HRP20220314T1 - Spojevi n-((het)arilmetil)-heteroaril-karboksamida kao plazma kallikrein inhibitori - Google Patents

Spojevi n-((het)arilmetil)-heteroaril-karboksamida kao plazma kallikrein inhibitori Download PDF

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HRP20220314T1
HRP20220314T1 HRP20220314TT HRP20220314T HRP20220314T1 HR P20220314 T1 HRP20220314 T1 HR P20220314T1 HR P20220314T T HRP20220314T T HR P20220314TT HR P20220314 T HRP20220314 T HR P20220314T HR P20220314 T1 HRP20220314 T1 HR P20220314T1
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methyl
phenyl
carboxamide
heteroaryl
membered
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HRP20220314TT
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Rebecca Louise DAVIE
Hannah Joy EDWARDS
David Michael Evans
Simon Teanby Hodgson
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Kalvista Pharmaceuticals Limited
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Claims (22)

1. Farmaceutski pripravak, naznačen time, da sadrži: (i) farmaceutski prihvatljiv nosač, razrjeđivač ili pomoćno sredstvo, i (ii) spoj formule (I), ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihove racemične i skalemične smjese), ili njegovu farmaceutski prihvatljivu sol ili solvat, pri čemu spoj formule (I) jest [image] u kojoj B je fenil supstituiran s 1 do 4 supstituenta odabrana od alkilab, alkoksi, OH, halogena, CN, heteroarila, COOR8, NHCOR8, CONR8R9, OCF3 i CF3; ili se B bira od benzotiofenila, benzofuranila i 5-članog ili 6-članog heterocikličkog prstena koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; pri čemu 5-člani ili 6-člani heterociklički prsten može biti aromatski ili nearomatski; i gdje je navedeni benzotiofenil, benzofuranil, ili navedeni 5-člani ili 6-člani heterociklički prsten supstituiran s 1 do 3 supstituenta odabrana od alkilab, alkoksi, OH, okso, halogena, CN, heteroarila, COOR8, NHCOR8, CONR8R9, OCF3 i CF3; W je C i X, Y i Z se neovisno biraju od C, N, O i S, tako da prsten koji sadrži W, X, Y i Z, jest peteročlani aromatski heterocikl; R5 i R6 su neovisno odsutni ili se neovisno biraju od H, alkila, cikloalkila, -NR8R9, CN, -NR8COR9 i CF3; gdje je prisutan najmanje jedan od R5 i R6 i on nije H; R7 jest H; A se bira od arila i heteroarila; pri čemu je aril supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, metilendioksi, etilendioksi, OH, halogen, CN, heteroaril, -(CH2)0-3-O-heteroaril, arilb, -O-arilb, -(CH2)1-3-arilb, -(CH2)1-3-heteroaril, -COOR10, -CONR10R11, -(CH2)0-3-NR10R11, OCF3 i CF3; i heteroaril je supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, OCF3, halogen, CN, aril, -(CH2)1-3-aril, -(CH2)0-3-NR10R11, heteroarilb, -COOR10, -CONR10R11 i CF3; R8 i R9 se neovisno biraju od H i alkila; alkil je linearni zasićeni ugljikovodik koji ima najviše do 10 atoma ugljika (C1-C10) ili razgranati zasićeni ugljikovodik s između 3 i 10 atoma ugljika (C3-C10); alkil može biti opcionalno supstituiran s jednim ili dva supstituenta neovisno odabrana od (C1-C6)alkoksi, OH, CN, CF3, COOR10, CONR10R11, fluoro i NR10R11; alkilb je linearni zasićeni ugljikovodik koji ima najviše do šest atoma ugljika ili razgranati zasićeni ugljikovodik s između 3 i 6 atoma ugljika (C3-C6); alkilb može biti opcionalno