Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

• i niotvovresl m ina pcraorctiycculliacr c aosm ipnohuibnitdosrs an odf L cRoRmKp2os (iLtioenuscin ceo-nRtaicihnin Rgep seaaidt compounds, as well as methods of uesnition provides processes for the preparation of the disclosed particular for the treatment and/or diagng them, for instance as a medicine or diagnostic agent, in as neurological disorders includedin nosis of diseases characterized by LRRK2 kinase activity such 10 g Parkinson’s disease and Alzheimer’s disease.
• o f dopaminergic e is a degenerative disorder of the central nervous system. It results from the death 15 symptoms are mo nveeumroennet-s in the midbrain. In the early stages of the disease the most obvious L aadtvearnc oend a slstaoge csog onfit tihvee related such as shaking, slowness of movement and difficulty with walking.
• Parkinson’s disease is generally considered to be sporadic, linked to Parkinsond’es, a d few mutations in the LRRK2 (leucine rich repeat kinase 2) gene have been dardarin, is a member ofi tsheeas leeuc (iWneO-2006068492 and WO2006045392).
• LRRK2 also known as 20 p 2 a 0 r L tic R u R la K r 2 in m t u h t e at b io ra n i s n, in bu fa t also in otherirc this rseupeesa tth krionuagsheo fuatm thiley b hoadviyn.g R mesixeeadr-clhineerasg hea kviena idseen aticfiteivdit oy,ve inr c o-segregates with autmilies with late-onset Parkinson Disease.
• n W e O ur 2 o 0 n 0 a 9 l 12 d 7 is 6 o 5 rd 2 e , r W s, O d 2 o 01 not ceolmopperdise LR mRaKc2ro kcinyaclsice i pnyhriabzitoolrosp,y inrim paidritniceula mro thieotisees fo (sre thee f torera etmxaemntp olef N onetheless, there is a1 c0o3n8t572).
• t 5i;tu wehnetsre sinele ecatcehd o frfo smai–dh -aClo1-, -OlkRyl36 is, - oNpRti2o3nRa2l4l,y - aOn-dC1 in-6daelkpyel,n adnednt -lSy- sCu1b-6satliktuytle;d with from 1 -3-
• R2 is o selected from–H, -halo, -OH, -C1-6alkyl, and -C3-6cycloalkyl; wherein each of said -C1-6alkyl is apntdio -nNaRlly13 and independently substituted with from 1 to 3 substituents selected from–halo,–OR27, 5 R3 is o selectedR f1r4o;m–H, -halo, -OH, -C1-6al
• R 4 and R8 areR1 e6a;ch independently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, - R, RN7R,1 R7R18
• Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally beingr oispintigon 1al tloy 3 an hde itneroatoms selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 OH, -C1-6alkyl, -O-C1-d6aelpkeynl,dently substituted with from 1 to 3 substituents selected from–halo, - optionally and independently su -Sb-sCti1tu-6taeldky wl,i and–NR19R20; wherein each of said -C1-6alkyl is 30 Het1 f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdel Hecette7d ar fero emac Oh, itnh
• R1 is R selected from–H,–halo, -OH, -C1-6alkdyrla,t -eO,- NC-1o-6xide form, or solvate thereof, wherein
• R5 isS a-Ctta1-c6ahlekdyl, to - ZN1R o6rR Z5
• each of said -C1-6alkyl is i s an
• each of said -C1-6alkyl is 20 a om 1 to 3 substituents selected from–halo,–OR28, R4 a Nnn
• s wuhbesrtietuinen etsac shele octfed sa friodm -–Ch1a-6laol,ky–lOH is, - oOp-tCio1n-6aalllkyyl, a -nSd- R and R, are each ind , -Het6, -Ar6 and–NR37R38
• R nd R38 are each indeeppeennddeently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2
• 3 7 a 30 -C3-6cycloalkyl, -Ar7 ntly selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, X1 is selected from–C1- a6anldky–lH-,e–t7O;-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR3-C1-6alkyl-, -NR3-C1-6alkyl-, -X2 is N
• 1 -l6lcyycle having from 1 to 3 het t l td from O, N and S; alk aynl,d -C in1d-6eaplkeynledneen,tl -yC1 s-6uablsktyilt-uCte3-d6
• a Zr4e a enadc Zh5 in are each independently selected from C and N; atnadched to X2
• 1 -6alkyl is optionally and independently subst cycloalkyl, -Ar1 and–Het1; wherein each of 20 from–halo, -OR35, -NR11R12, -O-C1-6alkyl, and -S-C1-ituted with from 1 to 3 substituents selected R s N a R ttached to O Z )-R R m–H,–ha6
• each of said -C1-6alkyl is 30 and -N
• a nd 8 are each independently and–NR37R38
