 -(2-fluoro-6metoksibenzil)-5-metil-2-oksopiridin-l(2H)-il]-heksanoil}amino)-3-(4metilfenil)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2,6-dimetilbenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil}amino)-3-(4-metilfenil)propanojsko kislino, (3S)-3({(2S)-2-[3-(3,5 -dimetilbenzil)- 5-metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(4metilfenil)propanoj sko kislino, (3 S)-3 -({(2S)-2-[3 -(2,6-diklorobenzil)- 5 -metil-2oksopiridin-l(2H)-il]heksanoil}amino)-3-(4-metilfenil)propanojsko kislino, (3S)-3({(2S)-2- [3 -(2-kloro-6-fluorobenzil)- 5-metil-2-oksopiridin-1 (2H)il]heksanoil}amino)-3-(4-metilfenil)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2,6difluorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4metilfenil)propanoj sko kislino, (3 S)-3 -(1 ,3 -benzodioksol- 5 -il)-3 -( {(2S)-2- [3 -(2,6difluorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2-kloro-6-fluorobenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil}amino)propanojsko kislino, (3 S)-3 -(1,3-benzodioksol5-il)-3-({(2S)-2-[3-(2,6-diklorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3(2,6-dimetilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(3,5-dimetilbenzil)-5-metil-2oksopiridin-l(2H)-il]heksanoil}amino)propanojsko kislino, (3S)-3-(l ,3-benzodioksol5-il)-3-({(2S)-2-[3-(2-fluoro-6-metoksibenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-1515 oksopiridin-l(2H)-il]heksanoil}amino)-3-(3,4-dietoksifenil)propanojsko kislino, (3S)3-(3,4-dietoksifenil)-3-({(2S)-2-[3-(2,6-difluorobenzil)-5-metil-2-oksopiridin-l(2H)iljheksanoil} amino)propanoj sko kislino, (3 S)-3-( {(2S)-2- [3 -(2,6-difluorobenzil)-5metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(3-etoksifenil)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2-kloro-6-iluorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)-3-(3-etoksifenil)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]-3-metilbutanoil}amino)-3-(4metilfenil)propanojsko kislino, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2oksopiridin-l(2H)-il]-4-metilpentanoil}amino)-3-(4-metilfenil)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridinl(2H)-il]-4-metilpentanoil}amino)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5il)-3 -({(2 S)-2- [3 -(2-klorobenzil)-5 -metil-2-oksopiridin-1 (2H) - il] -3 metilbutanoil} amino)propanoj sko kislino, (3 S)-3 -(1,3 -benzodioksol- 5 - i 1)-3 -({(2 S)-2[3 -(2-klorobenzil)-5-metil-2-oksopiridin-1 (2H)-il]-3 fenilpropanoil}amino)propanojsko kislino, (3S)-3-({2S)-2-[3-(2-klorobenzil)-5-metil2- oksopiridin-l(2H)-il]-3-fenilpropanoil}amino)-3-(4-metilfenil)propanojsko kislino, (3S)-3-(l,3-benzodioksol-5-il)-3-(((2R)-2-(l-benzil-5-metil-2-okso-l,2-dihidropiridin3- il)-heksanoil)amino)propanojsko kislino in njihove farmacevtsko sprejemljive soli.3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (1,1'-biphenyl-3-yl) propanoic acid, (3 S) -3- (1,1'-biphenyl-3-yl) -3 - ( {(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridinyl (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,1'-biphenyl -3-yl) -3 - ({(2S) -2 [3- (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, ( 3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (2'-methoxy-1,1'-biphenyl -3-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino ) -3- (2'-methoxy-1,1'-biphenyl-3-yl) propanoic acid, (3S) -3 - ({(2S) 2- [3- (2-chloro-6-methylbenzyl) -5 -methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (2'methoxy-1,1'-biphenyl-3-yl) propanoic acid, (3 S) -3 - ({ (2S) -2- [3- (2-fluoro-6methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] -hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2 - [3- (2,6-dimethylbenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 ({(2S) -2- [3- (3,5-dimethylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3 S) -3 - ({(2S) -2- [3- (2,6-dichlorobenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 ({(2S) -2- [3- (2-chloro-6-fluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2,6difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (2,6difluorobenzyl) -5-methyl-2-oxopyridine- 1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (2-chloro- 6-fluorobenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol5-yl) -3 - ({(2S) - 2- [3- (2,6-Dichlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hex sanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3 (2,6-dimethylbenzyl) -5-methyl-2 -oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (3 , 5-dimethylbenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol5-yl) -3 - ({(2S) - 2- [3- (2-Fluoro-6-methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-1515 oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3,4-diethoxyphenyl) propanoic acid, (3S) 3- (3. 4-Diethoxyphenyl) -3 - ({(2S) -2- [3- (2,6-difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) ylhexanoyl} amino) propanoic acid, (3 S) -3- ({(2S) -2- [3- (2,6-difluorobenzyl) -5methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3-ethoxyphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chloro-6-fluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (3 -ethoxyphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2chlorobenzyl) -5-methyl-2-o xopyridin-1 (2H) -yl] -3-methylbutanoyl} amino) -3- (4methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5- methyl-2oxopyridin-1 (2H) -yl] -4-methylpentanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3- ( {(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridinyl (2H) -yl] -4-methylpentanoyl} amino) propanoic acid, (3S) -3- (1,3-) benzodioxol-5yl) -3 - ({(2 S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] -3 methylbutanoyl} amino) propanoic acid, (3 S) -3 - (1,3-benzodioxol-5 - and 1) -3 - ({(2 S) -2 [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) ) -yl] -3-phenylpropanoyl} amino) propanoic acid, (3S) -3 - ({2S) -2- [3- (2-chlorobenzyl) -5-methyl2-oxopyridin-1 (2H) -yl] -3 -phenylpropanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2R) -2- (1-benzyl-5 -methyl-2-oxo-1,2-dihydropyridin-3-yl) -hexanoyl) amino) propanoic acid and their pharmaceutically acceptable salts.

Predložena najbolj prednostna spojina je (3S)-3-(l,3-benzodioksol-5-il)-3-((2S)-2-(3benzil-5-metil-2-okso-l(2H)-piridinil)heksanoilamino)propanojska kislina ali njena farmacevtsko sprejemljiva sol.The most preferred compound proposed is (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2S) -2- (3benzyl-5-methyl-2-oxo-1 (2H) -pyridinyl) hexanoylamino) propanoic acid or a pharmaceutically acceptable salt thereof.

Derivati s formulami I-V, ki so estri, karbamati, aminali, amidi, optični izomeri in predzdravila, so tudi predvideni.Derivatives of formulas I-V, which are esters, carbamates, aminals, amides, optical isomers and prodrugs, are also contemplated.

Predloženi izum se nanaša tudi na farmacevtske sestavke, ki obsegajo fiziološko sprejemljivo razredčilo in vsaj eno spojino v smislu predloženega izuma.The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.

Predloženi izum se nadalje nanaša na postopek za inhibiranje vezave a₄Pi-integrina na VCAM-1, ki obsega izpostavitev celice, ki izraža a₄Pi-integrin, celici, ki izražaThe present invention further relates to a method for inhibiting the binding of α ₄ Pi-integrin to VCAM-1, comprising exposing a cell expressing α ₄ Pi integrin to a cell expressing

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VCAM-1, v navzočnosti učinkovite inhibime količine spojine v smislu izuma.VCAM-1, in the presence of an effective inhibitory amount of a compound of the invention.

VCAM-1 je lahko na površini vaskulame endotelijske celice, antigen prezentirajoče celice ali drugega celičnega tipa. α₄βι je lahko na beli krvni celici, kot je npr. monocit, limfocit, granulocit, na matični celici ali katerikoli drugi celici, ki naravno izraža α₄βι·VCAM-1 may be on the surface of a vascular endothelial cell, a presenting cell antigen, or other cell type. α ₄ βι may be on a white blood cell such as e.g. monocyte, lymphocyte, granulocyte, on a stem cell or any other cell that naturally expresses α ₄ βι ·

Predloženi izum zagotavlja tudi postopek za zdravljenje bolezenskih stanj, posredovanih z α₄β,-vezavo, ki obsega dajanje učinkovite količine spojine v smislu izuma bodisi same ali v formulaciji prizadetemu pacientu.The present invention also provides a method for treating α ₄ β -binding mediated conditions comprising administering an effective amount of a compound of the invention either alone or in a formulation to an affected patient.

Izraz alkil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na C4-C12 ravno verižne ali razvejene, substituirane ali nesubstituirane nasičene radikale, izvedene iz nasičenih ogljikovodikov z odstranitvijo enega atoma vodika, razen če ni pred izrazom alkil oznaka C_x-C_y. Reprezentativni primeri za alkilne skupine med drugim vključujejo metil, etil, n-propil, izo-propil, n-butil, sek.butil, izo-butil in terc.butil.The term alkyl, as used herein, alone or in combination, refers to C4-C12 straight chain or branched, substituted or unsubstituted saturated radicals derived from saturated hydrocarbons by removal of one hydrogen atom, unless preceded by the expression C _x - C _y . Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.

Izraz alkenil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na substituiran ali nesubstituiran ravno verižen ali substituiran ali nesubstituiran razvejen alkenilni radikal, ki vsebuje od 2 do 10 atomov ogljika. Primeri za take radikale vključujejo, vendar neomejujoče, etenil, E- in Z-pentenil, decenil ipd.The term alkenyl as used herein, alone or in combination, refers to a substituted or unsubstituted straight chain or substituted or unsubstituted branched alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl, and the like.

Izraz alkinil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na substiuiran ali nesubstituiran ravno verižen ali substituiran ali nesubstituiran razvejen alkinilni radikal, ki vsebuje od 2 do 10 atomov ogljika. Primeri za take radikale vključujejo, vendar neomejujoče, etinil, propinil, propargil, butinil, heksinil, decinil, ipd.The term alkynyl as used herein, alone or in combination, refers to a substituted or unsubstituted straight chain or substituted or unsubstituted branched alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decinyl, and the like.

Izraz nižji, ki modificira alkil, alkenil, alkinil ali alkoksi, se nanaša na Ci-C₆ enoto za posebno funkcionalnost. Nižji alkil npr. pomeni Ci-C6alkil.The term lower, modifying alkyl, alkenyl, alkynyl or alkoxy, it refers to a Ci-C ₆ unit for a particular functionality. Lower alkyl e.g. is C 1 -C 6 alkyl.

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Izraz alifatski acil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikale s formulami alkil-C(O)-, alkenil-C(O)- in alkinil-C(O)- , izvedene iz alkan-, alken- ali alkinkarboksilne kisline, pri čemer so izrazi alkil, alkenil in alkinil, kot je definirano zgoraj. Primeri za take alifatske acilne radikale med drugim vključujejo, vendar neomejujoče, acetil, propionil, butiril, valeril, 4-metilvaleril, akriloil, krotil, propiolil in metilpropiolil.The term aliphatic acyl as used herein, alone or in combination, refers to radicals of alkyl-C (O) -, alkenyl-C (O) - and alkynyl-C (O) - radicals derived from alkane-, alkene - or alkynecarboxylic acids, the terms alkyl, alkenyl, and alkynyl as defined above. Examples of such aliphatic acyl radicals include, but are not limited to, acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propiolyl and methylpropiolyl.

Izraz cikloalkil, kot ga uporabljamo tukaj, se nanaša na alifatski obročni sistem s 3 do 10 atomi ogljika in 1 do 3 obroči med drugim vključno, vendar neomejujoče, ciklopropil, ciklopentil, cikloheksil, norbomil in adamantil. Cikloalkilne skupine so lahko nesubstituirane ali substituirane z enim, dvema ali tremi substituenti, neodvisno izbranimi izmed nižjega alkila, haloalkila, alkoksi, tioalkoksi, amino, alkilamino, dialkilamino, hidroksi, halo, merkapto, nitro, karboksaldehida, karboksi, alkoksikarbonila in karboksamida.The term cycloalkyl as used herein refers to an aliphatic ring system of 3 to 10 carbon atoms and 1 to 3 rings including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbomyl and adamantyl. Cycloalkyl groups may be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxyl, carboxyl, and carboxyl.

Cikloalkil vključuje cis ali trans oblike. Nadalje so lahko substituenti bodisi v endo ali ekso položajih v premoščenih bicikličnih sistemih.Cycloalkyl includes cis or trans forms. Furthermore, the substituents may be in either endo or exo positions in bridged bicycle systems.

Izraz cikloalkenil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na cikličen karbocikel, ki vsebuje od 4 do 8 atomov ogljika in eno ali več dvojnih vezi. Primeri za take cikloalkenilne radikale vključujejo, vendar neomejujoče, ciklopentenil, cikloheksenil, ciklopentadienil, ipd.The term cycloalkenyl as used herein, alone or in combination, refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl, and the like.

Izraz cikloalkilalkil, kot ga uporabljamo tukaj, se nanaša na cikloalkilno skupino, vezano na nižji alkilni radikal, vključno, vendar neomejujoče, na cikloheksilmetil.The term cycloalkylalkyl as used herein refers to a cycloalkyl group attached to a lower alkyl radical, including but not limited to cyclohexylmethyl.

Izraz halo ali halogen, kot ga uporabljamo tukaj, se na nanaša na J, Br, C1 ali F.The term halo or halogen as used herein refers to J, Br, C1 or F.

Izraz haloalkil, kot ga uporabljamo tukaj, se nanaša na nižji alkilni radikal, na katerega je pripet vsaj en halogenski substituent, med drugim npr. na klorometil, fluoroetil, trifluorometil in pentafluoroetil.The term haloalkyl as used herein refers to a lower alkyl radical to which at least one halogen substituent is attached, e.g. to chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl.

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Izraz alkoksi, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na alkiletrski radikal, pri čemer je izraz alkil, kot je definirano zgoraj. Primeri za prikladne alkiletrske radikale vključujejo, vendar neomejujoče, metoksi, etoksi, npropoksi, izo-propoksi, n-butoksi, izo-butoksi, sek.butoksi, terc.butoksi ipd.The term alkoxy as used herein, alone or in combination, refers to an alkyl ether radical, the term being alkyl as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

Izraz alkoksialkil, kot ga uporabljamo tukaj, se nanaša na R_y-O-R_z, kjer je R_y nižji alkil, kot je definiran zgoraj, in je R_z alkilen (-(CH₂)_W-), kjer je w celo število od 1 doThe term alkoxyalkyl as used herein refers to R _y -OR _z , where R _{y is} lower alkyl as defined above, and R _{z is} alkylene (- (CH ₂ ) _W -), where w is an integer from 1 to

6.6.

Izraz alkenoksi, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo alkenil-Ο-, pod pogojem, da radikal ni enolni eter, pri čemer je izraz alkenil, kot je definirano zgoraj. Primeri za prikladne alkenoksi radikale vključujejo, vendar neomejujoče, aliloksi, E- in Z- 3-metil-2-propenoksi ipd.The term alkenoxy as used herein, alone or in combination, refers to a radical of the formula alkenyl-Ο-, provided that the radical is not a single ether, the term alkenyl being as defined above. Examples of suitable alloxy radicals include, but are not limited to, allyloxy, E- and Z-3-methyl-2-propenoxy and the like.

Izraz alkinoksi, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo alkinil-Ο-, pod pogojem, da radikal ni -inolni eter. Primeri za prikladne alkinoksi radikale vključujejo, vendar neomejujoče, propargiloksi, 2butiniloksi ipd.The term alkoxy as used herein, alone or in combination, refers to a radical of the formula alkynyl-il-, provided that the radical is not an -inol ether. Examples of suitable alkoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.

Izraz tioalkoksi se nanaša na tioetrski radikal s formulo alkil-S-, pri čemer je alkil, kot je definirano zgoraj.The term thioalkoxy refers to a thioether radical of formula alkyl-S-, wherein alkyl is as defined above.

Izraz sulfonamido, kot ga uporabljamo tukaj, se nanaša na -SO₂NH₂.The term sulfonamido as used herein refers to -SO ₂ NH ₂ .

Izraz karboksaldehid, kot ga uporabljamo tukaj, se nanaša na -C(O)R, kjer je R vodik.The term carboxaldehyde as used herein refers to -C (O) R, where R is hydrogen.

Izraz karboksamid ali amid, kot ga uporabljamo tukaj, se nanaša na C(O)NR_aR_b, kjer sta R_a in R_b vsak neodvisno vodik, alkil ali katerikoli drug prikladen substituent.The term carboxamide or amide as used herein refers to C (O) NR _a R _b , wherein R _a and R _{b are} each independently hydrogen, alkyl or any other suitable substituent.

Izraz karboksi, kot ga uporabljamo tukaj, se nanaša na -C(O)O-.The term carboxy as used herein refers to -C (O) O-.

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Izraz alkoksialkoksi, kot ga uporabljamo tukaj, se nanaša na R^O-RdO-, kjer je R^ nižji alkil, kot je definiran zgoraj, in je R<j alkilen, kjer je alkilen -(CH₂)„'-, kjer je n' celo število od 1 do 6. Reprezentativni primeri za alkoksialkoksi skupine med drugim vključujejo metoksimetoksi, etoksimetoksi, t-butoksimetoksi.The term alkoxyalkoxy as used herein refers to R ^ O-RdO-, where R ^ is lower alkyl as defined above, and R <13> is alkylene, where alkylene is - (CH ₂ ) "'-, where n 'is an integer from 1 to 6. Representative examples of alkoxyalkoxy groups include, but are not limited to, methoxymethoxy, ethoxymethoxy, t-butoxymethoxy.

Izraz alkilamino, kot ga uporabljamo tukaj, se nanaša na RgNH-, kjer je R« nižja alkilna skupina, med drugim npr. etilamino, butilamino.The term alkylamino as used herein refers to RgNH-, wherein R1 is a lower alkyl group, for example e.g. ethylamino, butylamino.

Izraz alkenilamino, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo alkenil-NH ali (alkenil)₂N-, kjer je izraz alkenil, kot je definirano zgoraj, pod pogojem, da radikal ni enamin. Primer za tak alkenilamino radikal je alilamino radikal.The term alkenylamino as used herein, alone or in combination, refers to a radical of the formula alkenyl-NH or (alkenyl) ₂ N-, wherein the term alkenyl, as defined above, is provided that the radical is not enamine. An example of such an alkenylamino radical is the allylamino radical.

Izraz alkinilamino, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo alkinil-NH- ali (alkinil)₂N-, kjer je izraz alkinil, kot je definirano zgoraj, pod pogojem, da radikal ni amin. Primer za take alkinilamino radikale je propargil amino radikal.The term alkynylamino as used herein, alone or in combination, refers to a radical of the formula alkynyl-NH- or (alkynyl) ₂ N-, wherein the term is alkynyl as defined above, provided that the radical is not an amine. An example of such alkynylamino radicals is the propargyl amino radical.

Izraz dialkilamino, kot ga uporabljamo tukaj, se nanaša na R_fR_gN-, kjer sta R_f in R_g neodvisno izbrana izmed nižjega alkila, med drugim npr. dietilamino in metil propilamino.The term dialkylamino as used herein refers to R _f R _g N-, where R _f and R _{g are} independently selected from lower alkyl, for example e.g. diethylamino and methyl propylamino.

Izraz alkoksikarbonil, kot ga uporabljamo tukaj, se nanaša na alkoksilno skupino, kot je bila predhodno definirana, pripeto na matični molekulski delež preko karbonilne skupine. Primeri za alkoksikarbonil med drugim vključujejo metoksikarbonil, etoksikarbonil in izopropoksikarbonil.The term alkoxycarbonyl as used herein refers to an alkoxy group as previously defined attached to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and isopropoxycarbonyl.

Izraz aril ali aromatski, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na substituirano ali nesubstituirano karbociklično aromatsko skupino s pribl. 6 do 12 atomi ogljika, kot npr. fenil, nafitil, indenil, indanil, azulenil, fluorenil in antracenil; ali heterociklično aromatsko skupino, ki je aromatski obroč, ki vsebuje vsaj enThe term aryl or aromatic as used herein, alone or in combination, refers to a substituted or unsubstituted carbocyclic aromatic group of approx. 6 to 12 carbon atoms, such as e.g. phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group which is an aromatic ring containing at least one

-2020 endociklični N, O ali S atom, kot npr. furil, tienil, piridil, pirolil, oksazolil, tiazolil, imidazolil, pirazolil, 2-pirazolinil, pirazolidinil, izokaszolil, izotiazolil, 1,2,3oksadiazolil, 1,2,3-triazolil, 1,3,4-tiadiazolil, piridazinil, pirimidinil, pirazinil, 1,3,5triazinil, 1,3,5-tritianil, indolizinil, indolil, izoindolil, 3H-indolil, indolinil, benzo[b]furanil, 2,3-dihidrobenzofuranil, benzo[b]tiofenil, lH-indazolil, benzimidazolil, benztiazolil, purinil, 4H-kinolizinil, izokinolinil, cinolinil, ftalazinil, kinazolinil, kinoksalinil, 1,8-naftridinil, pteridinil, karbazolil, akridinil, fenazinil, fenotiazinil, fenoksiazinil, pirazolo[l,5-c]triazinil ipd. Aralkil in alkilaril imata izraz alkil, kot je definiran zgoraj. Obroči so lahko večkrat substituirani.-2020 an endocyclic N, O or S atom, such as e.g. furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isocasolyl, isothiazolyl, 1,2,3oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5triazinyl, 1,3,5-tritiyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1H- indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenothiazinyl, phenothiazinyl . Aralkyl and alkylaryl have the term alkyl as defined above. The rings may be substituted several times.

Izraz aralkil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na alkilni radikal, substituiran z arilom, kjer sta izraza alkil in aril, kot je definirano zgoraj. Primeri za prikladne aralkilne radikale vključujejo, vendar neomejujoče, fenilmetil, fenetil, fenilheksil, difenilmetil, piridilmetil, tetrazolil metil, furilmetil, imidazolil metil, indolilmetil, tienilpropil ipd.The term aralkyl as used herein, alone or in combination, refers to an alkyl radical substituted with aryl, wherein the terms alkyl and aryl are as defined above. Examples of suitable aralkyl radicals include, but are not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.

Izraz aralkenil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na alkenilni radikal, substituiran z arilom, pri čemer sta izraza aril in alkenil, kot je definirano zgoraj.The term aralkenyl as used herein, alone or in combination, refers to an aryl-substituted alkenyl radical, the terms aryl and alkenyl being as defined above.

Izraz arilamino, kot ga uporabljamo tukaj, sam ali v kombinaciji se nanaša na radikal s formulo aril-ΝΗ-, kjer je aril, kot je definirano zgoraj. Primeri za arilamino radikale vključujejo, vendar neomejujoče, fenilamino(anilido), naftilamino, 2-, 3- inThe term arylamino as used herein, alone or in combination, refers to a radical of the formula aryl-ΝΗ-, wherein aryl is as defined above. Examples of arylamine radicals include, but are not limited to, phenylamino (anilido), naphthylamino, 2-, 3- and

4-piridilamino ipd.4-pyridylamino and the like.

Izraz benzil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na C₆H₅CH₂-.The term benzyl, as used herein, alone or in combination, refers to C ₆ H ₅ CH ₂ -.

Izraz biaril, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo aril-aril, kjer je izraz aril, kot je definirano zgoraj.The term biaryl as used herein, alone or in combination, refers to a radical of the formula aryl-aryl, wherein the term aryl is as defined above.

-2121-2121

Izraz tioaril, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo aril-S-, kjer je izraz aril, kot je definirano zgoraj. Primer za tioarilni radikal je tiofenilni radikal.The term thioaryl as used herein, alone or in combination, refers to a radical of the formula aryl-S-, wherein the term aryl is as defined above. An example of a thioaryl radical is a thiophenyl radical.

Izraz aroil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na radikal s formulo aril-CO-, kjer je izraz aril, kot je definirano zgoraj. Primeri za prikladne aromatske acilne radikale vključujejo, vendar neomejujoče, benzoil, 4-halobenzoil, 4karboksibenzoil, naftoil, piridilkarbonil ipd.The term aroyl as used herein, alone or in combination, refers to a radical of the formula aryl-CO-, wherein the term aryl is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.

Izraz heterociklil, kot ga uporabljamo tukaj, sam ali v kombinaciji, se nanaša na nearomatski 3- do 10-členski obroč, ki vsebuje vsaj en endociklični N, O ali S atom. Heterocikel je lahko po izbiri fuzioniran z arilom. Heterocikel je lahko po izbiri tudi substituiran vsaj z enim substituentom, neodvisno izbranim iz skupine, ki jo med drugim sestavljajo vodik, halogen, hidroksil, amino, nitro, trifluorometil, trifluorometoksi, alkil, aralkil, alkenil, alkinil, aril, ciano, karboksi, karboalkoksi, karboksialkil, okso, arilsulfonil in aralkilaminokarbonil.The term heterocyclyl as used herein, alone or in combination, refers to a non-aromatic 3- to 10-membered ring containing at least one endocyclic N, O or S atom. The heterocycle may optionally be fused with aryl. The heterocycle may also be optionally substituted by at least one substituent independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl.

Izraz alkilheterociklil, kot ga uporabljamo tukaj, se nanaša na alkilno skupino, kot je bila predhodno definirana, pripeto na matični molekulski delež preko heterociklilne skupine, vključno, vendar neomejujoče, na 2-metil-5-tiazolil, 2-metil-l-pirolil in 5etil-2-tiofenil.The term alkylheterocyclyl as used herein refers to an alkyl group as previously defined, attached to the parent molecular moiety through a heterocyclyl group, including, but not limited to, 2-methyl-5-thiazolyl, 2-methyl-1-pyrrolyl and 5ethyl-2-thiophenyl.

Izraz heterociklilalkil, kot ga uporabljamo tukaj, se nanaša na heterociklilno skupino, kot je bila predhodno definirana, pripeto na matični molekulski delež preko alkilne skupine, vključno, vendar neomejujoče, na 2-tienilmetil, 2-piridinilmetil in 2(l-piperidinil)etil.The term heterocyclylalkyl as used herein refers to a heterocyclyl group as previously defined attached to the parent molecular moiety through an alkyl group, including, but not limited to, 2-thienylmethyl, 2-pyridinylmethyl and 2 (1-piperidinyl) ethyl .

Izraz aminal, kot ga uporabljamo tukaj, se nanaša na hemi-acetal s strukturo RhC(NRiRj)(NR_kRi-)-, kjer so R_h, R_;, Rj, R_k in Rj vsak neodvisno vodik, alkil ali katerikoli drug prikladen substituent.The term aminal as used herein refers to a hemi-acetal with the structure RhC (NRiRj) (NR _to Ri -) -, where R is _h , R _; , R j, R _k and R j are each independently hydrogen, alkyl or any other suitable substituent.

-2222-2222

Izraz ester, kot ga uporabljamo tukaj, se nanaša na -C(O)R_m, kjer je R_m vodik, alkil ali keterikoli drug prikladen substituent.The term ester as used herein refers to -C (O) R _m , where R _{m is} hydrogen, alkyl or any other suitable substituent.

Izraz karbamat, kot ga uporabljamo tukaj, se nanaša na spojine na osnovi karbamske kisline NH₂C(O)OH.The term carbamate as used herein refers to compounds based on carbamic acid NH ₂ C (O) OH.

Izraz optični izomeri, kot ga uporabljamo tukaj, se nanaša na spojine, ki se razlikujejo le v stereokemiji vsaj enega atoma, vključno enantiomere, diastereomere in racemate.The term optical isomers as used herein refers to compounds that differ only in the stereochemistry of at least one atom, including enantiomers, diastereomers and racemates.

Uporaba zgornjih izrazov je mišljena tako, da zajema substituirane in nesubstituirane deleže. Substitucija je lahko z eno ali več skupin, kot so npr. alkoholi, etri, estri, amidi, sulfoni, sulfidi, hidroksil, nitro, ciano, karboksi, amini, heteroatomi, nižji alkil, nižji alkoksi, nižji alkoksikarbonil, alkoksialkoksi, aciloksi, halogeni, trifluorometoksi, trifluorometil, alkil, aralkil, alkenil, alkinil, aril, ciano, karboksi, karboalkoksi, karboksialkil, cikloalkil, cikloalkilalkil, heterociklil, alkilheterociklil, heterociklilalkil, okso, arilsulfonil in aralkilaminokarbonil, ali katerimkoli substituentom iz prejšnjih odstavkov ali katerimkoli od tistih substituentov, ki so vezani bodisi direktno ali s prikladnimi linkerji. Linkerji so značilno kratke verige z 1 do 3 atomi, ki vsebujejo katerokoli kombinacijo -C-, -C(O)-, NH-, -S-, -S(O)-, -0-, -C(0)0- ali -S(O)O-. Obroči so lahko večkrat subtituirani.The use of the above expressions is intended to encompass substituted and unsubstituted portions. The substitution may be with one or more groups such as e.g. alcohols, ethers, esters, amides, sulfones, sulfides, hydroxyl, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkyloxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, aralkyl, aralkyl , aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl, or any substituents of the foregoing or any of the substituents, whether or not substituted. Linkers are typically short chains with 1 to 3 atoms containing any combination of -C-, -C (O) -, NH-, -S-, -S (O) -, -0-, -C (0) 0 - or -S (O) O-. The rings can be sub-referenced several times.

Izraz ki odvzema elektrone ali ki daje elektrone, se nanaša na sposobnost substituenta, da odvzema ali daje elektrone glede na vodikove, če je vodik zavzemal enak položaj v molekuli. Ti izrazi so dobro razumljivi strokovnjakom in so pojasnjeni v: Advanced Organic Chemistrv, J. March, 1985, str. 16-18, vključeno tukaj z referenco. Skupine, ki odvzemajo elektrone, med drugim vključujejo halo, nitro, karboksil, nižji alkenil, nižji alkinil, karboksaldehid, karboksamido, aril, kvatemi amonij, trifluorometil, sulfonil in aril nižji alkanoil. Skupine, ki dajejo elektrone, med drugim vključujejo skupine, kot so npr. hidroksi, nižji alkil, amino, nižji alkilamino, di(nižji alkil)amino, ariloksi, merkapto, nižji alkiltio, nižji alkilmerkapto in disulfid.The term electron withdrawing or electron donating refers to the ability of a substituent to withdraw or deliver electrons relative to hydrogen if the hydrogen has taken the same position in the molecule. These terms are well understood by those skilled in the art and are explained in: Advanced Organic Chemistry, J. March, 1985, p. 16-18, incorporated herein by reference. Electron-withdrawing groups include, but are not limited to, halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxamido, aryl, quaternary ammonium, trifluoromethyl, sulfonyl and aryl lower alkanoyl. Electron-giving groups include, but are not limited to, groups such as e.g. hydroxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto and disulfide.

-2323-2323

Strokovnjaki bodo upoštevali, da imajo navedeni substituenti lahko lastnosti za dajanje elektronov ali odvzemanje elektronov pri različnih kemičnih pogojih. Poleg tega predloženi izum predvideva tudi katerokoli kombinacijo substituentov, izbranih izmed zgoraj identificiranih skupin.It will be appreciated by those skilled in the art that said substituents may have electron-donating or electron-withdrawing properties under different chemical conditions. In addition, the present invention also provides for any combination of substituents selected from the groups identified above.

Najbolj prednostni substituenti, ki dajejo elektrone ali odvzemajo elektrone, so: halo, nitro, alkanoil, karboksaldehid, arilalkanoil, ariloksi, karboksil, karboksamid, ciano, sulfonil, sulfoksid, heterociklil, gvanidin, kvatemami amonij, nižji alkenil, nižji alkinil, sulfonijeve soli, hidroksi, nižji alkoksi, nižji alkil, amino, nižji alkilamino, di(nižji alkil)amino, amin nižji alkil merkapto, merkaptoalkil, alkiltio, alkilditio, karboksi nižji alkil, arilalkoksi, alkanoilamino, alkanoil(nižji alkil)amino, nižji alkilsulfonilamino, arilsulfonilamino, alkilsulfonil(nižji alkil)amino, arilsulfonil(nižji alkil)amino, nižji alkilkarboksamid, di(nižji alkil)karboksamid, sulfonamid, nižji alkilsulfonamid, di(nižji alkil)sulfonamid, nižji alkilsulfonil in arilsulfonil.The most preferred electron-donating or electron-withdrawing substituents are: halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenylammonium, lower alkenylamino, lower alkenylammonium , hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di (lower alkyl) amino, amine lower alkyl mercapto, mercaptoalkyl, alkylthio, alkyldithio, carboxy lower alkyl, arylalkoxy, alkanoylamino, alkanoyl (lower alkyl) amino, lower alkylsulfon arylsulfonylamino, alkylsulfonyl (lower alkyl) amino, arylsulfonyl (lower alkyl) amino, lower alkylcarboxamide, di (lower alkyl) carboxamide, sulfonamide, lower alkylsulfonamide, di (lower alkyl) sulfonamide, lower alkylsulfonyl and arylsulfonyl.

Kot uporabljamo tukaj, je izraz sestavek namenjen, da obsega produkt, ki obsega specificirane sestavine v specificiranih količinah kot tudi katerikoli produkt, ki je rezultat direktne ali indirektne kombinacije specificiranih sestavin v specificiranih količinah.As used herein, the term composition is intended to include a product comprising specified ingredients in specified amounts as well as any product resulting from a direct or indirect combination of specified ingredients in specified quantities.

Obroč, ki vključuje Y v formuli II ali obroč Q v formulah I in V, je lahko monocikličen heterocikel ali aromatski obroč ali je lahko bicikličen obroč. Kadar več kot en Y pomeni C(R²)(R³), so lahko substituenti C iz vsakega Y združeni, da tvorijo obroč. Poleg tega sta v obročih, ki vključujejo Y, dve neodvisni R , R, R in R skupini, vzeti skupaj, lahko vezani, da tvorita obroč.A ring comprising Y in formula II or ring Q in formulas I and V may be a monocyclic heterocycle or an aromatic ring or may be a bicyclic ring. When more than one Y is C (R ² ) (R ³ ), the substituents C from each Y may be combined to form a ring. In addition, in rings involving Y, two independent R, R, R and R groups, taken together, may be bonded to form a ring.

Prikladni substituenti za arilne, alkilne, cikloalkilne, heterociklilne skupine ali obroč, ki vključuje Y, definiran zgoraj, kadar je navzoč, vključujejo alkohole, amine, heteroatome ali katerokoli kombinacijo arilnih, alkilnih, cikloalkilnih ali heterociklilnih skupin bodisi vezanih direktno ali preko prikladnih linkerjev. Linkerji so značilno kratke verige z 1-3 atomi, ki vsebujejo katerokoli kombinacijo C, C=O,Suitable substituents for aryl, alkyl, cycloalkyl, heterocyclyl groups, or a ring comprising Y, when present above, include alcohols, amines, heteroatoms or any combination of aryl, alkyl, cycloalkyl or heterocyclyl groups either bonded directly or via suitable linkers. Linkers are typically short chains with 1-3 atoms containing any combination of C, C = O,

-2424-2424

C0₂, O, N, S, S=O, SO₂, kot npr. etri, amidi, amini, sečnine, sulfamidi, sulfonamidi ipd.C0 ₂ , O, N, S, S = O, SO ₂ , such as e.g. ethers, amides, amines, ureas, sulfamides, sulfonamides and the like.

V formulah I in III-V definirane R skupine R¹ in R¹⁷ potencialno često zamenjujejo njihove pridružene obroče. Za R¹, kadar je q nič, je pridružen obroč nesubstitutiran, pri čemer ima vodike na vsakem mestu, ki je na voljo. Podobno za R , kadar je s nič, je pridružen obroč nesubstituiran in ima vodike na vsakem mestu, ki je na voljo.In formulas I and III-V, the defined R groups R ¹ and R ¹⁷ potentially frequently replace their associated rings. For R ¹ , when q is zero, the associated ring is unsubstituted, with hydrogen at each available position. Similarly for R, when zero, the associated ring is unsubstituted and has hydrogen at each available site.

