ME02151B - Piranil aril metil benzohinazolinon kao pozitivni alosterni modulatori receptora m1 - Google Patents

Piranil aril metil benzohinazolinon kao pozitivni alosterni modulatori receptora m1

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Publication number
ME02151B
ME02151B MEP-2015-86A MEP8615A ME02151B ME 02151 B ME02151 B ME 02151B ME P8615 A MEP8615 A ME P8615A ME 02151 B ME02151 B ME 02151B
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methyl
alkyl
hydroxytetrahydro
pyran
benzo
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MEP-2015-86A
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Scott D Kuduk
Ronald K Chang
Thomas J Greshock
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Merck Sharp & Dohme
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Claims (15)

1. Jedinjenje formule (I):ili njegove farmaceutski prihvatljive soli, gdeX-Y je izabran iz grupe koju čine (1) -O-CRARB-,(2) -CRARB-O-,(3) - CRARB-SRC-,(4) -CRARB-NRC-, i(5) -NRC-CRARB-;gde su i RA i RB nezavisno izabrani iz grupe koju čine,(a) vodonik, i(b) -C1-6 alkil, iRC je izabran iz grupe koju čine,(a) vodonik,(b) -C(=O)-C1-6 alkil,(c) -C1-6 alkil,(d)-C(=O)-CH2-C6H5,(e) -S(=O)2-C1-6 alkil;R1 je izabran iz grupe koju čine (1) vodonik, i(2) hidroksi,uz uslov da kada X-Y je -O-CRARB-, -CRARB-O- ili - CRARB-SRC-, tada R1 je hidroksi u trans izomernom položaju kao što je prikazano:R2 je izabran iz grupe koju čine (1) -C6-10 aril, ili(2) -heteroaril, koji je aromatična ciklična grupa, koja ima od pet do dvanaest atoma u prstenu, atomi u prstenu su izabrani od C, O, N, N→O ili S, od kojih je najmanje jedan O, N, N→O ili S,pri čemu je aril ili heteroaril R2 grupa izborno supstituisana sa jednim ili više(a) halogena,(b) hidroksi,(c) -NR3R4,(d) -C1-6alkil,(e) -O-C1-6 alkil,(f) -C2-8 alkenil,(g) -C(=O)-(O)m-R5,(h) -C(=O)-NR5,(i) -S(=O)2-R5,(j) -SR5,(k) -CN;(l) -C6-10 aril,(m) heteroaril, koji je aromatična ciklična grupa, koja ima od pet do dvanaest atoma u prstenu, atomi u prstenu su izabrani od C, O, N, N→O ili S, od kojih je najmanje jedan O, N, N→O ili S,(n) Si(R6)3,(o) =S,gde je alkil, alkenil, aril ili heteroaril grupa izborno supstituisana sa jednim ili više(a) halogena,(b) hidroksil,(c) -C1-6 alkil,(d) -S-R6,(e) -NR8R9,(f) -O-C1-6 alkil,gde je alkil grupa izborno supstituisana sa jednim ili više halogena;R3 i R4, ili R8 i R9, nezavisno su izabrani iz grupe koju čine(1) vodonik, ili(2) -C1-6 alkil,gde je alkil izborno supstituisan sa jednim ili više(a) halogena,(b) hidroksil,(c) -O-C1-6 alkil,(d) -NR10R11,(e) -C(=O)-(O)n-C1-6 alkil,ili R3 i R4, ili R8 i R9, su vezani zajedno sa azotom za koji su vezani tako da formiraju 4-6 –člani karbociklični prsten, gde su jedan ili dva od atoma ugljenika u prstenu izborno zamenjeni azotom, kiseonikom ili sumporom, i prsten je izborno supstituisan sa jednim ili više(a) halogena,(b) hidroksil,(c) C1-6 alkil,(d) -O-C1-6 alkil,(e) -C(=O)-(O)n-C1-6 alkil;R5 je izabran iz grupe koju čine (1) vodonik,(2) -C1-6 alkil,(3) -C3-8 cikloalkil,(4) -C2-8 alkenil, ili(5) -C6-10 aril,gde je alkil, cikloalkil, alkenil ili aril izborno supstituisan sa jednim ili više(a) halogena,(b) hidroksil,(c) -C1-6 alkil,(d) -O-C1-6 alkil,(e) -C3-8 cikloalkil, ili(f) -C6-10 aril;R6 je izabran iz grupe koju čine (1) vodonik, ili(2) -C1-6 alkil;R10 i R11 su nezavisno izabrani iz grupe koju čine (1) vodonik, ili(2) -C1-6 alkil,gde je alkil izborno supstituisan sa jednim ili više(a) halogena,(b) hidroksil,(c) -O-C1-6 alkil,(d) -C(=O)-(O)n-C1-6 alkil,ili R10 i R11 su vezani zajedno sa azotom za koji su vezani tako da formiraju 4-6 člani karbocikličan prsten, gde su jedan ili dva od atoma ugljenika u prstenu izborno zamenjeni azotom, kiseonikom ili sumporom, i prsten je izborno supstituisan sa jednim ili više(a) halogena,(b) hidroksil,(c) C1-6 alkil,(d) -O-C1-6 alkil,(e) -C(=O)-(O)n-C1-6 alkil;m je 0 ili 1;n je 0, 1 ili 2.
