Phenylcyclopropylamine derivatives and their medical use

Abstract

The present invention relates to phenylcyclopropylamine derivatives. In particular, pharmaceutical compositions comprising phenylcyclopropylamine derivatives are provided. The compounds of this invention can, inter alia, be used for the treatment and the prevention of cancer as well as neurodegenerative diseases or disorders.

1 - 31 . (canceled) 
     
     
         32 . A method for treating or preventing a cancer comprising the administration to a subject in need of such treatment or prevention a therapeutically effective amount of a compound of formula I 
       
         
           
           
               
               
           
         
         wherein: 
         each of R1-R5 is independently chosen from —H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; 
         R6 is chosen from —H and alkyl; 
         R7 is chosen from —H, alkyl, and cycloalkyl; 
         R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents and wherein said 0-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or 
         R8 is -L-aryl wherein the ring or ring system of said -L-aryl has from 1-3 substituents and wherein said 1-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; 
         each L is independently chosen from —(CH 2 ) n —(CH 2 ) n —, —(CH 2 ) n NH(CH 2 ) n —, —(CH 2 ) n O(CH 2 ) n —, and —(CH 2 ) n S(CH 2 ) n —, and each n is independently chosen from 0, 1, 2, and 3; 
         or a pharmaceutically thereof. 
       
     
     
         33 . The method of  claim 32  wherein said cancer is chosen from breast cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, colorectal cancer, blood cancer, and skin cancer. 
     
     
         34 . The method of  claim 32  wherein said subject is a human. 
     
     
         35 . A method of identifying LSD1 selective and LSD1/MAO-B dual inhibitors comprising determining the ability of a test compound to inhibit LSD1, MAO-A, and MAO-B wherein a LSD1 selective inhibitor is identified when the test compound inhibits LSD1 to a greater extent than MAO-A and MAO-B and wherein a LSD1/MAO-B dual inhibitor is identified when the test compound inhibits LSD1 and MAO-B to a greater extent than it inhibits MAO-A wherein said test compound is a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         each of R1-R5 is independently chosen from —H, halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; 
         R6 is chosen from —H and alkyl; 
         R7 is chosen from —H, alkyl, and cycloalkyl; 
         R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents and wherein said 0-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, 0-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or 
         R8 is -L-aryl wherein the ring or ring system of said -L-aryl has from 1-3 substituents and wherein said 1-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-heterocyclyl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; 
         each L is independently chosen from —(CH 2 ) n —(CH 2 ) n —, —(CH 2 ) n NH(CH 2 ) n —, —(CH 2 ) n O(CH 2 ) n —, and —(CH 2 ) n S(CH 2 ) n , and each n is independently chosen from 0, 1, 2, and 3; 
         or a compound of Formula I where the phenyl ring attached to the cyclopropylamine moiety is replaced by an optionally substituted heteroaryl group and the other variables R6-R8 are as defined above. 
       
     
     
         36 . The method of  claim 32 , wherein R6 and R7 are —H. 
     
     
         37 . The method of  claim 32 , wherein L is independently chosen from —(CH 2 ) n —(CH 2 ) n — and —(CH 2 ) n O(CH 2 ) n —, and each n is independently chosen from 0, 1, 2, and 3. 
     
     
         38 . The method of  claim 32 , wherein L is —CH 2 — or a covalent bond. 
     
     
         39 . The method of  claim 32 , wherein L is a covalent bond. 
     
     
         40 . The method of  claim 32 , wherein:
 R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents and wherein said 0-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amino; or   R8 is -L-aryl, wherein said aryl is phenyl or naphtyl, wherein the ring or ring system of said -L-aryl has from 1-3 substituents and wherein said 1-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.   
     
     
         41 . The method of  claim 32 , wherein
 R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents and wherein said 0-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido; or   R8 is -L-phenyl, wherein the phenyl ring of said -L-phenyl has from 1-3 substituents and wherein said 1-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido.   
     
     
         42 . The method of  claim 32 , wherein R8 is a -L-heterocyclyl wherein the ring or ring system of said -L-heterocyclyl has from 0-3 substituents and wherein said 0-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanate, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. 
     
     
         43 . The method of  claim 32 , wherein R8 is -L-phenyl, wherein the phenyl ring of said -L-phenyl has from 1-3 substituents and wherein said 1-3 substituents are chosen from halo, alkyl, alkoxy, cycloalkoxy, haloalkyl, haloalkoxy, -L-aryl, -L-carbocyclyl, acylamino, acyloxy, alkylthio, cycloalkylthio, alkynyl, amino, alkylamino, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, arylthio, heteroarylthio, cyano, cyanato, haloaryl, hydroxyl, heteroaryloxy, heteroarylalkoxy, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethanesulfonamido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and C-amido. 
     
