Lysine demethylase inhibitors for diseases and disorders associated with Flaviviridae

A method of treating a symptom of Hepatitis C virus infection or a liver disease in an individual infected with Hepatitis C virus, the method comprising administering to an individual in need of such treatment a Lysine Specific Demethylase-1 (LSD1) inhibitor, wherein said LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound of formula (I) or an enantiomer, a diastereomer, or a racemic mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

• wherein:
• A is cyclyl optionally having 1, 2, 3, or 4 substituents A′;
• each A′ is independently selected from -L1-cyclyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, -CH2-CO-NH2, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfonyl, sulfinyl, sulfonamide, acyl, carboxyl, carbamate and urea, wherein the cyclyl moiety comprised in said -L1-cyclyl is optionally further substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl,
• nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cyano, sulfonyl, sulfinyl, sulfonamide, acyl, carboxyl, carbamate and urea;
• each L1 is independently selected from a covalent bond, -(CH2)1-6, -(CH2)0-3-O-(CH2)0-3-, -(CH2)0-3-NH-(CH2)0-3- and -(CH2)0-3-S-(CH2)0-3-;
• B is -L2-cyclyl, -H, -L2-CO-NH2, -L2-CO-NR1R2 or -L2-CO-R3, wherein the cyclyl moiety in said -L2-cyclyl is aryl, cycloalkyl or heterocycoloalkyl, and wherein the cyclyl moiety in said -L2-cyclyl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea;
• R1 and R2 are each independently selected from —H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, and -L-heterocyclyl, wherein said alkyl, said alkynyl or said alkenyl is optionally substituted with one or more groups independently selected from halo, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea, and further wherein the carbocycle moiety in said -L-carbocycle, the aryl moiety in said -L-aryl, or the heterocyclyl moiety in said -L-heterocyclyl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea;
• R3 is selected from —H, alkoxy, -L-carbocyclic, -L-heterocyclic, and —L-aryl, wherein the carbocyclic moiety in said —L-carbocyclic, the heterocyclic moiety in said -L-heterocyclic, or the aryl moiety in said -L-aryl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycioalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea;
• each L is independently selected from -(CH2)n-(CH2)n-, -(CH2)nC(═O)(CH2)n-, -(CH2)nC(═O)NH(CH2)n-, -(CH2)nNHC(═O)O(CH2)n-, -(CH2)nNHC(═O)NH(CH2)n-, -(CH2)nNHC(═S)S(CH2)n-, -(CH2)nOC(═O)S(CH2)n-,- (CH2)nNH(CH2)n-, -(CH2)nO(CH2)n-, -(CH2)nS(CH2)n-, and -(CH2)nNHC(═S)NH(CH2)n-, wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;
• and
• L2 is C1-12 alkylene which is optionally interrupted by one or more groups independently selected from -O-, -S-, -NH-, -N(alkyl)-, -CO-, -CO-NH- and -CO-N(alkyl)-.

A method of treating Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV) co-infection comprising administering to an individual in need of such treatment a Lysine Specific Demethylase-1 (LSD1) inhibitor and optionally a second anti-HCV agent or anti-HBV agent, wherein said LSD1 inhibitor is a 2-cyclylcyclopropan-1-amine compound of formula (I) or an enantiomer, a diastereomer, or a racemic mixture thereof, or a pharmaceutically acceptable salt or solvate thereof:

• wherein:
• A is cyclyl optionally having 1, 2, 3, or 4 substituents A′;
• each A′ is independently selected from -L1-cyclyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, -CH2-CO-NH2, alkylamino, hydroxyl, nitro, halo, haloalkyl, haloalkoxy, cyano, sulfonyl, sulfinyl, sulfonamide, acyl, carboxyl, carbamate and urea, wherein the cyclyl moiety comprised in said -L1-cyclyl is optionally further substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl,
• nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cyano, sulfonyl, sulfinyl, sulfonamide, acyl, carboxyl, carbamate and urea;
• each L1 is independently selected from a covalent bond, -(CH2)1-6-, -(CH2)0-3-O-(CH2)0-3-, -(CH2)0-3-NH-(CH2)0-3- and -(CH2)0-3-S-(CH2)0-3-;
• B is -L2-cyclyl, -H, -L2-CO-NH2, -L2-CO-NR1R2 or -L2-CO-R3, wherein the cyclyl moiety in said -L2-cyclyl is aryl, cycloalkyl or heterocycoloalkyl, and wherein the cyclyl moiety in said -L2-cyclyl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea;
• R1 and R2 are each independently selected from —H, alkyl, alkynyl, alkenyl, -L-carbocycle, -L-aryl, and -L-heterocyclyl, wherein said alkyl, said alkynyl or said alkenyl is optionally substituted with one or more groups independently selected from halo, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea, and further wherein the carbocycle moiety in said -L-carbocycle, the aryl moiety in said -L-aryl, or the heterocyclyl moiety in said -L-heterocyclyl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycloalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea;
• R3 is selected from —H, alkoxy, -L-carbocyclic, -L-heterocyclic, and —L-aryl, wherein the carbocyclic moiety in said —L-carbocyclic, the heterocyclic moiety in said -L-heterocyclic, or the aryl moiety in said -L-aryl is optionally substituted with one or more groups independently selected from halo, haloalkyl, haloalkoxy, haloaryl, aryl, arylalkoxy, aryloxy, arylalkyl, alkyl, alkenyl, alkynyl, alkoxy, amino, amido, alkylamino, hydroxyl, nitro, -CH2-CO-NH2, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylalkyl, cycloalkyl, cycloalkylalkoxy, cycloalkoxy, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkoxy, heterocycloalkoxy, heterocycloalkylalkyl, cyano, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfonyl, sulfinyl, sulfonamide, trihalomethanesulfonamido, acyl, acylamino, acyloxy, alkylthio, cycloalkylthio, heterocycioalkylthio, arylthio, heteroarylthio, carboxyl, carbamate and urea;
• each L is independently selected from -(CH2)n-(CH2)n-, -(CH2)nC(═O)(CH2)n-, -(CH2)nC(═O)NH(CH2)n-, -(CH2)nNHC(═O)O(CH2)n-, -(CH2)nNHC(═O)NH(CH2)n-, -(CH2)nNHC(═S)S(CH2)n-, -(CH2)nOC(═O)S(CH2)n-,- (CH2)nNH(CH2)n-, -(CH2)nO(CH2)n-, -(CH2)nS(CH2)n-, and -(CH2)nNHC(═S)NH(CH2)n-, wherein each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;
• and
• L2 is C1-12 alkylene which is optionally interrupted by one or more groups independently selected from -O-, -S-, -NH-, -N(alkyl)-, -CO-, -CO-NH- and -CO-N(alkyl)-.