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EP-4308096-B1 - HETEROAROYL AMIDES AS LRRK2 INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND USES THEREOF

EP4308096B1EP 4308096 B1EP4308096 B1EP 4308096B1EP-4308096-B1

Inventors

  • CHILDERS, KALEEN KONRAD
  • NEELAMKAVIL, SANTHOSH
  • LAPOINTE, Blair, T.
  • SIMOV, Vladimir
  • YEUNG, Charles, S.
  • ELLIS, J. MICHAEL
  • FULLER, Peter, H.
  • GULATI, ANMOL
  • GUNAYDIN, Hakan
  • KATTAR, SOLOMON, D.
  • KURUKULASURIYA, RAVI
  • METHOT, JOEY, L.
  • MORRIELLO, GREGORI, J.

Dates

Publication Date
20260513
Application Date
20220314

Claims (20)

  1. A compound having a structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein: A is a nitrogen containing heteroaryl selected from pyridyl, pyrimidinyl and pyridazinyl; R 1 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -(CH 2 ) n C 3-6 cycloalkyl, said alkyl and cycloalkyl optionally substituted with 1 to 3 groups selected from CF 3 and CN; R 2 is an N-linked heterocycloalkyl selected from a group consisting of pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydrofuronyl, azabicylohexanyl, azabicyloheptanyl, azaspiroheptanyl, azaspirononanyl, diazaspirononanyl, and azaspirooctanyl, said pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, tetrahydrofuronyl, azabicylohexanyl, azabicyloheptanyl, azaspiroheptanyl, azaspirononanyl, diazaspirononanyl, and azaspirooctanyl, unsubstituted or substituted with 1 to 4 groups independently selected from R 4 ; R 3 is selected from hydrogen, CH 3 , CF 3 , and cyclopropyl; each R 4 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkylOH, C 1-6 alkylCN, OC 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, oxetanyl, oxo, OH, halogen, said oxetanyl optionally substituted with 1 to 3 CH 3 groups; and n is selected from 0 to 3.
  2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A pyridyl.
  3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is pyrimidinyl.
  4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is pyridazinyl.
  5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , - (CH 2 ) n cyclopropyl, or -(CH 2 ) n cyclobutyl, said CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , - (CH 2 ) n cyclopropyl, or -(CH 2 ) n cyclobutyl optionally substituted with 1 to 3 groups selected from CN and CF 3 .
  6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl and tetrahydrofuronyl, said group unsubstituted or substituted with 1 to 4 groups independently selected from R 4 .
  7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof wherein R 2 is pyrrolidinyl, unsubstituted or substituted with 1 to 4 groups independently selected from R 4 .
  8. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof wherein R 2 is piperidinyl or piperazinyl, unsubstituted or substituted with 1 to 4 groups independently selected from R 4 .
  9. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of azabicylohexanyl, azabicyloheptanyl, azaspiroheptanyl, azaspirononanyl, diazaspirononanyl, and azaspirooctanyl, said group unsubstituted or substituted with 1 to 4 groups independently selected from R 4 .
  10. The compound according to any one of claims 1 to 5 and 9 or a pharmaceutically acceptable salt thereof wherein R 2 is selected from the group consisting of azabicylohexanyl, azabicyloheptanyl, and azaspiroheptanyl, said group unsubstituted or substituted with 1 to 4 groups independently selected from R 4 .
  11. The compound according to any one of claims 1 to 10 wherein R 4 is independently selected from the group consisting of hydrogen, CH 3 , OCH 3 , C(CH 3 ) 2 OH, C(CH 3 ) 2 CN, CF 3 , CH 2 F, C(CH3) 2 F, cyclopropyl, oxetanyl, oxo, OH, and fluoro, said oxetanyl optionally substituted with 1 to 3 groups of CH 3 .
  12. The compound according to claim 1 represented by structural Formula II: or a pharmaceutically acceptable salt thereof, wherein X, Y, and Z are represented and selected from the group consisting of: 1) X=Z=N, and Y=CH or C-CH3; 2) Y=N, Z=C, and X=C-CH3, C-CF3, or C-cyclopropyl; 3) Z=N, Y=C, and X= C-CH3, C-CF3, or C-cyclopropyl; 4) Y=Z=N and X=C-CH3 or C-cyclopropyl; 5) X=Y=N= and Z=CH; and 6) Z=CH, Y=CH or C-CH3 and X=N.
  13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof wherein when X, Y, and Z combined to form pyridyl selected from the group consisting of 2), 3), 5) and 6), R 1 is selected from the group consisting of CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , - (CH 2 ) n cyclopropyl, and -(CH 2 ) n cyclobutyl, said CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH(CH 3 )CF 3 , - (CH 2 ) n cyclopropyl, and -(CH 2 ) n cyclobutyl optionally substituted with 1 to 3 groups selected from CN and CF 3 ; R 2 is selected from pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl and tetrahydrofuronyl, R 3 is selected from the group consisting of hydrogen, CH 3 , CF 3 and cyclopropyl; and each R 4 is independently selected from the group consisting of hydrogen, CH 3 , OCH 3 , C(CH 3 ) 2 OH, C(CH 3 ) 2 CN, CF 3 , CH 2 F, C(CH3) 2 F, cyclopropyl, oxetanyl, oxo, OH, and fluoro, said oxetanyl optionally substituted with 1 to 3 CH 3 groups.
  14. The compound according to claim 12 wherein X, Y, and Z combined to form pyrimidinyl represented by group 1).
  15. The compound according to claim 12 wherein X, Y, and Z combined to form pyridazinyl represented by group 4).
