5,7-dihydro-pyrrolo-pyridine derivatives

Abstract

The present invention provides, in part, compounds of Formula I:or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein: R1, R2, L, A, and E are as described herein; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, N-oxides, or salts, and their uses for treating M4-mediated (or M4-associated) disorders including, e.g., Alzheimer's Disease, schizophrenia (e.g., its cognitive and negative symptoms), pain, addiction, and a sleep disorder.

1 . A method of treating an M4-associated disease or disorder in a subject in need thereof, comprising administering to the patient a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide, wherein:
 each R 1 , when present, is independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkylthio, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 6 )cycloalkyl, optionally substituted —O—(C 3 -C 6 )cycloalkyl, —N(R 3 )(R 4 ), —N(R 3 )(C═(O)(R 4 ), —C(═O)N(R 3 )(R 4 ), —O—C(═O)—N(R 3 )(R 4 ), —C(═O)—R 3 , and —C(═O)—OR 3 ; 
 a is an integer selected from 0, 1, 2, and 3; 
 each R 2 , when present, is independently selected from the group consisting of hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkylthio, optionally substituted (C 1 -C 6 )alkoxy, —N(R 3 )(R 4 ), —N(R 3 )(C═(O)(R 4 ), —C(═O)N(R 3 )(R 4 ), —O—C(═O)—N(R 3 )(R 4 ), —C(═O)—R 3 , and —C(═O)—OR 3 ; 
 b is an integer selected from 0, 1, 2, 3, and 4; 
 L is selected from —(CH 2 ) m —, —O—, and —NH—, wherein m is an integer selected from 1 and 2; 
 A is absent or selected from the group consisting of (C 3 -C 6 )cycloalkyl and (4- to 10-membered)heterocycloalkyl, wherein said cycloalkyl and heterocycloalkyl are each optionally substituted with one to five substituents independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkylthio, optionally substituted (C 1 -C 6 )alkoxy, —N(R 3 )(R 4 ), —N(R 3 )(C═(O)(R 4 ), —C(═O)N(R 3 )(R 4 ), —O—C(═O)—N(R 3 )(R 4 ), —C(═O)—R 3 , and —C(═O)—OR 3 ; 
 E is selected from (C 3 -C 12 )cycloalkyl, (C 6 -C 10 )aryl or (5- to 10-membered)heteroaryl, wherein said cycloalkyl, aryl, and heteroaryl are optionally substituted with one to five substituents independently selected from the group consisting of halogen, cyano, hydroxy, —SF 5 , nitro, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 2 -C 6 )alkenyl, optionally substituted (C 2 -C 6 )alkynyl, optionally substituted (C 1 -C 6 )alkylthio, optionally substituted (C 1 -C 6 )alkoxy, optionally substituted (C 3 -C 6 )cycloalkyl, methyloxetanyl, —N(R 3 )(R 4 ), —N(R 3 )(C═(O)R 4 ), —C(═O)N(R 3 )(R 4 ), —O—C(═O)—N(R 3 )(R 4 ), —C(═O)—R 3 , and —C(═O)—OR 3 , wherein aryl is selected from phenyl or naphthyl; 
 R 3  and R 4  at each occurrence are each independently selected from hydrogen and optionally substituted (C 1 -C 6 )alkyl; or R 3  and R 4  taken together with the nitrogen to which they are attached form an optionally substituted (4- to 6-membered)heterocycloalkyl; and 
 wherein the disease or disorder is selected from the group consisting of Alzheimer's Disease, schizophrenia or psychosis, pain, addiction, a sleep disorder, a cognitive disorder (e.g. mild cognitive impairment), Parkinson's Disease, Parkinson's Disease-levodopa-induced dyskinesia, Huntington's Disease, dyskinesia, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, atherosclerosis and mental and behavioral disorders due to drug dependence and abuse. 
 
     
     
         2 . The method according to  claim 1 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, L is —(CH 2 ) m — and m is an integer selected from 1 and 2. 
     
     
         3 . The method according to  claim 2 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, and m is 1. 
     
     
         4 . The method according to  claim 1 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, A is a (C 3 -C 8 )cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein said cycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, —N(R 3 )(R 4 ), optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy. 
     
     
         5 . The method according to  claim 4 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, A is cyclopropyl. 
     
     
         6 . The method according to  claim 1 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, A is a (4- to 6-membered)heterocycloalkyl selected from the group consisting of azetidinyl, dihydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydrotriazinyl, tetrahydropyrazolyl, tetrahydrooxazinyl, tetrahydropyrimidinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, tetrahydrooxazolyl, oxetanyl, dioxetanyl, dioxolanyl, dioxanyl, oxazinyl, and oxathiazinyl, wherein said heterocycloalkyl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, —N(R 3 )(R 4 ), optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy. 
     
