HRP20160636T1 - Derivati 1,2,4-triazin-4-amina - Google Patents

Derivati 1,2,4-triazin-4-amina Download PDF

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Publication number
HRP20160636T1
HRP20160636T1 HRP20160636TT HRP20160636T HRP20160636T1 HR P20160636 T1 HRP20160636 T1 HR P20160636T1 HR P20160636T T HRP20160636T T HR P20160636TT HR P20160636 T HRP20160636 T HR P20160636T HR P20160636 T1 HRP20160636 T1 HR P20160636T1
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Croatia
Prior art keywords
triazin
amine
phenyl
pyridin
chloro
Prior art date
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HRP20160636TT
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English (en)
Inventor
Miles Stuart Congreve
Stephen Philippe Andrews
Jonathan Stephen Mason
Christine Mary Richardson
Giles Albert Brown
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Heptares Therapeutics Limited
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Publication date
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Publication of HRP20160636T1 publication Critical patent/HRP20160636T1/hr

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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
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Claims (21)

1. Spoj s formulom lyd, [image] naznačen time da: B predstavlja CYBB ili HetBB; CYBB predstavlja fenil proizvoljno supstituiran s jednim ili više R4c supstituenata; HetBB predstavlja 6-članu aromatsku heterocikličku skupinu koja sadrži jedan ili više N atoma, te je navedena HetBB skupina proizvoljno supstituirana s jednim ili više R4d supstituenata; R4b, R4b', R4c i R4d predstavljaju, svaki puta neovisno, (a) halo, (b) CN, (c) C1-12 alkil, C2-12 alkenil, C2-12 alkinil, navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkila i C1-4 alkoksi), OR5a, S(O)qR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5f, N(R5g)(R5h), B1-C(G1)-B2-R5i, aril i Het1, (d) Cy3, navedena Cy3 skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi), OR6a, S(O)qR6b, S(O)2N(R6c)(R6d), N(R6e)S(O)2R6f, N(R6g)(R6h), B3-C(G1)-B4-R6i, aril i Het2, (e) Heta, navedena Heta skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi), OR7a, S(O)qR7b, S(O)2N(R7c)(R7d), N(R7e)S(O)2R7f, N(R7g)(R7h), B5-C(G1)-B6-R7i, aril i Het3, (f) OR8, (g) S(O)rR9a, (h) S(O)2N(R9b)(R9c), (i) N(R9d)S(O)2R9e, (j) N(R9f)(R9g), (k) B7-C(G1)-B8-R9h, (l) =O, (m) =S, rr2 predstavlja 0 do 2; ss i tt neovisno predstavljaju, pri svakoj pojavi 0 ili 1, pod uvjetom da ss i tt oba ne predstavljaju 0; L1 i L2 oba predstavljaju izravne veze; G1 predstavlja, svaki puta neovisno, O, S ili NR5j; R8 predstavlja, svaki puta neovisno, H, Cy3, Heta, arila, C1-8 alkil, C2-8 alkenil, C2-8 alkinil, C3-8 cikloalkil, navedenih zadnjih sedam skupina su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, -CN, C3-6 cikloalkil, aril, Het4, -C(O)OR10, -C(O)R11, -C(O)N(RN1)(RN2), S(O)rR9aa, S(O)2N(R9ba)(R9ca), N(R9da)S(O)2R9ea i N(R9fa)(R9ga); Cy3 predstavlja, svaki puta neovisno, 3- do 6-člani aromatski, potpuno zasićen ili djelomično nezasićen karbociklički prsten; Heta predstavlja, svaki puta neovisno, 3- do 6-člani heterociklički prsten, koji može biti aromatski, potpuno zasićen ili djelomično nezasićen i koji sadrži jedan ili više heteroatoma izabranih između O, S i N; R10 i R11 neovisno predstavljaju (a) H, (b) C1-6 alkil proizvoljno supstituiran s jednim ili više supstituenata koji su odabrani od halo, aril, -N(RN3)(RN4) i -ORa, (c) aril ili (d) C3-7 cikloalkil (navedena skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi); B1 do B8 neovisno predstavljaju, pri svakoj pojavi, izravnu vezu, O, S ili N(RN3); svaki arila neovisno predstavlja C6-14 karbocikličku aromatsku skupinu, navedena skupina može sadržavati jedan, dva ili tri prstena; svaki aril neovisno predstavlja C6-14 karbocikličku aromatsku skupinu, navedena skupina može sadržavati jedan, dva ili tri prstena i može biti supstituirana sa jednim ili više supstituenata koji se biraju od halo, C1-6 alkila, navedena posljednja skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od halo, -N(RN4)(RN5) i -ORa, i -ORa; Het1 do Het4 neovisno predstavljaju 4- do 14-člane heterocikličke skupine koje sadrže jedan ili više heteroatoma koji su odabrani od O, S i