HRP20120852T1 - Spirocikliäśki nitrili kao inhibitori proteaze - Google Patents

Spirocikliäśki nitrili kao inhibitori proteaze Download PDF

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Publication number
HRP20120852T1
HRP20120852T1 HRP20120852TT HRP20120852T HRP20120852T1 HR P20120852 T1 HRP20120852 T1 HR P20120852T1 HR P20120852T T HRP20120852T T HR P20120852TT HR P20120852 T HRP20120852 T HR P20120852T HR P20120852 T1 HRP20120852 T1 HR P20120852T1
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Croatia
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alkyl
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carboxamide
compound
cyanocyclopropylcarbamoyl
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HRP20120852TT
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English (en)
Inventor
Manfred Schudok
Michael Wagner
Armin Bauer
Anna Kohlmann
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Sanofi
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Publication of HRP20120852T1 publication Critical patent/HRP20120852T1/hr

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Claims (9)

1. Spoj formule Ia [image] i/ili svi stereoizomerni oblici spoja formule Ia i/ili smjese tih oblika u bilo kojem omjeru, i/ili fiziološki prihvatljiva sol spoja formule Ia, i/ili solvati ili hidrati spoja formule Ia, naznačen time što [image] radikal je spiro-spoj, gdje su podprsteni [image] i [image] u svakom slučaju isti ili različiti i svaki od njih je neovisno a) zasićeni ili djelomično zasićeni-(C3-C11)-cikloalkil, gdje je cikloalkil nepremošten, premošten ili kondenziran, te je nesupstituiran ili je neovisno, prema veličini prstena, mono-, di-, tri, tetra- ili pentasupstituiran s R4, ili b) zasićeni ili djelomično zasićeni, tro- do jedanaesteročlani heterocikl, koji, prema veličini prstena, može sadržavati jedan, dva, tri ili četiri ista ili različita heteroatoma iz skupine koju čine kisik, dušik ili sumpor, gdje je heterocikl nepremošten, premošten ili kondenziran, te je nesupstituiran ili je neovisno, prema veličini prstena, mono-, di-, tri-, tetra- ili pentasupstituiran s R4, gdje R4 je -NO2, -CN, =O, =S, -OH, -CF3, -SF5, -(C0-C3)-alkilen-S-R10, -O-CF3, -Si-(CH3)3, -(C0-C5)-alkilen-O-C(O)-R21, (C0-C5)-alkilen-C(O)-O-R10, -(C0-C3)-alkilen-O-R10, -(C0-C3)-alkilen-N(R21)-R22, -(C0-C3)-alkilen-N(R10)-S(O2)-R10, -(C0-C5)-alkilen-(C3-C8)-cikloalkil-R23, -S-CF3, -(C0-C5)-alkilen-(C1-C3)-fluoralkil, -(C0-C5)-alkilen-N(R10)-C(O)-R21, -(C0-C3)-alkilen-C(O)-N(R21)-R22, -(C0-C4)-alkil, gdje je alkil nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R9, -(C0-C4)-alkilen-aril, gdje se aril bira iz skupine koju čine fenil, indanil, indenil, naftil, gdje je aril nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, ili -(C0-C4)-alkilen-Het, gdje se Het bira iz skupine koju čine azetidinil, benzimidazolinil, benzimidazolil, benzofuranil, benzotiofenil, benzoksazolil, benzotiazolil, benzizoksazolil, benzizotiazolil, kinolinil, dioksolil, dioksanil, furanil, imidazolidinil, imidazolinil, imidazolil, indolinil, indolil, 