R¹, R², R³, R⁵, R⁷, R¹¹ in R¹³ v formulah I-V zgoraj so lahko npr. neodvisno, vendar neomejujoče, fenil, tienilmetil, izobutil, n-butil, 2-tienilmetil, l,3-tiazol-2-il-metil, benzil, tienil, 3-piridinilmetil, 3-metil-l-benzotiofen-2-il, alil, 3-metoksibenzil, propil, 2-etoksietil, ciklopropilmetil, benzilsulfanilmetil, benzilsulfonilmetil, fenilsulfanilmetil, fenetilsulfanilmetil, 3-fenilpropilsulfanilmetil, 4-((2toluidinokarbonil)amino)benzil, 2-piridiniletil, 2-(lH-indol-3-il)etil, lH-benzimidazol2-il, 4-piperidinilmetil, 3-hidroksi-4-metoksibenzil, 4-hidroksifenetil, 4-aminobenzil, fenilsulfonilmetil, 4-(acetilamino)fenil, 4-metoksifenil, 4-aminofenil, 4-klorofenil, (4(benzilsulfonil)amino)fenil, (4-(metilsulfonil)amino)fenil, 2-aminofenil, 2-metilfenil, izopropil, 2-okso-1-pirolidinil, 3-(metilsulfanil)propil, (propilsulfanil)metil, oktilsulfanilmetil, 3-aminofenil, 4-((2-toluidinokarbonil)amino)fenil, 2((metilbenzil)amino)benzil, metilsulfaniletil, etilsulfanilmetil, 2-klorobenzil, 2bromobenzil, 2-fluorobenzil, 2-kloro-6-fluorobenzil, 2-kloro-4-fluorobenzil, 2,4diklorobenzil, 2-kloro-6-metoksibenzil, 2-cianobenzil, 2,6-difluorobenzil, 2-kloro-5(trifluorometil)benzil, 2-kloro-6-metilbenzil, 2,6-dimetoksibenzil, 2-kloro-5(metilsulfonil)benzil, 2-kloro-6-cianobenzil, 2-kloro-6-etoksibenzil, 2-kloro-5metoksibenzil, 2-kloro-5-fluorobenzil, 5-kloro-2-fluorobenzil, etil, propil, butil, pentil, ciklopropil, terc.butilamino, propilamino, 4-metil-l-piperazinil, 1-azetidinil, 4morfolino, (4-karboksifenil)amino, pivaloilamino, ((terc.butilamino)karbonil)amino, trifluorometil, benziloksi, 2-(2-metoksietoksi)etoksi, 2-(2-(2metoksietoksi)etoksi)etoksi in 2-(2-(2-(2-metoksietoksi)etoksi)etoksi)etoksi. R⁶ in R⁸ sta lahko vezana, da tvorita obroč, kot je med drugim npr. ciklopropil, ciklobutil, ciklopentil, cikloheksil, 4-piperidinil in 4-tetrahidropiranil. R⁴ in R¹³ sta lahko vezana,R ¹ , R ² , R ³ , R ⁵ , R ⁷ , R ¹¹ and R ¹³ in formulas IV above may be e.g. independently but not limited to phenyl, thienylmethyl, isobutyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3-methyl-1-benzothiophen-2-yl , allyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, benzylsulfanylmethyl, benzylsulfonylmethyl, phenylsulfanylmethyl, phenethylsulfanylmethyl, 3-phenylpropylsulfanylmethyl, 4 - ((2-toluidinocarbonyl) amino) benzyl-2-pyridyl-2-pyridyl-2-pyridyl yl) ethyl, 1H-benzimidazol2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenyl, 4-aminobenzyl, phenylsulfonylmethyl, 4- (acetylamino) phenyl, 4-methoxyphenyl, 4-aminophenyl, 4-chlorophenyl , (4 (benzylsulfonyl) amino) phenyl, (4- (methylsulfonyl) amino) phenyl, 2-aminophenyl, 2-methylphenyl, isopropyl, 2-oxo-1-pyrrolidinyl, 3- (methylsulfanyl) propyl, (propylsulfanyl) methyl, octylsulfanylmethyl, 3-aminophenyl, 4 - ((2-toluidinocarbonyl) amino) phenyl, 2 ((methylbenzyl) amino) benzyl, methylsulfanylethyl, ethylsulfanylmethyl, 2-chlorobenzyl, 2bromobenzyl, 2-fluorobenzyl, 2-chloro-6-fluorobenzyl -chloro-4- fluorobenzyl, 2,4dichlorobenzyl, 2-chloro-6-methoxybenzyl, 2-cyanobenzyl, 2,6-difluorobenzyl, 2-chloro-5 (trifluoromethyl) benzyl, 2-chloro-6-methylbenzyl, 2,6-dimethoxybenzyl, 2- chloro-5 (methylsulfonyl) benzyl, 2-chloro-6-cyanobenzyl, 2-chloro-6-ethoxybenzyl, 2-chloro-5methoxybenzyl, 2-chloro-5-fluorobenzyl, 5-chloro-2-fluorobenzyl, ethyl, propyl, butyl, pentyl, cyclopropyl, tert-butylamino, propylamino, 4-methyl-1-piperazinyl, 1-azetidinyl, 4 morpholino, (4-carboxyphenyl) amino, pivaloylamino, ((tert-butylamino) carbonyl) amino, trifluoromethyl, benzyloxy, 2-benzyloxy - (2-methoxyethoxy) ethoxy, 2- (2- (2methoxyethoxy) ethoxy) ethoxy and 2- (2- (2- (2-methoxyethoxy) ethoxy) ethoxy) ethoxy. R ⁶ and R ⁸ may be bonded to form a ring, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-piperidinyl and 4-tetrahydropyranyl. R ⁴ and R ¹³ may be bonded,

-2525 da tvorita obroč, kot je med drugim npr. pirolidino, 1-piperidino, 4-metil-l-piperazino,-2525 to form a ring, such as e.g. pyrrolidino, 1-piperidino, 4-methyl-1-piperazino,

4-aceto-l-piperazino in 4-morfolino. R⁹ in R¹⁰ sta lahko vezana, da tvorita obroč, kot je med drugim ciklopropil, ciklobutil, ciklopentil in cikloheksil.4-aceto-1-piperazino and 4-morpholino. R ⁹ and R ¹⁰ may be bonded to form a ring such as, inter alia, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

R⁴ substituent v formulah I-III in R²¹ substituent v formuli IV zgoraj sta lahko, vendar neomejujoče, l,3-benzodioksol-5-il, 1-naftil, tienil, 4-izobutoksifenil, 2,6-dimetilfenil, aliloksifenil, 3-bromo-4-metoksifenil, 4-butoksifenil, l-benzofuran-2-il, 2-tienilmetil, fenil, metilsulfanil, fenilsulfanil, fenetilsulfanil, 4-bromo-2-tienil, 3-metil-2-tienil, 4,5dihidro-l,3-oksazol-2-il, 3-(trifluorometil)fenil, 4-(trifluorometoksi)fenil, 2,3-dihidrol,4-benzodioksin-6-il, 7-metoksi-l,3-benzodioksol-5-il, 3-etoksi-4-metoksifenil, 3,4dimetoksifenil, 3,4-dietoksifenil, 3-etoksifenil, 3-metoksi-4-metilfenil, 3,5-dimetoksi4-metilfenil, 3-propoksifenil, 3-butoksifenil, 3-(2-metoksietoksi)fenil, 3,4dipropoksifenil, 3-(difluorometoksi)fenil, 2-naftil, 3-izopropoksifenil, 1-metil-lHindol-5,il, 2,3-dihidro-l-benzofuran-5-il, l,3-dietil-2-okso-2,3-dihidro-lHbenzimidazol-5-il, 3-(trifluorometoksi)fenil, 1-metil-lH-indol-6-il, 3-(ciklopropoksi)fenil, 3-(ciklopropilmetoksi)fenil, 3-(difluorometoksi)fenil, 3-(1,1,2,2tetrafluoroetoksi)fenil, l-etil-lH-indol-5-il, 3-(dietilamino)fenil, 6-metoksi-2-nafitil, 3[(metilsulfonil)amino] fenil, 3 - [metil(metilsulfonil)amino] fenil, 3 - [etil(metilsulfonil)amino]fenil, 3-[etil(metilsulfonil)amino]fenil, lH-indol-5-il, 3-fluoro4-metoksifenil in 3-(difluorometil)fenil.The R ⁴ substituent in formulas I-III and the R ²¹ substituent in formula IV above may, but are not limited to, 1,3-benzodioxol-5-yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4-methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl, methylsulfanyl, phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-thienyl, 3-methyl-2-thienyl, 4. 5-dihydro-1,3-oxazol-2-yl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethoxy) phenyl, 2,3-dihydrol, 4-benzodioxin-6-yl, 7-methoxy-1,3-benzodioxole- 5-yl, 3-ethoxy-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 3-ethoxyphenyl, 3-methoxy-4-methylphenyl, 3,5-dimethoxy4-methylphenyl, 3-propoxyphenyl, 3-butoxyphenyl, 3- (2-methoxyethoxy) phenyl, 3,4-dipropoxyphenyl, 3- (difluoromethoxy) phenyl, 2-naphthyl, 3-isopropoxyphenyl, 1-methyl-1H-indol-5, yl, 2,3-dihydro-1-benzofuran-5- yl, 1,3-diethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl, 3- (trifluoromethoxy) phenyl, 1-methyl-1H-indol-6-yl, 3- (cyclopropoxy) phenyl, 3- (cyclopropylmethoxy) phenyl, 3- (difluoromethoxy) phenyl, 3- (1,1,2,2tetrafluoroethoxy) phenyl, 1-ethyl-1H-indol-5-yl, 3- (diethylamino) phenyl, 6-methoxy-2-naphthyl, 3 [(methylsulfonyl) amino] phenyl , 3- [methyl (methylsulfonyl) amino] phenyl, 3- [ethyl (methylsulfonyl) amino] phenyl, 3- [ethyl (methylsulfonyl) amino] phenyl, 1H-indol-5-yl, 3-fluoro4-methoxyphenyl and 3- (difluoromethyl) phenyl.

R⁶ in R⁸ substituenta v formulah I-V zgoraj sta lahko, vendar neomejujoče, vodik, butil, benzil, benziloksimetil, etil, propil, fenilsulfanilmetil, benzilsulfanilmetil, metilsulfaniletil, etilsulfanilmetil, metil ali karboksietil.The R ⁶ and R ⁸ substituents of Formulas IV above may, but are not limited to, hydrogen, butyl, benzyl, benzyloxymethyl, ethyl, propyl, phenylsulfanylmethyl, benzylsulfanylmethyl, methylsulfanylethyl, ethylsulfanylmethyl, methyl or carboxyethyl.

R⁴ in R¹³ sta lahko vezana, da tvorita obroč, ki je med drugim npr. 1-pirolidino, 1piperidino, 4-metil-l-piperazino, 4-acetil-l-piperazino in 4-morfolino.R ⁴ and R ¹³ may be bonded to form a ring, such as e.g. 1-Pyrrolidino, 1-piperidino, 4-methyl-1-piperazino, 4-acetyl-1-piperazino and 4-morpholino.

R in R sta lahko vezana, da tvorita obroč, ki je med drugim npr. ciklopropil, ciklobutil, ciklopentil in cikloheksil.R and R may be bonded to form a ring, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

-2626-2626

R⁹ in R¹⁰ sta lahko vezana, da tvorita obroč, ki je med drugim npr. ciklopropil, ciklobutil, ciklopentil in cikloheksil.R ⁹ and R ¹⁰ may be bonded to form a ring, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

OkrajšaveAbbreviations

Okrajšave, ki smo jih uporabili v shemah in spodnjih Primerih so: BOC za tbutiloksikarbonil; EtOAc za etil acetat; DMF za dimetilformamid; THF za tetrahidrofuran; Tos za p-toluensulfonil; DCC za dicikloheksilkarbodiimid; HOBT zaThe abbreviations used in the schemes and Examples below are: BOC for tbutyloxycarbonyl; EtOAc for ethyl acetate; DMF for dimethylformamide; THF for tetrahydrofuran; Tos for p-toluenesulfonyl; DCC for dicyclohexylcarbodiimide; HOBT for

1-hidroksibenzotriazol; TFAA za trifluoroacetanhidrid; NMM za N-metil morfolin; DIPEA za diizopropiletilamin; DCM za metilen diklorid; LHMDS za litijev heksametil disilazid; NaHMDS za natrijev heksametil disilazid; CDI za 1,1'karbonildiimidazol HBTU za O-benzotriazol-l-il-N,N,N', N'-tetrametiluronijev heksafluorofosfat, EDCI za l-[3-(dimetilamino)propil]-3-etilkarbodiimid hidroklorid, TBS za fiziološko raztopino soli, pufrano s TRIS in RT za sobno temperaturo.1-hydroxybenzotriazole; TFAA for trifluoroacetic anhydride; NMM for N-methyl morpholine; DIPEA for diisopropylethylamine; DCM for methylene dichloride; LHMDS for lithium hexamethyl disilazide; NaHMDS for sodium hexamethyl disilazide; CDI for 1,1'carbonyldiimidazole HBTU for O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate, EDCI for 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride, TBS for saline buffered with TRIS and RT for room temperature.

Amino kisline imajo naslednje okrajšave: C za L-cistein; D za L-asparginsko kislino; E za L-glutaminsko kislino; G za glicin; H za L-histidin; I za L-izolevcin; L za Llevcin; N za L-asparagin; P za L-prolin; Q za L-glutamin; S za L-serin; T za L-treonin; V za L-valin in W za L-triptofan.The amino acids have the following abbreviations: C for L-cysteine; D for L-aspartic acid; E for L-glutamic acid; G for glycine; H for L-histidine; And for L-isoleucine; L for Llevcin; N for L-asparagine; P for L-proline; Q for L-glutamine; S for L-serine; T for L-threonine; V for L-valine and W for L-tryptophan.

Primeri za postopke, uporabljene za sintezo spojin, so ponazorjeni z naslednjimi shemami:Examples of the processes used for the synthesis of compounds are illustrated by the following schemes:

-2727-2727

CIH₃N-_z,CO₂MeCIH ₃ N- _z , CO ₂ Me

1)NaHC0₃ 1) NaHC0 ₃

2)C_zH_sCH02) C _with H _with CH0

POCI3, DMF ph N ^.CO₂Me °C ^Y' oPOCI3, DMF ph N ^ .CO ₂ Me ° C ^ Y 'o

.COjEt.COjEt

HBTUHBTU

diastereomer 9diastereomer 9

HPLC in - _Ph diastereoiner 10HPLC in - _Ph diastereoiner 10

Shema 1Scheme 1

-2828-2828

HjNHjN

rnoFtrnoFt

H₂N^A HCI i gH ₂ N ^ A HCI ig

Z<J 25Z <J 25

Boc₂OBoc ₂ O

a) DMSO, (COC1)₂ a) DMSO, (COC1) ₂

b) 26b) 26

BocBoc

N. .CHON. .CHO

NaBHiOAc), .COOEtNaBHiOAc), .COOEt

NBoCh O LNBoCh O L

L-VA/V' ^H LA,'L-VA / V ' ^H LA,'

HCI, dioksanHCI, dioxane

NaOH, THF H₂O, MeOHNaOH, THF H ₂ O, MeOH

Shema 2Scheme 2

-2929-2929

Shema 3, prikazana spodaj, ponazarja postopek, opisan v Primeru 11.Scheme 3, shown below, illustrates the procedure described in Example 11.

NaOH.THF H₂O, MeOHNaOH.THF H ₂ O, MeOH

Shema 3Scheme 3

-3030-3030

Shema 4, prikazana spodaj, ponazarja Primer 12.Scheme 4 shown below illustrates Example 12.

NaOH, THFNaOH, THF

-►-►

H₂O, MeOHH ₂ O, MeOH

Shema 4Scheme 4

-3131-3131

Shema 5, prikazana spodaj, ponazarja postopek iz Primera 13.Scheme 5, shown below, illustrates the procedure of Example 13.

Shema 5Scheme 5

Shema 6, prikazana spodaj, ponazarja postopek, opisan v Primeru 14.Scheme 6, shown below, illustrates the procedure described in Example 14.

Shema 6Scheme 6

-3232-3232

Shema 7, prikazana spodaj, ponazarja postopek, opisan v Primeru 15.Scheme 7, shown below, illustrates the procedure described in Example 15.

CS2CO3, THFCS2CO3, THF

Shema 7Scheme 7

-3333-3333

Shema 8, prikazana spodaj, ponazarja postopek, opisan v Primeru 16.Scheme 8, shown below, illustrates the procedure described in Example 16.

BrCH₂COOEt NaH, DMFBrCH ₂ COOEt NaH, DMF

Shema 8Scheme 8

Shema 9, prikazana spodaj, ponazarja postopek, opisan v Primeru 17.Scheme 9, shown below, illustrates the procedure described in Example 17.

Shema 9Scheme 9

-3434-3434

Shema 10, prikazana spodaj, ponazarja postopek, opisan v Primeru 18.Scheme 10, shown below, illustrates the procedure described in Example 18.

cihh₂n^Xcihh ₂ n ^ X

OMeOMe

COOH nh₂ COOH nh ₂

EDCI, HOBt, NMM.DMFEDCI, HOBt, NMM.DMF

U oIn o

nh₂ onh ₂ o

OMeOMe

CDI__CDI__

C1CH₂CH₂C1, 85 °CC1CH ₂ CH ₂ C1, 85 ° C

Shema 10Scheme 10

Shema 11, prikazana spodaj, ponazarja postopek, opisan v Primeru 19.Scheme 11, shown below, illustrates the procedure described in Example 19.

Shema 11Scheme 11

Shema 12, prikazana spodaj, ponazarja postopek, opisan v Primeru 20.Scheme 12, shown below, illustrates the procedure described in Example 20.

Shema 12Scheme 12

-3535-3535

Shema 13, prikazana spodaj, ponazarja postopek, opisan v Primeru 21.Scheme 13, shown below, illustrates the procedure described in Example 21.

Shema 13Scheme 13

Shema 14, prikazana spodaj, ponazarja postopek, opisan v Primeru 22.Scheme 14, shown below, illustrates the procedure described in Example 22.

a) iBuOCOCl, NMM, THF, DMF, 0 °Ca) iBuOCOCl, NMM, THF, DMF, 0 ° C

BF₃OEt₂, Et₃SiH,BF ₃ OEt ₂ , Et ₃ SiH,

C1CH₂CH₂C1, RT do refluksaC1CH ₂ CH ₂ C1, RT to reflux

a) NaHMDS DME, -40 °Ca) NaHMDS DME, -40 ° C

b) LiBrb) LiBr

c) 59 v DMF -40°C do 45°Cc) 59 in DMF -40 ° C to 45 ° C

Shema 14Scheme 14

-3636-3636

NaOHJHFNaOHJHF

HjO.MeOHHjO.MeOH

Shema 15Scheme 15

-3737-3737

H₂,Pd/C,H ₂ , Pd / C,

MeOH,AcOHMeOH, AcOH

Shema 16Scheme 16

-3838-3838

BrCHOBrCHO

EtOO ^COCEtEtOO ^ COCEt

Pd(OAc)₂, P(o-tolil)₃ NEts.DMF, 125 °CPd (OAc) ₂ , P (o-tolyl) ₃ NEts.DMF, 125 ° C

CHO °CCHO ° C

^ph-\ ^ph- \

Ph-/Ph- /

N-HN-H

a) s-BuLi, THF,-78 °Ca) s-BuLi, THF, -78 ° C

b) 170, THF,-78 °Cb) 170, THF, -78 ° C

H₂, Pd/C, AcOH EtOH, 35 °CH ₂ , Pd / C, AcOH EtOH, 35 ° C

Shema 17Scheme 17

-3939-3939

Podroben opis priprave reprezentativnih spojin v smislu izuma je naveden v Primerih.A detailed description of the preparation of representative compounds of the invention is provided in the Examples.

Spojine v smislu izuma lahko uporabimo v obliki farmacevtsko sprejemljivih soli, izvedenih iz anorganskih ali organskih kislin. Fraza farmacevtsko sprejemljiva sol pomeni tiste soli, ki so v obsegu medicinske presoje prikladne za uporabo v stiku s tkivi ljudi in nižjih živali brez nepotrebne toksičnosti, iritacije, alergijskega odziva ipd., in so v sorazmerju s sprejemljivim razmerjem korist/tveganje. Farmacevtsko sprejemljive soli so dobro znane v tehniki. S. M. Berge et al. npr. podrobno opisujejo farmacevtsko sprejemljive soli v: J. Pharmaceutical Sciences, 1977, 66: 1 et seq. Soli lahko pripravimo in situ med končno izolacijo in čiščenjem spojin v smislu izuma ali ločeno z reakcijo proste bazne funkcije s prikladno organsko kislino. Reprezentativne kislinske adicijske soli vključujejo, vendar neomejujoče, acetat, adipat, alginat, citrat, aspartat, benzoat, benzen sulfonat, bisulfat, butirat, kamforat, kafra sulfonat, diglukonat, glicerofosfat, hemisulfat, heptanoat, heksanoat, fumarat, hidroklorid, hidrobromid, hidrojodid, 2-hidroksietansulfonat (izotionat), laktat, maleat, metan sulfonat, nikotinat, 2-naftalen sulfonat, oksalat, palmitoat, pektinat, persulfat, 3fenilpropionat, pikrat, pivalat, propionat, sukcinat, tartrat, tiocianat, fosfat, glutamat, bikarbonat, p-toluen sulfonat in undekanoat. Bazične skupine, ki vsebujejo dušik, tudi lahko kvatemiziramo s sredstvi, kot so nižji alkil halogenidi, kot so npr. metil, etil, propil in butil kloridi, bromidi in jodidi; dialkil sulfati, kot npr. dimetil, dietil, dibutil in diamil sulfati; dolgoverižni halogenidi, kot npr. decil, lavril, miristil in stearil kloridi, bromidi in jodidi; arilalkil halogenidi, kot benzil in fenetil bromidi in drugi. Tako dobimo v vodi ali olju topne ali disperzibilne produkte. Primeri za kisline, ki jih lahko uporabimo, da tvorimo farmacevtsko sprejemljive kislinske adicijske soli, vključujejo anorganske kisline, kot so klorovodikova, bromovodikova, žveplova in fosforjeva kislina in organske kisline, kot so oksalna, maleinska, jantarna in citronska kislina.The compounds of the invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase pharmaceutically acceptable salt means those salts which, within the scope of medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are in proportion to the acceptable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. S. M. Berge et al. e.g. detail pharmaceutically acceptable salts in: J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrochloride, hydrochloride , 2-hydroxyethanesulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, phosphate, phosphate, phosphate, phosphate p-toluene sulfonate and undecanoate. The nitrogen-containing base groups can also be quaternized with agents such as lower alkyl halides such as e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as e.g. dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides, such as e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. Thus, water or oil-soluble or dispersible products are obtained. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids and organic acids such as oxalic, maleic, succinic and citric acid.

Bazične adicijske soli lahko pripravimo in situ med končno izolacijo in čiščenjem spojin v smislu izuma z reakcijo deleža, ki vsebuje karboksilno kislino, s prikladno bazo, kot je hidroksid, karbonat ali bikarbonat farmacevtsko sprejemljivegaThe base addition salts can be prepared in situ between the final isolation and purification of the compounds of the invention by reacting a carboxylic acid containing moiety with a suitable base such as hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable

-4040 kovinskega kationa ali z amoniakom ali organskim primarnim, sekundarnim ali terciarnim aminom. Farmacevtsko sprejemljive soli vključujejo, vendar neomejujoče, katione na osnovi alkalijskih kovin ali alkalnih zemeljskih kovin, kot npr. litijeve, natrijeve, kalijeve, kalcijeve, magnezijeve in aluminijeve soli ipd., in netoksične kvateme amonijeve in aminske katione, ki med drugim vključujejo amonij, tetrametilamonij, tetraetilamonij, metilamonij, dimetilamonij, trimetilamonij, trietilamonij, dietilamonij in etilamonij. Drugi reprezentativni organski amini, uporabni za tvorbo bazičnih adicijskih soli, vključujejo etilendiamin, etanolamin, dietanolamin, piperidin, piperazin ipd.-4040 metal cation or with ammonia or organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as e.g. lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like, and non-toxic quatemes ammonium and amine cations, including but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium and triethylammonium. Other representative organic amines useful for the formation of basic addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dozirne oblike za lokalno dajanje spojine v smislu izuma vključujejo praške, pršila, mazila in inhalante. Aktivno spojino zmešamo pri sterilnih pogojih s farmacevtsko sprejemljivim nosilcem in katerimikoli potrebnimi varovalnimi sredstvi, pufri ali poganjalnimi sredstvi, ki so lahko potrebni. Oftalmične formulacije, očesna mazila, praški in raztopine so prav tako predvideni, kot da so v obsegu predloženega izuma.Dosage forms for topical administration of a compound of the invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary protective agents, buffers or propellants that may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated to be within the scope of the present invention.

Aktualne dozirne nivoje aktivnih sestavin v farmacevtskih sestavkih v smislu izuma lahko spreminjamo, tako da dobimo količino aktivne spojine (spojin), kije učinkovita, da dosežemo želen terapevtski odziv za posebnega pacienta, sestavke in način dajanja. Izbran dozirni nivo bo odvisen od učinkovitosti posebne spojine, načina dajanja, resnosti stanja, ki ga zdravimo in stanja ter predhodne zdravniške zgodovine pacienta, ki ga zdravimo. Tako v stroki začnemo dozirati spojino pri nižjih nivojih, kot so potrebni, da dosežemo želen terapevtski učinek in postopno povečujemo dozo, dokler ne dosežemo želenega učinka.The actual dosage levels of the active ingredients in the pharmaceutical compositions of the invention can be varied to obtain the amount of active compound (s) that is effective to achieve the desired therapeutic response for the particular patient, compositions and route of administration. The dosage level chosen will depend on the efficacy of the particular compound, the route of administration, the severity of the condition being treated and the condition and the prior medical history of the patient being treated. Thus, in the art, the compound is dosed at lower levels than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

Za uporabo v zgornjih ali drugih zdravljenjih lahko terapevtsko učinkovito količino ene od spojin v smislu izuma uporabimo v čisti obliki, ali kjer take oblike obstajajo, v obliki farmacevtsko sprejemljive soli, estra ali predzdravila. Alternativno lahko spojino damo kot farmacevtski sestavek, ki vsebuje zadevno spojino, v kombinaciji z enim ali več farmacevtsko sprejemljivimi ekscipienti. Fraza terapevtsko učinkovita količina spojine v smislu izuma pomeni zadostno količino spojine za zdravljenjeFor use in the above or other treatments, a therapeutically effective amount of one of the compounds of the invention may be used in pure form, or where such forms exist, in the form of a pharmaceutically acceptable salt, ester or prodrug. Alternatively, the compound may be administered as a pharmaceutical composition containing the compound in combination with one or more pharmaceutically acceptable excipients. The phrase therapeutically effective amount of a compound of the invention means a sufficient amount of the compound to be treated

-4141 motenj pri sprejemljivem razmerju korist/tveganje, uporabno za katerokoli medicinsko zdravljenje. Razumljivo je, da bo celotno dnevno uporabo spojin in sestavkov v smislu izuma odločil lečeči zdravnik v obsegu medicinske presoje. Specifičen terapevtsko učinkovit dozirni nivo za kateregakoli posebnega pacienta je odvisen od številnih faktorjev, ki vključujejo: motnjo, ki jo zdravimo, in resnost motnje; aktivnosti specifične uporabljene spojine; specifičen uporabljen sestavek; starost, telesno maso, splošno zdravje, spol in dieto pacienta; čas dajanja, način dajanja in hitrost izločanja specifične uporabljene spojine; trajanje zdravljenja; zdravila, uporabljena v kombinaciji ali koincidenci s specifično uporabljeno spojino; in podobne faktorje, dobro znane v tehniki. Tako v stroki začnemo dozirati spojino pri nižjih nivojih, kot so potrebni, da dosežemo želen terapevtski učinek in postopno povečujemo dozo, dokler ne dosežemo želenega učinka.-4141 Disturbances in acceptable benefit / risk ratio applicable to any medical treatment. It is understood that the full daily use of the compounds and compositions of the invention will be decided by the treating physician within the scope of the medical judgment. The specific therapeutically effective dosage level for any particular patient depends on a number of factors including: the disorder being treated and the severity of the disorder; the activities of the specific compound used; the specific composition used; age, weight, overall health, gender and diet of the patient; the time of administration, the route of administration and the rate of elimination of the specific compound used; duration of treatment; drugs used in combination or coincidence with the specific compound used; and similar factors well known in the art. Thus, in the art, the compound is dosed at lower levels than necessary to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

Celotna dnevna doza spojin v smislu izuma, ki jo damo človeku ali nižji živali, je lahko v območju od pribl. 0,0001 do pribl. 1000 mg/kg/dan. Za namene oralnega dajanja so lahko bolj prednostne doze v območju od pribl. 0,001 do pribl. 5 mg/kg/dan. Če je želeno, lahko učinkovito dnevno dozo razdelimo v več doz za namene dajanja; tako lahko sestavki posameznih doz vsebujejo take količine ali njihove submultiple, daje izpopolnjena dnevna doza.The total daily dose of the compounds of the invention administered to a human or lower animal may be in the range of approx. 0.0001 to approx. 1000 mg / kg / day. For oral administration, doses in the range of approx. 0.001 to approx. 5 mg / kg / day. If desired, the effective daily dose can be divided into several doses for administration purposes; thus, the compositions of the individual doses may contain such amounts or their submultiples, to give a refined daily dose.

Predloženi izum zagotavlja tudi farmacevtske sestavke, ki obsegajo spojine v smislu izuma, formulirane skupaj z enim ali več netoksičnimi farmacevtsko sprejemljivimi nosilci. Farmacevtski sestavki so lahko specifično formulirani za oralno dajanje v trdni ali tekoči obliki, za parenteralno injekcijo ali za rektalno dajanje.The present invention also provides pharmaceutical compositions comprising the compounds of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

Farmacevtske sestavke v smislu izuma lahko damo ljudem in drugim sesalcem oralno, rektalno, parenteralno, intracistemalno, intravaginalno, intraperitonealno, lokalno (kot s praški, mazivi, kapljicami), bukalno ali kot oralno ali nazalno pršilo. Izraz parenteralno, kot ga uporabljamo tukaj, se nanaša na načine dajanja, ki vključujejo intravenozno, intramuskulamo, intraperitonealno, intrastemalno, subkutano in intraartikulamo injekcijo in infuzijo.The pharmaceutical compositions of the invention may be administered to humans and other mammals by oral, rectal, parenteral, intracystemal, intravaginal, intraperitoneal, topical (as with powders, lubricants, drops), buccal or as an oral or nasal spray. The term parenteral, as used herein, refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous, and intraarticular injection and infusion.

-4242-4242

Z drugega vidika predloženi izum zagotavlja farmacevtski sestavek, ki obsega komponento v smislu izuma in fiziološko sprejemljivo razredčilo. Predloženi izum vključuje eno ali več spojin, kot so opisane zgoraj, formuliranih v sestavke skupaj z enim ali več netoksičnimi fiziološko prenesljivimi ali sprejemljivimi razredčili, nosilci, adjuvansi ali vehikli, ki jih skupno imenujemo tukaj kot razredčila, za parenteralno injekcijo, za intranazalno dajanje, za oralno dajanje v trdni ali tekoči obliki, za rektalno ali lokalno dajanje ali podobno.In another aspect, the present invention provides a pharmaceutical composition comprising a component of the invention and a physiologically acceptable diluent. The present invention includes one or more compounds as described above, formulated into compositions together with one or more non-toxic physiologically acceptable or acceptable diluents, carriers, adjuvants or vehicles, collectively referred to herein as diluents, for parenteral injection, for intranasal administration, for oral administration in solid or liquid form, for rectal or topical administration or the like.

Sestavke lahko damo tudi skozi kateter za lokalno dajanje na ciljno mesto preko intrakoronamega stenta (cevasta naprava, sestavljena iz fine žične mreže) ali preko biorazgradljivega polimera. Spojine so lahko tudi kompleksirane na ligande, kot so npr. protitelesa, za ciljano dajanje.The compositions can also be administered through a catheter for topical administration via an intracoronal stent (tubular device consisting of a fine wire mesh) or via a biodegradable polymer. The compounds may also be complexed to ligands such as e.g. antibodies, for targeted administration.

Sestavki, prikladni za parenteralno injekcijo, lahko obsegajo fiziološko sprejemljive sterilne vodne ali nevodne raztopine, disperzije, suspenzije ali emulzije in sterilne praške za rekonstitucijo v sterilne in injekcijske raztopine ali disperzije. Primeri za prikladne vodne in nevodne nosilce, razredčila, topila ali vehikle vključujejo vodo, etanol, poliole (propilenglikol, polietilenglikol, glicerol ipd.), rastlinska olja (npr. olivno olje), injekcijske organske estre, kot npr. etiloleat, in njihove prikladne zmesi.Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile and injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous vehicles, diluents, solvents or solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (e.g. olive oil), injectable organic esters such as e.g. ethyloleate, and suitable mixtures thereof.

Ti sestavki lahko vsebujejo tudi adjuvanse, kot npr. varovalna, omočilna, emulgima in dispergirna sredstva. Preprečevanje delovanja mikroorganizmov lahko zagotovimo z različnimi antibakterijskimi in fungicidnimi sredstvi, npr. parabeni, klorobutanolom, fenolom, sorbinsko kislino ipd. Lahko je tudi želeno, da vključimo izotonična sredstva, npr. sladkorje, natrijev klorid ipd. Podaljšano absorpcijo injekcijske farmacevtske oblike lahko dosežemo z uporabo sredstev za zadrževanje absorpcije, npr. z aluminijevim monostearatom in želatino.These compositions may also contain adjuvants such as e.g. protective, wetting, emulsifying and dispersing agents. The prevention of the action of microorganisms can be ensured by various antibacterial and fungicidal agents, e.g. parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonic agents, e.g. sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be achieved by using absorption retention agents, e.g. with aluminum monostearate and gelatin.

Suspenzije lahko vsebujejo poleg aktivnih spojin tudi suspendima sredstva, kot npr. etoksilirane izostearilne alkohole, polioksietilen sorbitol in sorbitan estre,The suspensions may contain, in addition to the active compounds, suspending agents such as e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,

-4343 mikrokristalinično celulozo, aluminijev metahidroksid, bentonit, agar-agar in tragakant ali zmesi teh substanc ipd.-4343 Microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances and the like.

Prikladno fluidnost lahko vzdržujemo npr. z uporabo prevlečnih materialov, kot je npr. lecitin, z vzdrževanjem potrebne velikosti delcev v primeru disperzij in z uporabo površinsko aktivnih sredstev. Zato da podaljšamo učinek zdravila, je v nekaterih primerih želeno, da upočasnimo absorpcijo zdravila iz subkutane ali intramuskulame injekcije. To lahko dosežemo z uporabo tekoče suspenzije kristaliničnega ali amorfnega materiala s slabo topnostjo v vodi. Hitrost absorpcije zdravila je nato odvisna od njegove hitrosti raztapljanja, ki je lahko nadalje odvisna od velikosti kristalov in kristalinične oblike. Alternativno lahko zakasnjeno absorpcijo zdravilne oblike, ki jo damo parenteralno, izvedemo z raztapljanjem ali suspendiranjem zdravila v oljnem nosilcu.Suitable fluidity can be maintained e.g. using coating materials such as e.g. lecithin, maintaining the required particle size in the case of dispersions and using surfactants. In order to prolong the effect of the drug, in some cases it may be desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends on its rate of dissolution, which may further depend on the crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered dosage form can be accomplished by dissolving or suspending the drug in an oil carrier.

Injekcijske depojske oblike izdelamo s tvorbo mikroinkapsuliranih matric zdravila v biorazgradljivih polimerih, kot je npr. polilaktid-poliglikolid. Hitrost sproščanja zdravila lahko kontroliramo v odvisnosti od razmerja zdravila proti polimeru in narave posebnega uporabljenega polimera. Primeri za druge biorazgradljive polimere vključujejo poli(orto estre) in poli(anhidride). Depojske injekcijske formulacije so tudi lahko pripravljene z vključevanjem zdravila v liposome ali mikroemulzije, ki so kompatibilne s telesnimi tkivi. Injekcijske formulacije so lahko sterilizirane, npr. s filtracijo skozi filter, ki zadrži bakterije, ali z vgradnjo sterilizimih sredstev v obliki sterilnih trdnih sestavkov, ki se lahko raztopijo ali dispergirajo v sterilni vodi ali drugih sterilnih injekcijskih medijih tik pred uporabo.Injectable depot forms are made by forming microencapsulated drug matrices in biodegradable polymers, such as e.g. polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly (ortho esters) and poly (anhydrides). Depot injection formulations can also be prepared by incorporating the drug into liposomes or microemulsions that are compatible with body tissues. Injectable formulations may be sterilized, e.g. by filtration through a bacteria-retaining filter, or by the incorporation of sterilizers in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media immediately before use.

Trde dozirne oblike za oralno dajanje vključujejo kapsule, tablete, pilule, praške in granule. V takih trdnih dozirnih oblikah je lahko aktivna spojina zmešana vsaj z enim inertnim farmacevtsko sprejemljivim ekscipientom ali nosilcem, kot je npr. natrijev citrat ali dikalcijev fosfat, in/ali z: a) polnili ali ekstenderji, kot so npr. škrobi, laktoza, saharoza, glukoza, manitol in silicijeva kislina; b) vezivi, kot so npr. karboksimetilceluloza, alginati, želatina, polivinilpirolidon, saharoza in akacija; c)Hard oral dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert pharmaceutically acceptable excipient or carrier such as e.g. sodium citrate or dicalcium phosphate, and / or by: a) fillers or extenders, such as e.g. starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c)

-4444 vlažilnimi sredstvi, kot je npr. glicerol; d) denzintegracijskimi sredstvi, kot je npr. agar-agar, kalcijev karbonat, krompirjev ali tapiokin škrob, alginska kislina, določeni silikati in natrijev karbonat; e) sredstvi za zadrževanje raztopine, kot je npr. parafin; f) pospeševalci absorpcije, kot so npr. kvateme amonijeve spojine; g) omočilnimi sredstvi, kot sta npr. cetil alkohol in glicerol monostearat; h) absorbenti, kot sta npr. kaolin in bentonitna glina; in i) mazivi, kot so npr. smukec, kalcijev stearat, magnezijev stearat, trdni polietilen glikoli, natrijev lavril sulfat in njihove zmesi. V primeru kapsul, tablet in pilul, lahko dozirna oblika obsega tudi pufma sredstva.-4444 wetting agents, such as e.g. glycerol; d) densintegration agents, such as e.g. agar-agar, calcium carbonate, potato or tapiokin starch, alginic acid, certain silicates and sodium carbonate; e) solution retention agents such as e.g. paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as e.g. cetyl alcohol and glycerol monostearate; h) absorbents such as e.g. kaolin and bentonite clay; and i) lubricants such as 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 form may also comprise a buffering agent.

Trdne sestavke podobnega tipa lahko tudi uporabimo kot polnila v mehkih in trdih polnjenih želatinskih kapsulah z uporabo ekscipientov, kot so laktoza ali mlečni sladkor kot tudi polietilenglikoli z visoko molekulsko maso ipd. Trdne dozirne oblike tablet, dražejev, kapsul, pilul in granul lahko pripravimo s prevlekami in lupinami, kot so enterične in druge prevleke, dobro znane v tehniki farmacevtskega formuliranja. Le-ti lahko po izbiri vsebujejo motnila in so lahko take sestave, da sproščajo aktivno sestavino (sestavine) samo ali prednostno v določenem delu intestinalnega trakta, po izbiri na upočasnjen način. Primeri za vstavljive sestavke, ki jih lahko uporabimo, vključujejo polimerne snovi in voske.Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric and other coatings well known in the pharmaceutical formulation technique. They may optionally contain disorders and may be of such composition that they release the active ingredient (s) alone or preferably in a particular part of the intestinal tract, optionally in a slowed-down manner. Examples of insertable compositions that may be used include polymeric substances and waxes.

Aktivne spojine so lahko tudi v mikroinkapsulirani obliki, če je primemo, z enim ali več zgoraj navedenih ekscipientov.The active compounds may also be in microencapsulated form, if appropriate, with one or more of the excipients mentioned above.

Tekoče dozirne oblike za oralno dajanje vključujejo farmacevtsko sprejemljive emulzije, raztopine, suspenzije, sirupe in eliksirje. Poleg aktivnih spojin lahko tekoče dozirne oblike vsebujejo tudi inertna razredčila, ki se navadno uporabljajo v tehniki, kot so npr. voda ali druga topila, solubilizima sredstva in emulzij ska sredstva, kot npr. etil alkohol, izopropil alkohol, etil karbonat, etil acetat, benzil alkohol, benzil benzoat, propilenglikol, 1,3-butilen glikol, dimetil formamid, olja (zlasti olje bombažnih semen, arašidno olje, koruzno olje, olje pšeničnih kalčkov, olivno olje, ricinusovo olje in sezamovo olje), glicerol, tetrahidrofurfuril alkohol, polietilen glikoli in estri maščobnih kislin in sorbitana in njihove zmesi.Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may also contain inert diluents commonly used in the art, such as e.g. water or other solvents, solubilizing agents and emulsifying agents, such as e.g. ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular cottonseed oil, peanut oil, corn oil, wheat germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid and sorbitan esters and mixtures thereof.

-4545-4545

Poleg inertnih razredčil lahko oralni sestavki vključujejo tudi adjuvanse, kot so omočilna, emulgima in suspendima sredstva, sladila, arome in parfumi.In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavors and perfumes.

Sestavki za rektalno ali vaginalno dajanje so prednostno supozitoriji, ki jih lahko pripravimo z mešanjem spojin v smislu izuma s prikladnimi neiritativnimi ekscipienti ali nosilci, kot so npr. kokosovo maslo, polietilen glikol ali supozitomi vosek, ki so trdni pri sobni temperaturi, vendar pa so tekoči pri telesni temperaturi in se zato stalijo v rektumu ali vaginalni odprtini in sproščajo aktivno spojino.Rectal or vaginal administration compositions are preferably suppositories that can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers, such as e.g. coconut butter, polyethylene glycol or wax suppositories that are solid at room temperature but are liquid at body temperature and therefore melt in the rectum or vaginal opening and release the active compound.

Spojine v smislu predloženega izuma lahko damo v obliki liposomov. Kot je znano v tehniki, liposome na splošno izvedemo iz fosfolipidov ali drugih lipidnih snovi. Liposome tvorimo z mono- ali multilamelamo hidratiranimi tekočimi kristali, ki so dispergirani v vodnem mediju. Uporabimo lahko katerikoli netoksičen fiziološko sprejemljiv lipid, ki se da metabolizirati in je sposoben, da tvori liposome. Predloženi sestavki v liposomski obliki lahko vsebujejo poleg spojine v smislu predloženega izuma tudi stabilizatorje, varovalna sredstva, ekscipiente ipd. Prednostni lipidi so naravni in sintetični fosfolipidi in fosfatidil holini (lecitini), uporabljeni ločeno ali skupaj.The compounds of the present invention can be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multilamellar hydrated liquid crystals, which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable lipid that can be metabolised and capable of forming liposomes can be used. The present compositions in liposomal form may contain, in addition to the compound of the present invention, stabilizers, safeners, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.