  16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is selected from: ( R )- N -(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R )- N -(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R )-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide N -(5-(3-methoxyazetidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R )- N -(5-(3-(fluoromethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-(3-(2-hydroxypropan-2-yl)-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-(3-hydroxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide ( S )- N -(5-(3-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(5-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S )- N -(5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide ( R ) or ( S )- N -(5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-((2 R ,3 R )-3-hydroxy-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(5-((2 R ,3 S )-3-hydroxy-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or (S) N -(5-(3-hydroxy-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) N -(5-(3-hydroxy-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R, S ) or ( S, R ) N -(5-(3-(2-hydroxypropan-2-yl)-4-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R, S ) or ( S, R ) N -(5-(3-(2-hydroxypropan-2-yl)-4-methylpyrrolidin-1-yl)-2 (trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) N -(5-(3-(2-hydroxypropan-2-yl)-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) N -(5-(3-(2-hydroxypropan-2-yl)-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R) or (S) N -(5-(3-hydroxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R) or (S) N -(5-(3-hydroxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R, R) or (S, S) or (S, R), or (R, S) N -(5-(4-hydroxy-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R, R) or (S, S) or (S, R), or (R, S) N -(5-(4-hydroxy-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R, R) or (S, S) or (S, R), or (R, S) N -(5-(4-hydroxy-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or (S) N- (5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) N- (5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) 6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)- N -(5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide ( R ) or ( S ) N -(5-(3-(difluoromethyl)-3-hydroxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) N -(5-(3-hydroxy-3-methylpiperidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide ( S )-6-(1-methyl-1H-pyrazol-4-yl)- N -(5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide ( S )-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)- N -(5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide ( R ) or ( S ) N -(5-(3-cyclopropyl-3-hydroxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)picolinamide ( R ) or ( S ) N -(5-(3-cyclopropyl-3-hydroxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)picolinamide 6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)- N -(5-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)-2(trifluoromethyl)pyridin-3-yl)picolinamide ( S )-6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)- N -(5-(4-methyl-2-oxopyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide ( S )-6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)- N -(5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide N -(5-(5-azaspiro[2.4]heptan-5-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)picolinamide 6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)- N -(5-(3,3-difluoropyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide ( R )- N -(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)picolinamide ( R )-6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide 6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (R, R) or (S, S) or (S, R), or ( R, S ) 6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(4-hydroxy-2-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (R) or (S) 6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(3-hydroxy-3-methylpyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (S) -6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide 6-(1-cyclobutyl-1H-pyrazol-4-yl)- N -(5-(3-methoxyazetidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (R) -6-(1-cyclobutyl-1H-pyrazol-4-yl)- N -(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (S) -6-(1-cyclobutyl-1H-pyrazol-4-yl)- N -(5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide 6-(1-methyl-1H-pyrazol-4-yl)- N -(2-methyl-5-(3-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)picolinamide N- (5-(3,3-difluoropyrrolidin-1-yl)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-((2 S ,6 R )-2,6-dimethylmorpholino)-2-methylpyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-(3-(fluoromethyl)pyrrolidin-1-yl)-2-methylpyridin-3-yl)-6-(1-methyl-1 H- pyrazol-4-yl)picolinamide (S) - N -(2-methyl-5-(4-methyl-2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) -6-(1-methyl-1H-pyrazol-4-yl)- N -(2-methyl-5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)picolinamide (R) - N -(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide N -(5-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide N -(5-((3 S ,4 s ,5 R )-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide (S)-N -(5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide (S) - N -(5-(4-methyl-2-oxopyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide (R) - N -(2-cyclopropyl-5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) - N -(2-cyclopropyl-5-(4-methyl-2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R) - N -(2-cyclopropyl-5-(4-methyl-2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(2-oxopiperidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(3,3-dimethyl-2-oxopiperidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(4,4-dimethyl-2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(4-methyl-2-oxopiperazin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(3,3,4-trimethyl-2-oxopiperazin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(3,3-dimethyl-2-oxopyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(6-oxo-5-azaspiro[2.4]heptan-5-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R) - N -(2-cyclopropyl-5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) - N -(2-cyclopropyl-5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-((3S,5R)-3,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) - N -(2-cyclopropyl-5-(3-methoxypyrrolidin-1-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-((1S,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(8-methyl-5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(5-oxo-6-azaspiro[3.4]octan-6-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(1-oxo-2-azaspiro[4.4]nonan-2-yl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) - N -(2-cyclopropyl-5-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(2-cyclopropyl-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N -(5-((3 R ,4 S )-3-(2-hydroxypropan-2-yl)-4-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) - N -(5-(3-(2-hydroxypropan-2-yl)-3-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R) - N -(5-(3-(2-hydroxypropan-2-yl)-3-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (S) -6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)- N -(5-(3-(2-hydroxypropan-2-yl)-3-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide 6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)- N -(5-((3R,4S)-3-(2-hydroxypropan-2-yl)-4-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (R) -6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(3-(2-hydroxypropan-2-yl)-3-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (S) -6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-(3-(2-hydroxypropan-2-yl)-3-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide 6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-((3S,4R)-3-(2-hydroxypropan-2-yl)-4-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide 6-(1-ethyl-1H-pyrazol-4-yl)- N -(5-((3R,4S)-3-(2-hydroxypropan-2-yl)-4-methoxypyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)picolinamide (R) or (S) N-(5-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4 -yl)picolinamide (R) or (S) N-(5-((R)-3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-(trifluoromethyl)pyridin-3-yl)-6-(1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazol-4 -yl)picolinamide N-(2-((2R,6S)-2,6-dimethylmorpholino)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R)-N-(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide Meso 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-(tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-5-(trifluoromethyl)pyridin-4-yl)picolinamide N-(2-((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinatnide N-(2-((2R,3S)-3-hydroxy-2-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-(3-hydroxyazetidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-((3R,5S)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R, R) or (S, S) N-(2-(3-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R, R) or (S, S) N-(2-(3-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-(3-methoxyazetidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(2-(3-(difluoromethyl)pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R)-N-(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R) or (S) N-(2-(3-hydroxy-3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinatnide (R) or (S) N-(2-(3-hydroxy-3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (S)-6-(1-methyl-1H-pyrazol-4-yl)-N-(2-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)picolinamide 6-(1-methyl-1H-pyrazol-4-yl)-N-(2-(4-(oxetan-3-yl)piperidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)picolinamide (R)-N-(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-5-methylpyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R)-N-(2-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide N-(2-((2R,3S)-3-hydroxy-2-methylazetidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide N-(2-((2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide N-(2-((2S,4R)-4-hydroxy-2-methylpyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide 6-(1-methyl-1H-pyrazol-4-yl)-N-(5-methyl-2-morpholinopyridin-4-yl)picolinamide 6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(5-methyl-2-morpholinopyridin-4-yl)picolinamide 6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)picolinamide N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(trifluoromethyl)pyridin-4-yl)-6-(1-ethyl-1H-pyrazol-4-yl)picolinamide N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)-6-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)picolinamide N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)-6-(1-ethyl-1H-pyrazol-4-yl)picolinamide 6-(1-ethyl-1H-pyrazol-4-yl)-N-(5-methyl-2-morpholinopyridin-4-yl)picolinamide 6-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(5-methyl-2-morpholinopyridin-4-yl)picolinamide 6-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)picolinamide N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide N-(5-methyl-2-morpholinopyridin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide (R)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(6-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(6-((3S,4r,5R)-4-hydroxy-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(6-((3S,4r,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(6-(4-(2-hydroxypropan-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(6-(2-azaspiro[4.4]nonan-2-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R) or (S) N-(6-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R) or (S) N-(6-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R) or (S) N-(6-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-methylpyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-(6-((3S,4r,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinatnide (R)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N-(6-((3S,4r,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinatnide N-(6-(4-(3-methyloxetan-3-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N-(6-(3-(2-cyanopropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)picolinamide (R)-N-(2-cyclopropyl-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R)-N-(2-cyclopropyl-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N-(2-cyclopropyl-6-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide N-(2-cyclopropyl-6-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinatnide N-(2-cyclopropyl-6-(3-fluoroazetidin-1-yl)pyrimidin-4-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)picolinamide N-(2-cyclopropyl-6-(3,3-difluoroazetidin-1-yl)pyrimidin-4-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)picolinamide N-(2-cyclopropyl-6-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)pyrimidin-4-yl)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)picolinamide (R)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide (R)-6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)picolinamide N-(6-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinamide 6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)-N-(6-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-methylpyrimidin-4-yl)picolinamide 6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)-N-(6-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-methylpyrimidin-4-yl)picolinamide (R)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazol-4-yl)picolinamide (R)-6-(1-ethyl-1H-pyrazol-4-yl)-N-(6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)picolinamide 6-(1-ethyl-1H-pyrazol-4-yl)-N-(6-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-methylpyrimidin-4-yl)picolinamide (S)-6-(1-((1-cyanocyclopropyl)methyl)-1H-pyrazol-4-yl)-N-(6-(3-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-4-yl)picolinamide N-(6-((3S,4s,5R)-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1H-pyrazol-4-yl)picolinamide (R)-N-(6-(3-(2-fluoropropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide (R)-N-(6-(3-(2-fluoropropan-2-yl)pyrrolidin-1-yl)-2-methylpyrimidin-4-yl)-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)picolinatnide (R)-N-(5-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyridazin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide N-[6-[(3R)-3-(1-hydroxy-1-methyl-ethyl)pyrrolidin-1-yl]-3-methyl-pyridazin-4-yl]-6-(1-methylpyrazol-4-yl)pyridine-2-carboxamide N-[3-cyclopropyl-6-[(3R)-3-(1-hydroxy-1-methyl-ethyl)pyrrolidin-1-yl]pyridazin-4-yl]-6-(1-methylpyrazol-4-yl)pyridine-2-carboxamide (R)-N-(4-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-6-methylpyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide, and (R)-N-(4-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)pyridin-2-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide. (6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)- N -(4-((3 S ,4 r ,5 R )-4-hydroxy-3,4,5-trimethylpiperidin-1-yl)-6-methylpyridin-2-yl)picolinamide (R) -6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)- N -(4-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-6-methylpyridin-2-yl)picolinamide, and N -(2-((2 S ,6 R )-2,6-dimethylmorpholino)-5-methylpyridin-4-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide.
  17. A pharmaceutical composition comprising a compound of any of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  18. A compound of any of Claims 1 to 16 or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson's Disease.
  19. A compound according to any of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in therapy.
  20. A compound according to any of claims 1 to 16, or a pharmaceutically acceptable salt thereof, for use in the treatment of an indication selected from: abnormal motor symptoms associated with Parkinson's disease, non-motor symptoms associated with Parkinson's disease, Lewy body dementia, L-Dopa induced dyskinesias, Alzheimer's disease, mild cognitive impairment, the transition from mild cognitive impairment to Alzheimer's disease, tauopathy disorders characterized by hyperphosphorylation of tau such as argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, and Parkinson's disease linked to chromosome 17, neuroinflammation associated with of microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia, ALS, ischemic stroke, traumatic brain injury and spinal cord injury, lymphomas, leukemias, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hemolytic anemia, pure red cell aplasia, idiopathic thrombocytopenic pupura (ITP), Evans Syndrome, vasculitis, bullous skin disorder, type I diabetes mellitus, Sjorgen's syndrome, Delvic's disease, inflammatory myopathies, and ankylosing spondylitis, renal cancer, breast cancer, lung cancer, prostate cancer, and acute myelogenous leukemia (AML) in subjects expressing the LRRK2 G2019S mutation, papillary renal and thyroid carcinomas in a subject in whom LRRK2 is amplified or overexpressed, Crohn's disease and leprosy.