3H-indolil, izoindolinil, izoindolil, izokinolinil, izotiazolidinil, 2-izotiazolinil, izotiazolil, izoksazolil, izoksazolidinil, 2-izoksazolinil, morfolinil, oktahidroizokinolinil, oksazolil, oksazolidinil, pirimidinil, piperazinil, piperidinil, piranil, pirazinil, pirazolinil, pirazolil, piridazinil, piridil, pirimidinil, pirolidinil, pirolinil, 2H-pirolil, pirolil, tetrahidrofuranil, tetrahidroizokinolinil, tetrahidrokinolinil, tetrahidropiridinil, tiazolil, tienil, tienopiridinil, tiomorfolinil, tiofenil, gdje je taj Het radikal nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, R8 je halogen, karbamimidoil, -NO2, =O, -CF3, -SF5, -C(O)-O-R10, -CN, -C(O)-NH2, -OH, -NH, -O-CF3, -C(O)-N(R10)-R20, -N(R10)-R20, -(C3-C8)-cikloalkil, -O-(C1-C8)-alkil, -O-(C0-C4)-alkilen-(C3-C6)-cikloalkil, -(C1-C8)-alkil, -(C0-C4)-alkilen-(C3-C8)-cikloalkil, gdje je svaki od navedenih alkilnih radikala nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s halogenom, NH2, -OH, -O-CH3, -SO2-CH3 ili -SO2-CF3, R9 je halogen, -NO2, -CN, =O, -OH, -CF3, -C(O)-OR10, -C(O)-N(R21)-R22, -N(R21)-R22, -(C3-C8)-cikloalkil, -(C0-C3)-alkilen-O-R10, -Si-(CH3)3, -N(R10)-S(O)u-R10, gdje je u cijeli broj 1 ili 2, -S-R10, -SOr-R10, gdje je r cijeli broj 1 ili 2, -S(O)v-N(R10)-R20, gdje je v cijeli broj 1 ili 2, -C(O)-R10, -(C1-C8)-alkil, -(C1-C8)-alkoksi, fenil, feniloksi-, -(C1-C3)-fluoralkil, -O-R19, -NH-C(O)-NH-R10, -(C0-C4)-alkil-C(O)-O-C(R11, R19)-O-C(O)-R12, -NH-C(O)-NH-R21, -N(R21)-C(O)-R22, -(C0-C4)-alkil-C(O)-O-C(R11, R19)-O-C(O)-O-R12, -NH-C(O)-O-R10, -O-CF3 ili Het, gdje je Het definiran kao gore, te je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, R10 i R20 su isti ili različiti i svaki od njih je neovisno atom vodika, -(C1-C6)-alkil, -(C0-C4)-alkil-OH, -(C1-C3)-fluoralkil, -(C0-C4)-alkil-O-(C1-C4)-alkil, -(C0-C5)-alkil-(C3-C8)-cikloalkil, -(C0-C2)-alkilen-aril, gdje je aril definiran kao gore, te je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s -(C1-C6)-alkilom, -O-(C1-C6)-alkilom, halogenom ili -(C3-C8)-cikloalkilom, ili -(C0-C2)-alkilen-Het, gdje je Het definiran kao gore, te je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s -(C1-C6)-alkilom, -O-(C1-C6)-alkilom, halogenom ili -(C3-C8)-cikloalkilom, R11 i R19 su isti ili različiti i svaki od njih je neovisno atom vodika ili -(C1-C6)-alkil, R12 je -(C1-C6)-alkil, -(C1-C6)-alkil-OH, -(C1-C6)-alkil-O-(C1-C6)-alkil, -(C3-C8)-cikloalkil, -(C1-C6)-alkil-O-(C1-C8)-alkil-(C3-C8)-cikloalkil, -(C1-C6)-alkil-(C3-C8)-cikloalkil, gdje je cikloalkilni radikal nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s -OH, -O-(C1-C4)-alkilom ili R10, R21 i R22 su isti ili različiti i svaki od njih je neovisno atom vodika, -(C1-C6)-alkil, gdje je alkil nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, -(C0-C6)-alkilen-(C3-C8)-cikloalkil, -SOt-R10, gdje je t cijeli broj 1 ili 