Postopki za tvorbo liposomov so znani v tehniki, npr.: Prescott, Ed., Methods in Celi Biologv, Vol. XIV, Academic Press, New York, Ν.Υ. (1976), str. 33 in dalje.Methods for liposome formation are known in the art, for example: Prescott, Ed., Methods and Celi Biologv, Vol. XIV, Academic Press, New York, Ν.Υ. (1976), p. 33 onwards.

Izraz farmacevtsko sprejemljiva predzdravila, kot ga uporabljamo tukaj, pomeni tista predzdravila spojin v smislu izuma, ki so v obsegu medicinske presoje prikladna za uporabo v stiku s tkivi ljudi in nižjih živali brez neprimerne toksičnosti, iritacije, alergijskega odziva ipd., v sorazmerju s sprejemljivim razmerjem korist/tveganje in učinkovita pri njihovi nameravani uporabi, tudi amfoteme oblike spojin v smislu izuma, kjer je možno. Predzdravila v smislu predloženega izuma se lahko hitro transformirajo in vivo v matično spojino z zgornjo formulo, npr. s hidrolizo v krvi. Podrobna razlaga je navedena v: T. Higuchi in V. Stella, Pro-drugs as Novel Deliverv Svstems, V. 14 A.C.S. Symposium Series in v: Edward B. Roche, izd., BioreversibleThe term pharmaceutically acceptable prodrugs as used herein means those prodrugs of the compounds of the invention that are, within the scope of medical judgment, suitable for use in contact with human and lower animal tissues without undue toxicity, irritation, allergic response, etc., in proportion to acceptable benefit / risk ratio and effective in their intended use, including the amphotemic form of the compounds of the invention where possible. The prodrugs of the present invention can be rapidly transformed in vivo into a parent compound of the above formula, e.g. by hydrolysis in the blood. A detailed explanation is given in: T. Higuchi and V. Stella, Pro-drugs as Novel Deliverv Svstems, V. 14 A.C.S. Symposium Series and in: Edward B. Roche, ed., Bioreversible

-4646-4646

Carriers in Drug Design, American Pharmaceutical Asssociation in Pergamon Press (1987), vključeno tukaj z referenco.Carriers and Drug Design, American Pharmaceutical Asssociation, and Pergamon Press (1987), incorporated herein by reference.

Spojine v smislu izuma, ki se tvorijo z in vivo pretvorbo drugačne spojine, kot smo jo dali sesalcu, so predvidene, da so vključene v obsegu predloženega izuma.The compounds of the invention which are formed by in vivo conversion of a compound other than that administered to the mammal are intended to be included within the scope of the present invention.

Spojine v smislu izuma lahko obstajajo kot stereoizomeri, kjer so navzoči asimetrični ali kiralni centri. Ti stereoizomeri so R ali S, odvisno od konfiguracije substituentov okrog kiralnega atoma ogljika. Predloženi izum predvideva različne stereoizomere in njihove zmesi. Stereoizomeri vključujejo enantiomere in diastereomere in zmesi enantiomerov ali diastereomerov. Individualne stereoizomere spojin v smislu izuma lahko pripravimo sintetično iz komercialno dosegljivih izhodnih materialov, ki vsebujejo asimetrične ali kiralne centre, ali s pripravo racemnih zmesi in nato z ločitvijo, dobro znano strokovnjakom. Ti postopki za ločitev so ponazorjeni s Primeri z (1) dodajanjem zmesi enantiomerov kiralni pomožni snovi, ločevanjem dobljene zmesi diastereomerov s prekristalizacijo ali kromatografijo in sproščanjem optično čistega produkta od pomožne snovi, ali z (2) direktno ločitvijo zmesi optičnih enantiomerov na kiralnih kromatografskih kolonah.The compounds of the invention may exist as stereoisomers where asymmetric or chiral centers are present. These stereoisomers are R or S, depending on the configuration of the substituents around the chiral carbon atom. The present invention provides for different stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers. The individual stereoisomers of the compounds of the invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures and then by separation well known to those skilled in the art. These separation procedures are exemplified by Examples by (1) adding a mixture of enantiomers to a chiral auxiliary, separating the resulting diastereomer mixture by recrystallization or chromatography and releasing an optically pure product from an excipient, or (2) directly separating a mixture of optical enantiomers on chiral chromatographs .

Spojine v smislu izuma so lahko v nesolvatiranih kot tudi solvatiranih oblikah, vključno hidratnih oblikah, kot so hemihidrati. Na splošno so solvatirane oblike s farmacevtsko sprejemljivimi topili, kot sta med drugim npr. voda in etanol, ekvivalentne nesolvatiranim oblikam za namene izuma. Z drugega vidika predloženi izum predvideva postopek za inhibiranje vezave α₄βι-integrina na VCAM-1. Postopek v smislu predloženega izuma lahko uporabimo bodisi in vitro ali in vivo. V skladu s postopkom v smislu izuma izpostavimo celico, ki izraža α₄β!-integrin, celici, ki izraža VCAM-1 v navzočnosti učinkovite inhibime količine spojine v smislu izuma.The compounds of the invention may be in unsolvated as well as solvated forms, including hydrated forms such as hemihydrates. Generally, solvated forms are with pharmaceutically acceptable solvents such as e.g. water and ethanol equivalent to unsolvated forms for the purposes of the invention. In another aspect, the present invention provides a method of inhibiting the binding of α ₄ βι-integrin to VCAM-1. The process of the present invention can be used either in vitro or in vivo. In accordance with the method of the invention, a cell expressing α ₄ β-integrin is exposed to a cell expressing VCAM-1 in the presence of an effective inhibitory amount of the compound of the invention.

Celica, ki izraža a^-integrin, je lahko naravna bela krvna celica, mastocit ali drugi celični tip, ki naravno izraža α₄β! na celični površini, ali celica, transfektirana z ekspresijskim vektorjem, ki vsebuje polinukleotid (npr. genomska DNA ali cDNA), kiA ^ -integrin-expressing cell can be a natural white blood cell, mast cell, or other cell type that naturally expresses α ₄ β! on a cell surface, or a cell transfected with an expression vector containing a polynucleotide (e.g., genomic DNA or cDNA) that

-4747 kodira cc$i-integrin. V posebno prednostni izvedbi je a₄Pi-integrin navzoč na površini bele krvne celice, kot je npr. monocit, limfocit ali granulocit (npr. eozinofilec ali bazofilec).-4747 encodes cc $ i-integrin. In a particularly preferred embodiment, the α ₄ Pi integrin is present on the surface of the white blood cell, such as e.g. monocyte, lymphocyte, or granulocyte (e.g., eosinophil or basophil).

Celica, ki izraža VCAM-1, je lahko naravna celica (npr. endotelijska celica) ali celica, transfektirana z ekspresijskim vektorjem, ki vsebuje polinukleotid, ki kodira VCAM1. Postopki za proizvodnjo transfektiranih celic, ki izražajo VCAM-1, so dobro znani v tehniki.A cell expressing VCAM-1 may be a natural cell (e.g., an endothelial cell) or a cell transfected with an expression vector containing a polynucleotide encoding VCAM1. Methods for producing transfected cells expressing VCAM-1 are well known in the art.

Kjer VCAM-1 obstaja na površini celice, je ekspresija tega VCAM-1 prednostno inducirana z inflamatomimi citokini, kot so npr. tumor nekrotizirajoči faktor-a, interlevkin-4 in interlevkin-ΐβ.Where VCAM-1 exists on the cell surface, expression of this VCAM-1 is preferably induced by inflammatory cytokines, such as e.g. tumor necrotizing factor-a, interleukin-4, and interleukin-ΐβ.

Kjer so celice, ki izražajo ο^βι-integrin in VCAM-1, v živem organizmu, damo spojino v smislu izuma v učinkoviti količini živemu organizmu. Prednostno je spojina farmacevtski sestavek v smislu izuma. Postopek v smislu izuma je posebno koristen pri zdravljenju bolezni, povezanih z nekontrolirano migracijo belih krvnih celic v poškodovano tkivo. Take bolezni vključujejo, vendar neomejujoče, astmo, aterosklerozo, revmatoidni artritis, alergijo, multiplo sklerozo, lupus, vnetne črevesne bolezni, zavračanje presadkov, kontaktno hipersenzitivnost, tip I diabetes, levkemijo in možganski rak. Dajanje prednostno izvedemo z intravaskulamim, subkutanim, intranazalnim, transdermalnim ali oralnim dajanjem.Where cells expressing ο ^ βι-integrin and VCAM-1 are in a living organism, the compound of the invention is administered in an effective amount to a living organism. Preferably, the compound is a pharmaceutical composition of the invention. The method of the invention is particularly useful in the treatment of diseases associated with the uncontrolled migration of white blood cells into damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia and brain cancer. Administration is preferably by intravascular, subcutaneous, intranasal, transdermal or oral administration.

Predloženi izum zagotavlja tudi postopek za selektivno inhibiranje vezave α₄βιintegrina na protein, ki obsega eksponiranje integrina proteinu v navzočnosti učinkovite inhibime količine spojine v smislu izuma. V prednostni izvedbi je α₄βιintegrin izražen na površini celice bodisi naravne ali transformirane, da izraža α₄βιintegrin.The present invention also provides a method for selectively inhibiting the binding of α ₄ βιintegrina the protein comprising superscripting integrin to the protein in the presence of an effective amount of a compound inhibime invention. In a preferred embodiment, α ₄ βιintegrin is expressed on the cell surface either naturally or transformed to express α ₄ βιintegrin.

-4848-4848

Protein, na katerega se c^Pi-integrin veže, je lahko izražen bodisi na celični površini ali je del ekstracelulame matrice. Posebno prednostna proteina sta fibronektin ali invazin.The protein to which c ^ Pi integrin binds may be expressed either on the cell surface or as part of the extracellular matrix. Particularly preferred proteins are fibronectin or invasin.

Sposobnost spojin v smislu izuma, da inhibirajo vezavo, je podrobno opisana spodaj v Primerih. Ti Primeri so namenjeni za opis prednostnih izvedb in uporabe izuma in niso namenjeni za omejevanje izuma, če ni drugače navedeno v priloženih zahtevkih.The ability of the compounds of the invention to inhibit binding is described in detail in the Examples below. These Examples are intended to describe preferred embodiments and uses of the invention and are not intended to limit the invention unless otherwise stated in the appended claims.

-4949-4949

Primer 1Example 1

Spojino 8, (3S)-3-(l,3-benzodioksol-5-il)-3-((2R,S)-2-(3-benzil-5-metil-2-oksol(2H)-piridinil)heksanoilamino)propanojsko kislino s strukturo, prikazano spodaj, sintetiziramo kot sledi.Compound 8, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3-benzyl-5-methyl-2-oxol (2H) -pyridinyl) hexanoylamino) propanoic acid with the structure shown below is synthesized as follows.

PhPh

Strukture spojin, identificiranih s številko v tem Primeru, so navedene v shemi 1 zgoraj.The structures of the compounds identified by the number in this Example are listed in Scheme 1 above.

Stopnja 1: Raztopino 540 mg hidrokloridne soli metil estra 2-aminoheksanojske kisline 1 v 20 ml metilen klorida speremo s prebitkom nasičenega natrijevega bikarbonata. Organsko plast ločimo, posušimo nad magnezijevim sulfatom in koncentriramo v vakuumu, da dobimo 365 mg metil estra 2-aminoheksanojske kisline kot brezbarvno olje. Ta material združimo s 5 ml benzena, 0,28 ml propionaldehida in prebitkom magnezijevega sulfata. Po mešanju 15 minut reakcijsko zmes filtriramo in koncentriramo v vakuumu, da dobimo 420 mg spojine 2 kot brezbarvno olje. Spojino 2 uporabimo direktno brez nadaljnjega čiščenja.Step 1: A solution of 540 mg of the hydrochloride salt of 2-aminohexanoic acid methyl ester 1 in 20 ml of methylene chloride is washed with excess saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give 365 mg of 2-aminohexanoic acid methyl ester as a colorless oil. Combine this material with 5 ml of benzene, 0.28 ml of propionaldehyde and an excess of magnesium sulfate. After stirring for 15 minutes, the reaction mixture was filtered and concentrated in vacuo to give 420 mg of compound 2 as a colorless oil. Compound 2 was used directly without further purification.

Stopnja 2: V raztopino 1050 mg spojine 2 v 10 ml dietil etra, hlajeno na ledeni kopeli, pod nadtlakom dušikove atmosfere, dodamo 0,80 ml trietilamina in raztopino 964 mg 3-fenilpropanoil klorida v 2 ml dietil etra. Ledeno kopel odstranimo in reakcijsko zmes mešamo 30 minut. Reakcijsko zmes nato koncentriramo v vakuumu in preostali material nadalje ločimo s silikagelno kromatografijo z uporabo 15 % etil acetata/heksana kot eluenta, da dobimo 468 mg spojine 3 kot brezbarvno olje.Step 2: Add 0.80 ml of triethylamine and a solution of 964 mg of 3-phenylpropanoyl chloride in 2 ml of diethyl ether to a solution of 1050 mg of compound 2 in 10 ml of diethyl ether cooled in an ice bath under nitrogen pressure. The ice bath was removed and the reaction was stirred for 30 minutes. The reaction mixture was then concentrated in vacuo and the remaining material was further separated by silica gel chromatography using 15% ethyl acetate / hexane as eluent to give 468 mg of compound 3 as a colorless oil.

-5050-5050

Spojina 3: 'H NMR (CDC1₃): δ 0,87 (t, J = 7,0 Hz, 3H), 1,26 (m, 4H), 1,68 (dd, J = 7,0, 1,1 Hz, 3H), 1,74 (m, IH), 1,97 (m, IH), 2,70 (t, J = 7,9 Hz, 2H), 2,96 (t, J = 7,9 Hz, 2H), 3,68 (s, 3H), 4,96 (dd, J = 10,1, 5,3 Hz, IH), 5,32 (dq, J = 13,9, 7,0 Hz, IH), 6,13 (dd, J = 13,9, 1,1 Hz, IH), 7,20 (m, 2H), 7,25 (m, 3H).Compound 3: 1 H NMR (CDCl ₃ ): δ 0.87 (t, J = 7.0 Hz, 3H), 1.26 (m, 4H), 1.68 (dd, J = 7.0, 1 , 1 Hz, 3H), 1.74 (m, 1H), 1.97 (m, 1H), 2.70 (t, J = 7.9 Hz, 2H), 2.96 (t, J = 7 , 9 Hz, 2H), 3.68 (s, 3H), 4.96 (dd, J = 10.1, 5.3 Hz, 1H), 5.32 (dq, J = 13.9, 7, 0 Hz, 1H), 6.13 (dd, J = 13.9, 1.1 Hz, 1H), 7.20 (m, 2H), 7.25 (m, 3H).

Stopnja 3: N,N-dimetilformamid (1,63 ml) dodamo po kapljicah v bučko, hlajeno na ledu, ki vsebuje 4,57 ml fosforjevega oksiklorida, hermetično zaprtega pod nadtlakom dušikove atmosfere. Po 5 minutah damo reakcijsko raztopino s kanilo v bučko, ki vsebuje 2,22 g spojine 3. To zmes mešamo pri sobni temperaturi pod nadtlakom dušikove atmosfere 2 uri in jo nato segrevamo pri 75 °C 46 ur. Temno obarvano reakcijsko zmes zlijemo na led in mešamo s prebitkom natrijevega bikarbonata in etil acetata. Zmes nasitimo z natrijevim kloridom in organsko plast ločimo. Vodno plast ekstrahiramo (3-krat 100 ml) z etil acetatom. Združene organske materiale posušimo nad magnezijevim sulfatom in koncentriramo v vakuumu, da dobimo 1,70 g temno obarvanega olja. Z metilen kloridno ekstrakcijo (3-krat) vodne plasti, dobimo dodatnih 200 mg materiala po sušenju (MgSO₄) in kondenzaciji v vakuumu. Združena preostala olja nadalje očistimo s silikagelno kromatografijo z uporabo 20 % - 25 % etil acetata/heksana kot eluenta, da dobimo 815 mg spojine 4 kot rumeno olje. Spojina 4. *H NMR (CDC1₃): δ 0,87 (t, J = 7,2 Hz, 3H), 1,18 (m, IH), 1,31 (m, 3H), 1,87 (m, IH), 2,00 (d, J = 0,7 Hz, 3H), 2,16 (m, IH), 3,72 (s, 3H), 3,85 (br, s, 2H), 5,57 (dd, J =Step 3: N, N-dimethylformamide (1.63 ml) was added dropwise to an ice-cooled flask containing 4.57 ml of phosphorus oxychloride, sealed under nitrogen pressure. After 5 minutes, place the cannula reaction solution in a flask containing 2.22 g of compound 3. This mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then heated at 75 ° C for 46 hours. The dark colored reaction mixture was poured onto ice and stirred with excess sodium bicarbonate and ethyl acetate. The mixture was saturated with sodium chloride and the organic layer separated. The aqueous layer was extracted (3 times 100 ml) with ethyl acetate. The combined organic materials were dried over magnesium sulfate and concentrated in vacuo to give 1.70 g of a dark colored oil. By methylene chloride extraction (3 times) of the aqueous layer, an additional 200 mg of material was obtained after drying (MgSO ₄ ) and condensing in vacuo. The combined residual oils were further purified by silica gel chromatography using 20% - 25% ethyl acetate / hexane as eluent to give 815 mg of compound 4 as a yellow oil. Compound 4. 1 H NMR (CDCl ₃ ): δ 0.87 (t, J = 7.2 Hz, 3H), 1.18 (m, 1H), 1.31 (m, 3H), 1.87 ( m, 1H), 2.00 (d, J = 0.7 Hz, 3H), 2.16 (m, 1H), 3.72 (s, 3H), 3.85 (br, s, 2H). 5.57 (dd, J =

10,1, 5,7 Hz, IH), 6,82 (br, s, IH), 6,94 (br, s, IH), 7,23 (m, 3H), 7,30 (m, 2H).10.1, 5.7 Hz, 1H), 6.82 (br, s, 1H), 6.94 (br, s, 1H), 7.23 (m, 3H), 7.30 (m, 2H) ).

Stopnja 4: V raztopino 86 mg spojine 4 v 3 ml tetrahidrofurana dodamo 1 ml 2N natrijevega hidroksida in 2 ml metanola. Po popolni hidrolizi reakcijsko zmes nakisamo z 2N klorovodikovo kislino in nasitimo z natrijevim kloridom. Zmes ekstrahiramo (3-krat) z etil acetatom in združene ekstrakte posušimo z magnezijevim sulfatom in koncentriramo v vakuumu, da dobimo 80 mg spojine 5 kot svetlo rumeno olje. Spojina 5: Ή NMR (CDC1₃): δ 0,88 (t, J = 7,1 Hz, 3H), 1,18 (m, IH), 1,33 (m, 3H), 2,04 (d, J = 0,7 Hz, 3H), 2,07 (m, IH), 2,27 (m, IH), 3,86 (d, J = 16,1 Hz, IH), 3,90 (d, J = 16,1 Hz, IH), 5,04 (dd, J = 9,0, 6,8 Hz, IH), 6,96 (br, s, IH), 6,98 (br, s, IH), 7,23 (m, 3H), 7,31 (m, 2H).Step 4: To a solution of 86 mg of compound 4 in 3 ml of tetrahydrofuran is added 1 ml of 2N sodium hydroxide and 2 ml of methanol. After complete hydrolysis, the reaction mixture was acidified with 2N hydrochloric acid and saturated with sodium chloride. The mixture was extracted (3 times) with ethyl acetate and the combined extracts were dried with magnesium sulfate and concentrated in vacuo to give 80 mg of compound 5 as a light yellow oil. Compound 5: Ή NMR (CDCl ₃ ): δ 0.88 (t, J = 7.1 Hz, 3H), 1.18 (m, 1H), 1.33 (m, 3H), 2.04 (d , J = 0.7 Hz, 3H), 2.07 (m, 1H), 2.27 (m, 1H), 3.86 (d, J = 16.1 Hz, 1H), 3.90 (d , J = 16.1 Hz, 1H), 5.04 (dd, J = 9.0, 6.8 Hz, 1H), 6.96 (br, s, 1H), 6.98 (br, s, 1H), 7.23 (m, 3H), 7.31 (m, 2H).

-5151-5151

Stopnja 5: V raztopino 80 mg spojine 5 v 1 ml Ν,Ν-dimetilformamida pri sobni temperaturi in pod nadtlakom dušikove atmosfere dodamo 80 mg (S)-spojine 6, 0,057 ml diizopropiletilamina in 137 mg HBTU. Zmes mešamo 16 ur in jo nato zmešamo z etil acetatom/heksanom v razmerju 1:1. To zmes speremo z 2N klorovodikovo kislino, nasičenim natrijevim bikarbonatom, vodo (2-krat) in končno s slanico. Dobljeno raztopino posušimo nad magnezijevim sulfatom in koncentriramo v vakuumu, da dobimo 156 mg rumenega olja. Ta material nadalje očistimo s silikagelno kromatografijo z uporabo 25 % etil acetata kot eluenta, da dobimo 109 mg spojine 7 kot brezbarvno olje. Spojina 7: (najmanj polami diastereomer): ’Η-NMR (CDC1₃): δ 0,85 (t, J = 7,1 Hz, 3H), 1,11 (t, J = 7,1 Hz, 3H), 1,18 (m, IH), 1,30 (m, 3H), 1,78 (m, IH), 2,02 (d, J = 0,8 Hz, 3H), 2,14 (m, IH), 2,57 (dd, J = 15,4, 7,1 Hz, IH), 2,66 (dd, J = 15,4, 6,6 Hz, IH), 3,86 (br, s, 2H), 3,95 (q, J - 7,1 Hz, 2H), 5,17 (m, IH), 5,42 (t, J = 7,7 Hz, IH), 5,93 (s, 2H), 6,72 (m, 2H), 6,74 (m, IH), 6,90 (m, IH), 7,11 (br, s, IH),Step 5: To a solution of 80 mg of compound 5 in 1 ml of Ν, Ν-dimethylformamide at room temperature and under nitrogen pressure, 80 mg (S) -compounds 6, 0.057 ml of diisopropylethylamine and 137 mg of HBTU are added. The mixture was stirred for 16 hours and then mixed with ethyl acetate / hexane in a 1: 1 ratio. This mixture was washed with 2N hydrochloric acid, saturated sodium bicarbonate, water (2 times) and finally with brine. The resulting solution was dried over magnesium sulfate and concentrated in vacuo to give 156 mg of a yellow oil. This material was further purified by silica gel chromatography using 25% ethyl acetate as eluent to give 109 mg of compound 7 as a colorless oil. Compound 7: (least diastereomer polymers): 1 H-NMR (CDCl ₃ ): δ 0.85 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H) , 1.18 (m, 1H), 1.30 (m, 3H), 1.78 (m, 1H), 2.02 (d, J = 0.8 Hz, 3H), 2.14 (m, 1H), 2.57 (dd, J = 15.4, 7.1 Hz, 1H), 2.66 (dd, J = 15.4, 6.6 Hz, 1H), 3.86 (br, s , 2H), 3.95 (q, J = 7.1 Hz, 2H), 5.17 (m, 1H), 5.42 (t, J = 7.7 Hz, 1H), 5.93 (s , 2H), 6.72 (m, 2H), 6.74 (m, 1H), 6.90 (m, 1H), 7.11 (br, s, 1H),

7,23 (m, 3H), 7,30 (m, 2H), 7,37 (d, J = 7,7 Hz, IH).7.23 (m, 3H), 7.30 (m, 2H), 7.37 (d, J = 7.7 Hz, 1H).

Stopnja 6: Raztopino, sestavljeno iz 109 mg spojine 7, 3 ml tetrahidrofurana, 1 ml 2N natrijevega hidroksida in 2 ml metanola, mešamo pri sobni temperaturi do popolne hidrolize. Zmes nato razredčimo z vodo in ekstrahiramo z dietil etrom. Vodno plast nakisamo z 2N klorovodikovo kislino in ekstrahiramo (3-krat) z etil acetatom. Združene ekstrakte posušimo z magnezijevim sulfatom in koncentriramo v vakuumu, da dobimo 103 mg spojine 8, 1:1 diastereoizomemo zmes kot sivo belo peno.Step 6: A solution consisting of 109 mg of compound 7, 3 ml of tetrahydrofuran, 1 ml of 2N sodium hydroxide and 2 ml of methanol was stirred at room temperature until complete hydrolysis. The mixture was then diluted with water and extracted with diethyl ether. The aqueous layer was acidified with 2N hydrochloric acid and extracted (3 times) with ethyl acetate. The combined extracts were dried with magnesium sulfate and concentrated in vacuo to give 103 mg of compound 8, 1: 1 diastereoisomizing the mixture as a gray white foam.

Diastereomerno zmes ločimo s HPLC z reverzno fazo z uporabo gradienta 30-55 % acetonitrila/vode, da dobimo spojino 9 (R,S) in spojino 10 (S,S).The diastereomeric mixture was separated by reversed-phase HPLC using a gradient of 30-55% acetonitrile / water to give compound 9 (R, S) and compound 10 (S, S).

Spojina 9 (najbolj polaren diastereomer): *H NMR (CD₃SOCD₃): δ 0,83 (t, J = 7,1 Hz, 3H), 1,13 (m, 2H), 1,26 (m, 2H), 1,76 (m, IH), 1,96 (s prekrivajoč m, 4H), 2,62 (dd, J = 15,8, 6,6 Hz, IH), 2,70 (dd, J = 15,8, 8,4 Hz, IH), 3,69 (d, J = 14,8 Hz, IH), 3,73 (d, J = 14,8 Hz, IH), 5,09 (m, IH), 5,47 (dd, J = 9,2, 6,6 Hz, IH), 6,71 (dd, J = 8,0, 1,5 Hz, IH), 6,77 (d, J = 8,0 Hz, IH), 6,84 (d, J = 1,5 Hz, IH), 7,00 (d, J = 1,8 Hz, IH), 7,14-7,30 (m, 6H), 8,70 (d, J = 8,1 Hz, IH).Compound 9 (most polar diastereomer): * H NMR (CD ₃ SOCD ₃ ): δ 0.83 (t, J = 7.1 Hz, 3H), 1.13 (m, 2H), 1.26 (m. 2H), 1.76 (m, 1H), 1.96 (s overlapping m, 4H), 2.62 (dd, J = 15.8, 6.6 Hz, 1H), 2.70 (dd, J = 15.8, 8.4 Hz, 1H), 3.69 (d, J = 14.8 Hz, 1H), 3.73 (d, J = 14.8 Hz, 1H), 5.09 (m , 1H), 5.47 (dd, J = 9.2, 6.6 Hz, 1H), 6.71 (dd, J = 8.0, 1.5 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 1.5 Hz, 1H), 7.00 (d, J = 1.8 Hz, 1H), 7.14-7.30 ( m, 6H), 8.70 (d, J = 8.1 Hz, 1H).

-5252-5252

Spojina 10: (najmanj polaren diastereomer) NMR (CD3SOCD3): δ 0,76 (t, J = 7,3 Hz, 3H), 1,01 (m, 2H), 1,20 (m, 2H), 1,98 (br, s, 3H), 2,60 (dd, J = 15,8, 7,0 Hz, IH), 2,68 (dd, J = 15,8, 7,7 Hz, IH), 3,71 (d, J = 15,0 Hz, IH), 3,76 (d, J = 15,0 Hz, IH), 5,05 (ddd, J = 8,0, 7,7, 7,0 Hz, IH), 5,51 (dd, J = 9,2, 6,6 Hz, IH), 5,98 (s, 2H), 6,77 (dd, J = 8,0, 1,4 Hz, IH), 6,83 (d, J = 8,0 Hz, IH), 6,89 (d, J = 1,4 Hz, IH), 7,02 (d, J = 2,2 Hz, IH), 7,18 (m, IH), 7,25 (m, 4H), 7,38 (m, IH), 8,79 (d, J = 8,0 Hz, IH), 12,08 (br, s, IH).Compound 10: (least polar diastereomer) NMR (CD3SOCD3): δ 0.76 (t, J = 7.3 Hz, 3H), 1.01 (m, 2H), 1.20 (m, 2H), 1. 98 (br, s, 3H), 2.60 (dd, J = 15.8, 7.0 Hz, 1H), 2.68 (dd, J = 15.8, 7.7 Hz, 1H), 3 , 71 (d, J = 15.0 Hz, 1H), 3.76 (d, J = 15.0 Hz, 1H), 5.05 (ddd, J = 8.0, 7.7, 7.0 Hz, 1H), 5.51 (dd, J = 9.2, 6.6 Hz, 1H), 5.98 (s, 2H), 6.77 (dd, J = 8.0, 1.4 Hz) , 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H) ), 7.18 (m, 1H), 7.25 (m, 4H), 7.38 (m, 1H), 8.79 (d, J = 8.0 Hz, 1H), 12.08 (br , s, 1H).

Primer 2Example 2

Spojino 12, (3S)-3-((2R,S)-2-(3-benzil-5-metil-2-okso-l(2H)-piridinil)heksanoilamino)-3-(2,3-dihidro-l-benzofuran-5-il)propanojsko kislino, prikazano spodaj, sintetiziramo po postopku iz Primera 1, razen da s spojino A, prikazano spodaj, zamenjamo spojino 6 iz stopnje 5.Compound 12, (3S) -3 - ((2R, S) -2- (3-benzyl-5-methyl-2-oxo-1 (2H) -pyridinyl) hexanoylamino) -3- (2,3-dihydro- 1-Benzofuran-5-yl) propanoic acid, shown below, was synthesized according to the procedure of Example 1, except that with compound A shown below, the compound 6 from step 5 was replaced.

Primer 3Example 3

Spojino 13, (3S)-3-((2R,S)-2-(3-benzil-5-metil-2-okso-l(2H)-piridinil)heksanoilamino)-3-(4-metilfenil)propanojsko kislino, prikazano spodaj, dobimo po postopku iz Primera 1,Compound 13, (3S) -3 - ((2R, S) -2- (3-benzyl-5-methyl-2-oxo-1 (2H) -pyridinyl) hexanoylamino) -3- (4-methylphenyl) propanoic acid shown below is obtained by the procedure of Example 1,

-5353-5353

razen da s spojino B, prikazano spodaj, zamenjamo spojino 6 iz stopnje 5.except that with compound B shown below, we replace compound 6 from step 5.

Primer 4Example 4

Spoj ino 14, (3 S)-3 -((2R, S)-2-(3 -benzil-5 -metil-2-okso-1 (2H)-piridinil)heksanoilamino)-3-(4-fluorofenil)propanojsko kislino, prikazano spodaj, dobimo po postopku iz Primera 1,Compound 14, (3 S) -3 - ((2R, S) -2- (3-benzyl-5-methyl-2-oxo-1 (2H) -pyridinyl) hexanoylamino) -3- (4-fluorophenyl) the propanoic acid shown below is obtained by the procedure of Example 1,

razen da s spojino 11, prikazano spodaj, zamenjamo spojino 6 iz stopnje 5.except that the compound 11 shown below replaces the compound 6 from step 5.

-5454-5454

Primer 5Example 5

Spojino 15, (3S)-3-(l,3-benzodioksol-5-il)-3-((2R,S)-2-(3-(4-metoksibenzil)-5metil-2-okso-l(2H)-piridinil)heksanoilamino)propanojsko kislino, prikazano spodaj, lahko dobimo po postopku iz Primera 1,Compound 15, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3- (4-methoxybenzyl) -5methyl-2-oxo-1 (2H ) -pyridinyl) hexanoylamino) propanoic acid shown below can be obtained according to the procedure of Example 1,

razen da moramo s 3-(4-metoksifenil)-propanoilkloridom zamenjati 3-fenilpropanoil klorid iz stopnje 2.except that 3- (4-methoxyphenyl) -propanoyl chloride needs to be replaced by step 2 3-phenylpropanoyl chloride.

Primer 6Example 6

Spojino 16, (3S)-3-(l,3-benzodioksol-5-il)-3-((2R,S)-2-(3-(4-metilbenzil)-5metil-2-okso-l(2H)-piridinil)heksanoilamino)propanojsko kislino, prikazano spodaj, lahko dobimo po postopku iz Primera 1,Compound 16, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3- (4-methylbenzyl) -5methyl-2-oxo-1 (2H ) -pyridinyl) hexanoylamino) propanoic acid shown below can be obtained according to the procedure of Example 1,

razen da moramo s 3-(4-metilfenil)-propanoil kloridom zamenjati 3-fenilpropanoil klorid iz stopnje 2.except that 3- (4-methylphenyl) -propanoyl chloride needs to be replaced by Step 2 3-phenylpropanoyl chloride.

Primer 7Example 7

Spojino 17, (3S)-3-(l,3-benzodioksol-5-il)-3-((2R,S)-2-(3-(4-fluorobenzil)-5-metil-5555Compound 17, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3- (4-fluorobenzyl) -5-methyl-5555

2-okso-l(2H)-piridinil)heksanoilamino)propanojsko kislino, prikazano spodaj, dobimo po postopku iz Primera 1,2-Oxo-1 (2H) -pyridinyl) hexanoylamino) propanoic acid, shown below, was obtained according to the procedure of Example 1,

razen da s 3-(4-fluorofenil)-propanoil kloridom zamenjamo 3-fenilpropanoil klorid iz stopnje 2.except that 3- (4-fluorophenyl) -propanoyl chloride is substituted for Step 2 3-phenylpropanoyl chloride.

Primer 8Example 8

Spojino 18, (3S)-3-(l,3-benzodioksol-5-il)-3-((2R,S)-2-(3-(4-klorobenzil)-5-metil2-okso-l(2H)-piridinil)heksanoilamino)propanojsko kislino, prikazano spodaj, dobimo po postopku iz Primera 1,Compound 18, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3- (4-chlorobenzyl) -5-methyl2-oxo-1 (2H ) -pyridinyl) hexanoylamino) propanoic acid shown below is obtained according to the procedure of Example 1,

razen da s 3-(4-klorofenil)-propanoil kloridom zamenjamo 3-fenilpropanoil klorid iz stopnje 2.except that 3- (4-chlorophenyl) -propanoyl chloride is substituted for Step 2 3-phenylpropanoyl chloride.

Primer 9Example 9

Spojino 19, (3S)-3-(l,3-benzodioksol-5-il)-3-((2R,S)-2-(3-(3-klorobenzil)-5-metil2-okso-l(2H)-piridinil)heksanoilamino)propanojsko kislino, prikazano spodaj, dobimo po postopku iz Primera 1,Compound 19, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2R, S) -2- (3- (3-chlorobenzyl) -5-methyl2-oxo-1 (2H ) -pyridinyl) hexanoylamino) propanoic acid shown below is obtained according to the procedure of Example 1,

-5656-5656

razen da s 3-(3-klorofenil)-propanoil kloridom zamenjamo 3-fenilpropanoil klorid iz stopnje 2.except that 3- (3-chlorophenyl) -propanoyl chloride is substituted for Step 2 3-phenylpropanoyl chloride.

Primer 10Example 10

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2-okso-3-(2-tienilmetil)-limidazolidinil]heksanoil}amino)propanojske kisline (20).Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2-oxo-3- (2-thienylmethyl) -limidazolidinyl] hexanoyl} amino) propanoic acid (20).

Stopnja ena: V raztopino spojine 6 (680 mg, 2,87 mmol) in N-terc.butoksikarbonil-Lnorlevcina (696 mg, 3,01 mmol) v DMF (14,4 ml) pri sobni temperaturi pod atmosfero suhega dušika zaporedoma dodamo N,N-diizopropiletilamin (0,52 ml, 3,0 mmol) in HBTU (1,25 g, 3,3 mmol). Dobljeno zmes mešamo pri sobni temperaturi preko noči, nato jo razredčimo z zmesjo heksanr.etil acetat v razmerju 1:1 in speremo z 2N HCL, H₂O, nasičeno NaHCO₃, H₂O (3-krat) in slanico. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 22 (1,27 g, 98 %) kot svetlo rumeno trdno snov.Step One: To a solution of Compound 6 (680 mg, 2.87 mmol) and N-tert.butoxycarbonyl-Lnorleucine (696 mg, 3.01 mmol) in DMF (14.4 ml) was added successively at room temperature under a dry nitrogen atmosphere. N, N-diisopropylethylamine (0.52 ml, 3.0 mmol) and HBTU (1.25 g, 3.3 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with a 1: 1 ratio of hexane-ethyl acetate and washed with 2N HCL, H ₂ O, saturated NaHCO ₃ , H ₂ O (3 times) and brine. The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure to give 22 (1.27 g, 98%) as a pale yellow solid.

Stopnja dve: V bučko, ki vsebuje 22 (1,27 g, 2,82 mmol), zatesnjeno z gumastim septumom pri sobni temperaturi pod atmosfero suhega dušika, dodamo z injekcijsko iglo HC1 (7,2 ml, 4,0 M v dioksanu, 28,8 mmol). Iglo za dušik odstranimo in zmes v zatesnjeni bučki mešamo 1 uro. Zmes razredčimo s CH₂C1₂ in speremo z nasičenim NaHCO₃. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 23 (892 mg, 90 %) kot svetlo rumeno olje.Step two: Add a HC1 needle (7.2 ml, 4.0 M in dioxane) to a flask containing 22 (1.27 g, 2.82 mmol), sealed with a rubber septum at room temperature under a dry nitrogen atmosphere. , 28.8 mmol). The nitrogen needle was removed and the mixture was stirred for 1 hour in a sealed flask. The mixture was diluted with CH ₂ C1 ₂ and washed with saturated NaHCO ₃ . The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure to give 23 (892 mg, 90%) as a pale yellow oil.

Stopnja tri: V raztopino etanolamina (1,70 g, 27,8 mmol) in 2-tiofenkarboksaldehida (0,52 ml, 5,6 mmol) v 1,2-dikloroetanu (22 ml) pri sobni temperaturi pod atmosferoStep Three: To a solution of ethanolamine (1.70 g, 27.8 mmol) and 2-thiophenecarboxaldehyde (0.52 ml, 5.6 mmol) in 1,2-dichloroethane (22 ml) at room temperature under atmosphere

-5757 suhega dušika dodamo natrijev triacetoksi borhidrid (1,66 g, 7,8 mmol). Dobljeno zmes mešamo pri sobni temperaturi preko noči, nato jo razredčimo s CH2CI2 in speremo z zmesjo iz nasičenega NaHCO₃ in slanice v razmerju 1:1. Vodno fazo ekstrahiramo z CH₂C1₂ in organske faze združimo, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo 24 (840 mg, 97 %) kot bledo rumeno olje.-5757 of dry nitrogen was added sodium triacetoxy borohydride (1.66 g, 7.8 mmol). The resulting mixture was stirred at room temperature overnight, then diluted with CH 2 Cl 2 and washed with a mixture of saturated NaHCO ₃ and brine in a 1: 1 ratio. The aqueous phase was extracted with CH ₂ Cl ₂ and the organic phases were combined, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 24 (840 mg, 97%) as a pale yellow oil.

Stopnja štiri: Raztopino aminalne spojine 24 (840 mg, 5,41 mmol) v metanolu (10 ml) mešamo pri sobni temperaturi 30 minut, ohladimo na 0 °C in nato dodamo natrijev borhidrid (106 mg, 2,8 mmol). Zmes pustimo, da se segreje na sobno temperaturo in jo nato mešamo 1 uro. Zmes pogasimo z dodajanjem vode po kapljicah, nato razredčimo s CH₂C1₂ in zmesjo iz nasičenega NaHCO₃ in slanice v razmerju 1:1. Vodno fazo ekstrahiramo s CH₂C1₂ (2-krat) in organske faze združimo, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo 25 (420 mg, 49 %) kot bledo rumeno viskozno olje.Step four: A solution of amine compound 24 (840 mg, 5.41 mmol) in methanol (10 mL) was stirred at room temperature for 30 minutes, cooled to 0 ° C and then sodium borohydride (106 mg, 2.8 mmol) added. The mixture was allowed to warm to room temperature and then stirred for 1 hour. The mixture was quenched by the addition of water dropwise, then diluted with CH ₂ Cl ₂ and a mixture of saturated NaHCO ₃ and brine in a 1: 1 ratio. The aqueous phase was extracted with CH ₂ Cl ₂ (2 times) and the organic phases were combined, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 25 (420 mg, 49%) as a pale yellow viscous oil.