     
         7 . The method according to  claim 6 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, A is a (4- to 6-membered)heterocycloalkyl and the heterocycloalkyl is azetidinyl. 
     
     
         8 . The method according to  claim 1 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, E is a (5- to 10-membered)heteroaryl selected from the group consisting of triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothiofuranyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridinyl, purinyl, imidazopyridinyl, imidazopyrimidinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, thienopyridinyl, triazolopyrimidinyl, triazolopyridinyl, anthranilyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, —N(R 3 )(R 4 ), optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy. 
     
     
         9 . The method according to  claim 8 , wherein in the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, E is a (5- to 6-membered)nitrogen-containing heteroaryl selected from the group consisting of triazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl, wherein said nitrogen-containing heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, —N(R 3 )(R 4 ), optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy. 
     
     
         10 . The method of  claim 1 , wherein the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide is a compound of Formula Ia: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1 , when present, is independently selected from the group consisting of halogen, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy; 
 a is an integer selected from 1, 2 and 3; 
 R 2 , when present, is an optionally substituted (C 1 -C 6 )alkyl; 
 b is an integer selected from 0 and 1; 
 E is a (5- to 6-membered)heteroaryl, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, or —N(R 3 )(R 4 ), wherein R 3  and R 4  at each occurrence are each independently selected from hydrogen and optionally substituted (C 1 -C 6 )alkyl. 
 
     
     
         11 . The method according to  claim 10 , wherein in the compound of Formula Ia, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, E is a (5- to 6-membered)nitrogen-containing heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. 
     
     
         12 . The method according to  claim 11 , wherein in the compound of Formula Ia, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, the (5- to 6-membered)nitrogen-containing heteroaryl is pyridinyl. 
     
     
         13 . The method according to  claim 11 , wherein in the compound of Formula Ia, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, the (5- to 6-membered)nitrogen-containing heteroaryl is pyrimidinyl. 
     
     
         14 . The method of  claim 1 , wherein the compound of Formula I, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound of the N-oxide, is a compound of Formula Ib: 
       
         
           
           
               
               
           
         
       
       wherein:
 each R 1 , when present, is independently selected from the group consisting of halogen, optionally substituted (C 1 -C 6 )alkyl, and optionally substituted (C 1 -C 6 )alkoxy; 
 a is an integer selected from 1, 2 and 3; 
 R 2 , when present, is an optionally substituted (C 1 -C 6 )alkyl; 
 b is an integer selected from 0 and 1; 
 E is a (5- to 6-membered)heteroaryl, wherein said heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, cyano, hydroxy, optionally substituted (C 1 -C 6 )alkyl, optionally substituted (C 1 -C 6 )alkoxy, or —N(R 3 )(R 4 ), wherein R 3  and R 4  at each occurrence are each independently selected from hydrogen and optionally substituted (C 1 -C 6 )alkyl. 
 
     
     
         15 . The method according to  claim 14 , wherein in the compound of Formula Ib, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, E is a (5- to 6-membered)nitrogen-containing heteroaryl selected from the group consisting of pyrazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl. 
     
     
         16 . The method according to  claim 11 , wherein in the compound of Formula Ib, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, the (5- to 6-membered)nitrogen-containing heteroaryl is pyrimidinyl. 
     
     
         17 . The method according to  claim 11 , wherein in the compound of Formula Ib, the N-oxide thereof, or the pharmaceutically acceptable salt of the compound or the N-oxide, the (5- to 6-membered)nitrogen-containing heteroaryl is pyridinyl. 
     
     
         18 . The method according to  claim 1 , wherein the compound of Formula I is 1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[1-(pyridin-3-yl)azetidin-3-yl]ethanone, or an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide. 
     
     
         19 . The method according to  claim 1 , wherein the compound of Formula I is 1-[2-(Methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethanone, an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide. 
     
     
         20 . The method according to  claim 1 , wherein the compound of Formula I is 1-(2,4-Dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethanone, an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide. 
     
     
         21 . The method according to  claim 1 , wherein the compound of Formula I is 1-(3-Chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-{1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}ethanone, an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide. 
     
     
         22 . The method according to  claim 1 , wherein the compound of Formula I is 1-[3-chloro-2-(methoxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(difluoromethyl)pyridin-4-yl]azetidin-3-yl}ethanone, an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide. 
     
     
         23 . The method according to  claim 1 , wherein the compound of Formula I is 1-(3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-[trans-2-(pyrimidin-5-yl)cyclopropyl]ethanone, an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide. 
     
     
         24 - 26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the M4 associated disease or disorder is a disease or disorder selected from the group consisting of Alzheimer's Disease, schizophrenia, pain, addiction, and a sleep disorder. 
     
     
         28 . The method according to  claim 1 , wherein the compound of Formula I is 1-[2-(hydroxymethyl)-4-methyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethanone, an N-oxide thereof, or a pharmaceutically acceptable salt of the compound or the N-oxide.