2, -(C1-C3)-fluoralkil, -O-R12, -(C0-C6)-alkilen-aril, gdje je aril definiran kao gore, a svaki od alkilena i arila je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8 ili -(C0-C6)-alkilen-Het, gdje je Het definiran kao gore, a svaki od alkilena i Het je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, R21 i R22, zajedno s atomom dušika na kojeg su vezani, tvore četiri- do osmeročlani monociklički heterociklički prsten, koji, uz atom dušika, dodatno, prema veličini prstena, može sadržavati jedan ili dva ista ili različita heteroatoma iz skupine koju čine kisik, dušik ili sumpor, te gdje je heterocikl nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, R23 je atom vodika, -OH ili -O-(C1-C4)-alkil, X je kovalentna veza, -N(R7)- ili -O-, gdje je R7 atom vodika, -(C0-C4)-alkilen-(C3-C6)-cikloalkil ili -(C1-C4)-alkil, Y je -C(O)-, -C(S)- ili -S(O2)-, p je cijeli broj 1 ili 2, R27 je atom vodika, -(C1-C6)-alkil, halogen, -(C0-C4)-alkilen-(C3-C6)-cikloalkil, -(C0-C4)-alkilen-Het, gdje je Het definiran kao gore, te je nesupstituiran ili je supstituiran s halogenom, -(C1-C6)-alkilom, -O-(C1-C3)-fluoralkilom ili -O-(C1-C6)-alkilom, ili -(C0-C2)-alkilen-fenil, gdje je fenil nesupstituiran ili je supstituiran s halogenom, -(C1-C6)-alkilom, -O-(C1-C3)-fluoralkilom ili -O-(C1-C6)-alkilom, R26 je atom vodika, -(C1-C4)-alkil ili -(C0-C4)-alkilen-(C3-C6)-cikloalkil, R24 i R25 su isti ili različiti i svaki od njih je neovisno atom vodika, -(C1-C6)-alkil, -(C1-C3)-fluoralkil, -(C0-C4)-alkilen-(C3-C6)-cikloalkil, -(C0-C4)-alkilen-aril, gdje je aril definiran kao gore, te je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, ili -(C0-C4)-alkilen-Het, gdje je Het definiran kao gore, te je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, R24 i R25, zajedno s atomom ugljika na kojeg su vezani, tvore tro- do šesteročlani cikloalkilni prsten, koji je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R10 ili fluorom, R24 i R25, zajedno s atomom ugljika na kojeg su vezani, tvore tro- do šesteročlani heterocikloalkilni radikal, koji je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R10 ili fluorom.
2. Spoj formule I u skladu s patentnim zahtjevom 1, naznačen time što se podprsten [image] bira iz sljedeće skupine [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] gdje isprekidane linije označuju određeno mjesto vezanja na drugi podprsten, gdje jednostruke veze u nabrojanim strukturama mogu djelomično biti zamijenjene dvostrukim vezama, ili s njima mogu biti kondenziran daljnji prstenasti sustavi, te gdje se podprsten [image] bira iz sljedeće skupine [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] gdje isprekidane linije označuju određeno mjesto vezanja na drugi podprsten, jednostruke veze u nabrojanim strukturama mogu djelomično biti zamijenjene dvostrukim vezama, dva podprstena A i B su nesupstituirani ili su neovisno mono- do tetrasupstituirani s R4, a svaki od radikala X, Y, R27, p, R26, R24, R25 i R4 je definiran kao u patentnom zahtjevu 1.