• 2 is NRl-,tdd f -O-; w–Che1-r6eailnky el-a,c–hO o-Cf1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1-6alkyl-, - from 1 to 3 substituents selected f sroamid– -Cha1-l6oa,lk -Oyl-H, is -C o1p-6tiaolnkyall,ly -O a-nCd1-6 inadlkeypl,e -nSd-eCn1t-l6yal substituted with -N R32; kyl, -phenyl and 10 Ar1, AR31 beinp A
• I -7- R1 isR4 s,e -leScOte2-dR f4r,o -mCN–,H -N,–Rh9-aSloO,2 --ORH4,, -C -C1-6
• R 2 is op s t elected from–H, -halo, -OH, -C 1-6 alkyl, and -C 3-6 cycloalkyl; whereidn - eSa-Cch1-6 oaflk syal;id -C 1
• Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle op 35 comprising 1 to 3 heteroatoms selected from O tionally b OeHin,g - oCp , N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 1t-6ioanlkayllly and independently substituted with from 1 to 3 substituents selected from–halo, - optionally and i,nd -Oep-Cen1-d6aelnktyl, -S-C1-6alkyl, and–NR19R20; wherein each of said -C1-6alkyl is Het1 f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdly
• R1 is selected from–H,–halo, -OH, -C1-6alkyl, -O-C1-drate, N-oxide form, or solvate thereof, wherein 15 R 6
• Ra3lk3,yl R,3 -4S,- RC35 36 are each indepen 1- 6 inadlkeypl,en -dCe3n-6tclyyc sluobaslktiytul,te -dA wr6ith an frdom–Het6; wherein each of said -C1-6alkyl is optionally and C 1 to 3 substituents selected from–halo,–OH, -O-C1-6
• Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally being opintigon 1al tloy 3 an hde itnedroeatoms selected from O, N and S; each of said Ar1, Ar4, Ar5, Ar6, and Ar7 5 OH, -C1-6alkyl, -O-C1-6alkpyel,nd -ently substituted with from 1 to 3 substituents selected from–halo, - Het1 and independently substitutedS w-Cith1-6 falkyl,–NR19R20; wherein each of said -C1-6alkyl is optionally f,ro Hmet21, H toet 34, h Heetet5r,o Haetot6m,s an sdel Hecette7d ar fero
• Z2, Z3, Z4 and Z5 are each independently selected from C and N. 20 I tn
• 2 7 aRnd38 R;28 are each independently selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2: -10- R37 a -Cnd3-6 Rcy38c,lo aarelk eyla,c -hAr i7nd aenpde–nHdeetn7tly selected from–H, -halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, X1 is
• 2 isN sRe2l-e,c atendd f -rOom-; w–Che1-r6eailnky el-a,c–hO o-Cf1 s-6aaidlky -Cl-,1-–6aSlk-Cyl1--6 iaslk oypl-t,io -nCa1l-6lyalk aynld-N iRnd3-eCp1e-6nadlkeynlt-l,y -N suRb2s-Ctit1u-6talkyl-, - from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl ed with 10 Ar1, - c AN
• the present invention provides a compound of Formula Ia or a stereoisomer, wheomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, s aebloer
• a d s farid Het8 is a saturated 3- to 10-membered heterocycle having from 1 to 3 heteroatoms 40 pploym. O, N and S; and wherein the further definitions and provisions as defined herein -11- I tnau ato fmurethr,e rra ecmbodiment, the present invention provides a compound of Formula I or a stereoisomer, whe emic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, 5 R A1 ar
• R 5 is s seleecctted frroomm––HH, a -nhda–dheanltoly; selected from C and N;
• R 2 is selec lo and -C1-6alkyl;
• R 3 is selectteedd f frroomm––HH a anndd - -CC1-6
• 10 X X1 is selected from–O-C1-6alkyl-, -lNkyRl;3-C1-6alkyl- H2et is8 s isele act 3e-d t foro 1m0- -mC1e-6mablkyl-,–O-C1-6alkyl-, -NR,2 --NCR3
• R 2 is selec o and -C1-6alkyl
• R 3 ted from–H and -C1-6alkyl
• X 1 i iss s seelleecctteedd f frroomm––OH-C and -C1-6,a -lkyl;
• H 2et is8 s -NNRR3
• Z2c,y Zcl3o,a Zl4ky aln;d an Zd5 are each C.
• the present invention provides a compound of Formula I or a stereoisomer, A arn,d ra Ace2m isic C,. metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein 35 -12- I t n au a to f m ur e th r, e r r a e c m em bo ic d , im m e e n ta t, b t o h l e ite p , r p e r s o e - n o t r in p v re e d n r ti u o g n , p sa ro lt v , id h e yd s r a ate co , m N- p o o x
• H et is 8 selected from–O-C1-6alky R3-C1-6alkyl-, -NR3-, 1 is t 0
• M ore in particular the present invention provides a compound selected from the list comprising:
• the present invention provides a compound according to this the numbering as prov iisde lidnk ined Fo torm thuela a Iry olr oCDC.
• the present invention provides a compound according to Inhis ye intv ae fnutriothne,r w phaerrteiciunla srai edm cboomdp
• p iound is the S-enantiomer.