supstituiran s jednim ili dva supstituenta neovisno odabrana od (C1-C6)alkoksi, OH, CN, CF3, COOR10, CONR10R11 i fluoro; cikloalkil je monociklički zasićeni ugljikovodik s između 3 i 6 atoma ugljika; alkoksi je linearni O-vezani ugljikovodik s između 1 i 6 atoma ugljika (C1-C6) ili razgranati O-vezani ugljikovodik s između 3 i 6 atoma ugljika (C3-C6); alkoksi može biti opcionalno supstituiran s jednim ili dva supstituenta neovisno odabrana od OH, CN, CF3, CONR10R11, fluoro i NR10R11; aril je fenil, bifenil ili naftil; aril može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, metilendioksi, etilendioksi, OH, halogen, CN, heteroaril, -(CH2)0-3-O-heteroaril, arilb, -O-arilb, -(CH2)1-3-arilb, -(CH2)1-3-heteroaril, -COOR10, -CONR10R11, -(CH2)0-3-NR10R11, OCF3 i CF3; arilb je fenil, bifenil ili naftil, koji može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, halogen, CN, -COOR10, -CONR10R11, CF3 i NR10R11; heteroaril je 5-člani, 6-člani, 9-člani ili 10-člani monociklički ili biciklički aromatski prsten, koji tamo gdje je moguće, sadrži 1, 2, 3 ili 4 člana prstena koji se neovisno biraju od N, NR8, S i O; heteroaril može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, OCF3, halogen, CN, aril, -(CH2)1-3-aril, -(CH2)0-3-NR10R11, heteroarilb, -COOR10, -CONR10R11 i CF3; heteroarilb je 5-člani, 6-člani, 9-člani ili 10-člani monociklički ili biciklički aromatski prsten, koji tamo gdje je moguće, sadrži 1, 2 ili 3 člana prstena koji se neovisno biraju od N, NR8, S i O; pri čemu heteroarilb može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, halogen, CN, aril, -(CH2)1-3-aril, -COOR10, -CONR10R11, CF3 i NR10R11; R10 i R11 se neovisno biraju od H, alkila, arilab i heteroarilab ili R10 i R11 zajedno s atomom dušika s kojim su vezani, tvore 4-člani, 5-člani, 6-člani ili 7-člani heterociklički prsten koji sadrži ugljik, koji opcionalno sadrži dodatni heteroatom odabran od N, S i O, koji može biti zasićen ili nezasićen s jednom ili dvije dvostruke veze i koji može biti opcionalno monosupstituiran ili disupstituiran sa supstituentima odabranima od okso, alkila, alkoksi, OH, halogena i CF3.
2. Spoj formule (I), ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihove racemične i skalemične smjese), ili njegovu farmaceutski prihvatljivu sol ili solvat, naznačen time, da je za uporabu u medicini, pri čemu je spoj formule (I) kao što je definiran u patentnom zahtjevu 1.
3. Spoj formule (I), ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), naznačen time, da je za uporabu u postupku liječenja bolesti ili stanja kod koje/kojega se implicira plazma kallikrein aktivnost, pri čemu se bolest ili stanje kod koje/kojega se implicira plazma kallikrein aktivnost, bira od oslabljene oštrine vida, dijabetičke retinopatije, dijabetičkog makularnog edema, hereditarnog angioedema, dijabetesa, pankreatitisa, cerebralne hemoragije, nefropatije, kardiomiopatije, neuropatije, upalne bolesti crijeva, artritisa, upale, septičkog šoka, hipotenzije, raka, respiratornog distres sindroma odraslih, diseminirane intravaskularne koagulacije, operativnog zahvata za kardiopulmonarnu premosnicu i krvarenja nakon operativnog kirurškog zahvata, gdje je spoj formule (I) kao što je definiran u patentnom zahtjevu 1.