3. Spoj formule Ia u skladu s patentnim zahtjevom 1, naznačen time što se podprstene [image] i [image] u svakom slučaju bira između ciklopropana, ciklobutana, ciklopentana, cikloheksana, cikloheptana, ciklooktana, biciklo[4.2.0]oktana, oktahidroindena, dekalina, dekahidrobenzocikloheptena, dodekahidroheptalena, biciklo[3.1.1]heptana, biciklo[2.2.1]heptana, biciklo[3.3.0]oktana, biciklo[2.2.2]oktana, spiro[2.5]oktana, spiro[3.4]oktana, azepana, azepina, azetidina, aziridina, azirina, azokana, benzimidazolina, 2,3-dihidrobenzo[b]tiofena, 1,3-dihidrobenzo[c]tiofena, 2,3-dihidrobenzofurana, 2,3-dihidrobenzooksazola, 2,3-dihidrobenzotiazola, 1,3-dihidroisobenzofurana, 4,5-dihidroizotiazola, 2,3-dihidroizoksazola, 2,5-dihidroizoksazola, 4,5-dihidroizoksazola, 5,6-dihidro-4H-[1,2]oksazina, benzo[1,3]dioksola, 1,4-diazepana, 1,2-diazepina, 1,3-diazepina, 1,4-diazepina, diaziridina, diazirina, 1,4-diazokana, dioksana, 1,3-dioksana, dioksazina, [1,3]dioksepana, 1,4-diazokana, dioksola, dioksolana, 1,3-dioksolana, 1,3-dioksolena, [1,3]ditiana, [1,3]ditiolana, heksahidropiridazina, heksahidropirimidina, imidazolina, imidazolidina, indana, indolina, izoindolina, izotiazolidina, izotiazolina, izoksazolina, izoksazolidina, 2-izoksazolina, morfolina, [1,3,4]oksadiazinana, [1,3,5]oksadiazinana, [1,2,3]oksadiazolidina, [1,3,4]oksadiazolidina, 1,2-oksatiepana, 1,2-oksatiolana, [1,3]oksatiolana, 1,4-oksazepana, 1,2-oksazina, 1,3-oksazina, 1,4-oksazina, oksazinana, 1,3-oksazinana, oksazokana, oksaziridina, oksazolidina, oksepana, oksetana, oksirana, oksokana, piperazina, piperidina, pirana, pirazolina, pirazolidina, pirolidina, pirolidinona, pirolina, tetrahidrokinolina, tetrahidrofurana, tetrahidroizokinolina, 1,2,3,4-tetrahidronaftalena, tetrahidropirana, tetrahidropiridina, 1,2,3,4-tetrahidropirimidina, 1,2,5,6-tetrahidropirimidina, tetrahidrotiofena, tetrazina, tiadiazina, [1,2,6]tiadiazinana, [1,3,4]tiadiazolidina, 1,2-tiazina, 1,3-tiazina, 1,4-tiazina, [1,2]tiazinana, [1,3]tiazinana, tiazolidina, tiazolina, tiepana, tietana, tiomorfolina, tiopirana, 1,2,3-triazina, 1,2,4-triazina, 1,3,5-triazina, [1,2,4]triazinana ili [1,2,4]triazolidina, gdje je svaki od dva podprstena nesupstituiran ili je neovisno, prema veličini prstena, mono-, di-, tri-, tetra- ili pentasupstituiran s R4, gdje je svaki od radikala X, Y, R27, p, R26, R24, R25 i R4 definiran kao u patentnom zahtjevu 1.
4. Spoj formule Ia u skladu s patentnim zahtjevom 1, naznačen time što se svakog od podprstena [image] i [image] neovisno bira iz skupine koju čine azetidin, ciklopropil, ciklobutil, ciklopentil, cikloheksil, 1,3-dihidroisobenzofuran, 2,3-dihidroizoksazol, 2,5-dihidroizoksazol, 4,5-dihidroizoksazol, 1,3-dioksan, dioksolan, 1,3-dioksolan, imidazolidin, indan, morfolin, 1,3-oksazinan, oksazolidin, piperazin, piperidin, pirolidin, tetrahidrofuran i 1,2,3,4-tetrahidronaftalen, gdje je svaki od dva podprstena nesupstituiran ili je neovisno, prema veličini prstena, mono-, di- ili trisupstituiran s R4, R4 je =O, =S, -(C0-C3)-alkilen-C(O)-O-R10, -(C0-C3)-alkilen-N(R21)-R22, -(C0-C3)-alkilen-NH-C(O)-R21, -(C0-C4)-alkilen-(C3-C6)-cikloalkil-R23, -(C0-C3)-alkilen-O-R10, -(C0-C4)-alkilen-fenil, gdje je fenil nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R8, ili -(C0-C4)-alkil, gdje je alkil nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R9, R8 je fluor, klor, brom, -O-(C1-C3)-fluoralkil ili -O-(C1-C4)-alkil, R9 je halogen, -NO2, -CN, =O -OH, -CF, -C(O)-O-R10, -C(O)-N(R21)-R22, -N(R21)-R22, -(C3-C8)-cikloalkil, -(C0-C3)-alkilen-O-R10, -Si-(CH3)3, -N(R10)-S(O)u-R10, gdje je u cijeli broj 1 ili 2, -S-R10, -SO-R10, gdje je r cijeli broj 1 ili 2, -S(O)v-N(R10)-R20, gdje je v cijeli broj 1 ili 2, -C(O)-R10, -(C1-C8)-alkil, -(C1-C8)-alkoksi, fenil, feniloksi-, -(C1-C3)-fluoralkil, -O-R19, -NH-C(O)-NH-R10, -(C0-C4)-alkil-C(O)-O-C(R11, R19)-O-C(O)-R12, -NH-C(O)-NH-R21, -N(R21)-C(O)-R22, -(C0-C4)-alkil-C(O)-O-C(R11, R19)-O-C(O)-O-R12, -NH-C(O)-O-R10 ili -O-CF3, R10 i R20 su isti ili različiti i svaki od njih je neovisno atom vodika ili -(C1-C6)-alkil, R11 i R19 su isti ili različiti i svaki od njih je neovisno atom vodika ili -(C1-C6)-alkil, R12 je -(C1-C6)-alkil, -(C1-C6)-alkil-OH, -(C1-C6)-alkil-O-(C1-C6)-alkil, -(C3-C8)-cikloalkil, -(C1-C6)-alkil-O-(C1-C8)-alkil-(C3-C8)-cikloalkil, -(C1-C6)-alkil-(C3-C8)-cikloalkil, gdje je cikloalkilni radikal nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s -OH, -O-(C1-C4)-alkilom ili R10, R21 i R22 su isti ili različiti i svaki od njih je neovisno atom vodika, -(C1-C6)-alkil, -O-R12, -(C0-C6)-alkilen-(C3-C8)-cikloalkil, -SO-R10, gdje je t cijeli broj 1 ili 2, ili -(C1-C3)-fluoralkil, R23 je atom vodika, -OH ili -O-(C1-C4)-alkil, X je kovalentna veza ili -N(R7)-, gdje je R7 atom vodika ili -(C1-C4)-alkil, Y je -C(O)- ili -S(O2)-, p je cijeli broj 1 ili 2, R26 je atom vodika, R27 je atom vodika, -(C0-C4)-alkilen-(C3-C6)-cikloalkil, -(C1-C6)-alkil, -(C0-C2)-alkilen-fenil, gdje je fenil nesupstituiran ili je supstituiran s halogenom, -(C1-C6)-alkilom, -O-(C1-C3)-fluoralkilom ili -O-(C1-C6)-alkilom, ili -(C0-C2)-alkilen-piridil, R24 i R25 su isti ili različiti i svaki od njih je neovisno atom vodika, -(C1-C4)-alkil ili -(C0-C4)-alkilen-(C3-C6)-cikloalkil, R24 i R25, zajedno s atomom ugljika na kojeg su vezani, tvore cikloalkilni prsten, koji se bira iz skupine koju čine ciklopropil, ciklobutil, ciklopentil i cikloheksil, te je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R10 ili fluorom, R24 i R25, zajedno s atomom ugljika na kojeg su vezani, tvore tro- do šesteročlani heterocikloalkilni radikal, kojeg se bira iz skupine koju čine aziridin, azetidin, diazetidin, diaziridin, heksohidropiridazin, heksohidropirimidin, imidazolidin, morfolin, oksadiazinan, oksadiazolidin, oksatianan, oksatiolan, oksazetidin, oksazolidin, oksetan, oksiran, piperazin, piperidin, pirazolidin, pirolidin, tetrahidrofuran, tetrahidropiran, tetrahidrotiofen, tetrahidrotiopiran, tetrazinan, tiadiazolidin, tiazetidin, tiaziridin, tiazolidin, tietan, thiiran, tiomorfolin, triazetidin, triazinan ili triazolidin, koji je nesupstituiran ili je neovisno mono-, di- ili trisupstituiran s R10 ili fluorom.