Description

BACKGROUND OF THE INVENTION Parkinson's disease (PD) is a common neurodegenerative disease caused by progressive loss of mid-brain dopaminergic neurons leading to abnormal motor symptoms such as bradykinesia, rigidity and resting tremor. Many PD patients also experience a variety of non-motor symptoms including cognitive dysfunction, autonomic dysfunction, emotional changes and sleep disruption. The combined motor and non-motor symptoms of Parkinson's disease severely impact patient quality of life. While the majority of PD cases are idiopathic, there are several genetic determinants such as mutations in SNCA, Parkin, PINK1, DJ-1 and LRRK2. Linkage analysis studies have demonstrated that multiple missense mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene lead to an autosomal late onset form of PD. LRRK2 is a 286 kDa cytoplasmic protein containing kinase and GTPase domains as well as multiple protein-protein interaction domains. See for example, Aasly et al., Annals of Neurology, Vol. 57(5), May 2005, pp. 762-765; Adams et al., Brain, Vol. 128, 2005, pp. 2777-85; Gilks et al., Lancet, Vol. 365, Jan. 29, 2005, pp. 415-416, Nichols et al., Lancet, Vol. 365, Jan. 29, 2005, pp. 410-412, and U. Kumari and E. Tan, FEBS journal 276 (2009) pp. 6455-6463. In vitro biochemical studies have demonstrated that LRRK2 proteins harboring the PD associated proteins generally confer increased kinase activity and decreased GTP hydrolysis compared to the wild type protein (Guo et al., Experimental Cell Research, Vol, 313, 2007, pp. 3658-3670) thereby suggesting that small molecule LRRK2 kinase inhibitors may be able to block aberrant LRRK2-dependent signaling in PD. In support of this notion, it has been reported that inhibitors of LRRK2 are protective in models of PD (Lee et al., Nature Medicine, Vol 16, 2010, pp. 998-1000). LRRK2 expression is highest in the same brain regions that are affected by PD. LRRK2 is found in Lewy bodies, a pathological hallmark of PD as well as other neurodegenerative diseases such as Lewy body dementia (Zhu et al., Molecular Neurodegeneration, Vol 30, 2006, pp. 1-17). Further, LRRK2 mRNA levels are increased in the striatum of MPTP-treated marmosets, an experimental model of Parkinson's disease, and the level of increased mRNA correlates with the level of L-Dopa induced dyskinesia suggesting that inhibition of LRRK2 kinase activity may have utility in ameliorating L-Dopa induced dyskinesias. These and other recent studies indicate that a potent, selective and brain penetrant LRRK2 kinase inhibitor could be a therapeutic treatment for PD. (Lee et al., Nat. Med. 2010 Sep;16(9):998-1000; Zhu, et al., Mol. Neurodegeneration 2006 Nov 30;1:17; Daher, et al., J Biol Chem. 2015 Aug 7; 290(32):19433-44; Volpicelli-Daley et al., J Neurosci. 2016 Jul 13; 36(28):7415-27). LRRK2 mutations have been associated with Alzheimer's-like pathology (Zimprach et al., Neuron. 2004 Nov 18;44(4):601-7) and the LRRK2 R1628P variant has been associated with an increased risk of developing AD (Zhao et al., Neurobiol Aging. 2011 Nov; 32(11):1990-3). Mutations in LRRK2 have also been identified that are clinically associated with the transition from mild cognitive impairment to Alzheimer's disease (see WO2007149798). Together these data suggest that LRRK2 inhibitors may be useful in the treatment of Alzheimer's disease and other dementias and related neurodegenerative disorders. LRRK2 has been reported to phosphorylate tubulin-associated tau and this phosphorylation is enhanced by the kinase activating LRRK2 mutation G2019S (Kawakami et al., PLoS One. 2012; 7(1):e30834; Bailey et al., Acta Neuropathol. 2013 Dec; 126(6):809-27.). Additionally, over expression of LRRK2 in a tau transgenic mouse model resulted in the aggregation of insoluble tau and its phosphorylation at multiple epitopes (Bailey et al., 2013). Hyperphosphorylation of tau has also been observed in LRRK2 R1441G overexpressing transgenic mice (Li et al., Nat Neurosci. 2009 Jul; 12(7):826-8.). Inhibition of LRRK2 kinase activity may therefore be useful in the treatment of tauopathy disorders characterized by hyperphosphorylated of tau such as argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinson's linked to chromosome 17 (Goedert and Jakes Biochim Biophys Acta. 2005 Jan 3.). A growing body of evidence suggests a role for LRRK2 in immune cell function in the brain with LRRK2 inhibitors demonstrated to attenuate microglial inflammatory responses (Moehle et al., J Neurosci. 2012 Feb 1;32(5):1602-11.). As neuroinflammation is a hallmark of a number of neurodegenerative diseases such PD, AD, MS, HIV-induced dementia, ALS, ischemic stroke, MS, traumatic brain injury and spinal cord injury, LRRK2 kinases inhibitors may have utility in the treatment of neuroinflammation in these disorders. Significantly elevated levels of LRRK2 mRNA have been observed in muscle biopsy s