Cyclopropylamine inhibitors of oxidases

Abstract

The invention relates to cyclopropylamine compounds, in particular the compounds of Formula (I) as described and defined herein, and their use in therapy, including, e.g., the treatment or prevention of cancer.

1 - 27 . (canceled) 
     
     
         28 . A method of treating or preventing cancer, a neurological disease or condition, a viral infection, or reactivation of a virus after latency, the method comprising administering, to a subject in need of such treatment or prevention, a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         E is —X 3 ═X 4 —, —N(R3)-, —S—, or —O—; 
         X 1  and X 2  are each independently C(R2) or N; 
         X 3  and X 4 , when present, are each independently C(R2) or N; 
         L1 is —NH— or —NH—CH 2 —; 
         G is a cyclyl group; 
         each R1 is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl; 
         each R2 is independently chosen from —H, alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl, wherein each R2 group has 1, 2, or 3 independently chosen optional substituents, and further wherein two R2 groups bound to adjacent carbon atoms can be taken together to form a heterocyclyl or aryl group having 1, 2, or 3 independently chosen optional substituents; wherein said optional substituents are each independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfinyl, sulfonyl, sulfonamide, urea and carbamate; 
         R3 is —H or an (C1-C6)alkyl group; 
         each L2 is independently chosen from alkylene and heteroalkylene; and 
         n is 0, 1, 2, 3, 4 or 5; 
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         29 . The method of  claim 28 , wherein said cancer is chosen from breast cancer, lung cancer, prostate cancer, colorectal cancer, brain cancer, skin cancer, blood cancer, leukemia and lymphoma. 
     
     
         30 - 31 . (canceled) 
     
     
         32 . The method of  claim 28 , wherein said neurological disease or condition is chosen from depression, Alzheimer's disease, Huntington disease, Parkinson's disease, and or Dementia with Lewy Bodies. 
     
     
         33 . (canceled) 
     
     
         34 . A method of modulating histone methylation levels in a mammalian cell, the method comprising administering a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         E is —X 3 ═X 4 —, —N(R3)-, —S—, or —O—; 
         X 1  and X 2  are each independently C(R2) or N; 
         X 3  and X 4 , when present, are each independently C(R2) or N; 
         L1 is —NH— or —NH—CH—; 
         G is a cyclyl group; 
         each R1 is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl; 
         each R2 is independently chosen from —H, alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl, wherein each R2 group has 1, 2, or 3 independently chosen optional substituents, and further wherein two R2 groups bound to adjacent carbon atoms can be taken together to form a heterocyclyl or aryl group having 1, 2, or 3 independently chosen optional substituents; wherein said optional substituents are each independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido, cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfinyl, sulfonyl, sulfonamide, urea and carbamate; 
         R3 is —H or an (C1-C6)alkyl group; 
         each L2 is independently chosen from alkylene and heteroalkylene; and 
         n is 0, 1, 2, 3, 4 or 5; 
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         35 . The method of  claim 34 , wherein histone-3 lysine-4 methylation levels are modulated. 
     
     
         36 . The method of  claim 34 , wherein histone-3 lysine-9 methylation levels are modulated. 
     
     
         37 . A method of modulating gene expression levels in a mammalian cell, the method comprising administering a compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         E is —X 3 ═X 4 —, —N(R3)-, —S— or —O—; 
         X 1  and X 2  are each independently C(R2) or N; 
         X 3  and X 4 , when present, are each independently C(R2) or N; 
         L1 is —NH— or —NH—CH 2 —; 
         G is a cyclyl group; 
         each R1 is independently chosen from alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl; 
         each R2 is independently chosen from —H, alkyl, alkenyl, alkynyl, cyclyl, -L2-cyclyl, -L2-amino, -L2-hydroxyl, amino, amido, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfinyl, sulfonyl, sulfonamide, hydroxyl, alkoxy, urea, carbamate, acyl, and carboxyl, wherein each R2 group has 1, 2, or 3 independently chosen optional substituents, and further wherein two R2 groups bound to adjacent carbon atoms can be taken together to form a heterocycyl or aryl group having 1, 2, or 3 independently chosen optional substituents; wherein said optional substituents are each independently chosen from alkyl, alkanoyl, heteroalkyl, heterocyclyl, haloalkyl, cycloalkyl, carbocyclyl, arylalkoxy, heterocyclylalkoxy, aryl, aryloxy, heterocyclyloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, carboxamido cyano, halogen, hydroxyl, amino, aminoalkyl, amidoalkyl, amido, nitro, thiol, alkylthio, arylthio, sulfinyl, sulfonyl, sulfonamide, urea and carbamate; 
         R3 is —H or an (C1-C6)alkyl group; 
         each L2 is independently chosen from alkylene and heteroalkylene; and 
         n is 0, 1, 2, 3, 4 or 5; 
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         38 - 46 . (canceled) 
     
     
         47 . The method of  claim 28 , wherein said subject is a human. 
     