2. Jedinjenje prema patentnom zahtevu 1, gde R1 je hidroksi.
3. Jedinjenje prema patentnom zahtevu 2, gde R1 hidroksi grupa je u trans izomernom položaju:
4. Jedinjenje prema bilo kom od patentnih zahteva 1-3, gde X-Y je -O-CRARB- ili -CRARB-O-, gde su i RA i RB vodonik.
5. Jedinjenje prema bilo kom od patentnih zahteva 1-4, gde R2 je -C6-10 aril; ili gde R2 je heteroaril, pri čemu heteroaril grupa ima pet ili šest atoma u prstenu, atomi u prstenu su izabrani od C, N, N→O i S, pri čemu su jedan ili dva atoma u prstenu N, N→O ili S; ili gde R2 je heteroaril, pri čemu heteroaril grupa ima devet ili deset atoma u prstenu, atomi u prstenu su izabrani od C, O, N, N→O i S, gde su jedan, dva ili tri od atoma u prstenu N, N→O, O ili S.
6. Jedinjenje prema patentnom zahtevu 1, gde jedinjenje formule (I) je jedinjenje formule (III): ili njegova farmaceutski prihvatljiva so, gde su X, Y i R2 kao što su opisano u prethodnom tekstu, i R7 je izabran iz grupe koju čine (1) halogen, (2) hidroksi, (3) -NR3R4, (4) -C1-6 alkil, (5) -O-C1-6 alkil, (6) -C2-8 alkenil, (7) -C(=O)-(O)m-R5, (9) -C(=O)-NR5, (10) -S(=O)2-R5, (11) -SR5, (12) -CN; (13) -C6-10aril, (14) heteroaril, koji je aromatična ciklična grupa, koja ima pet do dvanaest atoma u prstenu, pri čemu su atomi iz prstena izabrani od C, O, N, N→O ili S, od kojih je najmanje jedan O, N, N→O ili S, (15) Si(R6)3, (16) =S, ili (17) vodonik, gde je alkil, alkenil, aril ili heteroaril grupa izborno supstituisana sa jednim ili više (a) halogena, (b) -C1-6 alkil, (c) -S-R6, (d) -NR8R9, (e) -O-C1-6 alkil, gde je alkil grupa izborno supstituisana sa jednim ili više halogena.
7. Jedinjenje prema patentnom zahtevu 6, gde R7 je izabran iz grupe koju čine (1) halogen, (2) hidroksi, (3) -NR3R4, (4) -C1-6 alkil, (5) -O-C1-6 alkil, (6) -S(=O)2-R5, ili (7) -SR5.
8. Jedinjenje prema patentnom zahtevu 6 ili 7, gde X-Y je izabran iz grupe koju čine (1) -O-CRARB-, ili (2) -CRARB-O-.
9. Jedinjenje prema patentnom zahtevu 1, gde jedinjenje formule (I) je jedinjenje formule (IV): gde R2 je kao što je definisan u patentnom zahetvu 1.
10. Jedinjenje prema patentnom zahtevu 9, gde R2 je -C6-10 aril; ili gde R2 je heteroaril, pri čemu heteroaril grupa ima pet ili šest atoma u prstenu, atomi u prstenu su izabrani od C, N, N→O i S, pri čemu su jedan ili dva atoma u prstenu N, N→O ili S; ili gde R2 je heteroaril, pri čemu heteroaril grupa ima devet ili deset atoma u prstenu, atomi u prstenu su izabrani od C, O, N, N→O i S, gde su jedan, dva ili tri od atoma u prstenu N, N→O, O ili S.