     
         44 . The method of  claim 32 , wherein the substituents on the cyclopropyl ring have the trans configuration. 
     
     
         45 . The method of  claim 32 , wherein the compound is chosen from:
 (trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanamine;   (trans)-N-(4-fluorobenzyl)-2-phenylcyclopropanaminium;   4-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile;   (trans)-N-(4-cyanobenzyl)-2-phenylcyclopropanaminium;   (trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanamine;   (trans)-2-phenyl-N-(4-(trifluoromethyl)benzyl)cyclopropanaminium;   (trans)-2-phenyl-N-(pyridin-2-ylmethyl)cyclopropanamine;   (trans)-2-phenyl-N-(pyridin-3-ylmethyl)cyclopropanamine;   (trans)-2-phenyl-N-(pyridin-4-ylmethyl)cyclopropanamine;   (trans)-N-((6-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;   (trans)-2-phenyl-N-(thiazol-2-ylmethyl)cyclopropanamine;   (trans)-2-phenyl-N-(thiophen-2-ylethyl)cyclopropanamine;   (trans)-N-((3-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((4-bromothiophen-2-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(3,4-dichlorobenzyl)-2-phenylcyclopropanamine;   (trans)-N-(3-fluorobenzyl)-2-phenylcyclopropanaminium;   (trans)-N-(2-fluorobenzyl)-2-phenylcyclopropanamine;   (trans)-2-phenyl-N-(quinolin-4-ylmethyl)cyclopropanamine;   (trans)-N-(3-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-2-phenyl-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)cyclopropanamine;   (trans)-N-((6-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((4-methylpyridin-2-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((6-methoxypyridin-2-yl)methyl)-2-phenylcyclopropanamine;   2-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-3-ol;   (trans)-N-((6-bromopyridin-2-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(4-(benzyloxy)benzyl)-2-phenylcyclopropanamine;   (trans)-2-phenyl-N-(quinolin-2-ylmethyl)cyclopropanamine;   (trans)-2-phenyl-N-((5-(trifluoromethyl)pyridin-2-yl)methyl)cyclopropanamine,   (trans)-N-((3-fluoropyridin-2-ylmethyl)-2-phenylcyclopropanamine;   (trans)-2-phenyl-N-(quinolin-3-ylmethyl)cyclopropanamine;   (trans)-N-((6-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((5-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((2-methoxypyridin-3-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((3H-indol-3-ylmethyl)-2-phenylcyclopropanamine;   3-(((trans)-2-phenylcyclopropylamino)methyl)benzonitrile;   (trans)-N-(2-methoxybenzyl)-2-phenylcyclopropanamine;   3-(((trans)-2-phenylcyclopropylamino)methyl)pyridin-2-amine;   (trans)-N-((2-chloropyridin-3-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-((2,3-dihydrobenzafuren-5-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(benzo[d][1,3]dioxol-5-ylmethyl)-2-phenylcyclopropanamine;   (trans)-N-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(2,6-difluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-2-phenyl-N-(4-(trifluoromethoxy)benzyl)cyclopropanamine;   (trans)-N-(5-fluoro-2-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-((4-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(2-fluoro-6-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-((2-methoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((4,7-dimethoxynaphthalen-1-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(4-methoxy-3-methylbenzyl)-2-phenylcyclopropanamine;   (trans)-N-(3-chloro-4-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(3-fluoro-4-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(4-methoxy-2-methylbenzyl)-2-phenylcyclopropanamine;   (trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-yl)methyl)-2-phenylcyclopropanamine,   (trans)-N-((3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-((2,2-dimethylchroman-6-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(4-methoxy-2,3-dimethylbenzyl)-2-phenylcyclopropanamine;   (trans)-N-(4-methoxy-2,5-dimethylbenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2-fluoro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(3-chloro-4,5-dimethoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2-chloro-3,4-dimethoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2,4-dimethoxy-6-methylbenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2,5-dimethoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2,3-dimethoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-(2-chloro-3-methoxybenzyl)-2-phenylcyclopropanamine;   (trans)-N-((1H-indol-5-yl)methyl)-2-phenylcyclopropanamine;   (trans)-N-(1-(4-methoxyphenyl)ethyl)62-phenylcyclopropanamine;   (trans)-N-(1-(3,4-dimethoxyphenyl)ethyl)-2-phenylcyclopropanamine;   (trans)-N-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)-2-phenylcyclopropanamine;   (trans)-N-(1-(5-fluoro-2-methoxyphenyl)ethyl)-2-phenylcyclopropanamine;   (trans)-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)-2-phenylcyclopropanamine;   (trans)-N-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2-phenylcyclopropanamine;   
       and pharmaceutically acceptable salts of any thereof.