N, navedene heterocikličke skupine mogu sadržavati jedan, dva ili tri prstena i mogu biti supstituirane s jednim ili više supstituenata koji se biraju od halo, C1-6 alkila, navedena posljednja skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od halo, -N(RN6)(RN7) i -ORa, i -ORa; RN1 do RN7 neovisno predstavljaju H, C1-6 alkil ili C3-6 cikloalkil, navedene zadnje dvije skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo i -ORa; Ra predstavlja, svaki puta neovisno, (a) H; (b) C1-12 alkil, C2-12 alkenil, C2-12 alkinil, C3-12 cikloalkil, C4-12 cikloalkenil, navedenih zadnjih pet skupina su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-8 cikloalkil (navedene zadnje četiri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi), OR12a, S(O)qR12b, S(O)2N(R12c)(R12d), N(R12e)S(O)2R12f, N(R12g)(R12h), B9-C(G2)-B10-R12i, aril1 i Hetb, i navedene C3-12 cikloalkil ili C4-12 cikloalkenil skupine mogu dodatno biti supstituirane s =O, (c) S(O)rR13a, (d) S(O)2N(R13b)(R13c) ili (e) C(O)-B11-R13d; R5a do R5j, R6a do R6i , R7a do R7i, R9a do R9h, R9aa do R99a, R12a do R12i i R13a do R13d neovisno predstavljaju, pri svakoj pojavi, (a) H, (b) C1-10 alkil, C2-10 alkenil, C2-10 alkinil navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil, C3-6 cikloalkil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi), OR5aa, S(O)qR5ab, S(O)2N(R5ac)(R5ad), N(R5ae)S(O1)2R5af, N(R5ag)(R5ah), B12-C(G2)-B13-R5ai, aril1 i Hetc; (c) C3-10 cikloalkil, ili C4-10 cikloalkenil (navedene zadnje dvije skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, OH, =O, C1-6 alkil i C1-6 alkoksi), (d) Hetd; G2 predstavlja, neovisno pri svakoj pojavi, O, S, ili NR5aj; R5aa do R5aj neovisno predstavljaju pri svakoj pojavi, (a) H, (b) C1-4 alkil, C2-4 alkenil, C2-4 alkinil navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-4 alkil, C2-4 alkenil, C2-4 alkinil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi), (c) C3-6 cikloalkil, ili C4-6 cikloalkenil (navedene zadnje dvije skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, OH, =O, C1-4 alkil i C1-4 alkoksi), (d) Hete, ili R5ag i R5ah mogu predstavljati, zajedno s atomom dušika na koji su vezani, 3- do 10-člani heterociklički prsten, koji može biti aromatski, potpuno zasićen ili djelomično nezasićen i koji dodatno može sadržavati jedan ili više heteroatoma odabranih od O, S i N, navedeni heterociklički prsten je proizvoljno supstituiran s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi); B9 do B13 neovisno predstavljaju izravnu vezu, O, S ili N(RN8); aril1 predstavlja, svaki puta neovisno, C6-10 karbocikličku aromatsku skupinu, navedena skupina može sadržavati jedan ili dva prstena i može biti supstituirana sa jednim ili više supstituenata koji se biraju od halo, C1-6 alkil, navedena posljednja skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od halo, -N(RN10)(RN11) i C1-6 alkoksi (navedeni posljednji supstituent je proizvoljno supstituiran s jednim ili više halogenih atoma), i C1-6 alkoksi (navedeni posljednji supstituent je proizvoljno supstituiran s jednim ili više halogenih atoma); RN8, RN10 i RN11 neovisno predstavljaju H, C1-6 alkil ili C3-6 cikloalkil, navedene zadnje dvije skupine su proizvoljno supstituirane s jednim ili više halogenih atoma; Hetb predstavlja 5- ili 6-člani heterociklički prsten koji može biti aromatski, potpuno zasićen ili djelomično nezasićen i koji sadrži jedan ili više heteroatoma izabranih između O, S i N, navedena heterociklička skupina može biti supstituirana sa jednim ili više supstituenata koji se biraju od halo, =O i C1-6 alkil; Hetc do Hete neovisno predstavljaju, 3- do 6-člani heterociklički prsten, koji može biti aromatski, potpuno zasićen ili djelomično nezasićen i koji sadrži jedan ili više heteroatoma izabranih između O, S i N, navedene Hetc do Hete skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, C1-6 alkil, C2-6 alkenil, C2-6 alkinil (navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od OH, =O, halo, C1-4 alkil i C1-4 alkoksi); q i r neovisno predstavljaju pri svakoj pojavi 0, 1 ili 2; i osim ako nije drugačije navedeno alkil, alkenil, alkinil, cikloalkil i alkilni dio alkoksi skupina mogu biti supstituirani s jednim ili više halogenih atoma; ili njihova farmaceutski prihvatljiva sol ili solvat.