     
         48 . The method of  claim 28 , wherein L1 is —NH—. 
     
     
         49 . The method of  claim 28 , wherein L1 is —NH—CH s —. 
     
     
         50 . The method of  claim 28 , wherein G is aryl or heterocyclyl. 
     
     
         51 . The method of  claim 28 , wherein G is aryl or heteroaryl. 
     
     
         52 . The method of  claim 28 , wherein G is heterocyclyl. 
     
     
         53 . The method of  claim 28 , wherein E is —X 3 ═X 4 —. 
     
     
         54 . The method of  claim 53 , wherein one of X 1 , X 2 , X 3 , and X 4  is N or C(R2) and the other ones of X 1 , X 2 , X 3 , and X 4  are each independently C(R2). 
     
     
         55 . The method of  claim 53 , wherein one of X 1 , X 2 , X 3  and X 4  is N and the other ones of X 1 , X 2 , X 3  and X 4  are each independently C(R2). 
     
     
         56 . The method of  claim 28 , wherein each R1 is independently chosen from lower alkyl, lower alkynyl, amido, halo, lower haloalkyl, cyano, hydroxyl, and alkoxy. 
     
     
         57 . The method of  claim 28 , wherein each R2 is —H. 
     
     
         58 . The method of  claim 28 , wherein the compound of Formula (I) is in the trans configuration in respect of the substituents on the cyclopropyl ring. 
     
     
         59 . The method of  claim 28 , wherein the compound of formula (I) is chosen from:
 5-((trans)-2-aminocyclopropyl)-N-(3-chlorophenyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-chlorophenyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(3-methoxyphenyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-methoxyphenyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-p-tolylpyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-m-tolylpyridin-2-amine;   4-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzonitrile;   3-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzonitrile;   3-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzamide;   4-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)benzamide;   5-((trans)-2-aminocyclopropyl)-N-(3-chlorobenzyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-chlorobenzyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(3-(trifluoromethyl)benzyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-(trifluoromethyl)benzyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(3-methylbenzyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-methylbenzyl)pyridin-2-amine;   3-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzonitrile;   4-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzonitrile;   5-((trans)-2-aminocyclopropyl)-N-(3-methoxybenzyl)pyridin-2-amine;   5-((trans)-2-aminocyclopropyl)-N-(4-methoxybenzyl)pyridin-2-amine;   4-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)phenol;   3-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzamide;   4-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)benzamide;   4-((5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)methyl)phenol;   5-((trans)-2-aminocyclopropyl)-N-(3-ethynylphenyl)pyridin-2-amine;   N-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-1H-indol-7-amine;   N-(5-((trans)-2-aminocyclopropyl)pyridin-2-yl)-1H-indazol-7-amine;   3-(5-((trans)-2-aminocyclopropyl)pyridin-2-ylamino)phenol;   4-((trans)-2-aminocyclopropyl)-N-(4-methylbenzyl)aniline;   4-((trans)-2-aminocyclopropyl)-N-(4-(trifluoromethyl)benzyl)aniline;   4-((trans)-2-aminocyclopropyl)-N-(3-chlorobenzyl)aniline;   3-(((4-((trans)-2-aminocyclopropyl)phenyl)amino)methyl)benzonitrile;   4-((trans)-2-aminocyclopropyl)-N-(p-tolyl)aniline;   4-((trans)-2-aminocyclopropyl)-N-(4-chlorophenyl)aniline;   3-((4-((trans)-2-aminocyclopropyl)phenyl)amino)benzonitrile;   N-(4-((trans)-2-aminocyclopropyl)phenyl)-3-methoxyaniline;   3-((4-((trans)-2-aminocyclopropyl)phenyl)amino)benzamide;   and pharmaceutically acceptable salts or solvates thereof.