Stopnja pet: Raztopino spojine 25 (420 mg, 2,67 mmol) in di-terc.butil dikarbonata (650 mg, 2,98 mmol) v CH₂C1₂ (10 ml) mešamo pri sobni temperaturi pod atmosfero suhega dušika 20 minut in nato koncentriramo. Ostanek filtriramo skozi silikagel z eluiranjem s heksani:etil acetat v razmerju 7:3 s povečevanjem do razmerja 3:2, da dobimo 26 (610 mg, 88 %) kot brezbarvno viskozno olje.Step Five: A solution of compound 25 (420 mg, 2.67 mmol) and di-tert-butyl dicarbonate (650 mg, 2.98 mmol) in CH ₂ Cl ₂ (10 ml) was stirred at room temperature under a dry nitrogen atmosphere for 20 minutes and then concentrate. The residue was filtered through silica gel eluting with hexanes: ethyl acetate at a ratio of 7: 3 by increasing to a ratio of 3: 2 to give 26 (610 mg, 88%) as a colorless viscous oil.

Stopnja šest: V raztopino metilsulfoksida (0,49 ml, 6,9 mmol) v CH₂C1₂ (11 ml), ohlajeno na -78 °C pod atmosfero suhega dušika, dodamo z injekcijsko iglo oksalil klorid (1,7 ml, 2,0 M v CH₂C1₂, 3,4 mmol). Dobljeno zmes mešamo pri -78 °C 15 minut in nato dodamo s kanilo raztopino spojine 26 (590 mg, 2,3 mmol) v CH₂C1₂ (10 ml) istočasno z izpiranjem s CH₂C1₂ (5 ml). Zmes mešamo pri -78 °C 30 minut, dodamo trietilamin (0,96 ml, 6,9 mmol) in zmes pustimo, da se segreje na sobno temperaturo. Zmes razredčimo s CH₂C1₂ in speremo z nasičenim NaHCO. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 27 (630 mg) kot svetlo rumeno olje. Ta material uporabimo brez čiščenja.Step Six: To a solution of methylsulfoxide (0.49 ml, 6.9 mmol) in CH ₂ Cl ₂ (11 ml) cooled to -78 ° C under an atmosphere of dry nitrogen, oxalyl chloride (1.7 ml,) was added with a needle. 2.0 M in CH ₂ Cl ₂ , 3.4 mmol). The resulting mixture was stirred at -78 ° C for 15 minutes and then a cannula solution of compound 26 (590 mg, 2.3 mmol) in CH ₂ Cl ₂ (10 ml) was added simultaneously with washing with CH ₂ Cl ₂ (5 ml). The mixture was stirred at -78 ° C for 30 minutes, triethylamine (0.96 ml, 6.9 mmol) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with CH ₂ C1 ₂ and washed with saturated NaHCO. The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure to give 27 (630 mg) as a pale yellow oil. Use this material without cleaning.

-5858-5858

Stopnja sedem: V raztopino spojine 27 (102 mg, 0,40 mmol) in 23 (140 mg, 0,40 mmol) v 1,2-dikloroetanu (4 ml) pri sobni temperaturi pod atmosfero suhega dušika dodamo natrijev triacetoksiborhidrid (119 mg, 0,56 mmol). Dobljeno zmes mešamo 2 uri, nato jo razredčimo z etil acetatom in speremo z nasičenim NaHCO₃ in slanico. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 28 (232 mg) kot svetlo rumeno olje. Ta material uporabimo brez čiščenja.Step seven: To a solution of Compound 27 (102 mg, 0.40 mmol) and 23 (140 mg, 0.40 mmol) in 1,2-dichloroethane (4 ml) at room temperature under a dry nitrogen atmosphere was added sodium triacetoxyborohydride (119 mg , 0.56 mmol). The resulting mixture was stirred for 2 hours, then diluted with ethyl acetate and washed with saturated NaHCO ₃ and brine. The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure to give 28 (232 mg) as a pale yellow oil. Use this material without cleaning.

Stopnja osem: V bučko, ki vsebuje 28 (232 mg surovega materiala, 0,40 mmol teoretično iz prejšnje stopnje) zatesnjeno z gumastim septumom pri sobni temperaturi pod atmosfero suhega dušika, dodamo z injekcijsko iglo HCI (1,95 ml, 4,0M v dioksanu, 7,8 mmol). Iglo za dušik odstranimo in zmes v zatesnjeni bučki mešamo 15 minut. Zmes razredčimo s CH2CI2 in speremo z zmesjo iz nasičenega NaHCO₃ in slanice v razmerju 1:1. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 29 (180 mg) kot svetlo rumeno olje. Ta material uporabimo brez čiščenja.Step Eight: To a flask containing 28 (232 mg of crude material, 0.40 mmol theoretically from the previous step) sealed with a rubber septum at room temperature under an atmosphere of dry nitrogen was added with a HCI injection needle (1.95 ml, 4.0M in dioxane, 7.8 mmol). The nitrogen needle was removed and the mixture was stirred in a sealed flask for 15 minutes. The mixture was diluted with CH 2 Cl 2 and washed with a mixture of saturated NaHCO ₃ and brine in a 1: 1 ratio. The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure to give 29 (180 mg) as a pale yellow oil. Use this material without cleaning.

Stopnja devet: V raztopino spojine 29 (180 mg surovega materiala, 0,40 mmol teoretično iz prejšnje stopnje) v 1,2-dikloroetanu (3,7 ml) pri sobni temperaturi pod atmosfero suhega dušika dodamo karbonildiimidazol (66 mg, 0,41 mmol). Zmes segrejemo na 50 °C (temperatura oljne kopeli) za 1 uro in jo nato koncentriramo. Ostanek prevzamemo v etilacetatu in speremo z 2N HCI, H₂O, nasičenim NaHCO₃ in slanico. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pod znižanim tlakom. Ostanek filtriramo skozi silikagel z eluiranjem s heksani:etil acetat v razmerju 3:2 s povečevanjem do razmerja 1:1, da dobimo 30 (114 mg, 55 % za 3 stopnje) kot brezbarvno olje.Step nine: To a solution of Compound 29 (180 mg of crude material, 0.40 mmol theoretically from the previous step) in 1,2-dichloroethane (3.7 ml) at room temperature under a dry nitrogen atmosphere was added carbonyldiimidazole (66 mg, 0.41 mmol). The mixture was heated to 50 ° C (oil bath temperature) for 1 hour and then concentrated. The residue was taken up in ethyl acetate and washed with 2N HCl, H ₂ O, saturated NaHCO ₃ and brine. The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was filtered through silica gel eluting with hexanes: ethyl acetate in a 3: 2 ratio, increasing to a 1: 1 ratio to give 30 (114 mg, 55% for 3 steps) as a colorless oil.

Stopnja deset: V raztopino spojine 30 (114 mg, 0,22 mmol) v THF (3 ml) pri sobni temperaturi dodamo NaOH (1 ml, 2N v H₂O, 2 mmol) in metanol (dovolj, da dobimo bistro raztopino, približno 2 ml). Dobljeno zmes mešamo 15 minut, nato jo razredčimo z vodo in ekstrahiramo z etrom. Vodno fazo nakisamo s HCI (2N) inStep Ten: To a solution of compound 30 (114 mg, 0.22 mmol) in THF (3 ml) at room temperature was added NaOH (1 ml, 2N in H ₂ O, 2 mmol) and methanol (enough to give a clear solution. about 2 ml). The resulting mixture was stirred for 15 minutes, then diluted with water and extracted with ether. The aqueous phase is acidified with HCl (2N) and

-5959 ekstrahiramo z etil acetatom. Etil acetatno plast speremo s slanico, posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 20 (111 mg, 100 %) kot belo peno. Ή NMR (400 MHz, CD₃SOCD₃) δ 0,82 (t, J = 7,3 Hz, 3H), 1,09 (m, 2H), 1,25 (m, 2H), 1,48 (m, IH), 1,64 (m, IH), 2,61 (dd, J = 15,8, 7,0 Hz, IH), 2,70 (dd, J = 15,8, 8,0 Hz, IH), 3,20 (m, 3H), 3,50 (m, IH), 4,27 (dd, J = 9,5, 5,9 Hz, IH), 4,38 (d, J = 15,6 Hz, IH), 4,54 (d, J = 15,6 Hz, IH), 5,08 (ddd, J = 8,1, 8,0, 7,0 Hz, IH), 5,91 (s, 2H), 6,76 (dd, J = 8,0, 1,5 Hz, IH), 6,83 (d, J = 8,0 Hz, IH),-5959 was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO ₄ and filtered, and the filtrate was concentrated under reduced pressure to give 20 (111 mg, 100%) as a white foam. Ή NMR (400 MHz, CD ₃ SOCD ₃ ) δ 0.82 (t, J = 7.3 Hz, 3H), 1.09 (m, 2H), 1.25 (m, 2H), 1.48 ( m, 1H), 1.64 (m, 1H), 2.61 (dd, J = 15.8, 7.0 Hz, 1H), 2.70 (dd, J = 15.8, 8.0 Hz) , 1H), 3.20 (m, 3H), 3.50 (m, 1H), 4.27 (dd, J = 9.5, 5.9 Hz, 1H), 4.38 (d, J = 15.6 Hz, 1H), 4.54 (d, J = 15.6 Hz, 1H), 5.08 (ddd, J = 8.1, 8.0, 7.0 Hz, 1H), 5. 91 (s, 2H), 6.76 (dd, J = 8.0, 1.5 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H),

6,88 (d, J = 1,5 Hz, IH), 6,99 (m, 2H), 7,43 (dd, J = 4,4, 1,8 Hz, IH), 8,43 (d, J = 8,1 Hz, IH).6.88 (d, J = 1.5 Hz, 1H), 6.99 (m, 2H), 7.43 (dd, J = 4.4, 1.8 Hz, 1H), 8.43 (d , J = 8.1 Hz, 1H).

Sintetične postopke, podobne tistim, opisanim zgoraj, lahko uporabimo, da dobimo spojine, kot so: (3S)-(l,3-benzodioksol-5-il)-3-(((2S)-2-(2-okso-3-(2-tienilmetil) tetrahidro-1 (2H)-pirimidinil)heksanoil)amino)propanojska kislina, (3 S)-3-(1,3benzodioksol-5-il)-3-(((2S)-2-(2-okso-4-(2-tienil)-3-(2-tienilmetil)tetrahidro-l((2H)pirimidinil)heksanoil)amino)propanojska kislina in (3S)-3-(l,3-benzodioksol-5-il)-3(((2S)-2-(2-okso-3-(2-tienilmetil)-l,3-diazepan-l-il)heksanoil)amino)propanojska kislina.Synthetic procedures similar to those described above can be used to obtain compounds such as: (3S) - (1,3-benzodioxol-5-yl) -3 - (((2S) -2- (2-oxo- 3- (2-thienylmethyl) tetrahydro-1 (2H) -pyrimidinyl) hexanoyl) amino) propanoic acid, (3S) -3- (1,3benzodioxol-5-yl) -3 - (((2S) -2- (2-Oxo-4- (2-thienyl) -3- (2-thienylmethyl) tetrahydro-1 ((2H) pyrimidinyl) hexanoyl) amino) propanoic acid and (3S) -3- (1,3-benzodioxole-5 -yl) -3 ((((2S) -2- (2-oxo-3- (2-thienylmethyl) -1,3-diazepan-1-yl) hexanoyl) amino) propanoic acid.

Primer 11Example 11

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2-okso-3-(fenilkarbonil)-l(2H)piridinil]heksanoil}amino)propanojske kisline (31).Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2-oxo-3- (phenylcarbonyl) -1 (2H) pyridinyl] hexanoyl} amino) propanoic acids (31).

-6060-6060

Stopnja ena: Raztopino spojine 23 (541 mg, 1,54 mmol) in etil benzoilacetata (0,53 ml, 3,09 mmol) v toluenu (15 ml) segrevamo ob refluksu 2 uri. Dobljeno zmes ohladimo na sobno temperaturo in koncentriramo pri znižanem tlaku. Ostanek prekristaliziramo iz heksani/CH₂Cl2, da dobimo spojino 32 (310 mg, 40 %) kot bledo rumeno trdno snov.Step One: A solution of Compound 23 (541 mg, 1.54 mmol) and ethyl benzoyl acetate (0.53 mL, 3.09 mmol) in toluene (15 mL) was heated at reflux for 2 hours. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was recrystallized from hexanes / CH ₂ Cl ₂ to give compound 32 (310 mg, 40%) as a pale yellow solid.

Stopnja dve: V suspenzijo spojine 32 (851 mg, 1,71 mmol) v etanolu (absolutni, 6,8 ml) in ledoctu (0,34 ml) pri sobni temperaturi pod dušikom dodamo 3(dimetilamino)akrolein (1,02 ml, 10,2 mmol) z injekcijsko iglo. Dobljeno zmes segrevamo ob refluksu preko noči, ohladimo na sobno temperaturo in razredčimo z etil acetatom. To zmes speremo s HC1 (2N, dvakrat) in slanico. Organsko fazo posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksanketil acetat v razmerju 3:2, da dobimo 33 (476 mg, 52 %) kot svetlo rumeno olje.Step two: Add 3 (dimethylamino) acrolein (1.02 ml) to a suspension of Compound 32 (851 mg, 1.71 mmol) in ethanol (absolute, 6.8 ml) and glacial (0.34 ml) at room temperature under nitrogen. , 10.2 mmol) with an injection needle. The resulting mixture was refluxed overnight, cooled to room temperature and diluted with ethyl acetate. This mixture was washed with HCl (2N, twice) and brine. The organic phase was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3: 2 hexanethyl acetate to give 33 (476 mg, 52%) as a pale yellow oil.

Stopnja tri: V raztopino spojine 33 (115 mg, 0,22 mmol) v THF (6 ml) pri sobni temperaturi dodamo vodni NaOH (2N, 2 ml) in metanol (4 ml). Dobljeno raztopino mešamo 15 minut, razredčimo z vodo in ekstrahiramo z Et₂O. Vodno fazo nakisamo s HC1 (2N) in ekstrahiramo z etil acetatom. Etil acetatno plast speremo z vodo in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo (3 S)-3 -(1,3 -benzodioksol-5 - il) - 3 -({(2 S)-2- [2-okso-3 -(fenilkarbonil)-1 (2H)piridinil] heksanoil}amino)propanojsko kisino (31, 100 mg, 92 %) kot bledo rumeno peno. Ή NMR (400 MHz, CD₃SO₂CD₃): δ 0,81 (t, J = 7,3 Hz, 3H), 1,08 (m, 2H), 1,25 (m, 2H), 1,80 (m, IH), 1,93 (m, IH), 2,61 (dd, J = 15,8, 6,8 Hz, IH), 2,68 (dd, J =Step three: To a solution of compound 33 (115 mg, 0.22 mmol) in THF (6 ml) at room temperature was added aqueous NaOH (2N, 2 ml) and methanol (4 ml). The resulting solution was stirred for 15 minutes, diluted with water and extracted with Et ₂ O. The aqueous phase was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give (3 S) -3 - (1,3-benzodioxol-5-yl) -3 - ({(2 S) -2- [2-oxo-3 - (phenylcarbonyl) -1 (2H) Pyridinyl] hexanoyl} amino) propanoic acid (31, 100 mg, 92%) as a pale yellow foam. Ή NMR (400 MHz, CD ₃ SO ₂ CD ₃ ): δ 0.81 (t, J = 7.3 Hz, 3H), 1.08 (m, 2H), 1.25 (m, 2H), 1 , 80 (m, 1H), 1.93 (m, 1H), 2.61 (dd, J = 15.8, 6.8 Hz, 1H), 2.68 (dd, J =

15,8, 7,9 Hz, IH), 5,09 (m, IH), 5,49 (dd, J = 9,5, 6,2 Hz, IH), 5,98 (s, 2H), 6,24 (t, J = 7,0 Hz, IH), 6,78 (dd, J = 8,1, 1,4 Hz, IH), 6,84 (d, J = 8,1 Hz, IH), 6,89 (d, J = 1,4 Hz, IH), 7,49 (t, J = 7,7 Hz, 2H), 7,62 (m, IH), 7,70 (m, 3H), 7,97 (dd, J = 7,0, 2,2 Hz, IH), 8,87 (d, J = 8,1 Hz, IH), 12,11 (br, s, IH).15.8, 7.9 Hz, 1H), 5.09 (m, 1H), 5.49 (dd, J = 9.5, 6.2 Hz, 1H), 5.98 (s, 2H). 6.24 (t, J = 7.0 Hz, 1H), 6.78 (dd, J = 8.1, 1.4 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H) ), 6.89 (d, J = 1.4 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.62 (m, 1H), 7.70 (m, 3H) ), 7.97 (dd, J = 7.0, 2.2 Hz, 1H), 8.87 (d, J = 8.1 Hz, 1H), 12.11 (br, s, 1H).

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Primer 12Example 12

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2-okso-3-(fenilmetil)-l(2H)piridinil]heksanoil}amino)propanojske kisline (34).Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2-oxo-3- (phenylmethyl) -1 (2H) pyridinyl] hexanoyl} amino) propanoic acids (34).

Stopnja ena: V raztopino spojine 33 (88 mg, 0,17 mmol) v etanolu (absolutni, 4 ml) pri sobni temperaturi dodamo NaBH₄ (12,5 mg, 0,33 mmol). Dobljeno zmes mešamo 20 minut in jo nato pogasimo s HC1 (2N, 2 ml). Dobljeno zmes razredčimo z vodo in etil acetatom in organsko plast speremo z nasičenim vodnim NaHCCf in slanico. Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 35 (85 mg, 96 %) kot bledo rumeno olje. Ta material uporabimo brez čiščenja.Step One: To a solution of compound 33 (88 mg, 0.17 mmol) in ethanol (absolute, 4 mL) at room temperature was added NaBH ₄ (12.5 mg, 0.33 mmol). The resulting mixture was stirred for 20 minutes and then quenched with HCl (2N, 2 ml). The resulting mixture was diluted with water and ethyl acetate and the organic layer was washed with saturated aqueous NaHCO 3 and brine. The organic layer was dried over MgSO ₄ and filtered and the filtrate concentrated under reduced pressure to give 35 (85 mg, 96%) as a pale yellow oil. Use this material without cleaning.

Stopnja dve: V raztopino spojine 35 (85 mg, 0,16 mmol) v etil acetatu (4 ml) pri sobni temperaturi pod dušikom dodamo Pd/C (10 % osnove suhe mase, Degussa tip E101 NE/W, ~50 % vsebnost vode, 36 mmol). Atmosfero nadomestimo z vodikom (5-krat izmenjava med vakuumom in vodikom iz balona) in zmes temeljito mešamo 1,5 ure. Zmes filtiriramo skozi celite in filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 7:3, da dobimo 36 (32 mg, 39 %) kot brezbarvno olje.Step two: To a solution of compound 35 (85 mg, 0.16 mmol) in ethyl acetate (4 ml) at room temperature under nitrogen was added Pd / C (10% dry weight basis, Degussa type E101 NE / W, ~ 50% content of water, 36 mmol). The atmosphere was replaced with hydrogen (5 times the exchange between vacuum and hydrogen from a balloon) and the mixture was stirred thoroughly for 1.5 hours. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate in a 7: 3 ratio to give 36 (32 mg, 39%) as a colorless oil.

Stopnja tri: V raztopino spojine 36 (32 mg, 0,062 mmol) v THF (3 ml) pri sobni temperaturi dodamo vodni NaOH (2N, 1 ml) in metanol (2 ml). Dobljeno raztopino mešamo 15 minut, razredčimo z vodo in ekstrahiramo z Et₂O. Vodno fazo nakisamo sStep three: To a solution of compound 36 (32 mg, 0.062 mmol) in THF (3 ml) at room temperature was added aqueous NaOH (2N, 1 ml) and methanol (2 ml). The resulting solution was stirred for 15 minutes, diluted with water and extracted with Et ₂ O. The aqueous phase was acidified with

-6262-6262

HC1 (2N) in ekstrahiramo z etil acetatom. Etil acetatno plast speremo z vodo in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku. Ostanek prevzamemo v acetonitrilu (3 ml) in vodi (7 ml) in zmes liofiliziramo, da dobimo (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2-okso-3-(fenilmetil)-l(2H)-piridinil]heksanoil}amino)propanojsko kislino (34, 31 mg, 100 %) kot bel prašek. Ή NMR (400 MHz, CD3SO2CD3): δ 0,76 (t, J = 7,3 Hz, 3H), 1,01 (m, 2H), 1,22 (m, 2H), 1,70 (m, IH), 1,87 (m, IH), 2,60 (dd, J = 15,8, 7,0 Hz, IH), 2,68 (dd, J = 15,8, 7,9 Hz, IH), 3,72 (d, J = 15,0 Hz, IH), 3,77 (d, J = 15,0 Hz, IH), 5,06 (m, IH), 5,54 (dd, J = 9,2,HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up in acetonitrile (3 ml) and water (7 ml) and the mixture lyophilized to give (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2 -oxo-3- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid (34, 31 mg, 100%) as a white powder. Ή NMR (400 MHz, CD3SO2CD3): δ 0.76 (t, J = 7.3 Hz, 3H), 1.01 (m, 2H), 1.22 (m, 2H), 1.70 (m, 1H), 1.87 (m, 1H), 2.60 (dd, J = 15.8, 7.0 Hz, 1H), 2.68 (dd, J = 15.8, 7.9 Hz, 1H ), 3.72 (d, J = 15.0 Hz, 1H), 3.77 (d, J = 15.0 Hz, 1H), 5.06 (m, 1H), 5.54 (dd, J) = 9.2,

6,6 Hz, IH), 5,98 (s, 2H), 6,16 (t, J = 7,0 Hz, IH), 6,77 (dd, J = 8,1, 1,4 Hz, IH), 6,83 (d, J = 8,1 Hz, IH), 6,89 (d, J = 1,4 Hz, IH), 7,13 (m, IH), 7,18 (m, IH), 7,26 (m, 4H),6.6 Hz, 1H), 5.98 (s, 2H), 6.16 (t, J = 7.0 Hz, 1H), 6.77 (dd, J = 8.1, 1.4 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 7.13 (m, 1H), 7.18 (m, 1H). 1H), 7.26 (m, 4H),

7,59 (dd, J = 7,0, 1,8 Hz, IH), 8,83 (d, J = 8,1 Hz, IH), 12,11 (br, s, IH).7.59 (dd, J = 7.0, 1.8 Hz, 1H), 8.83 (d, J = 8.1 Hz, 1H), 12.11 (br, s, 1H).

Primer 13Example 13

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-[({l-[2-okso-3-(fenilmetil)-l(2H)piridinil]cikloheksil}karbonil)amino]propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({1- [2-oxo-3- (phenylmethyl) -1 (2H) pyridinyl] cyclohexyl} carbonyl) amino] propanoic acid.

Stopnja ena: V raztopino 3-benzilpiridina (1,65 g, 9,77 mmol) v acetonu (3,5 ml) dodamo l-kloro-2,4-dinitrobenzen (2,00 g, 9,56 mmol) in zmes mešamo ob refluksu preko noči. Zmes ohladimo na sobno temperaturo, razredčimo z acetonom in topilo dekantiramo od oborine. Surovo trdno snov speremo z acetonom (2-krat) in dietiletrom (1-krat) in vsakokrat dekantiramo, da dobimo 37 (3,57 g, 100 %) kot sivo trdno snov.Step One: To a solution of 3-benzylpyridine (1.65 g, 9.77 mmol) in acetone (3.5 ml) was added l-chloro-2,4-dinitrobenzene (2.00 g, 9.56 mmol) and the mixture stirred at reflux overnight. The mixture was cooled to room temperature, diluted with acetone and the solvent decanted from the precipitate. The crude solid was washed with acetone (2 times) and diethyl ether (1 time) and decanted each time to give 37 (3.57 g, 100%) as a gray solid.

Stopnja dve: V raztopino 1-amino-1-hidroksimetilcikloheksana (0,45 g, 3,5 mmol) v n-butanolu (8,75 ml) dodamo trdni N-(2,4-dinitrofenil)-3-benzilpiridinijev klorid (37,Step two: To a solution of 1-amino-1-hydroxymethylcyclohexane (0.45 g, 3.5 mmol) in n-butanol (8.75 ml) was added solid N- (2,4-dinitrophenyl) -3-benzylpyridinium chloride ( 37,

1,23 g, 3,3 mmol). Dobljeno raztopino segrevamo ob refluksu 2,5 dni pod atmosfero dušika. Zmes ohladimo, razredčimo z vodo in filtriramo. Filtrat naalkalimo s koncentriranim NH₄OH (2 ml) in ekstrahiramo z etil acetatom. Vodno plast1.23 g, 3.3 mmol). The resulting solution was heated at reflux for 2.5 days under a nitrogen atmosphere. The mixture was cooled, diluted with water and filtered. The filtrate was basified with concentrated NH ₄ OH (2 ml) and extracted with ethyl acetate. Water layer

-6363 koncentriramo do suhega, da dobimo 38 (0,56 g) kot rumeno olje, ki ga uporabimo brez nadaljnjega čiščenja.-6363 was concentrated to dryness to give 38 (0.56 g) as a yellow oil, which was used without further purification.

Stopnja tri: V raztopino surovega 38 (0,56 g, 3,5 mmol teoretično) v vodi (10 ml) dodamo po kapljicah preko dodatnega lija raztopino kalijevega železovega(III)cianida (3,3 g, 10 mmol) v vodi (15 ml) v 30 minutah pri 0 °C. Nato dodamo raztopino KOH (0,76 g, 13,5 mmol) v vodi (5 ml) v 30 minutah. Dodamo toluen (10 ml) in raztopino mešamo 1 uro pri 0 °C. Plasti ločimo in vodno ponovno ekstrahiramo s toluenom. Združene ekstrakte posušimo nad Na₂SO₄ in filtiramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek kromatografiramo na silikagelu z eluiranjem s heksani:etil acetatom v razmerju 7:13, da dobimo 39 (20 mg, 1,9 %, dve stopnji).Step three: To a solution of crude 38 (0.56 g, 3.5 mmol theoretically) in water (10 ml) was added dropwise a solution of potassium iron (III) cyanide (3.3 g, 10 mmol) in water (10 g). 15 ml) in 30 minutes at 0 ° C. Then a solution of KOH (0.76 g, 13.5 mmol) in water (5 ml) was added over 30 minutes. Toluene (10 ml) was added and the solution was stirred at 0 ° C for 1 hour. The layers were separated and the aqueous extracted again with toluene. The combined extracts were dried over Na ₂ SO ₄ and filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexanes: ethyl acetate at 7:13 to give 39 (20 mg, 1.9%, two steps).

Stopnja štiri: V suspenzijo spojine 39 (20 mg, 0,068 mmol) v vodnem KOH (1 M, 0,70 ml) dodamo kalijev persulfat (0,073 g, 0,270 mmol) in rutenijev (III) klorid (1 mg, katalitičen) in THF (0,25 ml). Zmes mešamo 1 uro in ekstrahiramo z diklorometanom. Vodno plast nakisamo in ekstrahiramo z etil acetatom (3-krat). Etil acetatne ekstrakte združimo, posušimo nad MgSO₄ in filtiramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo 40 (0,0148 g, 70 %) kot rumeno rjavo trdno snov.Step four: To a suspension of compound 39 (20 mg, 0.068 mmol) in aqueous KOH (1 M, 0.70 mL) was added potassium persulfate (0.073 g, 0.270 mmol) and ruthenium (III) chloride (1 mg, catalytic) and THF (0.25 ml). The mixture was stirred for 1 hour and extracted with dichloromethane. The aqueous layer was acidified and extracted with ethyl acetate (3 times). The ethyl acetate extracts were combined, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 40 (0.0148 g, 70%) as a yellow-brown solid.

(3S)-3-(l,3-benzodioksol-5-il)-3-[({l-[2-okso-3-(fenilmetil)-l(2H)piridinil]cikloheksil}karbonil)amino]propanojsko kislino pripravimo iz 40 po postopkih, opisanih v Primeru 1. 'H NMR (400 MHz, CD3SO2CD3): δ 1,40 (m, 4H),(3S) -3- (1,3-benzodioxol-5-yl) -3 - [({1- [2-oxo-3- (phenylmethyl) -1 (2H) pyridinyl] cyclohexyl} carbonyl) amino] propanoic acid prepared from 40 according to the procedures described in Example 1. 1 H NMR (400 MHz, CD 3 SO 2 CD 3): δ 1.40 (m, 4H),

1,68 (m, 2H), 2,04 (m, 2H), 2,60 (d, J = 7,0 Hz, 2H), 3,67 (d, J = 15,2 Hz, IH), 3,72 (d, J = 15,2 Hz, IH), 5,12 (m, IH), 5,95 (m, 2H), 6,19 (t, J = 7,0 Hz, IH), 6,74 (dd, J =1.68 (m, 2H), 2.04 (m, 2H), 2.60 (d, J = 7.0 Hz, 2H), 3.67 (d, J = 15.2 Hz, 1H), 3.72 (d, J = 15.2 Hz, 1H), 5.12 (m, 1H), 5.95 (m, 2H), 6.19 (t, J = 7.0 Hz, 1H). 6.74 (dd, J =

7,8, 1,4 Hz, IH), 6,76 (d, J = 7,8 Hz, IH), 6,90 (d, J = 1,4 Hz, IH), 7,10 (d, J = 5,8 Hz, IH), 7,20 (m, 5H), 7,57 (d, J = 8,4 Hz, IH), 7,66 (dd, J = 7,7, 1,8 Hz, IH).7.8, 1.4 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 5.8 Hz, 1H), 7.20 (m, 5H), 7.57 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 7.7, 1.8 Hz, 1H).

Primer 14Example 14

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2-okso-5-(fenilmetil)-l(2H)-piridinil]heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-5- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid.

-6464-6464

Stopnja ena: V zmes spojine 41 (pripravljeno po postopkih, opisanih v Primeru 13, 1,75 g surovega oranžnega olja, 5,0 mmol teoretično) v vodi (25 ml) pri 0 °C dodamo po kapljicah preko dodatnega lija raztopino kalijevega železovega (Ill)cianida (4,7 g, 14 mmol) v vodi (22 ml) v 30 minutah. Nato dodamo raztopino KOH (1,1 g, 19 mmol) v vodi (7 ml) v 30 minutah. Dodamo toluen (15 ml) in raztopino mešamo 1 uro pri 0 °C. Plasti ločimo in vodno ekstrahiramo ponovno s toluenom. Združene ekstrakte posušimo nad Na₂SO₄ in filtriramo ter filtrat koncentriramo pod znižanim tlakom. Ostanek kromatografiramo na silikagelu z eluiranjem s heksani:etil acetatom v razmerju 7:13, da dobimo 42 (glavni produkt, 0,36 g, 29 %) in 43 (manjši produkt, 0,10 g, 7,0%).Step One: To a mixture of compound 41 (prepared according to the procedures described in Example 13, 1.75 g of crude orange oil, 5.0 mmol theoretically) in water (25 ml) at 0 ° C was added dropwise a solution of potassium iron. (Ill) cyanide (4.7 g, 14 mmol) in water (22 ml) in 30 minutes. Then a solution of KOH (1.1 g, 19 mmol) in water (7 ml) was added over 30 minutes. Toluene (15 ml) was added and the solution was stirred at 0 ° C for 1 hour. The layers were separated and the aqueous extracted again with toluene. The combined extracts were dried over Na ₂ SO ₄ and filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexanes: ethyl acetate at a ratio of 7:13 to give 42 (major product, 0.36 g, 29%) and 43 (minor product, 0.10 g, 7.0%).

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2-okso-5-(fenilmetil)-l(2H)-piridinil]heksanoil}amino)propanojsko kislino pripravimo iz 42 po postopkih, opisanih v Primerih 1 in 13. ^JH NMR (400 MHz, CD₃SO₂CD₃) δ: 0,77 (t, J = 7,3 Hz, 3H), 1,00 (m, 2H), 1,20 (m, 2H), 1,75 (m, IH), 1,88 (m, IH), 2,65 (m, 2H), 3,70 (s, 2H), 5,08 (m, IH), 5,49 (dd, J = 9,9, 6,2 Hz, IH), 5,98 (s, 2H), 6,32 (d, J = 9,2 Hz, IH), 6,77 (dd, J = 8,1, 1,5 Hz, IH), 6,83 (d, J = 9,2 Hz, IH), 6,89 (d, J = 1,5 Hz, IH), 7,20 (m, 4H), 7,28 (m, 4H), 7,61 (d, J = 2,6 Hz, IH), 8,81 (d, J = 8,1 Hz, IH), 12,10 (br, s, IH).(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-5- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid is prepared from 42 according to the procedures described in Examples 1 and 13. ¹ H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ) δ: 0.77 (t, J = 7.3 Hz, 3H), 1.00 (m, 2H ), 1.20 (m, 2H), 1.75 (m, 1H), 1.88 (m, 1H), 2.65 (m, 2H), 3.70 (s, 2H), 5.08 (m, 1H), 5.49 (dd, J = 9.9, 6.2 Hz, 1H), 5.98 (s, 2H), 6.32 (d, J = 9.2 Hz, 1H) , 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 7.20 (m, 4H), 7.28 (m, 4H), 7.61 (d, J = 2.6 Hz, 1H), 8.81 (d, J = 8.1 Hz). 1H), 12.10 (br, s, 1H).

Primer 15Example 15

Sinteza (3 S)-3 -(1,3 -benzodioksol-5 - i l)-3 -({(2 S )-2 - [(3 S)-2,5 -diokso-3 -(fenilmetil)4-(2-tiofenilmetil)tetrahidro-l(2H)-pirazinil]heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2 - [(3S) -2,5-dioxo-3 - (phenylmethyl) 4- (2-Thiophenylmethyl) tetrahydro-1 (2H) -pyrazinyl] hexanoyl} amino) propanoic acid.

Stopnja 1: V raztopino metil estra fenilalanina (2,32 g, 12,9 mmol) v DCE (50 ml) pri sobni temperaturi dodamo 2-tiofenkarboksaldehid (1,2 ml, 12,9 mmol) in NaBH (OAc)₃ (4,11 g, 19,4 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 24 ur, razredčimo s CH₂C1₂ (300 ml) in speremo z vodo (300 ml). Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 9:1, da dobimo 44 (2,78 g, 78 %).Step 1: To a solution of phenylalanine methyl ester (2.32 g, 12.9 mmol) in DCE (50 ml) at room temperature was added 2-thiophenecarboxaldehyde (1.2 ml, 12.9 mmol) and NaBH (OAc) ₃ ( 4.11 g, 19.4 mmol). The reaction mixture was stirred at room temperature for 24 hours, diluted with CH ₂ Cl ₂ (300 ml) and washed with water (300 ml). The organic layer was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate in a ratio of 9: 1 to give 44 (2.78 g, 78%).

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Stopnja 2: V raztopino spojine 44 (1,50 g, 5,45 mmol) v metanolu (10 ml), tetrahidrofuranu (10 ml) in vodi (10 ml) dodamo natrijev hidroksid (880 mg, 21,8 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 48 ur. Zmes koncentriramo pri znižanem tlaku do vodne raztopine in nato liofiliziramo, da dobimo 45 (1,42 g).Step 2: Add sodium hydroxide (880 mg, 21.8 mmol) to a solution of compound 44 (1.50 g, 5.45 mmol) in methanol (10 ml), tetrahydrofuran (10 ml) and water (10 ml). The reaction mixture was stirred at room temperature for 48 hours. The mixture was concentrated under reduced pressure to an aqueous solution and then lyophilized to give 45 (1.42 g).

Stopnja 3: V raztopino spojine 45 (500 mg, 1,91 mmol) in hidroklorida norlevcin metil estra (382 mg, 2,10 mmol) v DMF (10 ml) pri sobni temperaturi dodamo l-[3(dimetilamino)propil]-3-etilkarbodiimid hidroklorid (401 mg, 2,10 mmol), 1hidroksibenzotriazol (238 mg, 2,10 mmol) in 4-metilmorfolin (0,23 ml, 2,10 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 24 ur in nato zmes prevzamemo v etil acetatu (200 ml) in speremo z vodo (2-krat, 200 ml). Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksanr.etil acetatom v razmerju 9:1, da dobimo 46 (422 mg, 57 %).Step 3: To a solution of compound 45 (500 mg, 1.91 mmol) and hydrochloride of norleucine methyl ester (382 mg, 2.10 mmol) in DMF (10 ml) was added 1- [3 (dimethylamino) propyl] at room temperature - 3-ethylcarbodiimide hydrochloride (401 mg, 2.10 mmol), 1 hydroxybenzotriazole (238 mg, 2.10 mmol) and 4-methylmorpholine (0.23 ml, 2.10 mmol). The reaction mixture was stirred at room temperature for 24 hours and then the mixture was taken up in ethyl acetate (200 ml) and washed with water (2 times, 200 ml). The organic layer was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane-ethyl acetate at a ratio of 9: 1 to give 46 (422 mg, 57%).

Stopnja 4: V raztopino spojine 46 (415 mg, 1,07 mmol), DCE (10 ml) in trietilamina (0,15 ml, 1,07 mmol) pri 0 °C dodamo bromoacetil bromid (0,090 ml, 1,07 mmol), in reakcijsko zmes segrejemo na sobno temperaturo ter mešamo 24 ur. Zmes prevzamemo v CH₂C1₂ (150 ml) in speremo z vodo (150 ml). Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 4:1, da dobimo 47 (381 mg, 70 %).Step 4: Bromoacetyl bromide (0.090 ml, 1.07 mmol) was added to a solution of compound 46 (415 mg, 1.07 mmol), DCE (10 ml) and triethylamine (0.15 ml, 1.07 mmol) at 0 ° C. ), and the reaction mixture was warmed to room temperature and stirred for 24 hours. The mixture was taken up in CH ₂ Cl ₂ (150 ml) and washed with water (150 ml). The organic layer was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 4: 1 hexanes: ethyl acetate to give 47 (381 mg, 70%).

Stopnja 5: V raztopino spojine 47 (375 mg, 0,74 mmol) v THF (8 ml) dodamo Cs₂CO₃ (360 mg, 1,10 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 4 ure. Zmes prevzamemo v etil acetatu (150 ml) in speremo z vodo (150 ml). Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 4:1, da dobimo 48 (145,0 mg, 46 %).Step 5: To a solution of compound 47 (375 mg, 0.74 mmol) in THF (8 mL) was added Cs ₂ CO ₃ (360 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was taken up in ethyl acetate (150 ml) and washed with water (150 ml). The organic layer was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 4: 1 hexanes: ethyl acetate to give 48 (145.0 mg, 46%).

(3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[(3S)-2,5-diokso-3-(fenilmetil)-4-(2-6666 tiofenilmetil)tetrahidro-l(2H)-pirazinil]heksanoil}amino)propanojsko kislino pripravimo iz 48, po postopkih, opisanih v Primeru 1. MS: izrač.: (M - H)' = 604,2 m/z; ugot.: (M - H)' = 604,4 m/z.(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2 - [(3S) -2,5-dioxo-3- (phenylmethyl) -4- (2- 6666 Thiophenylmethyl) tetrahydro-1 (2H) -pyrazinyl] hexanoyl} amino) propanoic acid was prepared from 48 according to the procedures described in Example 1. MS: Calculated: (M - H) '= 604.2 m / z; found: (M - H) '= 604.4 m / z.