• the compounds and m edicine.T n h s e a c c o c m or p d o in u g nds to a t n h d is c in o v m e p n o ti s o i n tion a s re a s c u c i o ta rd ble for use as a human or veterinary i nhibiting the activity of a kinase, in particular LRRK2 kininagse t,o an tdhi msa iynv been utiosend a forer th seuitable for 15 a dnisde/aosre. prevention of neurological disorders such as Alzheimer’s disease or Pa trrekiantsmoenn’st
• I onf a a f nineaulr ooblojegcictiavle d,i tshoerd perer,se suncth inv aesn Atioln provides a method for the prevention and/or treatment 20 c toom thpisri isninvegn atidomn.inistering to a subject iznh neeimeedr’ tshe driesoefa ase co omrp Poaurknidns oorn a’s c doimsepaosseit;io snai adc mcoertdhinogd
• R 2 is aunbstituted6 with from 1 to 3 substituents selected from–halo, -OR36, -NR23R24, -O-C1-6alkyl, is sed
• each of said -C1-6alkyl is –OH, -O-C1-6alkyl, -S-C1-6alkyl, -C3-6cycloalkyl, -Het o 3 substituents selected from–halo, R dently selected from–H, - 6
• R 7 and R28 are each indepen C , 1 -- A 6a r6 lk a y n l, d -C – 3 N -6 R cy 37 c R l 38
• R37 and R38 are each independently selected from–H, -halo, -OH, -C1-6alkoyall,k -yOl- aCn1d-6 -aHlkeytl2,: -S-C1- X 6
• each of said -C1-6alkyl is optio cycloalkyl, -O-C3-6cycloalkyl, -Ar1 and–Het1; 20 substituents selected from–halo, -O nally a11nRd12 i,n -dOe-pCe1n-6daelknytlly, a snudbs -Stit-uCte1-d6a wlkiythl; from 1 to 3 R5 is 6 a a lk tt y a l c , he -S d - t C o1- Z1
• substituents selected from– 4 8 are ea pRe1n6d;ently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- R R 6a 7 l,k Ryl 9 ,, - RN 1 R17
• a 2r isa sleklyelc-,te adnd fro -NmR- ,–3
• Ar 4 Ar5, Ar6 7 are each independently aalk 5y-l-, to -N 1R02--m, aend -O-;
• o ptionally comprising 1 to 3 heteroatoms selected from O, N and Smbered aromatic cycle Ar5, Ar6, and Ar7 being optionally and independently substitute; each of said Ar1, Ar4, 10 s w u h b e s r t e it i u n e e n a ts ch se o l f e s c a te id d - f C ro 1- m 6al – ky h l a i l s o, o - p O tio H n , a - l C ly 1- a 6a n l d ky in l, d - e O p - e C1-6alkyl, -S-C1d-6al wkyitlh, a fnrodm–N 1R1 t9oR203;
• each of said -C1-6alkyl- is optionally and independently S -C1-6alkyl, -phenyl, and -NR33R3 uents selected from–halo, -OH, -C1-6alkyl, -O-C1-6alkyl, - 25 X 4
• 2 is selected from–C1-6alkyl-,–O-C1-6alkyl-,–S-C1-6alkyl-, -C1-6alkyl-NR2-C1-6alkyl-, -NR2-C1- 6 saulbksytl-it,ut -eNdR w2-i,th a fnrdom -O 1-; to w 3he sruebinsti etuaecnhts o sfe sleacidted -C fr1o-6malk–yhl-al ios, o -OptHio,n -aCll1y-6a alknydl, i -nOd-eCp1e-6nadlkently S-C1-6
• 1 -6alkyl is optionall ; - wherein each of said - Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-mhaelmo;bered heterocycl 35 having from 1 to 3 heteroatoms selected from O, N e
• t arp ach independently selected from C and N;
• R 4 and R8 are each independently selected from–halo,–OH, -C1-6alkyl, -O-C1-6alkyl, -S-C1- R R 6alkyl, -NR17R18, -C3-6cycloalkyl, -O-C3-6
• each of said -C1-6alkyl is —OH, -O-C1-6alkydlependently substituted with from 1 to 3 substituents selected from–halo, R and R8, are each , in -S d - e C p 1 e -6 n a d lk e y n l t , -C3-6cycloalkyl, -Het6, -Ar6 and–NR37R38
• R and R8 are each independenlyt selected from–H, -C1-6alkyl, -C3-6cycloalkyl and -Het2
• each of said -C1-6alkyl- is optionally and independently S-C th from 1 to 3 substituents selected from–halo, -OH, -C1-6alkyl, -O-C1-6
• n g Ad be 1r7 -N in to aR y
• each of said -C1-6alkyl i pti lly an h d e e r p e e in nd w e h n e tl n y R su 1 b
• R is–h ; stituted with from 1 to 3 substituents selected from 3 op sa

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