11. Jedinjenje prema patentnom zahtevu 1, koje je izabrano iz grupe koju čine 6-[(6-Hloropiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[(6-metiltio)piridin-3-il)metil]benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-[(6-metilpiridin-3-il)metil]benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[6-(1-metil-1H-pirazol-4-il)piridin-3-il]metil}benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[6-(1H-pirazol-1-il)piridin-3-il]metil}benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-(piridin-3-ilmetil)benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-[(6-metoksipiridin-3-il)metil]benzo[h]hinazolin-4(3H)-on; 5-({3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-4-okso-3,4-dihidrobenzo[h]hinazolin-6-il}metil)piridin-2-karbonitril; 6-[(6-Etilpiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(6-Acetilpiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-{[6-(1-Hidroksi-1-metiletil)piridin-3-il]metil}-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-(4-morfolin-4-ilbenzil)benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[6-(1,3-thiazol-4-il)piridin-3-il]metil}benzo[h]hinazolin-4(3H)-on; 6-[(6-Hloro-1-oksidopiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(2-Hloropiridin-4-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[6-(metilsulfonil)piridin-3-il]metil}benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[6-(metilsulfinil)piridin-3-il]metil}benzo[h]hinazolin-4(3H)-on; 5-({3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]4-okso-3,4-dihidrobenzo[h]hinazolin-6-il}metil)piridin-2-karboksilna kiselina; 5-({3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-4-okso-3,4-dihidrobenzo[h]hinazolin-6-il}metil)-N,N-dimetilpiridin-2-karboksamid; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-{[6-(1-metoksi-1-metiletil)piridin-3-il]metil}benzo[h]hinazolin-4(3H)-on; 6-{[6-(Hidroksimetil)piridin-3-il]metil}-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-{[6-(Fluorometil)piridin-3-il]metil}-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-{[6-(Difluorometil)piridin-3-il]metil}-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(2-Hloro-1-oksidopiridin-4-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(2-Fluoropiridin-4-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 3-[(3R,4S)-3-Hidroksitetrahidro-2H-piran-4-il]-6-[(2-metoksipiridin-4-il)metil]benzo[h]hinazolin-4(3H)-on; 6-[(6-Etioksipiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(6-Hidroksipiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-{[6-(Difluorometoksi)piridin-3-il]metil}-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-{[2-(Difluorometoksi)piridin-4-il]metil}-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(3-Bromo-1-metil-1H-pirolo[2,3-b]piridin-4-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(1-Etil-1H-pirolo[2,3-b]piridin-4-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-piran-4-il]benzo[h]hinazolin-4(3H)-on; 6-[(6-Hloropiridin-3-il)metil]-3-[(3R,4S)-3-hidroksitetrahidro-2H-tiopiran-4-il]benzo[h]hinazolin-4(3H)-on; 3-[(3S,4S)-4-Hidroksitetrahidro-2H-piran-3-il]-6-[(6’-metil-2,3-bipiridin-5-il)metil]benzo[h]hinazolin-4(3H)-on; 6-[(6-Hloropiridin-3-il)metil]-3-piperidin-4-ilbenzo[h]hinazolin-4(3H)-on; ili njegova farmaceutski prihvatljiva so.
12. Jedinjenje prema patentnom zahtevu 1, koje je izabrano iz grupe koju čine ili njegova farmaceutski prihvatljiva so.
13. Farmacetska kompozicija koja sadrži terapeutski efikasnu količinu jedinjenja prema bilo kom od patentnih zahteva 1-12, ili njegovu farmaceutski prihvatljivu so, i farmaceutski prihvatljiv nosač.
14. Jedinjenje prema bilo kom od patentnih zahteva 1-12, ili njegova farmaceutski prihvatljiva so, za upotrebu u lečenju bolesti ili poremećaja posredovanog preko muskarinskog M1 receptora, pri čemu je bolest ili poremećaj izabran iz grupe koju čine Alchajmerova bolest, šizofrenija, bol ili poremećaji spavanja.
15. Upotreba jedinjenja prema patentnom zahtevu 1, ili njegove farmaceutski prihvatljive soli, za proizvodnju leka za lečenje bolesti ili poremećaja posredovanog preko muskarinskog M1 receptora, gde je bolest ili poremećaj izabran iz grupe koju čine Alchajmerova bolest, šizofrenija, bol ili poremećaji spavanja.
MEP-2015-86A 2009-08-31 2010-08-26 Piranil aril metil benzohinazolinon kao pozitivni alosterni modulatori receptora m1 ME02151B (me)

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