Primer 16Example 16

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2-okso-3-(fenilmetil)-2,3-dihidro-lHbenzimidazol- Ι-il]acetil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-3- (phenylmethyl) -2,3-dihydro-1H-benzimidazol-1-yl] acetyl} amino) propanoic acid.

Stopnja ena: Zmes l-fluoro-2-nitrobenzena (0,50 g, 3,54 mmol), benzilamina (0,38 g,Step One: A mixture of 1-fluoro-2-nitrobenzene (0.50 g, 3.54 mmol), benzylamine (0.38 g,

3,54 mmol) in K₂CO₃ (0,98 g, 7,08 mmol) v DMF (10 ml) mešamo pri sobni temperaturi preko noči. Zmes nato razdelimo med EtOAc in vodo. Organsko plast speremo z vodo in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo do suhega, da dobimo 49 (0,79 g, 98 %) kot oranžno trdno snov.3.54 mmol) and K ₂ CO ₃ (0.98 g, 7.08 mmol) in DMF (10 ml) were stirred at room temperature overnight. The mixture was then partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated to dryness to give 49 (0.79 g, 98%) as an orange solid.

Stopnja dve: V raztopino spojine 49 (0,79 g, 3,5 mmol) v etanolu (7,0 ml) in ocetni kisini (7,0 ml) pri sobni temperaturi dodamo Fe-prašek (2,44 g, 34,6 mmol) in suspenzijo temeljito mešamo pri 40 °C, dokler s tankoplastno kromatografijo ne zaznamo popolne porabe 49. Zmes filtriramo skozi Celite z izpiranjem s kloroformom. Filtrat razredčimo z nasičenim natrijevim bikarbonatom in kloroformsko plast posušimo nad Na₂SO₄ ter filtriramo. Filtrat koncentriramo pri znižanem tlaku in ostanek očistimo s kromatografijo na silikagelu (heksani:etil acetat v razmerju 4:1 s povečevanjem do razmerja 1:1), da dobimo spojino 50 (0,35 g, 50 %).Step two: To a solution of compound 49 (0.79 g, 3.5 mmol) in ethanol (7.0 mL) and acetic acid (7.0 mL) was added Fe-powder (2.44 g, 34, at room temperature). 6 mmol) and the suspension was stirred thoroughly at 40 ° C until complete consumption was detected by thin layer chromatography 49. The mixture was filtered through Celite by washing with chloroform. The filtrate was diluted with saturated sodium bicarbonate and the chloroform layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (hexanes: ethyl acetate in 4: 1 ratio increasing to 1: 1 ratio) to give compound 50 (0.35 g, 50%).

Stopnja tri: Raztopino spojine 50 (0,25 g, 1,26 mmol) in CDI (0,22 g, 1,4 mmol) v CH₂C1₂ (12 ml) mešamo pri sobni temperaturi preko noči. Zmes razredčimo z EtOAc in speremo z IN HCI (3-krat) in slanico. Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku, da dobimo 51 (0,23 g, 82 %) kot rjavo trdno snov.Step Three: A solution of compound 50 (0.25 g, 1.26 mmol) and CDI (0.22 g, 1.4 mmol) in CH ₂ Cl ₂ (12 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc and washed with IN HCl (3 times) and brine. The organic layer was dried over MgSO ₄ and filtered, and the filtrate was concentrated under reduced pressure to give 51 (0.23 g, 82%) as a brown solid.

-6767-6767

Stopnja štiri: V raztopino spojine 51 (0,19 g, 0,85 mmol) v brezvodnem DMF (5 ml) pri 0 °C dodamo NaH (60 % disperzija v mineralnem olju, 0,044 g, 1,1 mmol). Zmes mešamo pri 0 °C 10 minut pred dodatkom etil bromoacetata (0,21 g, 0,13 mmol). Zmes po mešanju pri sobni temperaturi preko noči zlijemo v zmes ledu in vode in ekstrahiramo z EtOAc (2-krat). Organsko plast speremo z vodo in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo 52 (0,25 g, 95 %) kot rjavo trdno snov.Step four: To a solution of compound 51 (0.19 g, 0.85 mmol) in anhydrous DMF (5 mL) at 0 ° C was added NaH (60% dispersion in mineral oil, 0.044 g, 1.1 mmol). The mixture was stirred at 0 ° C for 10 minutes before the addition of ethyl bromoacetate (0.21 g, 0.13 mmol). After stirring at room temperature overnight, the mixture was poured into a mixture of ice and water and extracted with EtOAc (2 times). The organic layer was washed with water and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 52 (0.25 g, 95%) as a brown solid.

(3 S)-3 -(1,3 -benzodioksol-5 - i 1)-3 -({2- [2-okso-3 -(fenilmetil)-2,3 -dihidro-1Hbenzimidazol-l-il]acetil}amino)propanojsko kislino pripravimo iz 52 po postopkih, opisanih v Primeru 1. ’H NMR (400 MHz, CD₃COCD₃): δ 2,79 (m, 2H), 4,56 (m, 2H), 5,02 (s, 2H), 5,31 (m, IH), 5,90 (s, 2H), 6,92 (m, 7H), 7,25 (m, 5H), 7,91 (d, J =(3S) -3- (1,3-benzodioxol-5 - and 1) -3 - ({2- [2-oxo-3- (phenylmethyl) -2,3-dihydro-1H-benzimidazol-1-yl] acetyl } amino) propanoic acid was prepared from 52 according to the procedures described in Example 1. 1 H NMR (400 MHz, CD ₃ COCD ₃ ): δ 2.79 (m, 2H), 4.56 (m, 2H), 5. 02 (s, 2H), 5.31 (m, 1H), 5.90 (s, 2H), 6.92 (m, 7H), 7.25 (m, 5H), 7.91 (d, J) =

8,4 Hz, IH), 10,79 (br, S, IH).8.4 Hz, 1H), 10.79 (br, S, 1H).

Primer 17Example 17

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[5,5-dimetil-2,4-diokso-3-(fenilmetil)tetrahidro- lH-imidazol- l-il]heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [5,5-dimethyl-2,4-dioxo-3- (phenylmethyl) tetrahydro-1H-imidazol-1 -yl] hexanoyl} amino) propanoic acid.

Stopnja ena: V raztopino 5,5-dimetilhidantoina (2,00 g, 15,6 mmol) v DMF (30 ml) pri sobni temperaturi dodamo K₂CO₃ (6,5 g, 47 mmol) in benzil klorid (2,20 ml, 18,7 mmol). Dobljeno zmes mešamo preko noči, razredčimo z vodo in ekstrahiramo z etil acetatom. Organsko plast speremo s slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku in ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 6:1 s povečevanjem do razmerja 3:1, da dobimo 53 (3,21 g, 94 %).Step One: To a solution of 5,5-dimethylhydantoin (2.00 g, 15.6 mmol) in DMF (30 ml) at room temperature was added K ₂ CO ₃ (6.5 g, 47 mmol) and benzyl chloride (2, 20 ml, 18.7 mmol). The resulting mixture was stirred overnight, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluting with hexanes: ethyl acetate in a ratio of 6: 1 by increasing to a ratio of 3: 1 to give 53 (3.21 g, 94%).

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[5,5-dimetil-2,4-diokso-3-(fenilmetil)tetrahidro-lH-imidazol-l-il]heksanoil}amino)propanojsko kislino pripravimo iz 53 po postopkih, opisanih v Primerih 1 in 16. Tal.: 53-55 °C.(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [5,5-dimethyl-2,4-dioxo-3- (phenylmethyl) tetrahydro-1H-imidazol-1- yl] hexanoyl} amino) propanoic acid was prepared from 53 according to the procedures described in Examples 1 and 16. Melting point: 53-55 ° C.

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Primer 18Example 18

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2,4-diokso-l-(fenilmetil)-l,4dihidro-3 (2H)-kinazolinil]heksanoil} amino)propanoj ske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2,4-dioxo-1- (phenylmethyl) -1,4-dihydro-3 (2H) -quinazolinyl] hexanoyl} amino) propanoic acid.

Stopnja ena: V raztopino antranilne kisline (450 mg, 3,30 mmol) in hidroklorida norlevcin metil estra (500 mg, 2,75 mmol) v dimetilformamidu (10 ml) pri sobni temperaturi dodamo l-[3-(dimetilamino)propil]-3-etilkarbodiimid hidroklorid (640 mg, 3,30 mmol), 1-hidroksibenzo triazol (450 mg, 3,30 mmol) in 4-metilmorfolin (610 mg, 5,50 mmol). Reakcijsko zmes mešamo pri sobni temperaturi 24 ur, nato pa zmes prevzamemo v etil acetatu (200 ml) in speremo z vodo (2-krat 200 ml). Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 4:1 s povečevanjem do razmerja 1:1, da dobimo 54 (860 mg, 99 %).Step One: Add 1- [3- (dimethylamino) propyl] to a solution of anthranilic acid (450 mg, 3.30 mmol) and the hydrochloride of norleucine methyl ester (500 mg, 2.75 mmol) in dimethylformamide (10 ml) at room temperature] -3-ethylcarbodiimide hydrochloride (640 mg, 3.30 mmol), 1-hydroxybenzo triazole (450 mg, 3.30 mmol) and 4-methylmorpholine (610 mg, 5.50 mmol). The reaction mixture was stirred at room temperature for 24 hours, then the mixture was taken up in ethyl acetate (200 ml) and washed with water (2 times 200 ml). The organic layer was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate in a 4: 1 ratio by increasing to a 1: 1 ratio to give 54 (860 mg, 99%).

Stopnja dve: V raztopino spojine 54 (0,86 g, 3,26 mmol) in CDI (0,79 g, 4,89 mmol) v brezvodnem C1CH₂CH₂C1 (30 ml) segrevamo pri 85 °C preko noči. Zmes ohladimo na sobno temperaturo in koncentriramo ter ostanek prevzamemo v EtOAc. Organsko plast speremo z IN HC1 (3-krat) in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat nato koncentriramo pod znižanim tlakom in ostanek očistimo s silikagelno kromatografijo (heksani:EtOAc 5:1 s povečevanjem do 1:1), da dobimo 55 kot belo trdno snov (0,67 g, 71 %).Step two: To a solution of compound 54 (0.86 g, 3.26 mmol) and CDI (0.79 g, 4.89 mmol) in anhydrous C1CH ₂ CH ₂ C1 (30 ml) was heated at 85 ° C overnight. The mixture was cooled to room temperature and concentrated and the residue taken up in EtOAc. The organic layer was washed with 1N HCl (3 times) and brine, dried over MgSO ₄ and filtered. The filtrate was then concentrated under reduced pressure and the residue purified by silica gel chromatography (hexanes: EtOAc 5: 1 with increasing to 1: 1) to give 55 as a white solid (0.67 g, 71%).

(3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2,4-diokso-l-(fenilmetil)-l,4-dihidro3(2H)-kinazolinil]heksanoil}amino)propanojsko kislino pripravimo iz 55 po postopkih, opisanih v Primerih 1 in 16. *H NMR (400 MHz, CD₃SO₂CD₃): δ 0,80 (m, 3H), 1,1-1,6 (m, 4H), 2,03 (m, IH), 2,20 (m, IH), 2,63 (m, 2H), 5,20 (m, 2H), 5,35 (m, IH), 5,47 (m, IH), 5,91 (d, J = 11,0 Hz, IH), 5,96 (d, J = 3,3 Hz, IH), 6,64-6,87 (m, 3H), 7,30 (m, 6H), 7,68 (m, IH), 8,14 (m, 2H), 12,09 (br, s, IH).(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2,4-dioxo-1- (phenylmethyl) -1,4-dihydro3 (2H) - quinazolinyl] hexanoyl} amino) propanoic acid was prepared from 55 according to the procedures described in Examples 1 and 16. 1 H NMR (400 MHz, CD ₃ SO ₂ CD ₃ ): δ 0.80 (m, 3H), 1.1- 1.6 (m, 4H), 2.03 (m, 1H), 2.20 (m, 1H), 2.63 (m, 2H), 5.20 (m, 2H), 5.35 (m , 1H), 5.47 (m, 1H), 5.91 (d, J = 11.0 Hz, 1H), 5.96 (d, J = 3.3 Hz, 1H), 6.64-6 , 87 (m, 3H), 7.30 (m, 6H), 7.68 (m, 1H), 8.14 (m, 2H), 12.09 (br, s, 1H).

-6969-6969

Primer 19Example 19

Sinteza (3 S)-3 -(1 ,3 -benzodioksol-5 - il)-3 -({2- [3 -metil-6-okso- 5 -(fenilmetil)-1 (6H)piridazinil]heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [3-methyl-6-oxo-5- (phenylmethyl) -1 (6H) pyridazinyl] hexanoyl} amino ) propanoic acid.

Stopnja ena: V zmes dihidropiridazinona (2,50 g, 19,21 mmol) v EtOH (6 ml) pri sobni temperaturi, dodamo benzaldehid (2,04 g, 19,21 mmol) in trdni KOH (1,3 g, 23,05 mmol). To zmes segrevamo pri 85 °C preko noči, ohladimo na sobno temperaturo in zlijemo v zmes ledu in vode. Dobljeno zmes nakisamo na pH = 4 s koncentrirano HC1 in oborino zberemo s filtracijo z izpiranjem z vodo. Dobljeno trdno snov nato posušimo v vakuumu, da dobimo 56 (3,6 g, 85 %).Step One: To a mixture of dihydropyridazinone (2.50 g, 19.21 mmol) in EtOH (6 mL) at room temperature, benzaldehyde (2.04 g, 19.21 mmol) and solid KOH (1.3 g, 23) were added. , 05 mmol). This mixture was heated at 85 ° C overnight, cooled to room temperature and poured into a mixture of ice and water. The resulting mixture was acidified to pH = 4 with concentrated HCl and the precipitate was collected by filtration by washing with water. The resulting solid was then dried in vacuo to give 56 (3.6 g, 85%).

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[3-metil-6-okso-5-(fenilmetil)-l(6H)piridazinil]heksanoil}amino)propanojsko kislino pripravimo iz 56 po postopkih, opisanih v Primerih 1 in 16. 'il NMR (400 MHz, CD₃SO₂CD₃): δ 0,80 (m, 3H), 1,18 (m, 4H), 1,95 (m, 2H), 2,18 (s, 3H), 2,65 (m, 2H), 3,79 (m, 2H), 5,06 (m, IH), 5,26 (m, IH), 5,97 (d, J = 2,2 Hz, 2H), 6,81 (m, 3H), 6,98 (s, IH), 7,27 (m, 5H), 8,27 (m, IH), 12,14 (br. S, IH).(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [3-methyl-6-oxo-5- (phenylmethyl) -1 (6H) pyridazinyl] hexanoyl} amino) propanoic the acid was prepared from 56 according to the procedures described in Examples 1 and 16. 'or NMR (400 MHz, CD ₃ SO ₂ CD ₃ ): δ 0.80 (m, 3H), 1.18 (m, 4H), 1, 95 (m, 2H), 2.18 (s, 3H), 2.65 (m, 2H), 3.79 (m, 2H), 5.06 (m, 1H), 5.26 (m, 1H) ), 5.97 (d, J = 2.2 Hz, 2H), 6.81 (m, 3H), 6.98 (s, 1H), 7.27 (m, 5H), 8.27 (m , 1H), 12.14 (no. S, 1H).

Primer 20Example 20

Sinteza (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2-okso-3-(fenilmetil)-3,4-dihidro1 (2H)-kinazolinil]heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-3- (phenylmethyl) -3,4-dihydro1 (2H) -quinazolinyl] hexanoyl} amino ) propanoic acid.

Stopnja 1: Raztopino 2-nitrobenzilbromida (0,50 g, 2,31 mmol) in benzilamina (0,49 g, 4,62 mmol) v THF (5 ml) mešamo pri sobni temperaturi preko noči in jo nato razredčimo z EtOAc. Organsko plast speremo z IN NaOH (dvakrat) in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku in ostanek očistimo s silikagelno kromatografijo (heksani:EtOAc 3:1 s povečevanjem do 1:1), da dobimo 57 (0,5 g, 89 %) kot olje.Step 1: A solution of 2-nitrobenzyl bromide (0.50 g, 2.31 mmol) and benzylamine (0.49 g, 4.62 mmol) in THF (5 ml) was stirred at room temperature overnight and then diluted with EtOAc. The organic layer was washed with 1 N NaOH (twice) and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography (hexanes: EtOAc 3: 1 with increasing to 1: 1) to give 57 (0.5 g, 89%) as an oil.

-7070 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2-okso-3-(fenilmetil)-3,4-dihidro-l(2H)kinazolinil]heksanoil}amino)propanojsko kislino pripravimo s 57 po postopkih, opisanih v Primerih 1 in 16. Ή NMR (400 MHz, CD₃SO₂CD₃): δ 0,78 (m, 3H), 1,21 (m, 4H), 1,88 (m, IH), 2,14 (m, IH), 2,65 (m, 2H), 4,26 (m, 2H), 4,43 (m, IH), 4,80 (m, IH), 5,03 (m, IH), 5,18 (m, IH), 5,92 (d, J = 4,0 Hz, IH), 5,97 (s, IH), 6,70 (m, 2H), 6,80 (m, IH), 6,95 (m, 2H), 7,12 (m, 2H), 7,30 (m, 5H), 8,20 (m, IH), 12,09 (br, s, IH).-7070 (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-3- (phenylmethyl) -3,4-dihydro-1 (2H) quinazolinyl] hexanoyl } amino) propanoic acid was prepared by 57 according to the procedures described in Examples 1 and 16. Ή NMR (400 MHz, CD ₃ SO ₂ CD ₃ ): δ 0.78 (m, 3H), 1.21 (m, 4H) , 1.88 (m, 1H), 2.14 (m, 1H), 2.65 (m, 2H), 4.26 (m, 2H), 4.43 (m, 1H), 4.80 ( m, 1H), 5.03 (m, 1H), 5.18 (m, 1H), 5.92 (d, J = 4.0 Hz, 1H), 5.97 (s, 1H), 6. 70 (m, 2H), 6.80 (m, 1H), 6.95 (m, 2H), 7.12 (m, 2H), 7.30 (m, 5H), 8.20 (m, 1H) ), 12.09 (br, s, 1H).

Primer 21Example 21

Sinteza (3 S)-3 -(1,3 -benzodioksol- 5 - i 1) - 3 -({2- [2-okso-3 -(fenilmetil)-1 (2H)kinoksalinil] heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- (1,3-benzodioxol-5 - and 1) -3 - ({2- [2-oxo-3- (phenylmethyl) -1 (2H) quinoxalinyl] hexanoyl} amino) propanoic acid .

Stopnja ena: V raztopino 1,2-fenilendiamina (2,64 g, 14,4 mmol) in fenilpiruvične kisline (2,00 g, 12,2 mmol) v etanolu (absolutni, 20 ml) dodamo raztopino 2merkaptoetanola (1,6 ml) v 2N HC1 (18,3 ml). Dobljeno zmes segrevamo ob refluksu 2 uri, nato jo pustimo, da se ohladi na sobno temperaturo in filtriramo z izpiranjem oborine z etanolom (dvakrat). Oborino posušimo v vakuumu, da dobimo 58 (1,88 g, 65 %) kot belo trdno snov.Step One: To a solution of 1,2-phenylenediamine (2.64 g, 14.4 mmol) and phenylpyruvic acid (2.00 g, 12.2 mmol) in ethanol (absolute, 20 ml) was added a solution of 2mercaptoethanol (1.6 ml) in 2N HCl (18.3 ml). The resulting mixture was refluxed for 2 hours, then allowed to cool to room temperature and filtered by washing the precipitate with ethanol (twice). The precipitate was dried in vacuo to give 58 (1.88 g, 65%) as a white solid.

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2-okso-3-(fenilmetil)-l(2H)kinoksalinil]heksanoilamino)propanojsko kislino pripravimo iz 58 po postopkih, opisanih v Primerih 1 in 16. MS: izrač.: (M - H)' = 540,21; ugot.: (M - H) = 540,21.(3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-3- (phenylmethyl) -1 (2H) quinoxalinyl] hexanoylamino) propanoic acid was prepared from 58 by the procedures described in Examples 1 and 16. MS: calc .: (M - H) '= 540.21; found: (M - H) = 540.21.

Primer 22Example 22

Sinteza (3 S )-3 -(1,3 -benzodioksol-5-il-3 - ((2 S)-2-(3 -benzil-5-metil-2-okso-1 (2H)piridinil)heksanoilamino)propanojske kisline (10).Synthesis of (3 S) -3- (1,3-benzodioxol-5-yl-3 - ((2 S) -2- (3-benzyl-5-methyl-2-oxo-1 (2H) pyridinyl) hexanoylamino) propanoic acids (10).

-7171-7171

Stopnja ena: V raztopino (R)-(+)-2-bromoheksanojske kisline (410 mg, 2,1 mmol) in NMM (0,265 ml, 2,1 mmol) v THF (8 ml) pri 0 °C pod atmosfero suhega dušika, dodamo izobutil kloroformiat (0,27 ml, 2,1 mmol). Dobljeno suspenzijo mešamo pri 0 °C 10 minut pred dodatkom raztopine spojine 6 (500 mg, 2,1 mmol) v DMF (2 ml). Po 1 uri suspenzijo filtriramo ter filtrat koncentriramo pod znižanim tlakom. Ostanek prevzamemo v CH2CI2 in speremo s HC1 (IN, 2-krat). Združene organske plasti speremo s slanico. Organsko plast posušimo nad MgSO₄ in filtriramo ter koncentriramo pri znižanem tlaku, da dobimo 59 (840 mg, 96 % dobitek) kot rumeno olje. Ta material uporabimo brez nadaljenjega čiščenja.Step One: To a solution of (R) - (+) - 2-bromohexanoic acid (410 mg, 2.1 mmol) and NMM (0.265 ml, 2.1 mmol) in THF (8 ml) at 0 ° C under a dry atmosphere of nitrogen, isobutyl chloroformate (0.27 ml, 2.1 mmol) was added. The resulting suspension was stirred at 0 ° C for 10 minutes before adding a solution of compound 6 (500 mg, 2.1 mmol) in DMF (2 ml). After 1 hour, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in CH2Cl2 and washed with HCl (IN, 2 times). The combined organic layers are washed with brine. The organic layer was dried over MgSO ₄ and filtered and concentrated under reduced pressure to give 59 (840 mg, 96% yield) as a yellow oil. Use this material without further purification.

Stopnja dve: V raztopino 2-fluoro-5-metilpiridina (3,23 g, 30 mmol) v THF (60 ml), ohlajeno na -78 °C, pod atmosfero suhega dušika dodamo po kapljicah litijev diizopropilamid (22 ml, 2M raztopina v THF, 44 mmol). Dobljeno oranžno rdečo raztopino mešamo pri -78 °C 6 ur, nato pa dodamo benezaldehid (3,1 ml, 35 mmol). Reakcijsko zmes mešamo dodatnih 30 minut, pogasimo s H₂O (75 ml) in ekstrahiramo z EtOAc (2-krat). Združene organske plasti speremo s slanico, posušimo nad MgSO₄, filtriramo in koncentriramo pod znižanim tlakom, da dobimo 60 (6,5 g, kvant.) kot rumeno olje. Ta material uporabimo brez nadaljnjega čiščenja.Step two: To a solution of 2-fluoro-5-methylpyridine (3.23 g, 30 mmol) in THF (60 ml) cooled to -78 ° C, lithium diisopropylamide (22 ml, 2M solution) was added dropwise under an atmosphere of dry nitrogen. in THF, 44 mmol). The resulting orange-red solution was stirred at -78 [deg.] C. for 6 hours, then benezaldehyde (3.1 ml, 35 mmol) was added. The reaction mixture was stirred for an additional 30 minutes, quenched with H ₂ O (75 ml) and extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 60 (6.5 g, quant.) As a yellow oil. Use this material without further purification.

Stopnja tri: Raztopino spojine 60 (6,5 g, 30 mmol), bortrifluorid dietil eterata (13 ml, 100 mmol) in trietilsilana (9 ml, 60 mmol) v dikloroetanu (50 ml) segrevamo ob refluksu pod suho dušikovo atmosfero 1 uro. Dobljeno raztopino pustimo, da se ohladi na sobno temperaturo in jo pogasimo s H₂O (50 ml). Dobljeno zmes ekstrahiramo z EtOAc (2-krat). Združene organske plasti speremo s slanico, posušimo nad MgSO₄, filtriramo in koncentriramo pod znižanim tlakom, da dobimo 61 (5,9 g, 98 % dobitek) kot rumeno olje.Step Three: A solution of compound 60 (6.5 g, 30 mmol), diethyl etherate bortrifluoride (13 ml, 100 mmol) and triethylsilane (9 ml, 60 mmol) in dichloroethane (50 ml) was refluxed under dry nitrogen atmosphere for 1 hour . The resulting solution was allowed to cool to room temperature and quenched with H ₂ O (50 ml). The resulting mixture was extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 61 (5.9 g, 98% yield) as a yellow oil.

Stopnja štiri: Raztopino spojine 61 (5,9 g, 30 mmol) v dioksanu (2 ml) damo v HC1 (6N, 50 ml) in dobljeno zmes segrevamo ob refluksu 12 ur. Dobljeno raztopino pustimo, da se ohladi na sobno temperaturo in jo naalkalimo z dodatkom NaOH (2N). Dobljeno zmes ekstrahiramo z EtOAc (2-krat 100 ml) in združene organske plastiStep four: A solution of compound 61 (5.9 g, 30 mmol) in dioxane (2 ml) was added in HCl (6N, 50 ml) and the resulting mixture was refluxed for 12 hours. The resulting solution was allowed to cool to room temperature and basified with the addition of NaOH (2N). The resulting mixture was extracted with EtOAc (2 times 100 ml) and the combined organic layers

-7272 speremo s slanico, posušimo nad MgSO₄ in filtriramo. Dobljeni filtrat koncentriramo pod znižanim tlakom. Ostanek prekristaliziramo iz metanola/heksanov, da dobimo 62 (3,1 g, 51 % dobitek) kot sivo belo trdno snov.-7272 was washed with brine, dried over MgSO ₄ and filtered. The resulting filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol / hexanes to give 62 (3.1 g, 51% yield) as a gray-white solid.

Stopi a pet: V raztopino spojine 62 (48 mg, 0,24 mmol) v DME (1,5 ml) pod suho dušikovo atmosfero, ohlajeno na -40 °C, dodamo NaHMDS (0,25 ml, IM v THF, 0,25 mmol). Dobljeno suspenzijo mešamo pri -40 °C dodatnih 30 minut predno dodamo LiBr (21 mg, 0,25 mmol). Po dodatnih 10 minutah po kapljicah dodamo raztopino spojine 59 (100 mg, 0,24 mmol) v DMF (0,5 ml). Dobljeno zmes nato pustimo, da se segreje na sobno temperaturo in jo nato segrevamo pri 45 °C 3,5 ure. Zmes pustimo, da se ohladi na sobno temperaturo in jo pogasimo s HC1 (IN, 15 ml). Dobljeno zmes ekstrahiramo s CH₂C1₂ (dvakrat). Združene organske plasti speremo z vodnim natrijevim karbonatom (5 %) in slanico. Organsko fazo posušimo nad MgSO₄, filtriramo in koncentriramo pod znižanim tlakom. Ostanek prekristaliziramo iz metanola/heksanov, da dobimo 63 (39 mg, 31 %) kot bele kristale.Step five: To a solution of compound 62 (48 mg, 0.24 mmol) in DME (1.5 ml) under dry nitrogen atmosphere cooled to -40 ° C was added NaHMDS (0.25 ml, IM in THF, 0 , 25 mmol). The resulting suspension was stirred at -40 ° C for an additional 30 minutes before LiBr (21 mg, 0.25 mmol) was added. After a further 10 minutes, a solution of compound 59 (100 mg, 0.24 mmol) in DMF (0.5 ml) was added dropwise. The resulting mixture was then allowed to warm to room temperature and then heated at 45 ° C for 3.5 hours. The mixture was allowed to cool to room temperature and quenched with HCl (IN, 15 ml). The resulting mixture was extracted with CH ₂ Cl ₂ (twice). The combined organic layers were washed with aqueous sodium carbonate (5%) and brine. The organic phase was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was recrystallized from methanol / hexanes to give 63 (39 mg, 31%) as white crystals.

(3S)-3-(l,3-benzodioksol-5-il-3-((2S)-2-(3-benzil-5-metil-2-okso-l(2H)piridinil)heksanoilamino)propanojsko kislino (10) pripravimo iz 63 po postopkih, opisanih v Primeru 1.(3S) -3- (1,3-benzodioxol-5-yl-3 - ((2S) -2- (3-benzyl-5-methyl-2-oxo-1 (2H) pyridinyl) hexanoylamino) propanoic acid ( 10) is prepared from 63 according to the procedures described in Example 1.

Med spojinami, ki so reprezentativne za predloženi izum in jih lahko sintetiziramo po postopku iz Primera 22 z različnimi izhodnimi materiali, so: (3S)-3-{[(2S)-2-(3benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-(3',4'-dimetoksi-l,l'bifenil-4-il)-propanoj ska kislina, (3 S)-3 -({(2S)-2- [3 -(2-klorobenzil)- 5 -metil-2oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3' ,4'-dimetoksi-1,1 '-bifenil-4-il)propanoj ska kislina, (3S)-3-(l,l'-bifenil-4-il)-3-({/2S)-2-[3-(2-kloro-6-metilbenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil} amino)propanoj ska kislina, (3 S)-3 - [(2 S)-2-(3 -benzil5 -metil-2-oksopiridin-1 (2H)-il)heksanoilj amino} -3 -(1,1 '-bifenil-4-il)propanoj ska kislina, (3 S)-3-(1,1 '-bifenil-4-il)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridinl(2H)-il]-heksanoil}amino)propanojska kislina, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin-l(2H)-il)heksanoil]amino}-3-(4'-metil-l,r-bifenil-4-il)propanojskaAmong the compounds which are representative of the present invention and which can be synthesized according to the procedure of Example 22 with various starting materials are: (3S) -3 - {[(2S) -2- (3benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3 ', 4'-dimethoxy-1,1'-biphenyl-4-yl) -propionic acid, (3 S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3 ', 4'-dimethoxy-1,1' -biphenyl-4- yl) propanoic acid, (3S) -3- (1,1'-biphenyl-4-yl) -3 - ({/ 2S) -2- [3- (2-chloro-6-methylbenzyl) -5- methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3 - [(2S) -2- (3-benzyl5-methyl-2-oxopyridin-1 (2H) - yl) hexanoylamino} -3- (1,1'-biphenyl-4-yl) propanoic acid, (3S) -3- (1,1'-biphenyl-4-yl) -3 - ({(2S ) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridinyl (2H) -yl] -hexanoyl} amino) propanoic acid, (3S) -3 - {[(2S) -2- (3 -benzyl-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (4'-methyl-1,1'-biphenyl-4-yl) propanoic

-7373 kislina, (3 S)-3 -({(2 S)-2- [3 -(2-klorobenzil)-5 -metil-2-oksopiridin-1 (2H)iljheksanoil}amino)-3-(4'-metil-1,1 '-bifenil-4-il)propanojska kislina, (3 S)-3 -({(2S)-2[3-(2-kloro-6-metilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4'metil-1,1 ’-bifenil-4-il)propanojska kislina, (3 S)-3-{[(2S)-2-(3-benziI-5-metil-2oksopiridin-l(2H)il)heksanoil]amino}-3-(2',6'-dimetoksi-1, l'-bifenil-4-il)propanojska kislina, (3 S)-3 -({(2S)-2-[3 -(2-klorobenzil)- 5 -metil-2-oksopiridinl(2H)il]heksanoil}amino)-3-(2',6'-dimetoksi-l,l'-bifenil-4-il)propanojska kislina, (3S)-3-({(2S)-2-[3-(2-kloro-6-metilbenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)-3-(2',6'-dimetoksi-l,l'-bifenil-4-il)propanojska kislina, (3S)-3{[(2S)-2-(3-benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-(l,r-bifenil3 -il)propanoj ska kislina, (3 S)-3 -(1,1'-bi fenil-3 - il) - 3 -({(2 S)-2- [3 -(2-klorobenzil)-5 metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)propanoj ska kislina, (3 S)-3-( 1, Γbifenil-3 -il)-3 -({(2 S)-2-[3 -(2-kloro-6-metilbenzil)-5 -metil-2-oksopiridin-1 (2H)- i 1] heksanoil} amino)propanoj ska kislina, (3 S)-3 - {[(2 S)-2-(3 -benzil-5 -metil-2oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(2'-metoksi-1,1 '-bifenil-3 -il)propanoj ska kislina, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil} amino)-3 -(2'-metoksi-1,1 '-bifenil-3 -il)propanoj ska kislina, (3 S)-3 ({(2 S)-2- [3 -(2-kloro-6-metilbenzil)- 5 -metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)3 -(2'-metoksi-1,1 '-bifenil-3 -il)propanoj ska kislina, (3 S)-3 -({(2S)-2- [3 -(2-fluoro-6metoksibenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4metilfenil)propanoj ska kislina, (3 S)-3 -({ (2 S)-2- [3 -(2,6-dimetilbenzil)- 5-metil-2oksopiridin-l(2H)il]heksanoil}amino)-3-(4-metilfenil)propanojska kislina, (3S)-3({(2 S )-2- [3-(3,5 -dimetilbenzil)- 5 -metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-3 (4-metilfenil)propanojska kislina, (3S)-3-({(2S)-2-[3-(2,6-diklorobenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil} amino)-3-(4-metilfenil)propanoj ska kislina, (3 S)-3({(2 S)-2- [3 -(2-kloro-6-fluorobenzil)-5 -metil-2-oksopiridin-1 (2H)il]heksanoil}amino)-3-(4-metilfenil)propanojska kislina, (3S)-3-({(2S)-2-[3-(2,6difluorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4-metilfenil)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2,6-difluorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3S)3 -(1,3 -benzodioksol- 5 - i 1) - 3 -({(2 S)-2- [3 -(2-kloro-6-fluorobenzil)-5 -metil-2-okso-7474 piridin-1 (2H)-il]heksanoil} amino)propanojska kislina, (3 S)-3-( 1,3-benzodioksol5 -il)-3 -({(2S)-2- [3 -(2,6-diklorobenzil)-5 -metil-2-oksopiridin-1 (2H)il]heksanoil} amino)propanoj ska kislina, (3 S)-3 -(1,3 -benzodioksol-5 - i 1)-3 -({(2 S)2- [3-(2,6-dimetilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(3,5-dimetilbenzil)-5-metil-2oksopiridin-l(2H)il]heksanoil}amino)propanojska kislina, (3S)-3-(l,3-benzodioksol5-il)-3-({(2S)-2-[3-(2-fluoro-6-metoksibenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil} amino)propanoj ska kislina, (3 S)-3 -({(2 S)-2-[3 -(2-klorobenzil)-5 -metil-2oksopiridin-l(2H)-il]heksanoil}amino)-3-(3,4-dietoksifenil)propanojska kislina, (3S)3- (3,4-dietoksifenil)-3-({(2S)-2-[3-(2,6-difluorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil} amino)propanoj ska kislina, (3 S)-3 - {(2S)-2- [3 -(2,6-difluorobenzil)- 5 metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3 -etoksifenil)propanoj ska kislina, (3S)-3-{(2S)-2-[3-(2-kloro-6-fluorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil} amino)-3-(3-etoksifenil)propanoj ska kislina, (3 S)-3 -({(2S)-2- [3 -(2klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]-3-metilbutanoil}amino)-3-(4metilfenil)propanojska kislina, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-1 (2H)-il] -4-metilpentanoil} amino)-3 -(4-metilfenil)propanoj ska kislina, (3 S)3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)il] -4-metilpentanoil} amino)propanoj ska kislina, (3 S)-3 -(1 ,3 -benzodioksol-5 - il) - 3 ({(2 S)-2- [3 -(2-klorobenzil)-5-metil-2-oksopiridin-1 (2H) - il] -3 -metilbutanoil} amino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2-klorobenzil)-5metil-2-oksopiridin-1 (2H)-il] -3 -fenilpropanoil} amino)propanoj ska kislina, (3 S)-3(l,3-benzodioksol-5-il)-3-(((2R)-2-(l-benzil-5-metil-2-okso-l,2-dihidropiridin-3-il)heksanoil)amino)propanojska kislina in (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil2-oksopiridin-1 (2H)-il] -3-fenilpropanoil} amino)-3 -(4-metilfenil)propanoj ska kislina.-7373 Acid, (3 S) -3 - ({(2 S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) ylhexanoyl} amino) -3- (4 '-methyl-1,1'-biphenyl-4-yl) propanoic acid, (3 S) -3 - ({(2S) -2 [3- (2-chloro-6-methylbenzyl) -5-methyl-2 -oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4'methyl-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 - {[(2S) -2 - (3-benzyl-5-methyl-2oxopyridin-1 (2H) yl) hexanoyl] amino} -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3 S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridinyl (2H) yl] hexanoyl} amino) -3- (2 ', 6'-dimethoxy- 1,1'-Biphenyl-4-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 {[(2S) -2- (3 -benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (1,1'-biphenyl3-yl) propanoic acid, (3 S) -3- (1,1 ' -Biphenyl-3-yl) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid , (3 S) -3- (1, ifbifeni 1- 3 -yl) -3 - ({(2 S) -2- [3- (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) - and 1] hexanoyl} amino ) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (2'- methoxy-1,1'-biphenyl-3-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 ( 2H) yl] hexanoyl} amino) -3- (2'-methoxy-1,1'-biphenyl-3-yl) propanoic acid, (3 S) -3 ({(2 S) -2- [3 - (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) 3- (2'-methoxy-1,1'-biphenyl-3-yl) propanoic acid acid, (3S) -3 - ({(2S) -2- [3- (2-fluoro-6methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3 S) -3 - ({(2 S) -2- [3- (2,6-dimethylbenzyl) -5-methyl-2oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 ({(2S) -2- [3- (3,5-dimethylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl ] hexanoyl} amino) -3 (4-methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2,6-dichlorobenzyl) -5-methyl- 2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 ({(2S) -2- [3- (2-chloro-6- fluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- ( 2,6difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxole-5- yl) -3 - ({(2S) -2- [3- (2,6-difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) 3 - (1,3-benzodioxol-5-yl) -3 - ({(2 S) -2- [3- (2-chloro-6-fluorobenzyl) -5-methyl-2-oxo-7474 pyridine-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol5-yl) -3 - ({(2S) -2- [3- (2,6-dichlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5 - and 1) -3 - ({(2S 2- [3- (2,6-dimethylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxole-5) -yl) -3 - ({(2S) -2- [3- (3,5-dimethylbenzyl) -5-methyl-2oxopyridin-1 (2H) ) yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol5-yl) -3 - ({(2S) -2- [3- (2-fluoro-6-methoxybenzyl) -5 -methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3 S) -3 - ({(2 S) -2- [3- (2-chlorobenzyl) -5-methyl -2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3,4-diethoxyphenyl) propanoic acid, (3S) 3- (3,4-diethoxyphenyl) -3 - ({(2S) -2- [3- (2,6-difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, (3 S) -3 - {(2S) -2- [3 - (2,6-difluorobenzyl) -5 methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3-ethoxyphenyl) propanoic acid, (3S) -3 - {(2S) -2 - [3- (2-chloro-6-fluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (3-ethoxyphenyl) propanoic acid, (3 S) -3 - ({(2S) -2- [3- (2chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] -3-methylbutanoyl} amino) -3- (4methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] -4-methylpentanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) 3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] -4-methylpentanoyl} amino) propanoic acid, (3 S) - 3- (1,3-benzodioxol-5-yl) -3 ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] -3 -methylbutanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5methyl-2-oxopyridine -1 (2H) -yl] -3-phenylpropanoyl} amino) propanoic acid, (3S) -3 (1,3-benzodioxol-5-yl) -3 - (((2R) -2- (1- benzyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl) hexanoyl) amino) propanoic acid and (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) - 5-Methyl2-oxopyridin-1 (2H) -yl] -3-phenylpropanoyl} amino) -3- (4-methylphenyl) propanoic acid.