5. Spoj formule Ia u skladu s jednim ili više patentnih zahtjeva 1 do 4, naznačen time što se podprsten [image] bira iz skupine koju čine azetidin, ciklopropil, ciklobutil, ciklopentil, cikloheksil, 1,3-dihidroisobenzofuran, 1,3-dioksan, 1,3-dioksolan, imidazolidin, indan, morfolin, 1,3-oksazinan, piperazin, piperidin, pirolidin, tetrahidrofuran i 1,2,3,4-tetrahidronaftalen, a podprsten [image] se bira iz skupine koju čine azetidin, ciklopropil, ciklopentil, cikloheksil, morfolin, oksazolidin, piperidin i pirolidin, gdje su dva podprstena nesupstituirani ili su neovisno, prema veličini prstena, mono-, di- ili trisupstituirani s R4, gdje R4 je -O-(C1-C4)-alkil, =O, -(C0-C4)-alkilen-(C3-C6)-cikloalkil, -(C1-C4)-alkil ili -(C0-C4)-alkilen-fenil, gdje je fenil nesupstituiran ili je supstituiran s F, Cl, Br ili -O-(C1-C4)-alkilom, X je kovalentna veza ili -NH-, Y je -C(O)- ili -S(O2)-, p je cijeli broj 1, R27 je atom vodika, -(C1-C4)-alkil, 4-F-benzil ili benzil, R26 je atom vodika, R24 i R25 su isti ili različiti i svaki od njih je neovisno atom vodika, metil ili etil, R24 i R25, zajedno s atomom ugljika na kojeg su vezani, tvore ciklopropilni ili ciklobutilni radikal, ili R24 i R25, zajedno s atomom ugljika na kojeg su vezani, tvore piperidinski prsten, koji je nesupstituiran ili je supstituiran s -(C1-C4)-alkilom.
6. Spoj formule Ia u skladu s jednim ili više patentnih zahtjeva 1 do 5, naznačen time što je spoj N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-3-azaspiro[5.5]undekan-3-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-8-azaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-1,4-dioksa-8-azaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-azaspiro[5.5]undekan-2-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-8-azaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-3-azaspiro[5.5]undekan-3-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-(4-methoksifenil)-1-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-4-okso-1-fenil-1,3,8-triazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-1,5-dioksa-9-azaspiro[5.5]undekan-9-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-1-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-metil-1-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-3,3-dimetil-1-oksa-5,9-diazaspiro[5.5]undekan-9-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluor-4-fenilbutil]-8-azaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2,4-diokso-1,3,8-triazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-azaspiro[4.4]nonan-2-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-benzil-1-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-(4-fluorfenil)-1-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-3-fenil-1,5-dioksa-9-azaspiro[5.5]undekan-9-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-9-butil-3,9-diazaspiro[5.5]undekan-3-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-9-ciklopropil-3,9-diazaspiro[5.5]undekan-3-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]spiro[2.3]heksan-1-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2,2-dimetil-1-oksa-8-azaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-azaspiro[4.5]dekan-2-karboksamid, [image] , N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-1-oksa-4-azaspiro[4.5]dekan-4-karboksamid, N-(1-cijanociklopropil)-(S)-2-[3-(1,4-dioksaspiro[4.5]dec-8-il)ureido]-4,4-difluorpentoksid, [image] , N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-7-ciklopropil-2,7-diazaspiro[3.5]nonan-2-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-ciklopropil-2,7-diazaspiro[3.5]nonan-7-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-propil-2,7-diazaspiro[3.5]nonan-7-karboksamid, N-(1-cijanociklopropil)-(S)-2-(8-azaspiro[4.5]dekan-8-sulfonilamino)-4,4-difluorpentanamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-4-ciklopropil-1-oksa-4,9-diazaspiro[5.5]undekan-9-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-9-ciklopropil-1-oksa-4,9-diazaspiro[5.5]undekan-4-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-2-ciklopropilmetil-3-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-2-(4-methoksifenil)-1-okso-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-2-(4-methoksifenil)-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-2-ciklopropil-2,7-diazaspiro[3.5]nonan-7-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-2-ciklopropil-2,8-diazaspiro[4.5]dekan-8-