2. Spoj prema zahtjevu 1, naznačen time da R4b i R4b' predstavljaju, svaki puta neovisno (a) halo, (b) CN, (c) C1-4 alkil, C2-4 alkenil, C2-4 alkinil, navedene zadnje tri skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, OR5a, S(O)qR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5f, N(R5g)(R5h), B1-C(G1)-B2-R5i i Het1 (npr. jedan ili više supstituenata koji su odabrani od nitro, CN, OR5a, S(O)qR5b, S(O)2N(R5c)(R5d), N(R5e)S(O)2R5f, N(R5g)(R5h), B1-C(G1)-B2-R5i i Het1), (d) Cy3, navedena Cy3 skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od nitro, CN, OR6a, S(O)qR6b, S(O)2N(R6c)(R6d), N(R6e)S(O)2R6f, N(R6g)(R6h), B3-C(G1)-B4-R6i i Het2, (e) Heta, navedena Heta skupina je proizvoljno supstituirana s jednim ili više supstituenata koji su odabrani od halo, nitro, CN, OR7a, S(O)qR7b, S(O)2N(R7c)(R7d), N(R7e)S(O)2R7f, N(R7g)(R7h), B5-C(G1)-B6-R7i i Het3, (f) OR8, (g) S(O)rR9a, (h) S(O)2N(R9b)(R9c), (i) N(R9d)S(O)2R9e, (j) N(R9f)(R9g) ili (k) B7-C(G1)-B8-R9h, pri čemu R5a do R5i, R5a do R6i, R7a do R7i, R8, R9a do R9n, Cy3, Het1 do Het3, Heta, B1 do B8, G1, q i r su kako je definirano u zahtjevu 1.
3. Spoj prema zahtjevu 1 ili zahtjevu 2, naznačen time da: R4b' i R4b predstavljaju, svaki puta neovisno, ciklopropil, jodo, bromo, kloro, fluoro, etil, metil, d3-metil, izo-propil, -C=CH, fenil, CF3, CHF2, CH2F, CH2CF3, CF2CF3, CN, =O, OH, OCH(CH3)2, OCH3, OCH2CH3, OCH2F, OCHF2, OCH2CF3, OCF3, (CH2)3OH, CH2OH ili CH2OCH3, CH(CH3)OH, C(CH3)3OH, CH2CH2OH, NH2, N(CH3)2, N(H)CH2CH3, N(H)C(O)CH3, C(O)CH3, C(O)N(CH3)2, S(O)2CH3, S(O)CH3, SCH3, S(O)2CF3, azetidin, morfolin ili dioksolan.
4. Spoj u skladu s bilo kojim od zahtjeva 1 do 3, naznačen time da: (A) (1) R4b predstavlja, svaki puta neovisno, OH, OCH(CH3)2, OCH3, OCH2CH3, OCH2F, OCHF2, OCH2CH3, OCH2CF3, OCH3, OCF3, (CH2)3OH, CH2OH ili CH2OCH3, NH2, NHCH(CH3)2, NHCH3, NHCH2CH3, NHCH2CH3, NH(CH(CH3)2)2, NH(CH3)2, NH(CH2CH3)2 ili NH(CH2CH3)2); (2) zbroj ss i tt je 1; i (3) rr2 je 0; ili (B) (1) R4b predstavlja, svaki puta neovisno, CH2F ili, naročito, ciklopropil, kloro, fluoro, etil, metil, CF3, CHF2, CH2CF3, CF2CF3, OH, OCH(CH3)2, OCH3, OCH2CH3, OCH2F, OCHF2, OCH2CH3, OCH2CF3, OCH3, OCF3, (CH2)3OH, CH2OH ili CH2OCH3; (2) ss i tt su oba 1; i (3) rr2 je 0.
