Substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs as positive allosteric modulators of the muscarinic acetylcholine receptor m1

Abstract

In one aspect, the invention relates to substituted 2-(4-heterocyclylbenzyl)isoindolin-1-one analogs compounds, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the muscarinic acetylcholine receptor M 1 (mAChR M 1 ); synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
         1 . A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein L is selected from —(C═O)—, —(S═O)— and —(SO 2 )—; 
         wherein each of Z 1  and Z 2  are independently selected from Q 6  or CR 4 , provided that Z 1  and Z 2  are not simultaneously Q 6  or simultaneously CR 4 ; 
         wherein Q 1  is selected from N and CR 1a ; wherein Q 2  is selected from N and CR 1b ; wherein Q 3  is selected from N and CR 1c ; wherein Q 4  is selected from N and CR 1d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , and Q 4  are N;
 wherein each of R 1a , R 1b , R 1c , and R 1d , when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino; 
 
         wherein Q 5  is selected from N and CR 2a ; wherein Q 6  is selected from N and CR 2b ; wherein Q 7  is selected from N and CR 2c ; wherein Q 8  is selected from N and CR 2d ; and wherein 0, 1, or 2 of Q 5 , Q 6 , Q 7 , and Q 8  are N;
 wherein each of R 2a , R 2b , R 2c , and R 2d , when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino; 
 
         wherein each of R 3a  and R 3b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         wherein R 4  is selected from Ar 1 , Ar 2 , -L 2 -Ar 1 , -L 2 -Ar 2 , and Cy 1 ;
 wherein L 2  is selected from —CR 8a R 8b —, —O—, —NR 9 —, —S—, —(S═O)—, and —(SO 2 )—;
 wherein each of R 8a  and R 8b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
 wherein R 9  is selected from hydrogen and C1-C6 alkyl; 
 
 wherein Ar 1  is selected from phenyl, indenyl, and naphthalenyl; and substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; 
 wherein Ar 2  is selected from benzodioxolyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzooxadiazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, furanyl, furopyridinyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, indazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxoindolinyl, 2′-oxospiro[1,3]dioxolane-2,3′-indolinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and triazolyl; and wherein Ar 2  is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; and 
 wherein Cy 1  is a C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl, and wherein Cy 1  is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino, and wherein two of the substituents are optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 6-membered fused ring group; 
 
         wherein each of R 7a  and R 7b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         or a pharmaceutically acceptable salt, solvate, or polymorph thereof. 
       
     
     
         2 . The compound of  claim 1 , wherein L is —(C═O)—. 
     
     
         3 . The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 5a , R 5b , R 5c , and R 5d  is independently selected from hydrogen, halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino, provided that at least one of R 5a , R 5b , R 5c , and R 5d  is hydrogen; and wherein R 6  is selected from hydrogen and C1-C6 alkyl. 
       
     
     
         8 . The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein each of R 5a , R 5b , R 5c , and R 5d  is independently selected from hydrogen, halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino, provided that at least one of R 5a , R 5b , R 5c , and R 5d  is hydrogen; and wherein R 6  is selected from hydrogen and C1-C6 alkyl. 
     
     
         9 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of  claims 1 - 8 , or pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, and a pharmaceutically acceptable carrier. 
     
     
         10 . A method for the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal comprising the step of administering to the mammal a therapeutically effective amount of least one compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein L is selected from —(C═O)—, —(S═O)— and —(SO 2 )—; 
         wherein each of Z 1  and Z 2  are independently selected from Q 6  or CR 4 , provided that Z 1  and Z 2  are not simultaneously Q 6  or simultaneously CR 4 ; 
         wherein Q 1  is selected from N and CR 1a ; wherein Q 2  is selected from N and CR 1b ; wherein Q 3  is selected from N and CR 1c ; wherein Q 4  is selected from N and CR 1d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , and Q 4  are N;
 wherein each of R 1a , R 1b , R 1c , and R 1d , when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino; 
 
         wherein Q 5  is selected from N and CR 2a ; wherein Q 6  is selected from N and CR 2b ; wherein Q 7  is selected from N and CR 2c ; wherein Q 8  is selected from N and CR 2d ; and wherein 0, 1, or 2 of Q 5 , Q 6 , Q 7 , and Q 8  are N;
 wherein each of R 2a , R 2b , R 2c , and R 2d , when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino; 
 
         wherein each of R 3a  and R 3b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         wherein R 4  is selected from Ar 1 , Ar 2 , -L 2 -Ar 1 , -L 2 -Ar 2 , and Cy 1 ;
 wherein L 2  is selected from —CR 8a R 8b —, —O—, —NR 9 —, —S—, —(S═O)—, and —(SO 2 )—;
 wherein each of R 8a  and R 8b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
 wherein R 9  is selected from hydrogen and C1-C6 alkyl; 
 