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-9-ciklopropil-3,9-diazaspiro[5.5]undekan-3-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-7-ciklopropil-2,7-diazaspiro[3.5]nonan-2-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-7-propil-2,7-diazaspiro[3.5]nonan-2-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluor-4-fenilbutil]-9-ciklopropil-3,9-diazaspiro[5.5]undekan-3-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluor-4-fenilbutil]-2-ciklopropil-2,7-diazaspiro[3.5]nonan-7-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluor-4-fenilbutil]-2-propil-2,7-diazaspiro[3.5]nonan-7-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluor-4-fenilbutil]-7-ciklopropil-2,7-diazaspiro[3.5]nonan-2-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorbutil]-6-azaspiro[2.5]oktan-6-karboksamid, N-[(S)-1-(cijanometilkarbamoil)-3,3-difluorbutil]-6-azaspiro[2.5]oktan-6-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorheksil]-6-azaspiro[2.5]oktan-6-karboksamid, N-[(S)-1-(4-cijano-1-metilpiperidin-4-ilkarbamoil)-3,3-difluorbutil]-6-azaspiro[2.5]oktan-6-karboksamid, N-[(S)-1-(4-cijano-1-metilpiperidin-4-ilkarbamoil)-3,3-difluorheksil]-6-azaspiro[2.5]oktan-6-karboksamid, N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluorpentil]-6-azaspiro[2.5]oktan-6-karboksamid ili N-[(S)-1-(1-cijanociklopropilkarbamoil)-3,3-difluor-4-fenilbutil]-6-azaspiro[2.5]oktan-6-karboksamid.
7. Postupak dobivanja spoja formule Ia i/ili stereoizomernog oblika spoja formule Ia i/ili fiziološki prihvatljive soli spoja formule Ia i/ili solvata ili hidrata spoja formule Ia i/ili N-oksida spojeva formula Ia u skladu s jednim ili više patentnih zahtjeva 1 do 6, naznačen time što se sastoji u a) reakciji spoja formule II [image] gdje je svaki od A i B definiran kao u spoju formule Ia, sa spojem formule IIIa ili IIIb ili IIIc [image] gdje je svaki od X, R1, R2 i R3 definiran kao u spoju formule Ia, PG je esterska zaštitna skupina, a "aktivirani" znači da je amin prisutan u aktiviranom obliku, primjerice u obliku klorkarbonilnog spoja, kako bi se dobilo spoj formule IVa ili IVb [image] te reakciji dobivenih spojeva formule IVa ili IVb, nakon prevođenja estera u karboksilnu kiselinu, sa Z kako bi se dobilo spoj formule Ia, ili b) reakciji spoja formule Va ili Vb, gdje je svaki od A, B, X i Y definiran kao u spoju formule Ia [image] sa spojem formule VI, gdje je svaki od R1, R2 i R3 definiran kao u spoju formule Ia, a PG je esterska zaštitna skupina [image] kako bi se dobilo spoj formule IVa ili IVb, te reakciji dobivenog spoja formule IVa ili IVb, nakon prevođenja esterske zaštitne skupine u karboksilnu kiselinu, sa Z kako bi se dobilo spoj formule Ia, ili c) reakciji spoja formule VIIa ili VIIb, gdje je svaki od A, B i X definiran kao u spoju formule Ia [image] sa spojem formule VI [image] kako bi se dobilo spoj formule VIIIa ili VIIIb, te reakciji dobivenog spoja formule VIIIa ili VIIIb, nakon prevođenja estera u odgovarajuću karboksilnu kiselinu, sa Z kako bi se dobilo spoj formule Ia, ili d) reakciji spoja formule IX [image] s aminom Z, gdje Z je definiran kao u spoju formule Ia, kako bi se dobilo spoj formule X [image] prevođenju tako dobivenog spoja X uklanjanjem zaštitne skupine u spoj formule XI [image] te reakciji tog spoja XI sa spojem Va ili Vb, kao što je detaljno opisano pod b), kako bi se dobilo spoj formule Ia, ili e) odvajanju spoja formule Ia dobivenog postupcima a), b), c) ili d), ili pogodnog preteče formule Ia, koji, zbog svoje kemijske strukture, postoji u enantiomernim ili dijastereomernim oblicima, u čiste enantiomere ili dijastereomere tvorbom soli s enantiomerno čistim kiselinama ili bazama, kromatografijom na kiralnim nepokretnim fazama ili deriviranjem uz pomoć kiralnih enantiomerno čistih spojeva, poput aminokiselina, razdvajanju tako dobivenih dijastereomera, te uklanjanju kiralnih pomoćnih skupina, ili f) bilo izdvajanju spoja formule Ia dobivenog postupcima a), b), c) ili d) u slobodnom obliku ili njegovom otpuštanju iz fiziološki neprihvatljivih soli ili, u slučaju prisutnosti kiselih ili bazičnih skupina, njegovom prevođenju u fiziološki prihvatljive soli, ili g) prevođenju spoja formule Ia dobivenog postupcima a), b), c) ili d), ili pogodnog preteče formule Ia, koji, zbog svoje kemijske strukture, može tvoriti N-oksid, u N-oksid ili, u slučaju prisutnosti N-oksida, njegovom prevođenju u slobodni amin ili sol amina.