Primer 23Example 23

Sinteza (3 S)-3 -(1,3 -benzodioksol-5 -il)-3 - {[(2R)-2-(3 -benzil-4-hidroksi- 5 -metil-2oksopiridin-l(2H)-il)heksanoil]amino}propanojske kisline, 67, in (3S)-3-(l,3benzodioksol-5-il)-3-{[(2S)-2-(3-benzil-4-hidroksi-5-metil-2-oksopiridin-l(2H)-il)-7575 heksanoil]amino}propanojske kisline, 68.Synthesis of (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[(2R) -2- (3-benzyl-4-hydroxy-5-methyl-2oxopyridin-1 (2H) - yl) hexanoyl] amino} propanoic acid, 67, and (3S) -3- (1,3benzodioxol-5-yl) -3 - {[(2S) -2- (3-benzyl-4-hydroxy-5-methyl -2-Oxopyridin-1 (2H) -yl) -7575 hexanoyl] amino} propanoic acid, 68.

Stopnja ena: V raztopino metil propionilacetata (2,00 g, 15,4 mmol) v brezvodnem THF (62 ml), ohlajeno na 0 °C, pod atmosfero suhega dušika dodamo natrijev hidrid (60 % disperzija v mineralnem olju, 0,644 g, 16,1 mmol) v dveh delih. Dobljeno zmes mešamo 15 minut pri 0 °C, dodamo benzil bromid (2,75 g, 16,1 mmol) z injekcijsko iglo in nato zmes pustimo, da se segreje na sobno temperaturo preko noči. Dobljeno zmes zlijemo v HCI (2N) in ekstrahiramo z etil acetatom. Organsko plast speremo s slanico, posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pod znižanim tlakom. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etilacetatom v razmerju 9:1, da dobimo 64 (2,86 g, 84 % dobitek).Step One: To a solution of methyl propionyl acetate (2.00 g, 15.4 mmol) in anhydrous THF (62 ml) cooled to 0 ° C, sodium hydride (60% dispersion in mineral oil, 0.644 g, was added under dry nitrogen atmosphere). 16.1 mmol) in two parts. The resulting mixture was stirred for 15 minutes at 0 ° C, benzyl bromide (2.75 g, 16.1 mmol) was injected with a needle and then the mixture was allowed to warm to room temperature overnight. The resulting mixture was poured into HCl (2N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate in a ratio of 9: 1 to give 64 (2.86 g, 84% yield).

Stopnja dve: V suspenzijo natrijevega hidrida (60 % disperzija v mineralnem olju, 0,623 g, 15,6 mmol) v THF (52 ml) pri sobni temperaturi pod atmosfero suhega dušika dodamo Ν,Ν,Ν',Ν'-tetrametiletilendiamin (2,10 ml, 13,6 mmol). Dobljeno suspenzijo ohladimo na -20 °C in počasi dodamo raztopino 64 (2,86 g, 13,0 mmol) v THF (5 ml). Zmes pustimo, da se segreje na sobno temperaturo, mešamo 10 minut in jo nato ohladimo na -20 °C. V dobljeno raztopino dodamo po kapljicah z injekcijsko iglo nbutillitij (1,6 M v heksanih, 15,4 ml, 24,9 mmol). Zmes mešamo pri -20 °C dodatnih 15 minut, nato jo pogasimo s hitrim dodatkom metil formiata (1,00 ml, 16,2 mmol) z injekcijsko iglo in zmes pustimo, da se meša dodatnih 15 minut. Reakcijsko zmes previdno pogasimo s prebitkom vodne HCI (2N) in razredčimo s heksani. Heksansko plast speremo s slanico, posušimo nad MgSO₄, filtriramo in koncentriramo pri znižanem tlaku, da dobimo 65 (1,10 g, 34 %) kot rumeno olje. Ta material uporabimo brez nadaljnjega čiščenja.Step two: Add Ν, Ν, Ν ', Ν'-tetramethylethylenediamine (2) to a suspension of sodium hydride (60% dispersion in mineral oil, 0.623 g, 15.6 mmol) in THF (52 ml) at room temperature under a dry nitrogen atmosphere. (10 ml, 13.6 mmol). The resulting suspension was cooled to -20 ° C and a solution of 64 (2.86 g, 13.0 mmol) in THF (5 ml) was added slowly. The mixture was allowed to warm to room temperature, stirred for 10 minutes and then cooled to -20 ° C. Nbutillithium injection needle (1.6 M in hexanes, 15.4 ml, 24.9 mmol) was added dropwise to the resulting solution. The mixture was stirred at -20 ° C for an additional 15 minutes, then quenched by the rapid addition of methyl formate (1.00 ml, 16.2 mmol) with an injection needle and the mixture allowed to stir for an additional 15 minutes. The reaction mixture was carefully quenched with excess aqueous HCl (2N) and diluted with hexanes. The hexane layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 65 (1.10 g, 34%) as a yellow oil. Use this material without further purification.

Stopnja tri: Raztopino spojine 65 (0,75 g, 3,0 mmol) in 23 (0,75 g, 2,1 mmol) v metanolu (30 ml, 0,lM) segrevamo pri 45 °C pod dušikom 1 uro pred segrevanjem ob refluksu preko noči. Zmes ohladimo in koncentriramo do suhega. Ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetat v razmerju 2:1 s povečevanjem do etil acetata, da dobimo 66 (0,40 g, 35 % dobitek) kot belo peno.Step Three: A solution of compound 65 (0.75 g, 3.0 mmol) and 23 (0.75 g, 2.1 mmol) in methanol (30 ml, 0, 1 M) was heated at 45 ° C under nitrogen for 1 hour before by reflux overnight. The mixture was cooled and concentrated to dryness. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate in a 2: 1 ratio by increasing to ethyl acetate to give 66 (0.40 g, 35% yield) as a white foam.

-7676-7676

Stopnja štiri: V raztopino 66 (0,40 g, 0,73 mmol) v THF (3 ml) pri sobni temperaturi dodamo vodni NaOH (1 ml) in metanol (2 ml). Dobljeno raztopino mešamo 15 minut, razredčimo z vodo in ekstrahiramo z etil etrom. Vodno plast nakisamo s HC1 (2N) in ekstrahiramo z etil acetatom. Etil acetatno plast speremo z vodo in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku in ostanek očistimo s HPLC z reverzno fazo (A: 19:1 H₂0:CH₃CN + 0,1 % TFA; B:19:l CH₃CN:H₂0 + 0,1 % TFA; gradientna elucija 30 % B do 100 % B v 31 minutah; 254 nM). Frakcije, ki vsebujejo vsakega od diastereomerov ločeno razredčimo z vodo in ekstrahiramo z etil acetatom. Etil acetatne plasti ločeno speremo z vodo (3-krat) in slanico, posušimo nad MgSO₄ in filtriramo ter filtrate ločeno koncentriramo pri znižanem tlaku, da dobimo 3 (S)-3 -(1,3-benzodioksol- 5-il)-3 - {[(2-R)-2-(3 -benzil-4-hidroksi-5-metil-2oksopiridin-l(2H)-il)heksanoil]amino}propanojsko kislino, 67, (18 mg, 5 % dobitek) in (3S)-3-(l,3-benzodioksol-5-il)-3-{[(2S)-2-(3-benzil-4-hidroksi-5-metil-2oksopiridin-l(2H)-il)heksanoil]amino}propanojsko kislino, 68, (105 mg, 28 % dobitek). MS za 67: izrač.: (M+H)⁺ = 521,23; ugot.: (M+H)⁺ = 520,97. MS za 68: izrač.: (M+H)⁺ = 521,23; ugot.: (M+H)⁺ = 520,95.Step four: To a solution of 66 (0.40 g, 0.73 mmol) in THF (3 ml) at room temperature was added aqueous NaOH (1 ml) and methanol (2 ml). The resulting solution was stirred for 15 minutes, diluted with water and extracted with ethyl ether. The aqueous layer was acidified with HCl (2N) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue purified by reverse phase HPLC (A: 19: 1 H ₂ 0: CH ₃ CN + 0,1% TFA; B: 19: l CH ₃ CN: H ₂ 0 + 0,1% TFA; gradient elution of 30% B to 100% B in 31 minutes; 254 nM). The fractions containing each of the diastereomers were separately diluted with water and extracted with ethyl acetate. The ethyl acetate layers were washed separately with water (3 times) and brine, dried over MgSO ₄ and filtered, and the filtrate was separately concentrated under reduced pressure to give 3 (S) -3- (1,3-benzodioxol-5-yl) - 3 - {[(2-R) -2- (3-benzyl-4-hydroxy-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl] amino} propanoic acid, 67, (18 mg, 5% yield) ) and (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[(2S) -2- (3-benzyl-4-hydroxy-5-methyl-2oxopyridin-1 (2H) - yl) hexanoyl] amino} propanoic acid, 68, (105 mg, 28% yield). MS for 67: calc: (M + H) ⁺ = 521.23; found: (M + H) ⁺ = 520.97. MS for 68: calc: (M + H) ⁺ = 521.23; found: (M + H) ⁺ = 520.95.

Primer 24Example 24

Sinteza (3 S)-3 -(3 -izopropoksifenil)-3 - {2- [2-okso-4-(2-feniletil)piridin-1 (2H)iljheksanoil} amino)propanojske kisline.Synthesis of (3S) -3- (3-isopropoxyphenyl) -3- {2- [2-oxo-4- (2-phenylethyl) pyridin-1 (2H) ylhexanoyl} amino) propanoic acid.

Stopnja ena: V raztopino diizopropilamina (2,94 g, 29,1 mmol) v THF (20 ml), ohlajeno na -78 °C pod atmosfero suhega dušika dodamo z injekcijsko iglo butil litij (12,8 ml, 2,5 M raztopine v heksanih, 32,0 mmol) in mešamo pri -78 °C 15 minut. Raztopino damo s kanilo v raztopino 2-fluoro-4-metil-piridina (2,15 g, 9,40 mmol) v THF (20 ml), ohlajeno na -78 °C pod atmosfero suhega dušika. Dobljeno zmes mešamo pri -78 °C 4 ure in nato pogasimo z benzaldehidom (2,17 ml, 21,3 mmol). Dobljeno rumeno raztopino segrejemo na sobno temperaturo, razredčimo z vodo in ekstrahiramo z etil acetatom. Organsko plast speremo s slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pod znižanim tlakom in ostanek očistimo sStep One: To a solution of diisopropylamine (2.94 g, 29.1 mmol) in THF (20 ml) cooled to -78 ° C under an atmosphere of dry nitrogen was added a butyl lithium (12.8 ml, 2.5 M) injection needle solutions in hexanes, 32.0 mmol) and stirred at -78 ° C for 15 minutes. The solution was cannulated into a solution of 2-fluoro-4-methyl-pyridine (2.15 g, 9.40 mmol) in THF (20 ml) cooled to -78 ° C under an atmosphere of dry nitrogen. The resulting mixture was stirred at -78 ° C for 4 hours and then quenched with benzaldehyde (2.17 ml, 21.3 mmol). The resulting yellow solution was warmed to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by

-7777 silikagelno kromatografijo z eluiranjem s heksani.etil acetat v razmerju 7:3, da dobimo 69 (1,92 g, 94 %) kot rumeno olje.-7777 Silica gel chromatography eluting with hexanes.ethyl acetate at 7: 3 ratio to give 69 (1.92 g, 94%) as a yellow oil.

Stopnja dve: V raztopino spojine 69 (1,92 g, 8,84 mmol) v brezvodnem metanolu (20 ml) pri sobni temperaturi pod atmosfero suhega dušika dodamo paladij na oglju (1,00 g, 10 % Pd osnove suhe mase, Degussa tip E101 NE/W, moker, 50 mas.% vode) in 4 kaplje ledocta. Dušikovo atmosfero nadomestimo z vodikovo (5-krat izmenjava med vakuumom in vodikom, dovedenim iz balona) in zmes mešamo pri sobni temperaturi preko noči. Zmes filtriramo skozi Celite® 521 in filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z euliranjem s heksani:etil acetatom v razmerju 8:2, da dobimo 70 (0,98 g, 55 %) kot belo trdno snov.Step two: Palladium on charcoal (1.00 g, 10% Pd dry weight basis, Degussa) was added to a solution of compound 69 (1.92 g, 8.84 mmol) in anhydrous methanol (20 ml) at room temperature under an atmosphere of dry nitrogen. type E101 NE / W, wet, 50% water by weight) and 4 drops of ice. The nitrogen atmosphere was replaced with hydrogen (5 times the exchange between vacuum and hydrogen supplied from the balloon) and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite® 521 and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate at a ratio of 8: 2 to give 70 (0.98 g, 55%) as a white solid.

Stopnja tri: V raztopino spojine70 (0,90 g, 4,47 mmol) v vodikovem kloridu (2 ml, 4,0 M v dioksanu, 8,0 mmol) pri sobni temperaturi dodamo vodni vodikov klorid (6,0 M, 40 ml) in zmes segrevamo ob refluksu 3 ure. Raztopino ohladimo na sobno temperaturo, naalkalimo z vodnim natrijevim hidroksidom (2N) in ekstrahiramo z etil acetatom. Organsko plast speremo s slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo 71 (0,81 g, 91 %) kot bledo rumeno trdno snov. Ta material uporabimo brez nadaljnjega čiščenja.Step three: To a solution of compound 70 (0.90 g, 4.47 mmol) in hydrogen chloride (2 ml, 4.0 M in dioxane, 8.0 mmol) was added aqueous hydrogen chloride (6.0 M, 40 at room temperature). ml) and the mixture was heated at reflux for 3 hours. The solution was cooled to room temperature, basified with aqueous sodium hydroxide (2N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 71 (0.81 g, 91%) as a pale yellow solid. Use this material without further purification.

Stopnja štiri: V raztopino spojine 71 (0,20 g, 1,0 mmol) v metil sulfoksidu (4,0 ml) pri sobni temperaturi dodamo natrijev hidrid (60 mas ./mas. % disperzija v mineralnem olju, 0,12 g, 3,0 mmol). Zmes mešamo pri sobni temperaturi pod atmosfero suhega dušika 1 uro. V dobljeno zmes dodamo etil-2-bromoheksanoat (0,18 ml, 1,0 mmol) in zmes mešamo 30 minut. Zmes pogasimo s HC1 (2N, 50 ml) in ekstrahiramo z etil acetatom. Organsko plast speremo s slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pod znižanim tlakom in ostanek očistimo s silikagelno kromatografijo z eluiranjem s heksani:etil acetatom v razmerju 9:2 s povečevanjem do razmerja 8:2, da dobimo 72 (0,19 g, 0,55 mmol) kot trdno snov.Step four: To a solution of Compound 71 (0.20 g, 1.0 mmol) in methyl sulfoxide (4.0 ml) at room temperature was added sodium hydride (60% w / w dispersion in mineral oil, 0.12 g , 3.0 mmol). The mixture was stirred at room temperature under a dry nitrogen atmosphere for 1 hour. Ethyl 2-bromohexanoate (0.18 ml, 1.0 mmol) was added to the resulting mixture and the mixture was stirred for 30 minutes. The mixture was quenched with HCl (2N, 50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluting with hexanes: ethyl acetate in a 9: 2 ratio by increasing to a ratio of 8: 2 to give 72 (0.19 g, 0.55 mmol) as a solid.

-7878 (3 S)-3 -(3 -izopropoksifenil)-3 -({2- [2-okso-4-(2-feniletil)piridin-1 (2H)il]heksanoil}amino)propanojsko kislino pripravimo iz 72 po postopkih, opisanih v Primeru 1. MS: izrač.: (M-H)' = 517,27; ugot.: (M-H)' = 517,21.-7878 (3 S) -3- (3-Isopropoxyphenyl) -3 - ({2- [2-oxo-4- (2-phenylethyl) pyridin-1 (2H) yl] hexanoyl} amino) propanoic acid is prepared from 72 according to the procedures described in Example 1. MS: Calc .: (MH) '= 517.27; found: (M-H) '= 517.21.

Primer 25Example 25

Sinteza (3S)-3-[3-(difluorometil)fenil]-3-{2-[5-metil-2-okso-3-(fenilmetil)-l(2H)piridinil]heksanoil}amino)propanojske kisline.Synthesis of (3S) -3- [3- (difluoromethyl) phenyl] -3- {2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) pyridinyl] hexanoyl} amino) propanoic acid.

Stopnja ena: V raztopino 3-bromobenzaldehida, 73, (3,00 g, 16,2 mmol) v DMF (69 ml) pod atmosfero suhega dušika dodamo paladijev acetat (73 mg, 0,32 mmol), tri-otolilfosfm (197 mg, 0,65 mmol), etil akrilat (2,20 ml, 20,3 mmol) in trietilamin (4,50 ml, 32,4 mmol). Sistem deoksigeniramo (5-krat izmenjava med vakuumom in dušikom), zmes segrevamo pri 125 °C 19 ur in nato ohladimo na sobno temperaturo. Reakcijsko zmes zlijemo v vodo in ekstrahiramo z etrom. Organsko plast speremo s HC1 (4N) in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku, da dobimo 74 (2,74 g, 83 %), kar uporabimo brez nadaljnjega čiščenja.Step One: To a solution of 3-bromobenzaldehyde, 73, (3.00 g, 16.2 mmol) in DMF (69 ml), under the atmosphere of dry nitrogen, palladium acetate (73 mg, 0.32 mmol), tri-otolylphosphine (197 mg, 0.65 mmol), ethyl acrylate (2.20 ml, 20.3 mmol) and triethylamine (4.50 ml, 32.4 mmol). The system was deoxygenated (exchange between vacuum and nitrogen 5 times), the mixture was heated at 125 ° C for 19 hours and then cooled to room temperature. The reaction mixture was poured into water and extracted with ether. The organic layer was washed with HCl (4N) and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure to give 74 (2.74 g, 83%), which was used without further purification.

Stopnja dve. V bučko, ki vsebuje 74 (1,00 g, 4,9 mmol), pod atmosfero suhega dušika dodamo (dimetilamino) žveplov trifluorid (0,96 ml, 9,8 mmol) z injekcijsko iglo. Zmes segrevamo pri 90 °C za ščitnikom pred eksplozijo 25 minut in jo nato ohladimo na sobno temperaturo. Dobljeno zmes razredčimo s CH₂C1₂ in speremo z nasičenim NaHCO₃ in vodo. Organsko plast posušimo nad MgSO₄ in filtriramo ter filtrat koncentriramo pri znižanem tlaku. Ostanek očistimo s silikagelno kromatografijo z eluiranjem z etil acetatom:heksani v razmerju 1:5, da dobimo 75 (0,62 g, 56 %).Level two. To the flask containing 74 (1.00 g, 4.9 mmol) was added (dimethylamino) sulfur trifluoride (0.96 ml, 9.8 mmol) with an injection needle under an atmosphere of dry nitrogen. The mixture was heated at 90 [deg.] C. behind the blast shield for 25 minutes and then cooled to room temperature. The resulting mixture was diluted with CH ₂ Cl ₂ and washed with saturated NaHCO ₃ and water. The organic layer was dried over MgSO ₄ and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: hexanes in a ratio of 1: 5 to give 75 (0.62 g, 56%).

Stopnja tri: V raztopino (R)-(+)-N-benzil-a-metilbenzilamina (0,70 g, 3,3 mmol) v THF (6,7 ml), ohlajeno na -78 °C, pod atmosfero suhega dušika dodamo po kapljicah sek.BuLi (4,22 ml, 1,3M v cikloheksanu, 5,5 mmol). Dobljeno zmes mešamo pri -78 °C 30 minut in nato dodamo po kapljicah z injekcijo iglo raztopino spojine 75 (0,62 g,Step Three: To a solution of (R) - (+) - N-benzyl-α-methylbenzylamine (0.70 g, 3.3 mmol) in THF (6.7 ml) cooled to -78 ° C under a dry atmosphere of nitrogen was added dropwise to sec.BuLi (4.22 ml, 1.3M in cyclohexane, 5.5 mmol). The resulting mixture was stirred at -78 ° C for 30 minutes and then a solution of compound 75 (0.62 g,

-7979-7979

2,74 mmol) v THF (3,4 ml). Zmes mešamo pri -78 °C 5 ur in jo nato pogasimo z ledoctom (2 ml) v THF (5 ml). Reakcijsko zmes segrejemo na sobno temperaturo, zlijemo v 1:1 zmes nasičenega vodnega NaHCO₃: EtOAc. Organsko plast speremo s H₂O (2-krat) in slanico, posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku in ostanek očistimo s silikagelno kromatografijo z eluiranjem z etilacetatom:heksani v razmerju 1:5, da dobimo 76 (1,2 g, 100 %). Ta material še vedno vsebuje manjše nečistoče, vendar ga uporabimo brez nadaljnjega čiščenja.2.74 mmol) in THF (3.4 mL). The mixture was stirred at -78 ° C for 5 hours and then quenched with ice (2 ml) in THF (5 ml). The reaction mixture was warmed to room temperature, poured into a 1: 1 mixture of saturated aqueous NaHCO ₃ : EtOAc. The organic layer was washed with H ₂ O (2 times) and brine, dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluting with ethyl acetate: hexanes in a ratio of 1: 5 to give 76 (1.2 g, 100%). This material still contains minor impurities, but is used without further purification.

Stopnja štiri: V raztopino spojine 76 (0,50 g, 1,14 mmol) v EtOH (10 ml) pri sobni temperaturi pod atmosfero suhega dušika dodamo Pd/C, (10 % Pd na osnovi suhe mase, 50 mas.% vode, Degussa tip E101 NE/W, 0,25 g) in ledocet (0,5 ml). Atmosfero nadomestimo z vodikom (5-krat izmenjava med vakuumom in vodikom iz balona) in zmes segrevamo pri 35 °C 6 ur. Reakcijsko zmes ohladimo na sobno temperaturo, filtriramo skozi blazino Celite 521 in filtrat koncentriramo pri znižanem tlaku. Ostanek razredčimo s CHC1₃ in speremo z nasičenim vodnim NaHCO₃. Vodno plast ekstrahiramo s CHC1₃ (2-krat) in združene organske plasti posušimo nad MgSO₄ in filtriramo. Filtrat koncentriramo pri znižanem tlaku in ostanek očistimo s silikagelno kromatografijo z eluiranjem z MeOH:CHCl₃ v razmerju 1:10, da dobimo 77 (180 mg, 67 %).Step four: To a solution of compound 76 (0.50 g, 1.14 mmol) in EtOH (10 ml) at room temperature under an atmosphere of dry nitrogen was added Pd / C, (10% Pd based on dry weight, 50 wt% water) , Degussa type E101 NE / W, 0.25 g) and glacial acetate (0.5 ml). The atmosphere was replaced with hydrogen (exchange of vacuum and hydrogen from the balloon 5 times) and the mixture was heated at 35 ° C for 6 hours. The reaction mixture was cooled to room temperature, filtered through a Celite 521 pad, and the filtrate was concentrated under reduced pressure. The residue was diluted with CHC1 ₃ and washed with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with CHCl ₃ (2 times) and the combined organic layers were dried over MgSO ₄ and filtered. The filtrate was concentrated under reduced pressure and the residue purified by silica gel chromatography eluting with MeOH: CHCl ₃ at a ratio of 1:10 to give 77 (180 mg, 67%).

(3S)-3-[3-(difluorometil)fenil]-3-({2-[5-metil-2-okso-3-(fenilmetil)-l-(2H)piridinil]heksanoil}amino)propanojsko kislino sintetiziramo iz 77 po postopkih, opisanih v Primeru 1 MS: izrač.: (M-H)' = 509,23; ugot.: (M-H)' = 509,19.(3S) -3- [3- (difluoromethyl) phenyl] -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1- (2H) pyridinyl] hexanoyl} amino) propanoic acid is synthesized from 77 according to the procedures described in Example 1 MS: calc .: (MH) '= 509.23; found: (M-H) '= 509.19.

Primer 26Example 26

Sposobnost spojin v smislu izuma, da inhibirajo vezavo, je določena po postopku, pri katerem 26-aminokislinski peptid, ki vsebuje CS1 sekvenco fibronektina z Nterminalnim Cys (CDELPQLVTLPHPNLHGPEILDVPST) pripojimo na ovalbumin, aktiviran z maleimidom. Bovini serumski albumin (BSA) in ovalbumin, konjugiran s CS1, zasadimo na polistirenske ploščice s 96 vdolbinami pri 0,5 mg/ml v TBS (50The ability of the compounds of the invention to inhibit binding is determined by a method in which a 26-amino acid peptide containing a CS1 sequence of fibronectin with Nterminal Cys (CDELPQLVTLPHPNLHGPEILDVPST) is attached to maleimide-activated ovalbumin. Bovine serum albumin (BSA) and ovalbumin, conjugated with CS1, are seeded onto 96-well polystyrene plates at 0.5 mg / ml in TBS (50

-8080 mM Tris, pH 7,5; 150 mM NaCl) pri 4 °C za 16 ur. Ploščice speremo trikrat s TBS in blokiramo s TBS, ki vsebuje 3 % BSA, pri sobni temperaturi 4 ure. Blokirane ploščice speremo 3-krat v vezavnem pufru (TBS; 1 mM MgCl₂; 1 mM CaCl₂; 1 mM MnCl₂) pred preizkusom. Celice Ramos, fluorescenčno označene s kalceinom AM, resuspendiramo v vezavnem pufru (10 celic/ml) in razredčimo 1:2 z enakim pufrom s spojino ali brez nje. Celice damo takoj v vdolbine (2,5 χ 10⁵ celic/vdolbino) in inkubiramo 30 minut pri 37 °C. Po treh izpiranjih z vezavnim pufrom adherentne celice liziramo in jih kvantitativno določimo s fluorometrom. Rezultati so prikazani v tabelah 1, 2, 3 in 4. IC₅₀ je definiran kot doza, ki je potrebna, da dobimo 50 % inhibicijo. MS v tabeli 3 pomeni masno spektrometrijo, nd v tabelah pomeni ni določen. A v tabeli 2 pomeni inhibicijo, odstotek inhibicije pa označuje inhibicijo celične adhezije, kadar je spojina zajeta v preizkus pri koncentraciji 100 pm. Cim nižja je IC₅₀-vrednost in čim večji je odstotek inhibicije, tem bolj učinkovita je spojina pri preprečevanju celične adhezije.-8080 mM Tris, pH 7.5; 150 mM NaCl) at 4 ° C for 16 h. The plates were washed three times with TBS and blocked with TBS containing 3% BSA at room temperature for 4 hours. The blocked plates were washed 3 times in binding buffer (TBS; 1 mM MgCl ₂ ; 1 mM CaCl ₂ ; 1 mM MnCl ₂ ) before testing. Ramos cells, fluorescently labeled with calcein AM, were resuspended in binding buffer (10 cells / ml) and diluted 1: 2 with the same buffer, with or without the compound. Cells were immediately placed in wells (2.5 χ 10 ⁵ cells / well) and incubated for 30 minutes at 37 ° C. After three washes with binding buffer, the adherent cells were lysed and quantified with a fluorometer. The results are shown in Tables 1, 2, 3 and 4. IC ₅₀ is defined as the dose required to obtain 50% inhibition. MS in Table 3 means mass spectrometry, a nd in tables means not specified. A in Table 2 stands for inhibition, and the percentage of inhibition indicates inhibition of cell adhesion when the compound is included in the assay at a concentration of 100 µm. The lower the IC ₅₀ value and the higher the percentage of inhibition, the more effective the compound in preventing cell adhesion.

-8181-8181

Tabela 1Table 1

Spojina št. Compound no. IC₅₀(nM)IC ₅₀ (nM) Mas. spektr. podatki (m/z) Mas. the spectrum. data (m / z) 8 8 7 7 izrač.: (M-H) = 503,22 ugot.: (M-H) = 503,24 Calcd. (M-H) = 503.22 found: (M-H) = 503.24 9 9 2000 2000 izrač.: (M-H)' = 503,22 ugot.: (M-H)' = 503,24 Calcd. (M-H) '= 503.22 found: (M-H) '= 503.24 10 10 3 3 izrač.: (M-H)' = 503,22 ugot.: (M-H)' = 503,22 Calcd. (M-H) '= 503.22 found: (M-H) '= 503.22 12 12 40 40 izrač.: (M-H)'= 501,24 ugot.: (M-H)'= 501,27 Calcd. (M-H) '= 501.24 found: (M-H) '= 501.27 13 13 70 70 izrač.: (M-H)' = 473,24 ugot.: (M-H)' = 473,26 Calcd. (M-H) &lt; + &gt; = 473.24 found: (M-H) '= 473.26 14 14 150 150 izrač.: (M-H)' = 477,22 ugot.: (M-H)' = 477,25 Calcd. (M-H) &lt; + &gt; = 477.22 found: (M-H) '= 477.25 15 15 30 30 izrač.: (M+H)⁺= 535,25 ugot.: (M+H)⁺= 535,00Calc .: (M + H) ⁺ = 535.25 Found: (M + H) ⁺ = 535.00 16 16 35 35 izrač. :(M+H)⁺ = 519,25 ugot.: (M+H)⁺= 519,18calcd. : (M + H) ⁺ = 519.25 found: (M + H) ⁺ = 519.18 17 17 60 60 izrač.: (M-H)'= 521,21 ugot.: (M-H)'= 521,22 Calcd. (M-H) '= 521.21 found: (M-H) '= 521.22 19 19 6 6 izrač.: (M-H)'= 537,18 ugot.: (M-H)' = 537,22 Calcd. (M-H) '= 537.18 found: (M-H) '= 537.22

-8282-8282

Tabela 2Table 2

Spojina Compound ic₅₀ (μΜ)ic ₅₀ (μΜ) % A % A Mas. spektr. podatki (m/z) Mas. the spectrum. data (m / z) (3 S)-3 -(1,3 -benzodioksol-5-il)-3 -({(2 S)-2- [2- okso-3-(2-tienilmetil)-l-imidazolidinil] heksanoil} -amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2- oxo-3- (2-thienylmethyl) -1-imidazolidinyl] hexanoyl} -amino) propanoic acid 0,15 0.15 100 100 izrač.: (M-H)' = 486,37 ugot.: (M-H)' = 486,20 calcd. (M-H) '= 486,37 found: (M-H) '= 486,20 (3S)-3-(l,3-benzodioksol-5-il)-3-(((2S)-2-(2- okso-3-(2-tienilmetil)tetrahidro-1 (2H)- pirimidinil)heksanoil)amino)propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2S) -2- (2- oxo-3- (2-thienylmethyl) tetrahydro-1 (2H) - pyrimidinyl) hexanoyl) amino) propanoic acid 0,005 0,005 100 100 izrač.: (M-H)' = 500,18 ugot.: (M-H)' = 500,22 calcd. (M-H) '= 500.18 found: (M-H) '= 500.22 (3S)-3-(l,3-benzodioksol-5-il)-3-(((2S)-2-(2- okso-4-(2-tienil)-3-(2-tienilmetil)tetrahidro- l(2H)pirimidinil)heksanoil)amino)propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2S) -2- (2- oxo-4- (2-thienyl) -3- (2-thienylmethyl) tetrahydro- l (2H) pyrimidinyl) hexanoyl) amino) propanoic acid 0,05 0.05 100 100 izrač.: (M-H)' = 582,17 ugot.: (M-H)' = 582,21 calcd. (M-H) '= 582.17 found: (M-H) '= 582,21 (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2- okso-3-(2-tienilmetil)-1,3-diazepan-1 - il)heksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2- oxo-3- (2-thienylmethyl) -1,3-diazepan-1 - yl) hexanoyl} amino) propanoic acid nd nd nd nd nd nd

-8383-8383

Tabela 3Table 3

Spojina Compound Mas. spektr. podatki (m/z) Mas. the spectrum. data (m / z) IC₅₀(pM)IC ₅₀ (pM) (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2- [2,5-diokso-1 -(2-tiofenilmetil)-1,2,3,5- tetrahidro-4H-1,4-benzodiazepin-4- iljheksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2,5-dioxo-1- (2-thiophenylmethyl) -1,2,3,5- tetrahydro-4H-1,4-benzodiazepine-4- ylhexanoyl} amino) propanoic acid izrač.: (M-H)' = 576,18 ugot.: (M-H=' = 576,18 calcd. (M-H) '= 576,18 found: (M-H = '= 576,18 1,5 1.5 (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2- [(3S)-2,5-diokso-3-(fenilmetil)-4-(2- tiofenilmetil)tetrahidro-1 (2H)- piraziniljheksanoil} aminojpropanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [(3S) -2,5-dioxo-3- (phenylmethyl) -4- (2- thiophenylmethyl) tetrahydro-1 (2H) - pyrazinylhexanoyl} aminopropane ska acid izrač.: (M-H)' = 604,21 ugot.: (M-H)' = 604,24 calcd. (M-H) '= 604,21 found: (M-H) '= 604,24 6 6 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[3- (feniloksi)fenilj acetil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [3- (phenyloxy) phenyl acetyl} amino) propane acid izrač.: (M-H)' = 418.11 ugot.: (M-H)' = 418.12 calcd. (M-H) '= 418.11 found: (M-H) '= 418.12 >100 > 100 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3- [(2-tiofenilmetil)amino]-1 (2H)- piridiniljheksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3- [(2-thiophenylmethyl) amino] -1 (2H) - pyridinylhexanoyl} amino) propane acid izrač.: (M-H) = 510,17 ugot.: (M-H)' = 510,21 Calcd. (M-H) = 510.17 found: (M-H) '= 510,21 1,3 1.3 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3-(fenilmetil)-2,3-dihidro-lH- benzimidazol-1 -il] acetil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3- (phenylmethyl) -2,3-dihydro-1H- benzimidazol-1-yl] acetyl} amino) propane acid izrač.: (M-H)' = 472,15 ugot.: (M-H)' = 472,18 calcd. (M-H) '= 472,15 found: (M-H) '= 472,18 0,2 0.2 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3 -(fenilmetil)-2,3 -dihidro-1H- benzimidazol-1 -il]heksanoil} amino) propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3 - (phenylmethyl) -2,3-dihydro-1H- benzimidazol-1-yl] hexanoyl} amino) propanoic acid izrač.: (M-H)‘ = 528.21 ugot.: (M-H)' = 528.22 calcd. (M-H) '= 528.21 found: (M-H) '= 528.22 0,07 0.07

-8484-8484

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3-(fenilmetil)-l(2H)piridinil]butanoil} amino)propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3- (phenylmethyl) -1 (2H) pyridinyl] butanoyl} amino) propanoic acid izrač.: (M-H) = 461.17 ugot.: (M-H) = 461.18 Calcd. (M-H) = 461.17 found: (M-H) = 461.18 0,03 0.03 (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[2- okso-3 -(fenilkarbonil)-1 (2H)piridinil] heksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2- oxo-3- (phenylcarbonyl) -1 (2H) pyridinyl] hexanoyl} amino) propanoic acid izrač.: (M-H) = 503,18 ugot.: (M-H) = 503,18 Calcd. (M-H) = 503,18 found: (M-H) = 503,18 0,55 0.55 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3 -(fenilmetil)-1 (2H)p ir idini 1] acetil} amino)propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3 - (phenylmethyl) -1 (2H) pyridine 1] acetyl} amino) propanoic acid izrač.: (M-H) = 433,14 ugot.: (M-H) = 433,16 Calcd. (M-H) = 433,14 found: (M-H) = 433,16 0,45 0.45 (3S)-3-(l,3-benzodioksol-5-il)-3-[({l-[2okso-3 -(fenilmetil)-1 (2H)piridinil] cikloheksil} karboniljamino] propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - [({1- [2-oxo-3- (phenylmethyl) -1 (2H) pyridinyl] cyclohexyl} carbonylamino] propanoic acid izrač.: (M-H) = 501,20 ugot.: (M-H) = 501,24 Calcd. (M-H) = 501.20 found: (M-H) = 501,24 50 50 (3 S )-3-(1,3 -benzodioksol-5 -il)-3 -({(2 S)-2- [2- okso-3 -(fenilmetil)-1 (2H)piridinil]heksanoil} aminojpropanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2- oxo-3- (phenylmethyl) -1 (2H) pyridinyl] hexanoyl} aminopropanoic acid izrač.: (M-H) = 489,20 ugot.: (M-H) = 489,20 Calcd. (M-H) = 489,20 found: (M-H) = 489,20 0,004 0.004 (3 S)-3-( 1,3 -benzodioksol-5-il)-3 -({2- [2- okso-3-(fenilmetil)-2,3-dihidro-lH-imidazol- 1 -il]heksanoil}aminojpropanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3- (phenylmethyl) -2,3-dihydro-1H-imidazole- 1-yl] hexanoyl} aminopropanoic acid izrač.: (M-H) = 478,20 ugot.: (M-H) = 478,23 Calcd. (M-H) = 478,20 found: (M-H) = 478,23 0,06 0.06 (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2- [2,4-diokso-1 -(fenilmetil)-1,4-dihidro-3 (2H)- kinazolinil]heksanoil} aminojpropanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [2,4-dioxo-1- (phenylmethyl) -1,4-dihydro-3 (2H) - quinazolinyl] hexanoyl} aminopropane ska acid izrač.: (M-H) = 556.21 ugot.: (M-H) = 556.22 Calcd. (M-H) = 556.21 found: (M-H) = 556.22 0,1 0.1

-8585-8585

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[3-[(2- klorofenil)metil]-5-metil-2-okso- l(2H)piridinil]heksanoil}amino)propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [3 - [(2- chlorophenyl) methyl] -5-methyl-2-oxo- l (2H) pyridinyl] hexanoyl} amino) propanoic acid izrač: (M-H)' = 537,18 ugot.: (M-H) = 537,22 Calc'd: (M-H) '= 537,18 found: (M-H) = 537,22 0,01 0.01 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[5,5- dimetil-2,4-diokso-3-(fenilmetil)tetrahidro- lH-imidazol-1 -il]heksanoil} amino) propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [5,5- dimethyl-2,4-dioxo-3- (phenylmethyl) tetrahydro- 1H-imidazol-1-yl] hexanoyl} amino) propanoic acid izrač.: (M-H)' = 522,22 ugot.: (M-H)‘ = 522,22 calcd. (M-H) '= 522,22 found: (M-H) '= 522,22 20 20 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2okso-5-(fenilmetil)-l(2H)-piridinil] heksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2-oxo-5- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid izrač.: (M-H)' = 489.20 ugot.: (M-H)' = 489.21 calcd. (M-H) '= 489.20 found: (M-H) '= 489.21 0,04 0.04 (3 S )-3 -(1,3 -benzodioksol-5-il)-3-( {2-[2- okso-3 -(fenilmetil)-1 (2H)-kinoksalinil] heksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3- ({2- [2- oxo-3- (phenylmethyl) -1 (2H) -quinoxalinyl] hexanoyl} amino) propanoic acid izrač.: (M-H)' = 540,21 ugot.: (M-H)' = 540,21 calcd. (M-H) '= 540.21 found: (M-H) '= 540.21 100 100 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3 -(fenilmetil)-1 (2H)-p ir idinil] pentanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3- (phenylmethyl) -1 (2H) -pyridinyl] pentanoyl} amino) propanoic acid izrač.: (M-H)' = 475.18 ugot.: (M-H) = 475.19 calcd. (M-H) '= 475.18 found: (M-H) = 475.19 0,06 0.06 (3 S)-3 -(1 ,3 -benzodioksol-5-il)-3 -({2- [3 - metil-6-okso-5-(fenilmetil)-1 (6H)- piridaziniljheksanoil} amino)propanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [3 - methyl-6-oxo-5- (phenylmethyl) -1 (6H) - pyridazinylhexanoyl} amino) propane acid izrač.: (M-H)' = 504,21 ugot.: (M-H)' = 504,24 calcd. (M-H) '= 504,21 found: (M-H) '= 504.24 0,06 0.06 (3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- okso-3 -(fenilmetil)-3,4-dihidro-1 (2H)- kinazolinil]heksanoil}amino)propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- oxo-3 - (phenylmethyl) -3,4-dihydro-1 (2H) - quinazolinyl] hexanoyl} amino) propanoic acid izrač.: (M-H)' = 542,23 ugot.: (M-H)' = 542,26 calcd. (M-H) '= 542,23 found: (M-H) '= 542,26 0,4 0.4