4. Spoj formule (I), ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), naznačen time, da je za uporabu u postupku liječenja bolesti ili stanja kod koje/kojega se implicira plazma kallikrein aktivnost, pri čemu je bolest ili stanje kod koje/kojega se implicira plazma kallikrein aktivnost, retinalna vaskularna permeabilnost povezana s dijabetičkom retinopatijom i dijabetičkim makularnim edemom, gdje je spoj formule (I) kao što je definiran u patentnom zahtjevu 1.
5. Spoj formule (I), [image] naznačen time, da B je fenil supstituiran s 1 do 4 supstituenta odabrana od alkilab, alkoksi, OH, halogena, CN, heteroarila, COOR8, NHCOR8, CONR8R9, OCF3 i CF3; ili se B bira od benzotiofenila, benzofuranila i 5-članog ili 6-članog heterocikličkog prstena koji sadrži jedan ili dva heteroatoma odabrana od N, O i S; pri čemu 5-člani ili 6-člani heterociklički prsten može biti aromatski ili nearomatski; i gdje je navedeni benzotiofenil, benzofuranil, ili navedeni 5-člani ili 6-člani heterociklički prsten supstituiran s 1 do 3 supstituenta odabrana od alkilab, alkoksi, OH, okso, halogena, CN, heteroarila, COOR8, NHCOR8, CONR8R9, OCF3 i CF3; W je C i X, Y i Z se neovisno biraju od C, N, O i S, tako da prsten koji sadrži W, X, Y i Z, jest peteročlani aromatski heterocikl; R5 i R6 su neovisno odsutni ili se neovisno biraju od H, alkila, cikloalkila, -NR8R9, CN, -NR8COR9 i CF3; gdje je prisutan najmanje jedan od R5 i R6 i on nije H; R7 jest H; A se bira od arila i heteroarila; pri čemu je aril supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, metilendioksi, etilendioksi, OH, halogen, CN, heteroaril, -(CH2)0-3-O-heteroaril, arilb, -O-arilb, -(CH2)1-3-arilb, -(CH2)1-3-heteroaril, -COOR10, -CONR10R11, -(CH2)0-3-NR10R11, OCF3 i CF3; i heteroaril je supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, OCF3, halogen, CN, aril, -(CH2)1-3-aril, -(CH2)0-3-NR10R11, heteroarilb, -COOR10, -CONR10R11 i CF3; R8 i R9 se neovisno biraju od H i alkila; alkil je linearni zasićeni ugljikovodik koji ima najviše do 10 atoma ugljika (C1-C10) ili razgranati zasićeni ugljikovodik s između 3 i 10 atoma ugljika (C3-C10); alkil može biti opcionalno supstituiran s 1 ili 2 supstituenta neovisno odabrana od (C1-C6)alkoksi, OH, CN, CF3, COOR10, CONR10R11, fluoro i NR10R11; alkilb je linearni zasićeni ugljikovodik koji ima najviše do 6 atoma ugljika ili razgranati zasićeni ugljikovodik s između 3 i 6 atoma ugljika (C3-C6); alkilb može biti opcionalno supstituiran s 1 ili 2 supstituenta neovisno odabrana od (C1-C6)alkoksi, OH, CN, CF3, COOR10, CONR10R11 i fluoro; cikloalkil je monociklički zasićeni ugljikovodik s između 3 i 6 atoma ugljika; alkoksi je linearni O-vezani ugljikovodik s između 1 i 6 atoma ugljika (C1-C6) ili razgranati O-vezani ugljikovodik s između 3 i 6 atoma ugljika (C3-C6); alkoksi može biti opcionalno supstituiran s 1 ili 2 supstituenta neovisno odabrana od OH, CN, CF3, CONR10R11, fluoro i NR10R11; aril je fenil, bifenil ili naftil; aril može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, metilendioksi, etilendioksi, OH, halogen, CN, heteroaril, -(CH2)0-3-O-heteroaril, arilb, -O-arilb, -(CH2)1-3-arilb, -(CH2)1-3-heteroaril, -COOR10, -CONR10R11, -(CH2)0-3-NR10R11, OCF3 i CF3; arilb je fenil, bifenil ili naftil, koji može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, halogen, CN, -COOR10, -CONR10R11, CF3 i NR10R11; heteroaril je 5-člani, 6-člani, 9-člani ili 10-člani monociklički ili biciklički aromatski prsten, koji tamo gdje je moguće, sadrži 1, 2, 3 ili 4 člana prstena koji se neovisno biraju od N, NR8, S i O; heteroaril može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, OCF3, halogen, CN, aril, -(CH2)1-3-aril, -(CH2)0-3-NR10R11, heteroarilb, -COOR10, -CONR10R11 i CF3; heteroarilb je 5-člani, 6-člani, 9-člani ili 10-člani monociklički ili biciklički aromatski prsten, koji tamo gdje je moguće, sadrži 1, 2 ili 3 člana prstena koji se neovisno biraju od N, NR8, S i O; pri čemu heteroarilb može biti opcionalno supstituiran s 1, 2 ili 3 supstituenta neovisno odabrana od sljedećih: alkil, alkoksi, OH, halogen, CN, aril, -(CH2)1-3-aril, -COOR10, -CONR10R11, CF3 i NR10R11; R10 i R11 se neovisno biraju od H, alkila, arilab i heteroarilab, ili R10 i R11 zajedno s atomom dušika s kojim su vezani, tvore 4-člani, 5-člani, 6-člani ili 7-člani heterociklički prsten koji sadrži ugljik, koji opcionalno sadrži dodatni heteroatom odabran od N, S i O, koji može biti zasićen ili nezasićen s jednom ili dvije dvostruke veze i koji može biti opcionalno monosupstituiran ili disupstituiran sa supstituentima odabranima od okso, alkila, alkoksi, OH, halogena i CF3; i tautomeri, stereoizomeri (uključujući enantiomere, dijastereomere i njihove racemične i skalemične smjese), njegove farmaceutski prihvatljive soli i solvati; dok se spoj ne bira od: benzojeve kiseline, 3-[[[[1-[(3-klorofenil)metil]-3-metil-1H-pirazol-4-il]karbonil]amino]metil]-; benzojeve kiseline, 4-[[[[1-[(3-klorofenil)metil]-3-metil-1H-pirazol-4-il]karbonil]amino]metil]-; 2-furankarboksilne kiseline, 5-[[[[1-[(3-klorofenil)metil]-3-metil-1H-pirazol-4-il]karbonil]amino]metil]-; benzojeve kiseline, 5-[[[[1-[(3-klorofenil)metil]-3-metil-1H-pirazol-4-il]karbonil]amino]metil]-2-metoksi-; 3-furankarboksilne kiseline, 5-[[[[1-[(3-klorofenil)metil]-3-metil-1H-pirazol-4-il]karbonil]amino]metil]-2-metil-; i benzojeve kiseline, 4-[[[[1-[(3-klorofenil)metil]-3-metil-1H-pirazol-4-il]karbonil]amino]metil]-2-metoksi-.