 wherein Ar 1  is selected from phenyl, indenyl, and naphthalenyl; and substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; 
 wherein Ar 2  is selected from benzodioxolyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzooxadiazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, furanyl, furopyridinyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, indazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxoindolinyl, 2′-oxospiro[1,3]dioxolane-2,3′-indolinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and triazolyl; and wherein Ar 2  is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; and 
 wherein Cy 1  is a C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl, and wherein Cy 1  is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino, and wherein two of the substituents are optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 6-membered fused ring group; 
 
         wherein each of R 7a  and R 7b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         or a pharmaceutically acceptable salt, solvate, or polymorph thereof. 
       
     
     
         11 . The method of  claim 10 , wherein the mammal has been diagnosed with a need for treatment of the disorder prior to the administering step. 
     
     
         12 . The method of  claim 10 , further comprising the step of identifying a mammal in need of treatment of the disorder. 
     
     
         13 . The method of  claims 10  or  12 , wherein the disorder is associated with a mAChR M 1  dysfunction. 
     
     
         14 . The method of  claim 10 , wherein the disorder is a neurological and/or psychiatric disorder associated with mAChR M 1  dysfunction. 
     
     
         15 . The method of  claim 10 , wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder and a cognitive disorder. 
     
     
         16 . The method of  claim 15 , wherein the disorder is Alzheimer's disease. 
     
     
         17 . The method of  claim 10 , wherein the disorder is selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, conduct disorder, autistic disorder; movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders. 
     
     
         18 . A kit comprising at least one compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein L is selected from —(C═O)—, —(S═O)— and —(SO 2 )—; 
         wherein each of Z 1  and Z 2  are independently selected from Q 6  or CR 4 , provided that Z 1  and Z 2  are not simultaneously Q 6  or simultaneously CR 4 ; 
         wherein Q 1  is selected from N and CR 1a ; wherein Q 2  is selected from N and CR 1b ; wherein Q 3  is selected from N and CR 1c ; wherein Q 4  is selected from N and CR 1d ; and wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , and Q 4  are N;
 wherein each of R 1a , R 1b , R 1c , and R 1d , when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino; 
 
         wherein Q 5  is selected from N and CR 2a ; wherein Q 6  is selected from N and CR 2b ; wherein Q 7  is selected from N and CR 2c ; wherein Q 8  is selected from N and CR 2d ; and wherein 0, 1, or 2 of Q 5 , Q 6 , Q 7 , and Q 8  are N;
 wherein each of R 2a , R 2b , R 2c , and R 2d , when present, is independently selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 alkoxy-C1-C6 alkyl, C1-C6 alkylamino, C1-C6 haloalkyl-oxy-C1-C6 alkyl, C1-C6 polyhaloalkyl-oxy-C1-C6 alkyl, and C1-C6 dialkylamino; 
 
         wherein each of R 3a  and R 3b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         wherein R 4  is selected from Ar 1 , Ar 2 , -L 2 -Ar 1 , -L 2 -Ar 2 , and Cy 1 ;
 wherein L 2  is selected from —CR 8a R 8b —, —O—, —NR 9 —, —S—, —(S═O)—, and —(SO 2 )—;
 wherein each of R 8a  and R 8b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
 wherein R 9  is selected from hydrogen and C1-C6 alkyl; 
 
 wherein Ar 1  is selected from phenyl, indenyl, and naphthalenyl; and substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; 
 wherein Ar 2  is selected from benzodioxolyl, benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzooxadiazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, furanyl, furopyridinyl, imidazolyl, imidazopyrazinyl, imidazopyridinyl, indazolyl, indolinyl, indolyl, isoindolinyl, isoquinolinyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxoindolinyl, 2′-oxospiro[1,3]dioxolane-2,3′-indolinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolopyridinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and triazolyl; and wherein Ar 2  is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino; and 
 wherein Cy 1  is a C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl, and wherein Cy 1  is substituted with 0-3 substituents selected from halogen, hydroxyl, cyano, —NH 2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkylamino, and C1-C6 dialkylamino, and wherein two of the substituents are optionally covalently bonded, and together with the intermediate atoms, comprise an optionally substituted 3- to 6-membered fused ring group; 
 
         wherein each of R 7a  and R 7b  is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl; 
         or a pharmaceutically acceptable salt, solvate, or polymorph thereof. 
       
     
     
         19 . The kit of  claim 18 , wherein the at least one compound and the at least one agent are co-formulated. 
     
     
         20 . The kit of  claim 18 , wherein the at least one compound and the at least one agent are co-packaged.