-8686-8686

(3S)-3-(l,3-benzodioksol-5-il)-3-({2-[2- (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({2- [2- izrač.: (M-H) = Calcd. (M-H) = 2 2 okso-3-(fenilmetil)- 1(2H)- oxo-3- (phenylmethyl) -1 (2H) - 539,22 539,22 kinoliniljheksanoil} amino)propanoj ska quinolinylhexanoyl} amino) propane ugot.: (M-H) = found: (M-H) = kislina acid 539,22 539,22

Tabela 4Table 4

Spojina Compound ic₅₀ (nM)ic ₅₀ (nM) Mas. spektr. podatki (m/z) Mas. the spectrum. data (m / z) (3S)-3-{[(2S)-2-(3-benzil-5-metil-2- oksopiridin-1 (2H)-il)heksanoilj amino} -3 -(3,5 - dimetoksifenil)propanoj ska kislina (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2- oxopyridin-1 (2H) -yl) hexanoyl amino} -3- (3,5 - dimethoxyphenyl) propanoic acid 10 10 izmer.: (M-H) = 519,25; izrač.: (M-H) = 519,25 measured: (M-H) = 519.25; Calcd. (M-H) = 519.25 (3S)-3-{[(2S)-2-(3-benzil-5-metil-2- oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(3 - fluoro-4-metoksifenil)propanojska kislina (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2- oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (3 - fluoro-4-methoxyphenyl) propanoic acid 17 17 izmer.: (M-H) = 507,13; izrač.: (M-H) = 507,23 measured: (M-H) = 507.13; Calcd. (M-H) = 507.23 (3 S)-3-( 1,3-benzodioksol-5-il)-3- {[2-(3-benzil- 2-oksopiridin-1 (2H)- il)heksanoil] amino } pr opanoj ska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3- {[2- (3-benzyl- 2-Oxopyridine-1 (2H) - yl) hexanoyl] amino} acetic acid 30 30 izmer.: (M-H) = 489,17; izrač.: (M-H) = 489,20 measured: (M-H) = 489.17; Calcd. (M-H) = 489.20 (3 S)-3 - {[2 - (3 -benzil-5 -metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino} -3 -(3 - propoksifenil)propanoj ska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3 - propoxyphenyl) propanoic acid 10 10 izmer.: (M-H) = 517,19; izrač.: (M-H) = 517,27 measured: (M-H) = 517.19; Calcd. (M-H) = 517.27 (3 S)-3 - {[2-(3-benzil-2-oksopiridin-1 (2H)- il)heksanoil]amino}-3-(4-metoksi-2,3dimetilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-2-oxopyridin-1 (2H) - yl) hexanoyl] amino} -3- (4-methoxy-2,3dimethylphenyl) propanoic acid 300 300 izmer.: (M+H)⁺ = 504,94; izrač.: (M+H)⁺ = 505,27measured: (M + H) ⁺ = 504.94; Calcd. (M + H) ⁺ = 505.27 (3S)-3-{[(2S)-2-(3-benzil-5-metil-2- oksopiridin-l(2H)-il)heksanoil]amino}-3-(2',6'- dimetoksi-1,1 '-bifenil-4-il)propanoj ska kislina (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2- oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (2 ', 6'- dimethoxy-1,1'-biphenyl-4-yl) propanoic acid 200 200 izmer.: (M-H) = 595,18; izrač.: (M-H) = 595,28 measured: (M-H) = 595.18; Calcd. (M-H) = 595.28

-8787-8787

(3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin1 (2H)-il)heksanoil]amino} -3 -(3,4- dimetilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin (2H) -yl) hexanoyl] amino} -3 - (3,4- dimethylphenyl) propanoic acid 130 130 izmer.: (M-H) = 487,24; izrač.: (M-H)’ = 487,26 measured: (M-H) = 487.24; Calcd. (M-H) '= 487.26 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino} -3-(3- etoksifenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3- ethoxyphenyl) propanoic acid 35 35 izmer.: (M+H)⁺ = 504,99; izrač.: (M+H)⁺ = 505,27measured: (M + H) ⁺ = 504.99; Calcd. (M + H) ⁺ = 505.27 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- l(2H)-il)heksanoil]amino}-3-(3,4,5- trimetoksifenil)propanoj ska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3,4,5- trimethoxyphenyl) propanoic acid 33 33 izmer.: (M+H)⁺ = 550,93; izrač.: (M+H)⁺ = 551,28measured: (M + H) ⁺ = 550.93; Calcd. (M + H) ⁺ = 551.28 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin1 (2H)-il)heksanoil] amino } -3 -(4-metoksi-3,5 - dimetilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin (2H) -yl) hexanoyl] amino} -3- (4-methoxy-3,5 - dimethylphenyl) propanoic acid 140 140 izmer.: (M+H)⁺ = 518,98; izrač.: (M+H)⁺= 519,29measured: (M + H) ⁺ = 518.98; Calcd. (M + H) ⁺ = 519.29 (3 S)-3 - {[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoilJ amino } -3 -(6-metoksi-2- naftil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (6-methoxy-2- naphthyl) propanoic acid 40 40 izmer.: (M+H)⁺ = 540,98; izrač.: (M+H)⁺ = 541,27measured: (M + H) ⁺ = 540.98; Calcd. (M + H) ⁺ = 541.27 (3 S)-3 - {[2-(3 -benzil-5 -metil-2-oksopiridin- 1 (2H)-il)heksanoil]amino } -3 -(3 - butoksifenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3 - butoxyphenyl) propanoic acid 45 45 izmer.: (M+H)⁺= 533,03; izrač.: (M+H)⁺ = 533,30measured: (M + H) ⁺ = 533.03; Calcd. (M + H) ⁺ = 533.30 (3 S)-3 -(1,3 -benzodioksol-5 -il)- {[(2 S)-2-(3 - benzil-4-hidroksi-5-metil-2-oksopiridin-1 (2H)- il)heksanoil] amino }propanoj ska kislina (3 S) -3- (1,3-benzodioxol-5-yl) - {[(2 S) -2- (3 - benzyl-4-hydroxy-5-methyl-2-oxopyridin-1 (2H) - yl) hexanoyl] amino} propanoic acid 200 200 izmer.: (M+H)⁺ = 520,97; izrač.: (M+H)⁺ = 521,23measured: (M + H) ⁺ = 520.97; Calcd. (M + H) ⁺ = 521.23 (3S)-3-(l,3-benzodioksol-5-il)-3-{[(2R)-2-(3- benzil-4-hidroksi-5-metil-2-oksopiridin-l(2H)- il)heksanoil]amino}propanojska kislina (3S) -3- (1,3-benzodioxol-5-yl) -3 - {[(2R) -2- (3- benzyl-4-hydroxy-5-methyl-2-oxopyridin-1 (2H) - yl) hexanoyl] amino} propanoic acid 2000 2000 izmer.: (M+H)⁺ = 520,95; izrač.: (M+H)⁺= 521,23measured: (M + H) ⁺ = 520.95; Calcd. (M + H) ⁺ = 521.23 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -(3 - izopropoksifenil)propanoj ska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3 - isopropoxyphenyl) propanoic acid 4 4 izmer.: (M+H)⁺ = 518,99; izrač.: (M+H)⁺ = 519,29measured: (M + H) ⁺ = 518.99; Calcd. (M + H) ⁺ = 519.29 (3S)-3-({2-[3-(2,6-diklorobenzil)-5-metil-2- oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3 - izopropoksifenil)propanoj ska kislina (3S) -3 - ({2- [3- (2,6-dichlorobenzyl) -5-methyl-2- oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3 - isopropoxyphenyl) propanoic acid 275 275 izrač.: (M+H)⁺ = 587,21; ugot.: (M+H)⁺ = 586,95Calcd .: (M + H) ⁺ = 587.21; found: (M + H) ⁺ = 586.95

-8888-8888

(3S)-3-(3-izopropoksifenil)-3-({2-[2-okso-4-(2- feniletil)piridin- 1 (2H)il]heksanoil}amino)propanojska kislina (3S) -3- (3-isopropoxyphenyl) -3 - ({2- [2-oxo-4- (2- phenylethyl) pyridine- 1 (2H) yl] hexanoyl} amino) propanoic acid 95 95 izrač.: (M-H)'= 517,27; ugot.: (M-H)'= 517,21 Calcd. (M-H) '= 517.27; found: (M-H) '= 517.21 (3 S)-3 - {[2-(3 -benzil-5 -metil-2-oksop iridin- l(2H)-il)heksanoil]amino}-3-(3,5- dimetilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3,5- dimethylphenyl) propanoic acid 52 52 izrač.: (M-H)’= 487,26; ugot.: (M-H)' = 487,20 Calcd. (M-H) '= 487.26; found: (M-H) '= 487.20 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -(4-metoksi-2,5 - dimetilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (4-methoxy-2,5 - dimethylphenyl) propanoic acid 283 283 izrač.: (M-H)'= 517,27; ugot.: (M-H)'= 517,20 Calcd. (M-H) '= 517.27; found: (M-H) '= 517.20 (3 S)-3 -({2- [3 -(3-klorobenzil)-5 -metil-2oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3propoksifenil)propanoj ska kislina (3S) -3 - ({2- [3- (3-chlorobenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3propoxyphenyl) propanoic acid 23 23 izrač.: (M-H)'= 551,23; ugot.: (M-H)'= 551,22 Calcd. (M-H) '= 551.23; found: (M-H) '= 551.22 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino }-3-[3- (trifluorometil)fenil]propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- [3- (trifluoromethyl) phenyl] propanoic acid 250 250 izrač.: (M+H)⁺ = 529,23; ugot.: (M+H)⁺= 529,01Calcd .: (M + H) ⁺ = 529.23; found: (M + H) ⁺ = 529.01 (3 S)-3 - {[2-(3 -benzil- 5 -metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -[4- (trifluorometoksi)fenil]propanoj ska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- [4- (trifluoromethoxy) phenyl] propanoic acid 27 27 izrač.: (M+H)⁺= 545,23; ugot.: (M+H)⁺ = 544,97Calcd. (M + H) ⁺ = 545.23; found: (M + H) ⁺ = 544.97 (3S)-3-({2-[3-(3-klorobenzil)-5-metil-2- oksopiridin-l(2H)-il]heksanoil}amino)-3-(3- izopropoksifenil)propanoj ska kislina (3S) -3 - ({2- [3- (3-chlorobenzyl) -5-methyl-2- oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3- isopropoxyphenyl) propanoic acid 20 20 izrač.: (M+H)⁺= 553,25; ugot.: (M+H)⁺ = 552,95Calcd. (M + H) ⁺ = 553.25; found: (M + H) ⁺ = 552.95 (3 S)-3 -({2-[3 -(2-etoksibenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil}amino)-3-(3- izopropoksifenil)propanoj ska kislina (3S) -3 - ({2- [3- (2-ethoxybenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3- isopropoxyphenyl) propanoic acid 19 19 izrač.: (M+H)⁺ = 563,31; ugot.: (M+H)⁺= 563,17Calcd. (M + H) ⁺ = 563.31; found: (M + H) ⁺ = 563.17 (3S)-3-(3-izopropoksifenil)-3-({2-[3-(2- metoksibenzil)-5-metil-2-oksopiridin-1 (2H)- il]heksanoil}amino)propanojska kislina (3S) -3- (3-isopropoxyphenyl) -3 - ({2- [3- (2- methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) - yl] hexanoyl} amino) propanoic acid 4 4 izrač.: (M+H)⁺ = 549,30; ugot.: (M+H)⁺ = 549,13Calcd. (M + H) ⁺ = 549.30; found: (M + H) ⁺ = 549.13 (3 S)-3 - {[2-(3 -benzil- 5 -metil-2-oksopiridin- 1 (2H)- il)heksanoil] amino } - 3 - [3 - (trifluorometoksi)fenil]propanoj ska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- [3 - (trifluoromethoxy) phenyl] propanoic acid 40 40 izrač.: (M-H)'= 543,21; ugot.: (M-H)'= 543,16 Calc'd: (M-H) '= 543.21; found: (M-H) '= 543.16

-8989-8989

(3 S)-3 - {[2-(3 -benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -(3 -etoksi-4- metoksifenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (3-ethoxy-4- methoxyphenyl) propanoic acid 4 4 izrač.: (M-H)'= 533,27; ugot.: (M-H)' = 533,22 Calc'd: (M-H) '= 533.27; found: (M-H) '= 533.22 (3 S)-3 - {[2-(3 -benzil-5 -metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino} -3 -(4'-metil-1,1’- bifenil-4-il)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3 - (4'-methyl-1,1'- biphenyl-4-yl) propanoic acid 250 250 izrač.: (M-H)' = 549,28; ugot.: (M-H)' = 549,16 Calcd. (M-H) '= 549.28; found: (M-H) '= 549.16 (3 S)-3 - {[2-(3 -benzil- 5 -metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -(4-kloro-3 - izopropoksifenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (4-chloro-3 - isopropoxyphenyl) propanoic acid 25 25 izrač.: (M-H)' = 551,23; ugot.: (M-H)'= 551,20 Calcd. (M-H) '= 551.23; found: (M-H) '= 551.20 (3 S)-3 - {[2-(3 -benzil-5 -metil-2-oksopiridin- 1 (2H)-il)heksanoil]amino} -3-(4'-metoksi-1, Γ- bifenil-4-il)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (4'-methoxy-1, N- biphenyl-4-yl) propanoic acid 300 300 izrač.: (M-H)' = 565,27; ugot.: (M-H)'= 565,21 Calcd. (M-H) '= 565.27; found: (M-H) '= 565.21 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -(4-metoksi-3 - metilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (4-methoxy-3 - methylphenyl) propanoic acid 9 9 izrač.: (M-H)' = 503,25; ugot.: (M-H)'= 503,20 Calc'd: (M-H) '= 503.25; found: (M-H) '= 503.20 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino } -3 -fenilpropanoj ska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3-phenylpropane acid 10 10 izrač.: (M-H)' = 459,23; ugot.: (M-H)'= 459,18 Calcd. (M-H) '= 459.23; found: (M-H) '= 459.18 (3S)-3-{[2-(3-benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino }-3-(2,5- dimetilfenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino} -3- (2,5- dimethylphenyl) propanoic acid 300 300 izrač.: (M-H)'= 487,26; ugot.: (M-H)'= 487,21 Calcd. (M-H) '= 487.26; found: (M-H) '= 487.21 (3S)-3-({2-[3-(2-klorobenzil)-5-metil-2- oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(4metilfenil)propanojska kislina (3S) -3 - ({2- [3- (2-chlorobenzyl) -5-methyl-2- oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid 15 15 izrač.: (M-H)'= 507,21; ugot.: (M-H)'= 507,15 Calcd. (M-H) '= 507.21; found: (M-H) '= 507.15 (3S)-3-({2-[3-(2-klorobenzil)-5-metil-2- oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3- izopropoksifenil)propanoj ska kislina (3S) -3 - ({2- [3- (2-chlorobenzyl) -5-methyl-2- oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3- isopropoxyphenyl) propanoic acid 5 5 izrač.: (M-H)' = 551,23; ugot.: (M-H)' = 551,20 Calcd. (M-H) '= 551.23; found: (M-H) '= 551.20 (3 S)-3 -({2- [3 -(2-klorobenzil)-5-metil-2- oksopiridin-1 (2H)-il]heksanoil} amino)-3 - fenilpropanoj ska kislina (3S) -3 - ({2- [3- (2-chlorobenzyl) -5-methyl-2- oxopyridin-1 (2H) -yl] hexanoyl} amino) -3 - phenylpropanoic acid 12 12 izrač.: (M-H)'= 493,19; ugot.: (M-H)'= 493,12 Calcd. (M-H) '= 493.19; found: (M-H) '= 493.12

-9090-9090

(3 S)-3 - {[2-(3 -benzil-5-metil-2-oksopiridin- 1 (2H)-il)heksanoil] amino[-3-(3,5- difluorofenil)propanojska kislina (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridine- 1 (2H) -yl) hexanoyl] amino [-3- (3,5- difluorophenyl) propanoic acid 25 25 izrač.: (M-H)'= 495,21; ugot.: (M-H)'= 495,14 Calc'd (M-H) '= 495.21; found: (M-H) '= 495.14 (3S)-3-(2,3-dihidro-lH-inden-5-il)-3-({2-[5- metil-2-okso-3-(fenilmetil)-l(2H)- piridinil]heksanoil} amino)propanoj ska kislina (3S) -3- (2,3-dihydro-1H-inden-5-yl) -3 - ({2- [5- Methyl-2-oxo-3- (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl} amino) propanoic acid 63 63 izrač.: (M-H)' = 499,26; ugot.: (M-H)'= 499,23 Calcd. (M-H) '= 499.26; found: (M-H) '= 499.23 (3S)-3-({2-[3- [(2,3 -diklorofenil)metil] -5 -metil- 2-okso-1 (2H)-piridinil]heksanoil} amino)-3 - {3 - [(1 -metiletil)oksi] fenil [propanoj ska kislina (3S) -3 - ({2- [3- [(2,3-dichlorophenyl) methyl] -5-methyl- 2-oxo-1 (2H) -pyridinyl] hexanoyl} amino) -3- {3 - [(1-Methylethyl) oxy] phenyl [propanoic acid 68 68 izrač.: (M+H)⁺ = 586,20; ugot.: (M+H)⁺ = 586,88Calcd .: (M + H) ⁺ = 586.20; found: (M + H) ⁺ = 586.88 (3S)-3-[l,l’-bifenil]-3-il-3-({2-[5-metil-2-okso- 3 -(fenilmetil)-1 (2H)- piridinil]heksanoil}amino)propanojska kislina (3S) -3- [l, l'-biphenyl] -3-yl-3 - ({2- [5-methyl-2-oxo- 3 - (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl} amino) propanoic acid 250 250 izrač.: (M-H)' = 535,26; ugot: (M-H)'= 535,22 Calc'd: (M-H) '= 535.26; found: (M-H) &lt; + &gt; = 535.22 (3S)-3-({2-[3-{[2,4-dikloro-6- (metiloksi)fenil]metil} -5 -metil-2-okso-1 (2H)- piridiniljhekasnoil} amino)-3 - {3 - [(1 - metiletil)oksi] fenil [propanoj ska kislina (3S) -3 - ({2- [3 - {[2,4-dichloro-6- (methyloxy) phenyl] methyl} -5-methyl-2-oxo-1 (2H) - pyridinylhexanoyl} amino) -3 - {3 - [(1 - methylethyl) oxy] phenyl [propanoic acid 275 275 izrač.: (M+H)⁺ = 616,21; ugot.: (M+H)⁺ = 616,88Calcd. (M + H) ⁺ = 616.21; found: (M + H) ⁺ = 616.88 (3S)-3-(4-etilfenil)-3-({2-[5-metil-2-okso-3- (fenilmetil)-1 (2H)- piridinil]heksanoil[amino)propanojska kislina (3S) -3- (4-ethylphenyl) -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl [amino] propanoic acid 40 40 izrač.: (M-H)'= 487,26; ugot.: (M-H)' = 487,24 Calcd. (M-H) '= 487.26; found: (M-H) '= 487.24 (3S)-3-[4-(l-metiletil)fenil]-3-({2-[5-metil-2okso-3 -(fenilmetil)-1 (2H)- piridinil]heksanoil[amino)propanojska kislina (3S) -3- [4- (1-methylethyl) phenyl] -3 - ({2- [5-methyl-2oxo-3- (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl [amino] propanoic acid 160 160 izrač.: (M-H)' = 501,28; ugot.: (M-H)'= 501,27 Calcd. (M-H) '= 501.28; found: (M-H) '= 501.27 (3 S)-3 -(1 -metil-1 H-indol-6-il)-3 -({2- [5-metil-2- okso-3 -(fenilmetil)-1 (2H)- piridinil]heksanoil[amino)propanojska kislina (3S) -3- (1-methyl-1H-indol-6-yl) -3 - ({2- [5-methyl-2- oxo-3 - (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl [amino] propanoic acid 10 10 izrač.: (M-H)'= 512,25; ugot.: (M-H)'= 512,24 Calcd. (M-H) '= 512.25; found: (M-H) '= 512.24 (38)-3-( {2- [5 -metil-3 -(2-naftalenilmetil)-2- okso-1 (2H)-piridinil]heksanoil} amino)-3 -(4- metilfenil)propanojska kislina (38) -3- ({2- [5-methyl-3- (2-naphthalenylmethyl) -2- oxo-1 (2H) -pyridinyl] hexanoyl} amino) -3- (4- methylphenyl) propanoic acid 400 400 izrač.: (M-H)' = 523,26; ugot.: (M-H)'= 523,23 Calcd. (M-H) '= 523.26; found: (M-H) '= 523.23

-9191-9191

(3S)-3-{3-[(l -metiletil)oksi] fenil} -3 -({2- [5 - metil-3-(2-naftalenilmetil)-2-okso- l(2H)piridinil]heksanoil}amino)propanojska kislina (3S) -3- {3 - [(1-methylethyl) oxy] phenyl} -3 - ({2- [5 - methyl-3- (2-naphthalenylmethyl) -2-oxo- l (2H) pyridinyl] hexanoyl} amino) propanoic acid 20 20 izrač.: (M-H)’ = 567,29; ugot.: (M-H)' = 567,26 Calcd. (M-H) '= 567.29; found: (M-H) '= 567.26 (3S)-3-(2,3-dihidro-lH-inden-5-il)-3-({2-[5- metil-3 -(2-naftalenilmetil)-2-okso-1 (2H)- piridinil]heksanoil}amino)propanojska kislina (3S) -3- (2,3-dihydro-1H-inden-5-yl) -3 - ({2- [5- methyl-3- (2-naphthalenylmethyl) -2-oxo-1 (2H) - pyridinyl] hexanoyl} amino) propanoic acid 283 283 izrač.: (M-H)' = 549,28; ugot.: (M-H)' = 549,21 Calcd. (M-H) '= 549.28; found: (M-H) '= 549.21 (3S)-3-({2-[5-metil-3-(2-naftalenilmetil)-2- okso-l(2H)piridinil]heksanoil}amino)-3- fenilpropanojska kislina (3S) -3 - ({2- [5-methyl-3- (2-naphthalenylmethyl) -2- oxo-1 (2H) pyridinyl] hexanoyl} amino) -3- phenylpropanoic acid 30 30 izrač.: (M-H)' = 509,24; ugot.: (M-H)'= 509,19 Calcd. (M-H) '= 509.24; found: (M-H) '= 509.19 (2S)-2-( { 2- [5 -metil-2-okso-3 -(fenilmetil)- 1 (2H)piridinil]heksanoil} amino)-3 - fenilpropanojska kislina (2S) -2- ({2- [5-methyl-2-oxo-3 - (phenylmethyl) - 1 (2H) pyridinyl] hexanoyl} amino) -3 - phenylpropanoic acid >10000 > 10000 izrač.: (M-H)'= 459,23; ugot.: (M-H)' = 459,22 Calcd. (M-H) '= 459.23; found: (M-H) '= 459.22 (3 S)-3 -({ 2-[5-metil-2-okso-3 -(fenilmetil)- 1 (2H)piridinil]heksanoil} amino)-3 - [3 - (2 - metilpropil)fenil]propanojska kislina (3 S) -3 - ({2- [5-methyl-2-oxo-3 - (phenylmethyl) - 1 (2H) pyridinyl] hexanoyl} amino) -3- [3- (2 -) methylpropyl) phenyl] propanoic acid 10 10 izrač.: (M-H)'= 515,29; ugot.: (M-H)'= 515,28 Calcd. (M-H) '= 515.29; found: (M-H) '= 515.28 (3S)-3-[3-(dietilamino)fenil]-3-({2-[5-metil-2- okso-3-(fenilmetil)-l(2H)- piridinil]heksanoil}amino)propanojska kislina (3S) -3- [3- (diethylamino) phenyl] -3 - ({2- [5-methyl-2- oxo-3- (phenylmethyl) -l (2H) - pyridinyl] hexanoyl} amino) propanoic acid 10 10 izrač.: (M-H)'= 530,30; ugot.: (M-H)' = 530,25 Calcd. (M-H) '= 530.30; found: (M-H) '= 530.25 (3 S)-3 - [3 -(difluorometil)fenil] -3 -({2- [5-metil-2- okso-3-(fenilmetil)-1 (2H)- piridinil]heksanoil} amino)propanoj ska kislina (3S) -3- [3- (difluoromethyl) phenyl] -3 - ({2- [5-methyl-2- oxo-3- (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl} amino) propanoic acid 20 20 izrač.: (M-H)' = 509,23; ugot.: (M-H)'= 509,19 Calc'd (M-H) '= 509.23; found: (M-H) '= 509.19 (3 S)-3 - { 3 - [(1 -metiletil)oksi] fenil }-3-({2-[5- metil-3-[(2-metilfenil)metil]-2-okso- 1 (2H)piridinil]heksanoil} aminojpropanoj ska kislina (3 S) -3 - {3 - [(1-methylethyl) oxy] phenyl} -3 - ({2- [5- methyl-3 - [(2-methylphenyl) methyl] -2-oxo- 1 (2H) pyridinyl] hexanoyl} aminopropane acid 5 5 izrač.: (M+H)⁺ = 533,30; ugot.: (M+H)⁺ = 532,94Calcd. (M + H) ⁺ = 533.30; found: (M + H) ⁺ = 532.94 (2R)-2-( { 2- [5 -metil-2-okso-3 -(fenilmetil)- 1 (2H)-piridinil]heksanoil} amino)-3 - fenilpropanojska kislina (2R) -2- ({2- [5-methyl-2-oxo-3 - (phenylmethyl) - 1 (2H) -pyridinyl] hexanoyl} amino) -3 - phenylpropanoic acid 5000 5000 izrač.: (M-H)' = 459,23; ugot.: (M-H)'= 459,22 Calcd. (M-H) '= 459.23; found: (M-H) '= 459.22

-9292-9292

(3 S)-3 -(3 -fluorofenil)-3 -({2- [5 -metil-2-okso-3 - (fenilmetil)-1 (2H)- piridinil]heksanoil}amino)propanojska kislina (3S) -3- (3-fluorophenyl) -3 - ({2- [5-methyl-2-oxo-3 - (phenylmethyl) -1 (2H) - pyridinyl] hexanoyl} amino) propanoic acid 13 13 izrač.: (M-H)'= 477,21; ugot.: (M-H)' = 477,20 Calcd. (M-H) '= 477.21; found: (M-H) '= 477.20 (2R)-2-({2-[5-metil-2-okso-3-(fenilmetil)- l(2H)-piridinil]heksanoil}amino)-2- feniletanojska kislina (2R) -2 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) - 1 (2H) -pyridinyl] hexanoyl} amino) -2- phenylethanoic acid >10000 > 10000 izrač.: (M-H)'= 445,21; ugot.: (M-H)' = 444,94 Calcd. (M-H) '= 445.21; found: (M-H) '= 444.94 (3S)-3-({2-[3-[(2-kloro-4-fluorofenil)metil]-5- metil-2-okso-1 (2H)-piridinil]heksanoil}amino)- 3 - {3 - [(1 -metiletil)oksi] fenil} propanoj ska kislina (3S) -3 - ({2- [3 - [(2-chloro-4-fluorophenyl) methyl] -5- methyl-2-oxo-1 (2H) -pyridinyl] hexanoyl} amino) - 3 - {3 - [(1-methylethyl) oxy] phenyl} propane acid 17 17 izrač.: (M-H)' = 569,22; ugot.: (M-H)'= 569,18 Calcd. (M-H) '= 569.22; found: (M-H) '= 569.18 (38)-3-( { 2- [5-metil-3 - [(2-metilfenil)metil] -2- okso-1 (2H)-piridinil]heksanoil} amino)-3 - fenilpropanojska kislina (38) -3- ({2- [5-methyl-3 - [(2-methylphenyl) methyl] -2- oxo-1 (2H) -pyridinyl] hexanoyl} amino) -3 - phenylpropanoic acid 25 25 izrač.: (M+H)⁺ = 475,26; ugot.: (M+H)⁺ = 474,94Calcd. (M + H) ⁺ = 475.26; found: (M + H) ⁺ = 474.94 (3S)-3-{3-[(l -metiletil)oksi] fenil } -3 -({ 2- [5 - metil-2-okso-1 -(fenilmetil)-1,2-dihidro-3- piridinil]-2-fenilacetil}amino)propanojska kislina (3S) -3- {3 - [(1-methylethyl) oxy] phenyl} -3 - ({2- [5 - methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3- pyridinyl] -2-phenylacetyl} amino) propanoic acid 10 10 izrač.: (M+H)⁺= 539,25; ugot.: (M+H)⁺ = 538,91Calcd. (M + H) ⁺ = 539.25; found: (M + H) ⁺ = 538.91 (3S)-3-({2-[5 -metil-3 -(1 -naftalenilmetil)-2- okso-1 (2H)-piridinil]heksanoil} amino)-3 - fenilpropanojska kislina (3S) -3 - ({2- [5-methyl-3- (1-naphthalenylmethyl) -2- oxo-1 (2H) -pyridinyl] hexanoyl} amino) -3 - phenylpropanoic acid 350 350 izrač.: (M-H)' = 509,24; ugot.: (M-H)' = 509,22 Calcd. (M-H) '= 509.24; found: (M-H) &lt; + &gt; = 509.22 (3 S)-3 - {3 - [(1 -metiletil)oksi] fenil} -3 -({2- [5 - metil-3 -(1 -naftalenilmetil)-2-okso-1 (2H)piridinil]heksanoil} amino)propanoj ska kislina (3 S) -3 - {3 - [(1-methylethyl) oxy] phenyl} -3 - ({2- [5 - Methyl-3- (1-naphthalenylmethyl) -2-oxo-1 (2H) pyridinyl] hexanoyl} amino) propanoic acid 67 67 izrač.: (M-H)' = 567,29; ugot.: (M-H)' = 567,28 Calcd. (M-H) '= 567.29; found: (M-H) '= 567.28 (3 S)-3 - {4-metil-3 - [(1 -metiletil)oksi] fenil} -3- ({2- [5 -metil-2-okso-3 -(fenilmetil)- l(2H)piridinil]heksanoil}amino)propanojska kislina (3S) -3- {4-methyl-3 - [(1-methylethyl) oxy] phenyl} -3- ({2- [5-methyl-2-oxo-3 - (phenylmethyl) - l (2H) pyridinyl] hexanoyl} amino) propanoic acid 15 15 izrač.: (M-H)'= 531,29; ugot.: (M-H)'= 531,26 Calc'd: (M-H) '= 531.29; found: (M-H) '= 531.26

-93n-93n

Vse citirane reference so vključene tukaj kot referenca.All references cited are incorporated herein by reference.

Predloženi izum je ponazorjen s predhodnim opisom in Primeri. Predhodni opis je namenjen kot neomejujoča ponazoritev, ker bodo strokovnjakom postale očitne mnoge variante v zvezi z njim. Mišljeno je, da so vse take variante v obsegu in smislu priloženih zahtevkov zajete s tem.The present invention is illustrated by the foregoing description and Examples. The foregoing description is intended as a non-limiting illustration, as many variants will become apparent to those skilled in the art. It is intended that all such variants are covered by the scope and scope of the attached claims.

Možno je narediti spremembe pri sestavi, izvajanju in pripravi postopka v smislu predloženega izuma, opisanega tukaj, ne da bi se oddaljili od koncepta in obsega izuma, kot je definiran v naslednjih zahtevkih.It is possible to make changes to the composition, implementation and preparation of the process of the present invention described herein without departing from the concept and scope of the invention as defined in the following claims.

-94SEZNAM SEKVENC (1) SPLOŠNA INFORMACIJA (OMISSIS) (2) INFORMACIJA ZA SEQ ID NO: 1:-94LIST OF SEQUENCES (1) GENERAL INFORMATION (OMISSIS) (2) INFORMATION FOR SEQ ID NO: 1:

(i) ZNAČILNOSTI SEKVENCE:(i) SEQUENCE FEATURES:

(A) DOLŽINA: 26 aminokislin (B) TIP: aminokislina (C) VERIŽNOST: enojna (D) TOPOLOGIJA: linearna (ii) TIP MOLEKULE: protein (xi) OPIS SEKVENCE: SEQ ID NO: 1:(A) LENGTH: 26 amino acids (B) TYPE: amino acid (C) CHAIN: single (D) TOPOLOGY: linear (ii) MOLECULES TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1:

Cys Asp Glu Leu Pro Gin Leu Val Thr Leu Pro His Pro Asn Leu His 1 5 10 15Cys Asp Glu Leu Pro Gin Leu Val Thr Leu Pro His Pro Asn Leu His 1 5 10 15

Gly Pro Glu Ile Leu Asp Val Pro Ser ThrGly Pro Glu Ile Leu Asp Val Pro Ser Thr

Claims (20)