5. Spoj u skladu s bilo kojim od zahtjeva 1 do 4, naznačen time da spoj s formulom lyd je izabran sa popisa koji sadrži: (lxiii) 6-(2-kloropiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (lxxvi) 6-(2-kloro-6-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (lxxix) 6-(2-metoksi-6-(trifluorometil)piridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (lxxxvi) 6-(2-metoksipiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (xcvi) 6-(2,6-dimetoksipiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (xcvii) 6-(2,6-dimetilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (xcviii) 5-fenil-6-(2-(trifluorometil)piridin-4-il)-1,2,4-triazin-3-amin; (xcix) 6-(2-ciklopropilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (cii) 6-(2,6-dikloropiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (cix) 6-(2-kloro-6-metilpiridin-4-il)5-(3-fluorofenil)-1,2,4-triazin-3-amin; (cxiii) 6-(2-kloropiridin-4-il)-5-(4-fluorofenil)-1,2,4-triazin-3-amin; (cxiv) 6-(2-kloro-6-metilpiridin-4-il)-5-(4-fluorofenil)-1,2,4-triazin-3-amin; (cxvii) 5-(4-klorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; (cxviii) 6-(2-kloro-6-metilpiridin-4-il)-5-(4-klorofenil)-1,2,4-triazin-3-amin; (cxxi) 5-(3-klorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; (cxxii) 6-(2-kloro-6-metilpiridin-4-il)-5-(3-klorofenil)-1,2,4-triazin-3-amin; (cxxiv) 4-(3-amino-6-(2-kloro-6-metilpiridin-4-il)-1,2,4-triazin-5-il)benzonitril; (cxxvi) 5-(3-kloro-5-fluorofenil)-6-(2-kloro-6-metilpiridin-4-il)-1,2,4-triazin-3-amin; (cxxix) 6-(2-kloro-6-metilpiridin-4-il)-5-(3,5-difluorofenil)-1,2,4-triazin-3-amin; (cxxxii) 5-(3-kloro-4-fluorofenil)-6-(2-kloro-6-metilpiridin-4-il)-1,2,4-triazin-3-amin; (cxxxiii) 5-(3-kloro-4-fluorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; (cxxxvi) 6-(2-kloro-6-metilpiridin-4-il)-5-(3,4-difluorofenil)-1,2,4-triazin-3-amin; (cxxxvii) 6-(2-kloropiridin-4-il)-5-(3,4-difluorofenil)-1,2,4-triazin-3-amin; (cxl) 6-(2-kloro-6-metilpiridin-4-il)-5-(4-(metoksimetil)fenil)-1,2,4-triazin-3-amin; (cxli) 6-(2,6-dimetilpiridin-4-il)-5-(4-fluorofenil)-1,2,4-triazin-3-amin; (clvii) 4-(3-amino-6-(2-kloropiridin-4-il)-1,2,4-triazin-5-il)benzonitril; (clix) 6-(2-kloropiridin-4-il)-5-(4-(metoksimetil)fenil)-1,2,4-triazin-3-amin; (ccviii) 5-(3-kloro-5-fluorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; (ccix) 6-(2-kloropiridin-4-il)-5-(3,5-difluorofenil)-1,2,4-triazin-3-amin; (ccxi) 6-(2-kloro-6-metilpiridin-4-il)-5-(4-(difluorometoksi)fenil)-1,2,4-triazin-3-amin; (ccxii) 6-(2-kloropiridin-4-il)-5-(4-(difluorometoksi)fenil)-1,2-4-triazin-3-amin; (ccxvii) 5-(3-kloro-5-fluorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxviii) 5-(3,5-difluorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxix) 5-(3,4-difluorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxx) 5-(3-kloro-4-fluorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxxi) 5-(4-(difluorometoksi)fenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxxii) 6-(2,6-dimetilpiridin-4-il)-5-(3-fluorofenil)-1,2,4-triazin-3-amin; (ccxxiii) 5-(4-klorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxxiv) 4-(3-amino-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-5-il)benzonitril; (ccxxv) 5-(3-klorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (ccxxvi) 6-(2,6-dimetilpiridin-4-il)-5-(4-(metoksimetil)fenil)-1,2,4-triazin-3-amin; (ccxxxix) 5-(3-fluorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; (ccxli) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(3,4-difluorofenil)-1,2,4-triazin-3-amin; (ccxlii) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(3,5-difluorofenil)-1,2,4-triazin-3-amin; (ccxliii) 6-[2-(etilamino)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (ccxliv) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(3-fluorofenil)-1,2,4-triazin-3-amin; (ccxlv) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(4-fluorofenil)-1,2,4-triazin-3-amin; (ccxlvi) 