NOVEL 3,4-DISUBSTITUTED-1H-PYRROLO[2,3-b]PYRIDINES AND 4,5-DISUBSTITUTED-7H-PYRROLO[2,3-c]PYRIDAZINES AS LRRK2 INHIBITORS

Patent metadata

Field	Value
Publication number	US-2017002000-A1
Application number	US-201415104659-A
Country	US
Kind code	A1
Filing date	Dec 3, 2014
Priority date	Dec 17, 2013
Publication date	Jan 5, 2017
Grant date	—

Abstract

The present invention provides novel 3,4-disubstituted-1H-pyrrolo[2,3-b]pyridine derivatives and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazine derivatives of Formula I, and the pharmaceutically acceptable salts thereof

wherein R 1 , R 2 , R 3 , R 4 and X are as defined in the specification. The invention is also directed to pharmaceutical compositions comprising the compounds of formula I and to use of the compounds in the treatment of diseases associated with LRRK2, such as neurodegenerative diseases including Parkinson's disease or Alzheimer's disease, cancer, Crohn's disease or leprosy.

First claim

1 . A compound of Formula I

or a pharmaceutically acceptable salt thereof wherein
X is N or CR 5 ;
R 1 is —NR 6 R 7
R 2 is phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyridonyl or imidazo[1,2-b]pyridazinyl; each optionally substituted with one to three R 9 ;
R 3 is hydrogen, chloro or methyl;
R 4 is hydrogen, cyano, hydroxymethyl, methoxymethyl, cyanomethyl or —C(O) 2 CH 3 ;
R 5 is hydrogen or methyl;
R 6 and R 7 taken together with the nitrogen to which they are attached is selected from the group consisting of:

and
R 9 at each occurrence is independently selected from chloro, fluoro, cyano, methyl, methoxy, hydroxymethyl and —C(O)NH 2 .

2 .- 8 . (canceled)

9 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CR 5 .

10 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.

11 . (canceled)

12 . The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 6 and R 7 taken together with the nitrogen to which they are attached is

13 .- 14 . (canceled)

15 . A compound selected from the group consisting of:
3-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 2-fluoro-3-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]imidazo[1,2-b]pyridazine; 1-methyl-4-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-pyrrole-2-carbonitrile; 1-methyl-4-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1H-imidazole-2-carbonitrile; 1-methyl-4-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-c]pyridazin-5-yl]-1H-pyrrole-2-carbonitrile; 4-[2-chloro-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-1-methyl-1H-pyrrole-2-carbonitrile; 3-[2-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[6-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[5-(hydroxymethyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-(3-cyanophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-(3,6-dihydro-2H-pyran-4-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-cyano-2-fluorophenyl)-4-(dimethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 3-(5-fluoro-2-methoxyphenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-fluoro-5-methoxyphenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 2-methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 2-fluoro-3-[6-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 6-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridine-2-carbonitrile; 3-(3-chlorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-chloro-5-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(2,5-difluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(2-chlorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(2,3-difluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(2-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(5-chloro-2-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; {3-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}methanol; {4-fluoro-3-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}methanol; 3-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-methoxyphenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-chloro-2-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(morpholin-4-yl)-3-(2,3,5-trifluorophenyl)-1H-pyrrolo[2,3-b]pyridine; 3-(3,5-difluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(2-chloropyridin-3-yl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(morpholin-4-yl)-3-phenyl-1H-pyrrolo[2,3-b]pyridine; 3-(2,4-difluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-fluoro-5-methylphenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-fluoro-5-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-(2,3-difluoro-6-methoxyphenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 2-fluoro-5-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-(5-methoxypyridin-3-yl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 6-[2-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridine-2-carbonitrile; 3-(1-methyl-1H-pyrazol-4-yl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 3-(3-cyano-2-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 3-(3-fluoro-5-methylphenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-fluoro-3-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-fluoro-4-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-(hydroxymethyl)-5-[4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-(4-fluorophenyl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 2-methyl-3-(5-methylpyridin-3-yl)-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-chlorophenyl)-2-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 2-methyl-4-(morpholin-4-yl)-3-phenyl-1H-pyrrolo[2,3-b]pyridine; 3-(2-fluorophenyl)-2-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-(3-fluorophenyl)-2-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-fluoro-5-[2-methyl-4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 1-[3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-ol; 4-[(2S)-2-methylmorpholin-4-yl]-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(3,3-difluoropiperidin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine; {1-[3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}methanol; 3-(1-methyl-1H-pyrazol-4-yl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrrolo[2,3-b]pyridine; N,N-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine; 3-(1-methyl-1H-pyrazol-4-yl)-4-(thiomorpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine; 4-(3,3-difluoropyrrolidin-1-yl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-[4-(3,6-dihydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[4-(3-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-{4-[2-(methoxymethyl)morpholin-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 4-(morpholin-4-yl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine; 3-[4-(1,4-oxazepan-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[4-(4-hydroxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[4-(3-methoxypiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-[4-(6-oxa-3-azabicyclo[3.1.1]hept-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-{4-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 3-[4-(4-fluoropiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-{4-[(3R)-3-fluoropyrrolidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 3-{4-[(2R)-2-methylmorpholin-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 3-[4-(pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-{4-[(3S)-3-fluoropyrrolidin-1-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 3-[4-(3,3-difluoropiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]benzonitrile; 3-{4-[(2S)-2-methylmorpholin-4-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl}benzonitrile; 4-[4-(morpholin-4

Assignees

• Pfizer

Inventors

• Galatsis Paul
• Hayward Matthew Merrill
• Kormos Bethany Lyn
• Wager Travis T
• Zhang Lei
• Henderson Jaclyn Louise
• Kurumbail Ravi G
• Verhoest Patrick Robert
• Stepan Antonia Friederike

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title