PATENTNI ZAHTEVKI kjer krog Q pomeni enega ali več obročev, q je celo število od 0 do 6PATENT APPLICATIONS wherein the circle Q represents one or more rings, q is an integer from 0 to 6 M je izbran iz skupine, ki jo sestavljajo -C(R⁹)(R¹⁰)- in -(CH₂)_U-, kjer je u celo število od 0 do 3M is selected from the group consisting of -C (R ⁹ ) (R ¹⁰ ) - and - (CH ₂ ) _U -, where u is an integer from 0 to 3 J je izbran iz skupine, ki jo sestavljajo -0-, -S- in -NR¹²T je izbran iz skupine, ki jo sestavljata -C(0)- in -(CH₂)_b, kjer je b celo število od O do 3,J is selected from the group consisting of -O-, -S-, and -NR ¹² T is selected from the group consisting of -C (O) - and - (CH ₂ ) _b , where b is an integer of O to 3, L je izbran iz skupine, ki jo sestavljajo -0-, -NR¹³-, -S- in -(CH₂)_V, kjer je v celo število O ali 1,L is selected from the group consisting of -O-, -NR ¹³ -, -S- and - (CH ₂ ) _V , where v is an integer O or 1, X je izbran iz skupine, ki jo sestavljajo -C0₂B, -PO₃H₂, -SO₃H, -SO₂NH₂,X is selected from the group consisting of -C0 ₂ B, -PO ₃ H ₂ , -SO ₃ H, -SO ₂ NH ₂ , -SO₂NHCOR¹⁴, -OPO3H2, -C(0)NHC(0)R¹⁵, -C(O)NHSO2R¹⁶, tetrazolil, oksazolil in hidroksil-SO ₂ NHCOR ¹⁴ , -OPO3H2, -C (O) NHC (O) R ¹⁵ , -C (O) NHSO2R ¹⁶ , tetrazolyl, oxazolyl and hydroxyl R¹¹, R¹² in R¹³ so vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkinilamino, alkoksikarbonilna, heterocikloilna, -CH=N0H, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inR ¹¹ , R ¹² and R ¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NO, Haloalkyl, alkoxyalkyl, carboxaldehyde, carboxaldehyde, carboxaldehyde, carboxaldehyde cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carboxyalkyl, and carbamyl group -9696-9696 B, R¹, R⁴, R⁶, R⁸, R⁹, R¹⁰, R¹⁴, R¹⁵ in R¹⁶ so pri vsakem pojavljanju neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkilna, alifatska acilna,B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁴ , R ¹⁵ and R ¹⁶ are independently selected at each occurrence from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF₃, -CO₂H, -SH, -CN, -NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(Ci-C₃alkil)-C(O)(C!-C₃alkilna), -NHC(O)N(Cr C₃alkil)C(O)-NH(C_rC₃alkilna), -NHC(O)NH(C_rC₆alkilna), -NHSO₂(C_r C₃alkilna), -NHSO₂(arilna), alkoksialkilna, alkilamino, alkenilamino, di(C_r C₃)amino, -C(O)O-(C₁-C₃)alkilna, -C(O)NH-(C_rC₃)alkilna, -C(O)N(C_r C₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(C!-C₃alkilna), -SO₃(C_rC₃alkilna), sulfonamido, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, kjer so B, R¹, R⁴, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ in R¹⁶ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone, pri čemer, kadar je L -NR¹³-, lahko R⁴ in R¹³, vzeta skupaj, tvorita obroč in kjer R⁶ in R⁸, vzeta skupaj, lahko tvorita obroč in pri čemer, kadar je M -C(R⁹)(R¹⁰)-, lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč, ali njena farmacevtsko sprejemljiva sol.-CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C 1 -C ₃ alkyl) -C (O) (C ! -C ₃ alkyl), -NHC (O) N (Ci-C ₃ alkyl) C (O) -NH (C _r C ₃ alkyl), -NHC (O) NH (C _r C ₆ alkyl), -NHSO ₂ (C _r C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C _r C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, -C (O ) NH- (C _r C ₃ ) alkyl, -C (O) N (C _r C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide , cycloalkyl, cycloalkenyl, -cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkilheterociklilna, heterocyclylalkyl, sulfonyl, -SO ₂ - (C! -C ₃ alkyl), -SO ₃ (C _r C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C (O) NH (benzyl) group, wherein B, R ^1, R ^4, R ^6, R ^8, R ^9, R ^10, R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ and R ^{16 are} unsubstituted or substituted at least with one electron-donating or electron-withdrawing group, where, when L is -NR ¹³ -, R ⁴ and R ¹³ taken together can form a ring and where R ⁶ and R ⁸ taken together can form a ring and at wherein when M is -C (R ⁹ ) (R ¹⁰ ) -, R ⁹ and R ¹⁰ taken together may form a ring, or a pharmaceutically acceptable salt thereof. 2. Spojina po zahtevku 1, označena s tem, daje krog Q arilni, cikloalkilni, biarilni ali heterociklilni obroč.Compound according to claim 1, characterized in that the circle Q is an aryl, cycloalkyl, biaryl or heterocyclyl ring. 3. Spojina po zahtevku 1, označena s tem, da je derivat le-te, izbran iz skupine, ki jo sestavljajo estri, karbamati, aminali, amidi, optični izomeri in predzdravila.Compound according to claim 1, characterized in that the derivative thereof is selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 4. Spojina s strukturo4. Compound with structure -9797 kjer je Y pri vsakem pojavljanju neodvisno izbran iz skupine, ki jo sestavljajo C(O), N, CR⁷, C(R²)(R³), NR⁵, CH, O in S m je celo število od 2 do 5-9797 wherein Y at each occurrence is independently selected from the group consisting of C (O), N, CR ⁷ , C (R ² ) (R ³ ), NR ⁵ , CH, O and S m is an integer of 2 to 5 W je izbran iz skupine, ki jo sestavljajo C, N in CR²² W is selected from the group consisting of C, N and CR ²² T je izbran iz skupine, ki jo sestavljajo C(O) in (CH₂)b, kjer je b celo število odT is selected from the group consisting of C (O) and (CH ₂ ) b, where b is an integer of Odo 3Odo 3 L je izbran iz skupine, ki jo sestavljajo O, NR¹³, S in (CH₂)_n, kjer je n celo število Oali 1L is selected from the group consisting of O, NR ¹³ , S and (CH ₂ ) _n , where n is an integer Oali 1 R⁵, R¹¹ in R¹³ so pri vsakem pojavljanju vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkinilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inR ⁵ , R ¹¹ and R ¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde , carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, heterocyclylalkyl, heterocyclylalkyl, heterocyclylalkyl, heterocyclylalkyl, heterocyclylalkyl, heterocyclylalkyl, heterocyclylalkyl group and B, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰ in R²² so vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkilna, alifatska acilna, -CF₃, -CO₂H, -SH, -CN, -NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(Ci-C₃alkil)-C(O)(Ci-C₃alkilna), -NHC(O)N(C_i-C₃alkil)C(O)-NH(C₁C₃alkilna), -NHC(O)NH(C_rC₆alkilna), -NHSO₂(C₁-C₃alkilna), -NHSO₂(arilna,B, R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ²² are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, -CF ₃ , -CO ₂ H, -SH, -CN, -NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (Ci- C ₃ alkyl) -C (O) (C 1 -C ₃ alkyl), -NHC (O) N (C _and -C ₃ alkyl) C (O) -NH (C ₁ C ₃ alkyl), -NHC (O) NH (C _r C ₆ alkyl), -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl, -9898 alkoksialkilna, alkilamino, alkenilamino, di(Ci-C₃)amino, -C(O)O-(C_r C₃)alkilna, -C(O)NH-(C_rC₃)alkilna, -C(O)N(C_rC₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(Ci-C₃alkilna), -SO₃-(C_rC₃alkilna), sulfonamido, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, kjer so B, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³ in R²² nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone in pri čemer, kadar je L -NR¹³-, lahko R⁴ in R¹³, vzeta skupaj, tvorita obroč in pri čemer lahko R⁶ in R⁸, vzeta skupaj, tvorita obroč in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč, ali njena farmacevtsko sprejemljiva sol.-9898 alkoxyalkyl, alkylamino, alkenylamino, di (Ci-C ₃₎ amino, -C (O) O- (C _r C ₃₎ alkyl, -C (O) NH- (C _r C ₃₎ alkyl, -C ( O) N (C _r C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy , arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkilheterociklilna, heterocyclylalkyl, sulfonyl, -SO ₂ - (C-C ₃ alkyl), -SO ₃ - (C _r C ₃ alkyl), sulfonamido, carbamate , aryloxyalkyl and -C (O) NH (benzyl) group wherein B, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹³ and R ^{22 is} unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, and where, when L is -NR ¹³ -, R ⁴ and R ¹³ may be taken together to form a ring and wherein R ⁶ and R ⁸ taken together form a ring, and wherein R ⁹ and R ¹⁰ taken together can form a ring, or a pharmaceutically acceptable salt thereof. 5. Spojina po zahtevku 4, označena s tem, daje derivat le-te, izbran iz skupine, ki jo sestavljajo estri, karbamati, aminali, amidi, optični izomeri in predzdravila.Compound according to claim 4, characterized in that the derivative thereof is selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 6. Spojina s strukturo6. Compound with structure R⁴ kjer je q celo število od nič do 4,R ⁴ where q is an integer from zero to 4, T je izbran iz skupine, ki jo sestavljata C(O) in (CH₂)b, kjer je b celo število od 0 do 3T is selected from the group consisting of C (O) and (CH ₂ ) b, where b is an integer from 0 to 3 -9999-9999 L je izbran iz skupine, ki jo sestavljajo O, NR¹³, S in (CH₂)_n, kjer je n celo število Oali 1L is selected from the group consisting of O, NR ¹³ , S and (CH ₂ ) _n , where n is an integer Oali 1 R¹¹ in R¹³ sta vsak neodvisno izbrana iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkilnilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inR ¹¹ and R ¹³ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkylnylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxalkylalkyl, cycloalkylalkyl, cycloalkylalkyl, cycloalkenyl , cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and -C (aryl) and (C) aryl (benzyloxy) and (C) B, R¹, R⁴, R⁶, R⁸, R⁹ in R¹⁰ so pri vsakem pojavljanju neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkoksi, alifatska acilna, -CF₃, -CO₂H, -SH, -CN, -NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(C_rC₃alkil)-C(O)(Ci-C₃alkilna), -NHC(O)N(C₁-C₃alkil)C(O)NH(Ci-C₃ alkilna), -NHC(O)NH(C_rC₆alkilna), -NHSO₂(C₁-C₃alkilna), -NHSO₂(arilna), alkoksialkilna, alkilamino, alkenilamino, di(C]-C₃)amino, -C(O)O-(CiC₃)alkilna, -C(O)NH(C_rC₃)alkilna, -C(O)N(C₁-C₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksialdehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(Ci-C₃alkilna), -SO₃-(Ci-C₃alkilna), sulfonamido, karbamatna, ariloksialkilna in C(O)NH(benzilna) skupina, kjer so B, R¹, R⁴, R⁶, R⁸, R⁹, R¹⁰, R¹¹ in R¹³ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone in pri čemer, kadar je L -NR¹³-, lahko R⁴ in R¹³, vzeta skupaj, tvorita obroč in pri čemer lahko R in R , vzeta skupaj, tvorita obroč, in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč ali njena farmacevtsko sprejemljiva sol.B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ and R ¹⁰ are independently selected at each occurrence from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkoxy , aliphatic acyl, -CF _3, -CO ₂ H, -SH, -CN, -NO _2, -NH _2, -OH, alkynylamino, alkoxycarbonyl, heterocikloilna, carboxy, -N (C _r C ₃ alkyl) -C ( O) (Ci-C ₃ alkyl), -NHC (O) N (C ₁ -C ₃ alkyl) C (O) NH (Ci-C ₃ alkyl), -NHC (O) NH (C _r C ₆ alkyl) , -NHSO ₂ (C ₁ -C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, alkylamino, alkenylamino, di (C 1 -C ₃ ) amino, -C (O) O- (C ₁ -C ₃ ) alkyl, - C (O) NH (C _r C ₃ ) alkyl, -C (O) N (C ₁ -C ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, karboksialdehidna, carboxamide, cycloalkyl, cycloalkenyl, -cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkilheterociklilna, heterocyclylalkyl, sulfonyl, -SO ₂ - (C-C ₃ alkyl), -SO ₃ - (C 1 -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and C (O) NH (benzyl) groups wherein B, R ¹ , R ⁴ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ^{13 are} unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, and where, when L is -NR ¹³ -, R ⁴ and R ¹³ may be taken together to form a ring and wherein R and R taken together may form a ring, and wherein R ⁹ and R ¹⁰ together may form a ring or a pharmaceutically acceptable salt thereof. -100100-100100 7. Spojina po zahtevku 6, označena s tem, da je q ena ali dva, R¹ je pri vsakem pojavljanju neodvisno izbran iz skupine, ki jo sestavljata aralkil ali alkil, R⁶ je alkil, B, R⁸, R⁹, R¹⁰ in R¹¹ so vsak neodvisno vodik, T je -(CH₂)b-, pri čemer je b nič, L je -(CH₂)_n-, pri čemer je n nič in R⁴ je aril.Compound according to claim 6, characterized in that q is one or two, R ¹ at each occurrence is independently selected from the group consisting of aralkyl or alkyl, R ⁶ is alkyl, B, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently hydrogen, T is - (CH ₂ ) b -, where b is zero, L is - (CH ₂ ) _n -, where n is zero and R ⁴ is aryl. 8. Spojina po zahtevku 6, označena s tem, daje derivat le-te, izbran iz skupine, ki jo sestavljajo estri, karbamati, aminali, amidi, optični izomeri in predzdravila.A compound according to claim 6, characterized in that the derivative thereof is selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 9. Spojina s strukturo kjer je s celo število od nič do pet,9. A compound of structure wherein s is an integer from zero to five, R²¹ je izbran iz skupine, ki jo sestavljajo aril, alkilheterociklil, heterociklilalkil, heterocikloil, aralkil, alkilaril, alkil, aroil, ariloksi, cikloalkil, cikloalkenil, cikloalkinil, biaril, arilamino, tioaril in diarilaminoR ²¹ is selected from the group consisting of aryl, alkylheterocyclyl, heterocyclylalkyl, heterocycloyl, aralkyl, alkylaryl, alkyl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, biaryl, arylamino, thioaryl and diarylamino B, R⁶, R⁸, R⁹, R¹⁰, R¹⁷, R¹⁸, R¹⁹ in R²⁰ so pri vsakem pojavljanju vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkilna, alkenilna, alkinilna, alkoksi, alkenoksi, alkilnoksi, tioalkoksi, hidroksialkoksi, alifatska acilna, -CF3, -CO₂H, -SH, -CN, NO₂, -NH₂, OH, alkinilamino, alkoksikarbonilna, heterocikloilna, karboksi, -N(Ci-C₃-alkil)-C(O)(C₁-C₃alkilna), -NHC(O)N(C_r C₃alkil)C(O)NH(Ci-C₃alkilna), -NHC(O)NH(Ci-C₆alkilna), -NHSO₂(C,C₃alkilna), -NHSO₂(arilna, alkoksialkilna, alkilamino, alkenilamino, di(C_r C₃)amino, -C(O)O-(C,-C₃)alkilna, -C(O)NH(C,-C₃)alkilna, -C(O)N(C_r B, R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkyloxy, thioalkoxy, hydroxyalkoxy, aliphatic acyl, -CF3, -CO ₂ H, -SH, -CN, NO ₂ , -NH ₂ , OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (Ci-C ₃ - alkyl) -C (O) (C ₁ -C ₃ alkyl), -NHC (O) N (C _r C ₃ alkyl) C (O) NH (C 1 -C ₃ alkyl), -NHC (O) NH (Ci -C ₆ alkyl), -NHSO ₂ (C, C ₃ alkyl), -NHSO ₂ (aryl, alkoxyalkyl, alkylamino, alkenylamino, di (C _r C ₃ ) amino, -C (O) O- (C, -C ₃ ) alkyl, -C (O) NH (C, -C ₃ ) alkyl, -C (O) N (C _r -101101-101101 C₃alkilna)₂, -CH=NOH, -PO₃H₂, -OPO₃H₂, haloalkilna, alkoksialkoksi, karboksialdehidna, karboksiamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, sulfonilna, -SO₂-(C₁-C₃alkilna), -SO₃(Ci-C₃alkilna), sulfonamido, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inC ₃ alkyl) ₂ , -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , haloalkyl, alkoxyalkoxy, carboxyaldehyde, carboxyamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl , diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO ₂ - (C ₁ -C ₃ alkyl), -SO ₃ (C 1 -C ₃ alkyl), sulfonamido, carbamate, aryloxyalkyl and -C ( O) NH (benzyl) group and R^{11 *} je izbran iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkilnilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina, kjer so B, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹⁷, R¹⁸, R¹⁹, R²⁰ in R²¹ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone in pri čemer lahko R⁶ in R⁸, vzeta skupaj, tvorita obroč in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč in pri čemer lahko R¹⁸ in R¹⁹, vzeta skupaj, tvorita obroč in pri čemer lahko R¹⁹ in R²⁰, vzeta skupaj, tvorita obroč, ali njena farmacevtsko sprejemljiva sol.R ^{11 *} is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkylnylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxamide, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkyl, cycloalkenyl , aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and -C (O) NH (benzyl) ⁶ , wherein R is B, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ and R ²¹ unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, wherein R ⁶ and R ⁸ may be taken together, form a ring, and wherein R ⁹ and R ¹⁰ taken together can form a ring, and wherein R ¹⁸ and R ¹⁹ taken together can form a ring, and wherein R ¹⁹ and R ²⁰ taken together can form a ring, or a pharmaceutically acceptable salt thereof. 10. Spojina po zahtevku 9, označena s tem, da so B, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸ in R²⁰ vsak neodvisno vodik, R⁶ in R¹⁹ sta vsak neodvisno alkil, s je celo število od nič do tri, R¹⁷ je pri vsakem pojavljanju neodvisno izbran iz skupine, ki jo sestavljajo halogen, alkil, haloalkil, -CF₃, alkoksi in -OH in R²¹ je aril.A compound according to claim 9, characterized in that B, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ and R ^{20 are} each independently hydrogen, R ⁶ and R ¹⁹ are each independently alkyl, s is an integer from zero to three, R ¹⁷ at each occurrence is independently selected from the group consisting of halogen, alkyl, haloalkyl, -CF ₃ , alkoxy and -OH, and R ²¹ is aryl. 11. Spojina po zahtevku 9, označena s tem, daje derivat le-te, izbran iz skupine, ki jo sestavljajo estri, karbamati, aminali, amidi, optični izomeri in predzdravila.Compound according to claim 9, characterized in that the derivative thereof is selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. -102102-102102 12. Spojina po zahtevku 9, označena s tem, daje s nič, R⁶ je butil, B, R⁸, R⁹, R¹⁰, R¹¹, R¹⁸ in R²⁰ so vsak neodvisno vodik, in R²¹ je l,3-benzodioksol-5-il.Compound according to claim 9, characterized in that zero, R ⁶ is butyl, B, R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹⁸ and R ²⁰ are each independently hydrogen, and R ²¹ is 1, 3-benzodioxol-5-yl. 13. Spojina s strukturo kjer je krog Q obroč, kije izbran iz skupine, ki jo sestavljajo q je celo število od nič do štiri13. A compound of structure wherein the circle Q is a ring selected from the group consisting of q is an integer from zero to four B, R¹, R⁶, R⁸, R⁹ in R¹⁰ so vsak neodvisno izbrani iz skupine, ki jo sestavljajo vodik, halogen, alkil, alkenil, alkinil, alkoksi, alkenoksi, alkinoksi, tioalkoksi, hidroksialkil, alifatski acil, -CF₃, -CO₂H, -SH, -CN, NO₂, -NH₂, -OH, alkinilamino, alkoksikarbonil, heterocikloil, karboksi, -N(Ci-C₃alkil)-C(O)(CiC₃alkil), -NHC(O)NH(C_rC₃alkil), -NHC(O)N(C_rC₃alkil)C(O)NH(C_rC₃alkil), -NHSO₂(C_rC₃alkil), -NHSO₂(aril), alkoksialkil, -Ci-C₃alkilamino, alkenilamino, alkinilamino, di(Ci-C₃alkil)amino, -C(O)O-(Ci-C₃alkil), -C(O)NH-(C₁-C₃alkil), -CH=NOH, -PO₃H₂, -OPO₃H₂, -C(O)N(Cj-C₃alkil)₂, haloalkil, alkoksialkoksi, karboksaldehid, karboksamid, cikloalkil, cikloalkenil, cikloalkinil, cikloalkilalkil, aril, aroil, ariloksi, arilamino, biaril, tioaril,B, R ¹ , R ⁶ , R ⁸ , R ⁹ and R ¹⁰ are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, hydroxyalkyl, aliphatic acyl, - CF ₃ , -CO ₂ H, -SH, -CN, NO ₂ , -NH ₂ , -OH, alkynylamino, alkoxycarbonyl, heterocycloyl, carboxy, -N (C 1 -C ₃ alkyl) -C (O) (C ₁ -C ₃ alkyl ), -NHC (O) NH (C _r C ₃ alkyl), -NHC (O) N (C _r C ₃ alkyl) C (O) NH (C _r C ₃ alkyl), -NHSO ₂ (C _r C ₃ alkyl), -NHSO ₂ (aryl), alkoxyalkyl, -C 1 -C ₃ alkylamino, alkenylamino, alkynylamino, di (C 1 -C ₃ alkyl) amino, -C (O) O- (C 1 -C ₃ alkyl), -C (O) NH- (C ₁ -C ₃ alkyl), -CH = NOH, -PO ₃ H ₂ , -OPO ₃ H ₂ , -C (O) N (C 1 -C ₃ alkyl) ₂ , haloalkyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, -103103 diarilamino, heterociklil, alkilaril, aralkenil, aralkil, alkilheterociklil, heterociklilalkil, sulfonil, -SO₂-(Ci-C₃alkil), -SO₃-(Ci-C₃alkil), sulfonamido, ariloksialkil, karboksil, karbamat in -C(O)NH(benzil),-103103 diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, -SO ₂ - (C 1 -C ₃ alkyl), -SO ₃ - (C 1 -C ₃ alkyl), sulfonamido, aryloxyalkyl, carboxyl, carbamate -C (O) NH (benzyl), R⁵ in R¹¹ sta vsak neodvisno izbrana iz skupine, ki jo sestavljajo vodik, alkilna, alkenilna, alkinilna, hidroksialkilna, alifatska acilna, alkinilamino, alkoksikarbonilna, heterocikloilna, -CH=NOH, haloalkilna, alkoksialkilna, karboksaldehidna, karboksamidna, cikloalkilna, cikloalkenilna, cikloalkinilna, cikloalkilalkilna, arilna, aroilna, ariloksi, arilamino, biarilna, tioarilna, diarilamino, heterociklilna, alkilarilna, aralkenilna, aralkilna, alkilheterociklilna, heterociklilalkilna, karbamatna, ariloksialkilna in -C(O)NH(benzilna) skupina inR ⁵ and R ¹¹ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocycloyl, -CH = NOH, haloalkyl, alkoxyalkyl, carboxaldehyde, carboxylalkyl, cycloalkylalkyl, cycloalkylamide, , cycloalkynyl, cycloalkylalkyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, diarylamino, heterocyclyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, carbamate, aryloxyalkyl and (C) aryl (benzyloxy) and (C) aryloxyalkyl and (C) R je izbran iz skupine, ki jo sestavljajo aril, alkilheterociklil, heterociklilalkil, heterocikloil, aralkil, alkilaril, alkil, aroil, ariloksi, cikloalkil, cikloalkenil, cikloalkinil, biaril, arilamino, tioaril in diarilamino, kjer so B, R¹, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹ in R²¹ nesubstituirani ali substituirani vsaj z eno skupino, ki daje elektrone ali odvzema elektrone, pri čemer lahko R⁶ in R⁸, vzeta skupaj, tvorita obroč in pri čemer lahko R⁹ in R¹⁰, vzeta skupaj, tvorita obroč ali njena farmacevtsko sprejemljiva sol.R is selected from the group consisting of aryl, alkylheterocyclyl, heterocyclylalkyl, heterocycloyl, aralkyl, alkylaryl, alkyl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, biaryl, arylamino, thioaryl and diarylamino, wherein B, R ^1, R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ²¹ unsubstituted or substituted by at least one electron-donating or electron-withdrawing group, wherein R ⁶ and R ⁸ , taken together, may form a ring and wherein taken together, R ⁹ and R ¹⁰ may form a ring or a pharmaceutically acceptable salt thereof. 14. Spojina po zahtevku 13, označena s tem, daje derivat le-te, izbran iz skupine, ki jo sestavljajo estri, karbamati, aminali, amidi, optični izomeri in predzdravila.A compound according to claim 13 wherein the derivative thereof is selected from the group consisting of esters, carbamates, aminals, amides, optical isomers and prodrugs. 15. Spojina po zahtevku 13, označena s tem, da so B, R⁶, R⁸, R⁹, R¹⁰ in R¹¹ vsak neodvisno izbrani iz skupine, ki jo sestavljata vodik in alkil, R¹ in R⁵ sta pri vsakem pojavljanju neodvisno izbrana iz skupine, ki jo sestavljajo vodik, 2-tienilmetil, benzil in metil in R je aril.A compound according to claim 13, characterized in that B, R ⁶ , R ⁸ , R ⁹ , R ¹⁰ and R ^{11 are} each independently selected from the group consisting of hydrogen and alkyl, R ¹ and R ⁵ being at each occurrence independently selected from the group consisting of hydrogen, 2-thienylmethyl, benzyl and methyl and R is aryl. 16. Spojina, označena s tem, da je izbrana iz skupine, ki jo sestavljajo (3S)-(1,3benzodioksol-5-il)-3-(((2S)-2-(2-okso-3-(2-tienilmetil)tetrahidro-l(2H)-104104 pirimidinil)heksanoil)amino) propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3((2R,S)-2-(3-benzil-5-metil-2-okso-l(2H)piridinil)heksanoilamino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3((2R, S)-2-(3 -(3 -klorobenzil)-5 -metil-2-okso-1 (2H)piridinil)heksanoilamino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-(((2S)2-(2-okso-3-(fenilmetil)-l-(2H)-piridinil)heksanoil)amino)propanojska kislina, (3S)-3(l,3-benzodioksol-5-il)-3-((2-(3-klorofenil)metil)-5-metil-2-okso-l(2H)piridinil)heksanoil)amino)propanojska kislina, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin-l(2H)-il)heksanoil]amino}-3-(3,5-dimetoksifenil)propanojska kislina, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-(3fluoro-4-metoksifenil)propanoj ska kislina, (3 S)-3 - {[2-(3 -benzil- 5 -metil-2-oksopiridin1 (2H)-il)heksanoilj amino } -3 -(3 -izopropoksifenil)propanoj ska kislina, (3 S)-3 -({2- [3 (3 -klorobenzil)-5 -metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3 izopropoksifenil)propanojska kislina, (3S)-3-(3-izopropoksifenil)-3-· {2-[3-(2metoksibenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3 S) - 3 - {[2-(3 -benzil-5 -metil-2-oksopiridin-1 (2H)-il)heksanoil] amino }-3-(3 -etoksi-4metoksifenil)propanoj ska kislina, (3 S)-3 - {[2-(3 -benzil-5-metil-2-oksopiridin-1 (2H)il)heksanoil] amino } -3 -(4-metoksi-3 -metilfenil)propanoj ska kislina, (3S)-3-{[2-(3benzil-5-metil-2-oksopiridin-l(2H)-il)heksanoil]amino}-3-fenilpropanojska kislina, (3S)-3-({2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4metilfenil)propanoj ska kislina, (3 S)-3 -({ 2- [3 -(2-klorobenzil)-5 -metil-2-oksopiridin1 (2H)-il]heksanoil}amino)-3-(3-izopropoksifenil)propanojska kislina, (3 S)-3 -({2- [3 (2-klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-fenilpropanojska kislina, (3S)-3-(l-metil-lH-indol-6-il)-3-({2-[5-metil-2-okso-3-(fenilmetil)-l(2H)piridiniljheksanoil}amino)propanojska kislina, (3S)-3-{3-[(l-metiletil)oksi]fenil}-3({2-[5-metil-3-(2-naftalenilmetil)-2-okso-l(2H)-piridnil]heksanoil}amino) propanoj ska kislina, (3 S)-3 -({2- [5 -metil-2-okso-3 -(fenilmetil)-1 (2H)-piridinil] heksanoil} amino)-3 - [3 -(2-metilpropil)fenil]propanojska kislina, (3 S)-3 - [3 (difluorometil)fenil] -3 -({2- [5 -metil-2-okso-3 -(fenilmetil)-1 (2H)-piridinil]heksanoil} amino)propanojska kislina, (3S)-3-{3-[(l-metiletil)oksi]fenil}-3-({2-[5-metil-3-[(2metilfenil)metil]-2-okso-l(2H)-piridinil]heksanoil}amino)propanojska kislina, (3S)-3-105105 (3 -fluorofenil)-3 -({2- [5 -metil-2-okso-3 -(fenilmetil)-1 (2H)-piridinil]heksanoil} amino) propanojska kislina, (3S)-3-({2-[3-[(2-kloro-4-fluorofenil)metil]-5-metil-2-okso1 (2H)-piridinil]heksanoil} amino)-3 - { 3 - [(1 -metiletil)oksi] fenil }propanoj ska kislina in (3 S)-3 - {3 - [(1 -metiletil)oksi] fenil} -3 -({2- [5 -metil-2-okso-1 -(fenilmetil)-1,2-dihidro-3 piridinil]-2-fenilacetil}amino)propanojska kislina in njihove farmacevtsko sprejemljive soli.16. A compound selected from the group consisting of (3S) - (1,3benzodioxol-5-yl) -3 - (((2S) -2- (2-oxo-3- (2 -thienylmethyl) tetrahydro-1 (2H) -104104 pyrimidinyl) hexanoyl) amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 ((2R, S) -2- (3 -benzyl-5-methyl-2-oxo-1 (2H) pyridinyl) hexanoylamino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 ((2R, S) -2- (3- (3-chlorobenzyl) -5-methyl-2-oxo-1 (2H) pyridinyl) hexanoylamino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - (( (2S) 2- (2-Oxo-3- (phenylmethyl) -1- (2H) -pyridinyl) hexanoyl) amino) propanoic acid, (3S) -3 (1,3-benzodioxol-5-yl) -3- (((2- (3-chlorophenyl) methyl) -5-methyl-2-oxo-1 (2H) pyridinyl) hexanoyl) amino) propanoic acid, (3S) -3 - {[(2S) -2- (3- benzyl-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (3,5-dimethoxyphenyl) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl) -5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (3fluoro-4-methoxyphenyl) propanoic acid, (3S) -3 - {[2- (3-benzyl- 5-methyl-2-oxopyridin (2H) -yl) hexanoyl amino} -3- (3-isopropoxyphenyl) propanoic acid, (3 S) -3 - ({2- [3 (3-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl } amino) -3- (3 isopropoxyphenyl) propanoic acid, (3S) -3- (3-isopropoxyphenyl) -3- {{2- [3- (2methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3 S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (3 -Ethoxy-4methoxyphenyl) propanoic acid, (3S) -3 - {[2- (3-benzyl-5-methyl-2-oxopyridin-1 (2H) yl) hexanoyl] amino} -3- (4-methoxy -3-Methylphenyl) propanoic acid, (3S) -3 - {[2- (3benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3-phenylpropanoic acid, (3S) -3 - ({2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3 S) - 3 - ({2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin (2H) -yl] hexanoyl} amino) -3- (3-isopropoxyphenyl) propanoic acid, (3 S) -3 - ({2- [3 (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3-phenylp Ranoic acid, (3S) -3- (1-methyl-1H-indol-6-yl) -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) pyridinylhexanoyl} amino) propanoic acid, (3S) -3- {3 - [(1-methylethyl) oxy] phenyl} -3 ({2- [5-methyl-3- (2-naphthalenylmethyl) -2-oxo-1 (2H ) -pyridin] hexanoyl} amino) propanoic acid, (3S) -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) - 3- [3- (2-methylpropyl) phenyl] propanoic acid, (3 S) -3- [3 (difluoromethyl) phenyl] -3 - ({2- [5-methyl-2-oxo-3- (phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid, (3S) -3- {3 - [(1-methylethyl) oxy] phenyl} -3 - ({2- [5-methyl-3 - [( 2methylphenyl) methyl] -2-oxo-1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid, (3S) -3-105105 (3-fluorophenyl) -3 - ({2- [5-methyl-2-oxo -3- (Phenylmethyl) -1 (2H) -pyridinyl] hexanoyl} amino) propanoic acid, (3S) -3 - ({2- [3 - [(2-chloro-4-fluorophenyl) methyl] -5-methyl -2-oxo (2H) -pyridinyl] hexanoyl} amino) -3- {3 - [(1-methylethyl) oxy] phenyl} propanoic acid and (3 S) -3 - {3 - [(1-methylethyl) oxy] phenyl} - 3 - ({2- [5-Methyl-2-oxo-1- (phenylmethyl) -1,2-dihydro-3 pyridinyl] -2-phenylacetyl} amino) propanoic acid and their pharmaceutically acceptable salts. 17. Spojina, označena s tem, daje izbrana iz skupine, ki jo sestavljajo (3S)-3-{[(2S)-2(3 -benzil-5 -metil-2-oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(3 ',4'-dimetoksi-1,1'bifenil-4-il)propanoj ska kislina, 3 S)-3-({(2S)-2- [3 -(2-klorobenzil)-5 -metil-2oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(3',4'-dimetoksi-1,1 '-bifenil-4-il)propanoj ska kislina, (3S)-3-(l,l'-bifenil-4-il)-3-({(2S)-2-[3-(2-kloro-6-metilbenzil)-5-metil-2oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3S)-3-{[(2S)-2-(3-benzil5 -metil-2-oksopiridin-1 (2H)-il)heksanoil] amino} -3 -(1,1 '-bifenil-4-il)propanoj ska kislina, (3S)-3-(l,l'-bifenil-4-il)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin1 (2H)-il]heksanoil}amino)propanojska kislina, (3 S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin-1 (2H)-il)heksanoil] amino} -3-(4'-metil-1,1 '-bifenil-4-il)propanojska kislina, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)-3-(4'-metil-l,l'-bifenil-4-il)propanojska kislina, (3S)-3-({(2S)-2[3-(2-kloro-6-metilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4'metil-l,l'-bifenil-4-il)propanojska kislina, (3S)-3-{[(2S)-2-(3-benzil-5-metil-2oksopiridin-1 (2H)-il)heksanoil] amino } -3 -(2',6'-dimetoksi-1,1 '-bifenil-4-il)propanoj ska kislina, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)-3-(2',6'-dimetoksi-l,r-bifenil-4-il)propanojska kislina, (3S)-3({(2 S)-2- [3 -(2-kloro-6-metilbenzil)- 5-metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)3-(2',6'-dimetoksi-l,r-bifenil-4-il)propanojska kislina, (3S)-3-{[(2S)-2-(3-benzil-5metil-2-oksopiridin-1 (2H)-il)heksanoil] amino} -3-( 1,1 '-bifenil-3-il)propanojska kislina, (3 S)-3 -(1,1 '-bifenil-3 - i 1) - 3 -({(2 S)-2-[3 -(2-klorobenzil)- 5 -metil-2-oksopiridin1 (2H)-il]heksanoil}amino)propanojska kislina, (3 S)-3-(1,1 '-bifenil-3-il)-3-({(2S)-2-[3(2-kloro-6-metilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3 S)-3-{[(2S)-2-(3-benzil-5-metil-2-oksopiridin-1 (2H)-il)heksanoil]amino} -3-106106 (2'-metoksi-l,r-bifenil-3-il)propanojska kislina, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5metil-2-oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(2'-metoksi-1,1'-bi feni 1 - 3 il)propanoj ska kislina, (3 S)-3 -({(2S)-2-[3 -(2-kloro-6-metilbenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(2'-metoksi-1,1 '-bifenil-3-il)propanoj ska kislina, (3S)-3-({(2S)-2-[3-(2-fluoro-6-metoksibenzil)-5-metil-2-oksopiridin-l(2H)i 1] -heksanoil} amino)-3 -(4-metilfenil)propanoj ska kislina, (3 S)-3 -({(2 S)-2- [3-(2,6dimetilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(4metilfenil)propanojska kislina, (3S)-3-({(2S)-2-[3-(3,5-dimetilbenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil} amino)-3 -(4-metilfenil)propanoj ska kislina, (3 S)-3 ({(2S)-2-[3-(2,6-diklorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3(4-metilfenil)propanoj ska kislina, (3 S)-3 -({(2 S)-2- [3 -(2-kloro-6-fluorobenzil)-5 -metil2- oksopiridin- l(2H)-il]heksanoil}amino)-3-(4-metilfenil)propanojska kislina, (3 S)-3({(2S)-2-[3-(2,6-difluorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3(4-metilfenil)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2,6difluorobenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2-kloro-6-fluorobenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil} amino)propanojska kislina, (3 S)-3-( 1,3-benzodioksol5 - il) - 3 -({(2 S)-2- [3 -(2,6-diklorobenzil)- 5 -metil-2-oksopiridin-1 (2H)il]heksanoil} amino)propanojska kislina, (3 S)-3-(1,3-benzodioksol-5-il)-3-({(2S)-2-[3(2,6-dimetilbenzil)-5-metil-2-oksopiridin-l(2H)-il]heksanoil}amino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(3,5-dimetilbenzil)-5-metil-2oksopiridin-1 (2H)-il]heksanoil}amino)propanojska kislina, (3 S)-3 -(1,3-benzodioksol5-il)-3-({(2S)-2-[3-(2-fluoro-6-metoksibenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)propanojska kislina, (3S)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2oksopiridin-l(2H)-il]heksanoil}amino)-3-(3,4-dietoksifenil)propanojska kislina, (3S)3- (3,4-dietoksifenil)-3-({(2S)-2-[3-(2,6-difluorobenzil)-5-metil-2-oksopiridin-l(2H)il]heksanoil}amino)propanojska kislina, (3S)-3-({(2S)-2-[3-(2,6-difluorobenzil)-5metil-2-oksopiridin-l(2H)-il]heksanoil}amino)-3-(3-etoksifenil)propanojska kislina, (3 S)-3 -({(2S)-2- [3-(2-kloro-6-fluorobenzil)-5-metil-2-oksopiridin-1 (2H)il]heksanoil} amino)-3 -(3 -etoksifenil)propanoj ska kislina, (3 S)-3 -({(2S)-2- [3 -(2klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]-3-metilbutanoil}amino)-3-(4-107107 metilfenil)propanoj ska kislina, (3 S)-3 -({(2S)-2- [3 -(2-klorobenzil)-5-metil-2oksopiridin-1 (2H)-il]-4-metilpentanoil} amino)-3 -(4-metilfenil)propanoj ska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridinl(2H)-il]-4-metilpentanoil}amino)propanojska kislina, (38)-3-(1,3-benzodioksol-5-il)3-({(2S)-2-[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]-3metilbutanoil}amino)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-({(2S)-2[3-(2-klorobenzil)-5-metil-2-oksopiridin-l(2H)-il]-3fenilpropanoil}amino)propanojska kislina, (3S)-3-({2S)-2-[3-(2-klorobenzil)-5-metil2- oksopiridin-l(2H)-il]-3-fenilpropanoil}amino)-3-(4-metilfenil)propanojska kislina, (3S)-3-(l,3-benzodioksol-5-il)-3-(((2R)-2-(l-benzil-5-metil-2-okso-l,2-dihidropiridin3- il)-heksanoil)amino)propanojska kislina in njihove farmacevtsko sprejemljive soli.17. A compound selected from the group consisting of (3S) -3 - {[(2S) -2 (3-benzyl-5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl ] amino} -3 - (3 ', 4'-dimethoxy-1,1'biphenyl-4-yl) propanoic acid, 3 S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) ) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3 ', 4'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3S) - 3- (1,1'-biphenyl-4-yl) -3 - ({(2S) -2- [3- (2-chloro-6-methylbenzyl) -5-methyl-2oxopyridin-1 (2H) -yl ] hexanoyl} amino) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl5-methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3 - (1. 1'-biphenyl-4-yl) propanoic acid, (3S) -3- (1,1'-biphenyl-4-yl) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2oxopyridin-1 (2H) ) -yl) hexanoyl] amino} -3- (4'-methyl-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2 -chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (4'-methyl-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 - ({(2S) -2 [3- (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4 'methyl-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5-methyl-2oxopyridin-1 (2H) -yl) hexanoyl ] amino} -3 - (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2- chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3- (2 ', 6'-dimethoxy-1,1'-biphenyl-4-yl) propanoic acid, (3S) - 3 ({(2S) -2- [3- (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) 3- (2 ', 6' -Dimethoxy-1,1-biphenyl-4-yl) propanoic acid, (3S) -3 - {[(2S) -2- (3-benzyl-5methyl-2-oxopyridin-1 (2H) -yl) hexanoyl] amino} -3- (1,1'-biphenyl-3-yl) propanoic acid, (3 S) -3- (1,1 '-biphenyl-3 - and 1) -3 - ({(2 S) - 2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin (2H) -yl] hexanoyl} amino) propanoic acid, (3 S) -3- (1,1'-biphenyl-3-yl) -3 - ({(2S) -2- [3 (2-chloro-6-methylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3 S) - 3 - {[(2S) -2- (3-benzyl-5-methyl-2-ok sopyridin-1 (2H) -yl) hexanoyl] amino} -3-106106 (2'-methoxy-1,1'-biphenyl-3-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (2'-methoxy-1,1'-bi-phenyl 1- 3 yl) propanoic acid , (3S) -3 - ({(2S) -2- [3- (2-chloro-6-methylbenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3 - ( 2'-methoxy-1,1'-biphenyl-3-yl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2-fluoro-6-methoxybenzyl) -5-methyl -2-Oxopyridin-1 (2H) and 1] -hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- (2 , 6 dimethylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4methylphenyl) propanoic acid, (3S) -3 - ({(2S) -2- [3- ( 3,5-dimethylbenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3 S) -3 ({(2S) -2- [3- (2,6-Dichlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3 (4-methylphenyl) propanoic acid, (3 S) -3 - ({ (2S) -2- [3- (2-chloro-6-fluorobenzyl) -5-methyl2-oxopyridin-1 (2H) -yl] hexanoyl} amine no) -3- (4-methylphenyl) propanoic acid, (3S) -3 ({(2S) -2- [3- (2,6-difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3 (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (2 , 6difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S ) -2- [3- (2-chloro-6-fluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3 S) -3- (1,3-benzodioxole5) - yl) -3 - ({(2 S) -2- [3- (2,6-dichlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, (3 S ) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3 (2,6-dimethylbenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl ] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (3,5-dimethylbenzyl) -5-methyl -2oxopyridin-1 (2H) -yl] hexanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol5-yl) -3 - ({(2S) -2- [3- (2- fluoro-6-methoxybenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, (3S) -3 - ({(2S ) -2- [3- (2-chlorobenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3,4-diethoxyphenyl) propanoic acid, (3S) 3- (3 , 4-Diethoxyphenyl) -3 - ({(2S) -2- [3- (2,6-difluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) propanoic acid, (3S ) -3 - ({(2S) -2- [3- (2,6-difluorobenzyl) -5methyl-2-oxopyridin-1 (2H) -yl] hexanoyl} amino) -3- (3-ethoxyphenyl) propanoic acid , (3 S) -3 - ({(2S) -2- [3- (2-chloro-6-fluorobenzyl) -5-methyl-2-oxopyridin-1 (2H) yl] hexanoyl} amino) -3 - (3-Ethoxyphenyl) propanoic acid, (3 S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) -yl] -3-methylbutanoyl } amino) -3- (4-107107 methylphenyl) propanoic acid, (3 S) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2oxopyridin-1 (2H) -yl] -4-methylpentanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridinyl (2H) -yl] -4-methylpentanoyl} amino) propanoic acid, (38) -3- (1,3-benzodioxol-5-yl) 3 - ({(2S) -2- [3- (2-chlorobenzyl) -5-methyl-2-oxopyridin-1 (2H) - yl] -3methylbutanoyl} amino) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - ({(2S) -2 [3- (2-chlorobenzyl) -5-methyl- 2-Oxopyridin-1 (2H) -yl] -3-phenylpropanoyl} amino) propanoic acid, (3S) -3 - ({2S) -2- [3- (2-chlorobenzyl) -5-methyl2-oxopyridin-1 (2H) ) -yl] -3-phenylpropanoyl} amino) -3- (4-methylphenyl) propanoic acid, (3S) -3- (1,3-benzodioxol-5-yl) -3 - (((2R) -2- (1-Benzyl-5-methyl-2-oxo-1,2-dihydropyridin-3-yl) -hexanoyl) amino) propanoic acid and their pharmaceutically acceptable salts. 18. (3S)-3-(l,3-benzodioksol-5-il)-3-((2S)-2-(3-benzil-5-metil-2-okso-l(2H)-piridinil) heksanoilamino)propanojska kislina ali njena farmacevtsko sprejemljiva sol.18. (3S) -3- (1,3-benzodioxol-5-yl) -3 - ((2S) -2- (3-benzyl-5-methyl-2-oxo-1 (2H) -pyridinyl) hexanoylamino ) propanoic acid or a pharmaceutically acceptable salt thereof. 19. Farmacevtski sestavek, označen s tem, da obsega spojino po zahtevku 1 v farmacevtsko sprejemljivem nosilcu.A pharmaceutical composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier. 20. Uporaba spojine po zahtevku 1 za pripravo zdravila za selektivno inhibiranje vezave a₄P|-integrina pri sesalcu.Use of a compound according to claim 1 for the preparation of a medicament for selectively inhibiting the binding of α ₄ β-integrin in a mammal.