8. Medikament naznačen time što sadrži spoj formule Ia u skladu s jednim ili više patentnih zahtjeva 1 do 6 zajedno s farmaceutski i fiziološki prihvatljivom podlogom, aditivom i/ili drugim aktivnim sastojcima i/ili pomoćnim tvarima.
9. Upotreba spoja formule Ia u skladu s jednim ili više patentnih zahtjeva 1 do 6 u proizvodnji medikamenta za profilaksu, sekundarno sprječavanje i terapiju abnormalno povišene razgradnje kostiju, alergija, Alzheimerove bolesti, amiloidoze, ARDS, arterijske tromboze, astme, ateroma, ateroskleroze, autoimunih poremećaja, bakterijskih infekcija, bronhiolitisa, krvarenja u velikom mozgu, cerebrovaskularne ishemije, Huntingtonove koreje, kroničnih upala, CIPD (kronična upalna demijelinizirajuća poliradikuloneuropatija), Creutzfeldt-Jakobove bolesti, Crohnove bolesti, dijabetesa, osobito juvenilnog oblika, emfizema, encefalomijelitisa, endometrioze, upalnih poremećaja dišnih puteva, upalnog pankreatitisa, epilepsije, poremećaja naznačenih time što su prisutni pojačana angiogeneza, prekomjerna elastoliza u dišnim putevima, presatci tkiva, gingivitis, glomerulonefritis, glukokortikoidima izazvana osteoporoza, Gravesova bolest, Guillain-Barréov sindrom, Hashimotov tireoiditis, hepatitis, infekcija HIV-om, Huntingtonova bolest, hiperkalcemija, IBD, oštećeni imunosni sustav, intersticijski cistitis, lom kosti, gubitak koštane mase, rak, eritematozni lupus, malarija, metakromatska leukodistrofija, metastasizirajuća osteogeneza, metastaze, multipla skleroza, multipli mijelom, mišićna distrofija, miastenija gravis, neurodegenerativni poremećaji, neuropatska bol, kronična ili dijabetična neuropatija, postherpetična neuralgija, trigeminalna neuralgija, bolna dijabetična polineuropatija, postinzultna bol, postamputacijska bol, mijelopatska ili radikulopatska bol, atipična facijalna bol i kauzalgiiji slični sindromi, odbacivanje organ kod presađivanja, osteoartritis, imperfektna osteogeneza, osteoporoza, Pagetova bolest, pankreatitis, Parkinsonova bolest, pemfigus vulgaris, periodontitis, ruptura plakova, Pneumocistis carinii, pneumonitis, psorijaza, restenoza, reumatoidni artritis, skleroderma, sistemni eritematozni lupus, ozljeda mozga, ozljeda kralježnične moždine, invazija tumorskih stanica, virusna infekcija, ispadanje zubiju, rak dojke, rak crijeva, rak jajnika, rak grlića maternice, rak kože, tumor na mozgu, Kaposijev sarkom, leukemija B- i T-stanica, rak pluća, rak limfnog čvora, rak gušterače, rak i sarkomi prostate.
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