6. Farmaceutski pripravak prema patentnom zahtjevu 1; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4; ili spoj prema patentnom zahtjevu 5, naznačen time, da se B bira od fenila, tiofenila, benzotiofenila i piridila, od kojih je svaki supstituiran s 1 do 3 supstituenta odabrana od alkilab, alkoksi, halogena, CN, COOR8, CONR8R9, OCF3 i CF3; gdje su R8 i R9 kao što su definirani u patentnom zahtjevu 1, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
7. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 6, naznačen time, da se B bira od fenila i piridila, od kojih je svaki supstituiran s 1 do 3 supstituenta odabrana od alkilab, alkoksi, CF3 i halogena; gdje su alkilb i alkoksi kao što su definirani u patentnom zahtjevu 1, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
8. Farmaceutski pripravak prema patentnom zahtjevu 6; spoj za uporabu prema patentnom zahtjevu 6; ili spoj prema patentnom zahtjevu 6, naznačen time, da se B bira od piridila koji je supstituiran s 1 do 3 supstituenta odabrana od alkilab, alkoksi, CF3 i halogena; gdje su alkilb i alkoksi kao što su definirani u patentnom zahtjevu 1, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
9. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6 do 8; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6 do 8; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 8, naznačen time, da W je C i X, Y i Z se neovisno biraju od C i N, tako da prsten koji sadrži W, X, Y i Z, jest peteročlani aromatski heterocikl, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
10. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6 do 9; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6 do 9; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 9, naznačen time, da W je C i X je N i Y i Z se biraju od C i N, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
11. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6 do 10; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6 do 10; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 10, naznačen time, da R5 i R6 su neovisno odsutni ili se neovisno biraju od H, CH2OCH3, cikloalkila, -NR8R9, -NR8COR9, CN i CF3; gdje su cikloalkil, R8 i R9 kao što su definirani u patentnom zahtjevu 1; i pritom je prisutan najmanje jedan od R5 i R6 i on nije H, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
12. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1, 6, 7 ili 9 do 11; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6, 7 ili 9 do 11; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 7, ili 9 do 11, naznačen time, da R5 jest CH2OCH3, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
13. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6 do 12; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6 do 12; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 12, naznačen time, da A je fenil supstituiran s -(CH2)1-3-heteroarilom ili -(CH2)1-3-NR10R11, i opcionalno, s jednim ili dva dodatna supstituenta neovisno odabrana od alkila, halogena i CF3; pri čemu su alkil, heteroaril, R10 i R11, kao što su definirani u patentnom zahtjevu 1, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
14. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6 do 12; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6 do 12; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 12, naznačen time, da A je piridil supstituiran s heteroarilomb ili -NR10R11, i opcionalno, s jednim ili dva dodatna supstituenta neovisno odabrana od alkila, halogena i CF3; pri čemu su alkil, heteroarilb, R10 i R11 kao što su definirani u patentnom zahtjevu 1, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
15. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 13 ili 14; spoj za uporabu prema bilo kojem od patentnih zahtjeva 13 ili 14; ili spoj prema bilo kojem od patentnih zahtjeva 13 ili 14, naznačen time, da R10 i R11 zajedno s atomom dušika s kojim su vezani, tvore 5-člani ili 6-člani heterociklički prsten koji sadrži ugljik, koji opcionalno sadrži dodatni N atom, koji može biti zasićen ili nezasićen s jednom ili dvije dvostruke veze, i koji je opcionalno monosupstituiran ili disupstituiran sa supstituentima odabranima od okso, metila, Cl i F, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
16. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1 ili 6 do 12; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, ili 6 do 12; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 12, naznačen time, da se A bira od: [image] [image] [image] ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
17. Farmaceutski pripravak prema patentnom zahtjevu 16; spoj za uporabu prema patentnom zahtjevu 16; ili spoj prema patentnom zahtjevu 16, naznačen time, da se A bira od: [image] ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
18. Farmaceutski pripravak prema bilo kojem od patentnih zahtjeva 1, 6, 7 ili 9 do 11; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4, 6, 7, ili 9 do 11; ili spoj prema bilo kojem od patentnih zahtjeva 5 do 7 ili 9 do 11, naznačen time, da se A bira od: [image] ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat.