6-{2-[etil(metil)amino]-6-metilpiridin-4-il}-5-fenil-1,2,4-triazin-3-amin; (ccxlvii) 6-[2-(dimetilamino)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (ccxlviii) 1-[6-(2,6-d6-dimetilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (ccxlix) 6-[2-d3-metil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (ccl) 5-(4-fluorofenil)-6-[2-d3-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (ccli) 6-(2,6-dimetilpiridin-4-il)-5-(2-fluorofenil)-1,2,4-triazin-3-amin; (cclii) 6-(2-kloro-6-metilpiridin-4-il)-5-(2-fluorofenil)-1,2,4-triazin-3-amin; (ccliii) 6-(2,6-dimetilpiridin-4-il)-5-(4-metoksifenil)-1,2,4-triazin-3-amin; (ccliv) 6-(2-kloro-6-metilpiridin-4-il)-5-(4-metoksifenil)-1,2,4-triazin-3-amin; (cclv) 6-[2-(difluorometil)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclvi) 6-[2-kloro-6-(difluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclvii) 6-[2-kloro-6-(fluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclviii) 6-[2-(difluorometil)-6-metilpiridin-4-il]-5-(4-fluorofenil)-1,2,4-triazin-3-amin; (cclix) 6-[2,6-bis(fluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclx) 6-[2-(fluorometil)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxi) 6-(2-kloro-6-metilpiridin-4-il)-5-(2,5-difluorofenil)-1,2,4-triazin-3-amin; (cclxii) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(2-fluorofenil)-1,2,4-triazin-3-amin; (cclxiii) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(2,5-difluorofenil)-1,2,4-triazin-3-amin; (cclxiv) 6-[2-ciklopropil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxv) 6-[2-etil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxvi) 6-(2-ciklopropil-6-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (cclxvii) 5-(2-fluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (cclxviii) 5-(3-fluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (cclxix) 5-(4-fluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (cclxx) 5-(2,5-difluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (cclxxi) 5-(3,4-difluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (cclxxii) 5-(3,5-difluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; (cclxxiii) 6-[2-(azetidin-1-il)-6-(trifluorometil)piridin-4-il]-5-(4-fluorofenil)-1,2,4-triazin-3-amin; (cclxxiv) 6-[2-metil-6-(morfolin-4-il)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxxv) 6-(2-kloro-6-metilpiridin-4-il)-5-(4-etilfenil)-1,2,4-triazin-3-amin; (cclxxvi) 5-(2,5-difluorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; (cclxxvii) 6-(2,6-dimetilpiridin-4-il)-5-(4-metilfenil)-1,2,4-triazin-3-amin; (cclxxviii) 6-[2-(difluorometil)-6-metilpiridin-4-il]-5-(3-fluorofenil)-1,2,4-triazin-3-amin; (cclxxix) 6-[2-(difluorometil)-6-metilpiridin-4-il]-5-(2-fluorofenil)-1,2,4-triazin-3-amin; (cclxxxii) 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxxxiii) 6-[2,6-bis(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxxxv) 6-[2-metil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxxxvii) 6-[2-(dimetilamino)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (cclxxxviii) 6-(2-bromo-6-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (cclxxxix) 6-(2,6-dimetil-1-oksidopiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (ccxc) 4-(3-amino-5-fenil-1,2,4-triazin-6-il)-6-metilpiridin-2-karbonitril; (ccxcv) 6-[2-bromo-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (ccc) 6-(2-metil-6-d3-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; (cccii) 6-[2-(azetidin-1-il)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; (ccciii) 6-[2-(azetidin-1-il)-6-metilpiridin-4-il]-5-(4-fluorofenil)-1,2,4-triazin-3-amin; i (ccciv) 6-[2-(azetidin-1-il)-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin.
