The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders associated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5
The invention comprises methods of modulating the complement cascade in a mammal and for treating and/or preventing diseases and disorders associated with the complement pathway by administering a compound of Formula I or Formula II, such as, for example, 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one or a pharmaceutically acceptable salt thereof.
대표청구항▼
1. A method for treating a complement-associated disease or disorder selected from paroxysmal nocturnal hemoglobinuria, familial CD59 deficiency, cold agglutinin disease, hereditary angioedema, hemolytic anemia, and thrombocytopenia by modulating the complement system in a subject in need thereof co
1. A method for treating a complement-associated disease or disorder selected from paroxysmal nocturnal hemoglobinuria, familial CD59 deficiency, cold agglutinin disease, hereditary angioedema, hemolytic anemia, and thrombocytopenia by modulating the complement system in a subject in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, wherein: R1 and R3 are each independently selected from alkoxy, alkyl, amino, halogen, and hydrogen;R2 is selected from alkoxy, alkyl, alkenyl, alkynyl, amide, amino, halogen, and hydrogen;R5 and R7 are each independently selected from alkyl, alkoxy, amino, halogen, and hydrogen;R6 is selected from amino, amide, alkyl, hydrogen, hydroxyl, piperazinyl, and alkoxy, wherein the alkoxy is optionally substituted with one or more groups chosen from amide, amine, aryl, benzyloxy, carbamate, carboxy, heterocyclyl, hydroxyl, methoxy, and sulfonamide; andW is CH or N. 2. The method of claim 1, wherein W is CH; and R6 is selected from alkoxy substituted with one or more groups chosen from amide, amine, aryl, benzyloxy, carbamate, carboxy, heterocyclyl, hydroxyl, methoxy, and sulfonamide. 3. The method of claim 1, wherein: R6 is selected from hydrogen, methoxy, wherein n is 1, 2, or 3;R8 is selected from hydrogen or C1-C6 alkyl optionally substituted with one or more groups selected from methyl, phenyl, and pyridinyl;R9 and R10 are independently selected from unsubstituted C1-C6 alkyl, wherein R9 and R10 may be joined together with N to form a 3- to 12-membered ring. 4. The method of claim 1, wherein R6 is selected from 2-(hydroxy)ethoxy, 2-(pyrrolidin-1-yl)ethoxy, 4-isopropylpiperazin-1-yl, and 2-(isopropylamino)ethoxy. 5. The method of claim 1, wherein R6 is 2-(hydroxy)ethoxy; and R1 and R3 are methoxy. 6. The method of claim 1, wherein the compound of Formula I is selected from: 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-{3,5-dimethyl-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-5,7-dimethoxy-3,4-dihydroquinazolin-4-one;2-(3,5-dimethyl-4-{2-[(propan-2-yl)amino]ethoxy}phenyl)-5,7-dimethoxy-3,4-dihydroquinazolin-4-one;5,7-dimethoxy-2-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3,4-dihydroquinazolin-4-one;5,7-dimethoxy-2-{3-methoxy-5-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-3,4-dihydroquinazolin-4-one;2-{3,5-dimethyl-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-5,7-dimethoxy-3H,4H-pyrido[2,3-d]pyrimidin-4-one;2-{4-[2-(3,3-difluoropyrrolidin-1-yl)ethoxy]-3,5-dimethylphenyl}-5,7-dimethoxy-3,4-dihydroquinazolin-4-one;N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethyl}-2-methylpropanamide;5,7-dimethoxy-2-[4-(piperazin-1-yl)phenyl]-3,4-dihydroquinazolin-4-one;2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-3,4-dihydroquinazolin-4-one;N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethyl}acetamide;methyl N-{2-[4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy]ethyl}carbamate;2-[4-(2,3-dihydroxypropoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-3,4-dihydroquinazolin-4-one;N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methylbenzamide;2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate;2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)methanesulfonamide;4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-4-methoxybenzenesulfonamide;2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)-N2-methylphthalamide;2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;5,7-dimethoxy-2-(4-methoxy-3-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)-2-hydroxyacetamide;2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetic acid;N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide;5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(6, 7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)acetamide;N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6, 7-dimethoxyquinazolin-4(3H)-one;2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof. 7. The method of claim 1, wherein the compound of Formula I is [2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one], or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. 8. The method of claim 1, wherein the compound of Formula I is 2-{3,5-dimethyl-4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}-5,7-dimethoxy-3,4-dihydroquinazolin-4-one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. 9. The method of claim 1, wherein the compound of Formula I is 2-(3,5-dimethyl-4-{2-[(propan-2-yl)amino]ethoxy}phenyl)-5,7-dimethoxy-3,4-dihydroquinazolin-4-one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. 10. The method of claim 1, wherein the compound of Formula I is 5,7-dimethoxy-2-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-3,4-dihydroquinazolin-4-one, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. 11. A method for treating a complement-associated disease or disorder selected from paroxysmal nocturnal hemoglobinuria, familial CD59 deficiency, cold agglutinin disease, hereditary angioedema, hemolytic anemia, and thrombocytopenia by modulating the complement system in a subject in need thereof comprising administering a therapeutically effective amount of 2-{2-[(dimethylamino)methyl]-1H-indol-5-yl}-5,7-dimethoxy-3,4-dihydroquinazolin-4-one or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof. 12. The method of claim 1, wherein the complement-associated disease or disorder is paroxysmal nocturnal hemoglobinuria. 13. The method of claim 1, wherein the complement-associated disease or disorder is selected from familial CD59 deficiency, cold agglutinin disease, and hereditary angioedema (HAE). 14. The method of claim 1, wherein the subject is a human.
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