19. Farmaceutski pripravak prema patentnom zahtjevu 1; spoj za uporabu prema bilo kojem od patentnih zahtjeva 2 do 4; ili spoj prema patentnom zahtjevu 5, naznačen time, da se spoj bira od: 3-amino-1-[4-(2-okso-2H-piridin-1-ilmetil)-benzil]-1H-pirazol-4-karboksilna kiselina-2-fluoro-3-metoksi-benzilamid; N-[(2-fluoro-3-metoksifenil)metil]-1-({4-[(4-metilpirazol-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; N-[(2-fluoro-5-metoksifenil)metil]-1-({4-[(4-metilpirazol-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; N-{[2-fluoro-6-(trifluorometil)fenil]metil}-1-({4-[(4-metilpirazol-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; N-[(4-kloro-2,6-difluorofenil)metil]-1-({4-[(4-metilpirazol-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; N-{[3-kloro-2-fluoro-6-(trifluorometil)fenil]metil}-1-({4-[(4-metilpirazol-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; N-[(2-fluoro-4-metilfenil)metil]-1-({4-[(4-metilpirazol-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; N-[(5-kloro-1-benzotiofen-3-il)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-fluoro-6-(trifluorometil)fenil]metil}-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)-3-(trifluorometil)pirazol-4-karboksamid; 3-ciklopropil-N-[(2-fluoro-3-metoksifenil)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-fluoro-3-metoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-fluoro-3,6-dimetoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; 3-(dimetilamino)-N-[(2-fluoro-3-metoksifenil)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-fluoro-5-metoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-fluoro-4-metilfenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-(difluorometil)fenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-(difluorometil)-3-metoksifenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; 3-amino-N-{[2-fluoro-6-(trifluorometil)fenil]metil}-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; 3-acetamido-N-[(2-fluoro-3-metoksifenil)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(3-kloro-2,6-difluorofenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(5-kloro-2-cijanofenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(6-cijano-2-fluoro-3-metoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[5-metoksi-2-(trifluorometil)fenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-(difluorometil)-6-fluorofenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-(difluorometil)-5-metoksifenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-(difluorometil)-6-fluoro-3-metoksifenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-karbamoil-6-fluorofenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-karbamoil-5-metoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[3-(difluorometoksi)-2-fluorofenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-{[2-(difluorometoksi)-6-fluorofenil]metil}-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2,5-difluoro-3-metoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2-fluoro-6-metilfenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(6-kloro-2-fluoro-3-metoksifenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; 3-amino-N-[(2-fluoro-3-hidroksifenil)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(3-etil-2-fluorofenil)metil]-3-(metoksimetil)-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; 3-(metoksimetil)-N-[(3-metoksifenil)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; N-[(2,6-difluoro-3-metoksifenil)metil]-1-({4-[(5-fluoro-2-oksopiridin-1-il)metil]fenil}metil)-3-(metoksimetil)pirazol-4-karboksamid; 3-amino-N-[(7-kloro-4-metil-2,3-dihidro-1,4-benzoksazin-2-il)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid; 3-amino-N-[(7-kloro-3,4-dihidro-2H-1,4-benzoksazin-2-il)metil]-1-({4-[(2-oksopiridin-1-il)metil]fenil}metil)pirazol-4-karboksamid, i njihovih farmaceutski prihvatljivih soli i solvata.
20. Farmaceutski pripravak, naznačen time, da sadrži (i) spoj, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), njegovu farmaceutski prihvatljivu sol ili solvat, prema patentnom zahtjevu 5, i (ii) farmaceutski prihvatljiv nosač, razrjeđivač ili pomoćno sredstvo.
21. Spoj za uporabu prema bilo kojem od patentnih zahtjeva 3, 6 do 7, 9 do 11, 13 do 17, ili 19, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), naznačen time, da je za uporabu u postupku liječenja bolesti ili stanja kod koje/kojega se implicira plazma kallikrein aktivnost, pri čemu bolest ili stanje kod koje/kojega se implicira plazma kallikrein aktivnost, jest hereditarni angioedem.
22. Spoj prema bilo kojem od patentnih zahtjeva 3, 6 do 7, 9 do 11, 13 do 17, ili 19, ili tautomer, stereoizomer (uključujući enantiomer, dijastereomer i njihovu racemičnu i skalemičnu smjesu), naznačen time, da je za uporabu u postupku liječenja bolesti ili stanja kod koje/kojega se implicira plazma kallikrein aktivnost, pri čemu bolest ili stanje kod koje/kojega se implicira plazma kallikrein aktivnost, jest dijabetički makularni edem.
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