6. Spoj u skladu s bilo kojim od zahtjeva 1 do 5, naznačen time da spoj s formulom lyd je odabran iz skupa koji čine: 6-(2-kloropiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 6-(2-kloro-6-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 6-(2-metoksipiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 6-(2,6-dimetilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 5-fenil-6-(2-(trifluorometil)piridin-4-il)-1,2,4-triazin-3-amin; 6-(2-ciklopropilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 6-(2,6-dikloropiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 6-(2-kloro-6-metilpiridin-4-il)-5-(3-fluorofenil)-1,2,4-triazin-3-amin; 5-(4-klorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; 5-(3-klorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; 5-(3-kloro-4-fluorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; 6-(2,6-dimetilpiridin-4-il)-5-(4-fluorofenil)-1,2,4-triazin-3-amin; 5-(3,5-difluorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; 6-(2,6-dimetilpiridin-4-il)-5-(3-fluorofenil)-1,2,4-triazin-3-amin; 5-(4-klorofenil)-6-(2,6-dimetilpiridin-4-il)-1,2,4-triazin-3-amin; 5-(3-fluorofenil)-6-(2-kloropiridin-4-il)-1,2,4-triazin-3-amin; 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(4-fluorofenil)-1,2,4-triazin-3-amin; 6-[2-d3-metil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-(2-kloro-6-metilpiridin-4-il)-5-(2-fluorofenil)-1,2,4-triazin-3-amin; 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(2-fluorofenil)-1,2,4-triazin-3-amin; 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-(2,5-difluorofenil)-1,2,4-triazin-3-amin; 6-(2-ciklopropil-6-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin; 5-(2-fluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; 5-(3-fluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; 5-(4-fluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; 5-(3,5-difluorofenil)-6-[2-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; 6-[2-kloro-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-[2-bromo-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-[2-(azetidin-1-il)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-(2-kloro-6-metilpiridin-4-il)-5-(4-fluorofenil)-1,2,4-triazin-3-amin; 5-(4-fluorofenil)-6-[2-d3-metil-6-(trifluorometil)piridin-4-il]-1,2,4-triazin-3-amin; 6-[2-(difluorometil)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-[2-kloro-6-(difluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-[2-kloro-6-(fluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-[2-(fluorometil)-6-metilpiridin-4-il]-5-fenil-1,2,4-triazin-3-amin; 6-[2-metil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin; i 6-(2-bromo-6-metilpiridin-4-il)-5-fenil-1,2,4-triazin-3-amin.
7. Spoj naznačen time da je izabran iz skupine koju čine: 6-(2-kloro-6-metilpiridin-4-il)-5-(4-fluorofenil)-1,2,4-triazin-3-amin i 6-[2-metil-6-(trifluorometil)piridin-4-il]-5-fenil-1,2,4-triazin-3-amin, ili njihova farmaceutski prihvatljiva sol ili solvat.
8. Spoj u skladu s bilo kojim od zahtjeva 1 do 7, naznačen time da: B predstavlja CYBB ili HetBB skupinu, navedena skupina je ili nesupstituirana ili je supstituirana s jednim ili više supstituenata koji se biraju od fluoro, CN, OR8 ili C1-6 alkil proizvoljno supstituiran s jednim ili više supstituenata koji su odabrani od halo i OR5a, pri čemu R5a i R8 su kako je definirano u zahtjevu 1 proizvoljno pri čemu B predstavlja CYBB ili HetBB skupinu, navedena skupina je ili nesupstituirana ili je supstituirana s fluoro na 4-položaju u odnosu na točku vezanja na triazinski prsten.
9. Spoj s formulom lyd kako je definirano u bilo kojem od zahtjeva 1 do 7 naznačen time da je za uporabu za liječenje stanja ili poremećaja koji se može poboljšati inhibicijom A1 receptora ili A2a receptora pri čemu stanje ili poremećaj su odabrani od: zastoja srca; zatajenja bubrega; edema; raka; dijabetesa; proljeva; makularne degeneracije; depresije; bolesti kognitivnih funkcija; neurodegenerativne bolesti; poremećaja povezanog s pozornošću; ekstra piramidalnog sindroma; poremećaja abnormalnih pokreta; ciroze; fibroze jetre; masne jetre; dermalne fibroze; poremećaja spavanja; moždanog udara; ozljede mozga ili neuroupale; te ovisničkog ponašanja.
10. Uporaba spoja s formulom lyd kako je definirano u bilo kojem od zahtjeva 1 do 7 naznačena time da je za proizvodnju lijeka za liječenje stanja ili poremećaja koji se može poboljšati inhibicijom A1 receptora ili A2a receptora pri čemu stanje ili poremećaj je odabrano od: zastoja srca; zatajenja bubrega; edema; raka; dijabetesa; proljeva; makularne degeneracije; depresije; bolesti kognitivnih funkcija; neurodegenerativne bolesti; poremećaja povezanog s pozornošću; ekstra piramidalnog sindroma; poremećaja abnormalnih pokreta; ciroze; fibroze jetre; masne jetre; dermalne fibroze; poremećaja spavanja; moždanog udara; ozljede mozga ili neuroupale; te ovisničkog ponašanja.
11. Uporaba prema zahtjevu 10, ili spoj za uporabu prema zahtjevu 9, naznačeni time da stanje ili poremećaj koji poboljšava inhibicijom A2a receptora i je odabrano od depresije; bolesti kognitivnih funkcija; neurodegenerativne bolesti; poremećaja povezanog s pozornošću; ekstra piramidalnog sindroma; poremećaja abnormalnih pokreta; ciroze; fibroze jetre; masne jetre; dermalne fibroze; poremećaja spavanja; moždanog udara; ozljede mozga ili neuroupale; te ovisničkog ponašanja.
12. Uporaba prema zahtjevu 10 ili zahtjevu 11, ili spoj za uporabu prema zahtjevu 9 ili zahtjevu 11, naznačeni time da stanje ili poremećaj je migrena.
13. Uporaba prema zahtjevu 10 ili zahtjevu 11, ili spoj za uporabu prema zahtjevu 9 ili zahtjevu 11, naznačeni time da neurodegenerativna bolest je Parkinsonova bolest, Huntingtonova bolest, Alzheimerova bolest ili amiotrofična lateralna skleroza.
14. Uporaba, ili spoj za uporabu prema zahtjevu 13, naznačeni time da stanje ili poremećaj koji se može poboljšati inhibicijom A2a receptor je Parkinsonova bolest.
15. Uporaba prema zahtjevu 10 ili zahtjevu 11, ili spoj za uporabu prema zahtjevu 9 ili zahtjevu 11, naznačeni time da stanje ili poremećaj koji se može poboljšati inhibicijom A2a receptor je ovisno ponašanje ili ADHD.
16. Spoj za uporabu prema zahtjevu 9 ili zahtjevu 11, ili uporaba prema zahtjevu 10 ili zahtjevu 11, naznačeni time da stanje ili poremećaj koji se može poboljšati inhibicijom A1 receptor je ublažavanje oštećenja bubrega uzrokovanog akutnim zatajenjem bubrega, edem, zatajenje srca, kronična bolest bubrega i/ili ciroza.
17. Spoj s formulom lyd kako je definirano u bilo kojem od zahtjeva 1 do 7 naznačena time da je za uporabu za ublažavanje oštećenja bubrega uzrokovanog akutnim zatajenjem bubrega, edema, zatajenja srca, kronične bolesti bubrega i/ili ciroze.
18. Uporaba spoja s formulom lyd kako je definirano u bilo kojem od zahtjeva 1 do 7 naznačen time da je za proizvodnju lijeka za ublažavanje oštećenja bubrega uzrokovanog akutnim zatajenjem bubrega, edema, zatajenja srca, kronične bolesti bubrega i/ili ciroze.
19. Spoj s formulom lyd kako je zatraženo u bilo kojem od zahtjeva 1 do 7 naznačen time da je za uporabu u medicini.
20. Farmaceutska formulacija naznačena time da sadrži spoj s formulom lyd kako je definirano u bilo kojem od zahtjeva 1 do 7 u smjesi sa farmaceutski prihvatljivim pomoćnim sredstvom, sredstvom za razrjeđivanje ili nosačem.
21. Postupak za pripravu spoja s formulom lyd kako je definirano u bilo kojem od zahtjeva 1 do 7, naznačen time da postupak sadrži: (i) (a) reakciju spoja s formulom III, [image] pri čemu Lx1a predstavlja halogenid metala, -Sn(Rx1)3, derivat alkil-ciklotriboroksana, -B(OH)2, -B(ORx1)2, ili organosilan, pri čemu svaki ovdje navedeni Rx1 neovisno predstavlja C1-6 alkil skupinu, ili, u slučaju -B(ORx1)2, dvije Rx1 skupine mogu biti povezane zajedno tako da tvore 4- do 6-članu cikličku skupinu, L2 predstavlja izravnu vezu, R1 predstavlja H, i B je kako je definirano u zahtjevu 1, sa spojem s formulom IV, [image] pri čemu X1a predstavlja pogodnu izlaznu skupinu, i A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1; (b) reakciju spoja s formulom V, [image] pri čemu X1b predstavlja pogodnu izlaznu skupinu, L2 predstavlja izravnu vezu, R1 predstavlja H, i B je kako je definirano u zahtjevu 1, sa spojem s formulom VI, [image] pri čemu Lx1b predstavlja halogenid metala, -Sn(Rx1)3, derivat alkil-ciklotriboroksana, -B(OH)2, -B(ORx1)2, ili organosilan, pri čemu je svaki Rx1 kako je gore definirano, te A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1; (ii) (a) reakciju spoja s formulom XV, [image] pri čemu Lx3a predstavlja halogenid metala, -Sn(Rx1)3, derivat alkil-ciklotriboroksana, -B(OH)2, -B(ORx1)2, ili organosilan, u kojoj je svaki Rx1 kako je gore definirano, L1 predstavlja izravnu vezu, R1 predstavlja H, i A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1, sa spojem s formulom XVI, [image] pri čemu X3a predstavlja pogodnu izlaznu skupinu i B je kako je definirano u zahtjevu 1; (b) reakciju spoja s formulom XVII, [image] pri čemu X3b predstavlja pogodnu izlaznu skupinu, L1 predstavlja izravnu vezu, R1 predstavlja H, i A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1, sa spojem s formulom XVIII, [image] pri čemu Lx3b predstavlja halogenid metala, -Sn(Rx1)3, derivat alkil-ciklotriboroksana, -B(OH)2, -B(ORx1)2, ili organosilan, u kojoj je svaki Rx1 kako je gore definirano, i B je kako je definirano u zahtjevu 1; (iii) reakciju spoja s formulom XXVIII, [image] pri čemu X6 predstavlja pogodnu izlaznu skupinu tako da L1 i L2 predstavljaju izravne veze, A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1, i B je kako je definirano u zahtjevu 1, sa spojem s formulom XXIX, [image] pri čemu R1 je H; (iv) reakciju spoja s formulom XXX, [image] pri čemu Rx2 predstavlja pogodnu izlaznu skupinu, L1 i L2 predstavljaju izravne veze, A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1, i B je kako je definirano u zahtjevu 1, ili njegov zaštićeni derivat, sa spojem s formulom XXIX, pri čemu R1 je H; (v) reakciju spoja s formulom XXXI, [image] pri čemu A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1, i B je kako je definirano u zahtjevu 1, sa spojem s formulom XXXII, [image] pri čemu R1 je H; (vii) za spojeve s formulom lyd u kojoj B predstavlja HetBB skupinu koja sadrži dušik koji je vezan preko dušikovog atoma u sklopu sustava prstena, reakciju spoja s formulom XIX, [image] pri čemu X4a predstavlja pogodnu izlaznu skupinu, L1 predstavlja izravnu vezu, R1 predstavlja H, i A predstavlja potrebnu supstituiranu piridin-4-il skupinu kako je definirano u zahtjevu 1, sa spojem s formulom XXXIV, [image] pri čemu HetB1 ima isto značenje kao HetBB kako je definirano iznad, osim što je HetB1 heterocikal koji sadrži dušik koji je vezan na H-atom prikazan za spoj s formulom XXXIV preko dušikovog atoma u heterociklu; te (ix) za spojeve s formulom lyd u kojoj jedan od R4b' R4b, R4c i R4d predstavlja -OH, reakciju spoja s formulom lyd u kojoj jedan od R4b', R4b,R4c i R4d predstavlja-OR4y, pri čemu R4y predstavlja C1-6 alkil, C2-6 alkenil, C2-6 alkinil ili C3-6 cikloalkil, navedene skupine su proizvoljno supstituirane s jednim ili više supstituenata koji su odabrani od halo, C1-4 alkila i arila, sa sredstvom za dealkiliranje.
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US20230021177A1 (en) 2023-01-19
CA2789279A1 (en) 2011-08-11
SMT201600198B (it) 2016-08-31
PL2531492T3 (pl) 2016-10-31
CY1117780T1 (el) 2017-05-17
KR20120124480A (ko) 2012-11-13
HUE028640T2 (en) 2016-12-28
US20170291888A1 (en) 2017-10-12
BR112012019540B1 (pt) 2021-09-28
RU2012137779A (ru) 2014-03-10
IL221160A (en) 2015-09-24
CN102822150A (zh) 2012-12-12
WO2011095625A1 (en) 2011-08-11
AU2011212430A1 (en) 2012-08-23
DK2531492T3 (en) 2016-07-04
US20130029963A1 (en) 2013-01-31
US20190047978A1 (en) 2019-02-14
EP2531492B1 (en) 2016-04-13
KR101838093B1 (ko) 2018-03-13
MX352415B (es) 2017-11-22
SG183146A1 (en) 2012-09-27
AU2011212430B2 (en) 2014-05-29
BR112012019540A2 (pt) 2017-12-12

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