CHUNG WOOK JOON (US)
DAVIES HUW (US)
DU YUHONG (US)
BONI YANNICK (US)
FU HAIAN (US)
ARCHER DAVID (US)
CHILDRENS HEALTHCARE ATLANTA INC (US)
CLAIMS 1. A compound having the following formula or salt thereof wherein R1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10; R2 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R10; or R1 and R2 and the attached nitrogen come together to form a carbocyclyl, aryl, or heterocyclyl optionally substituted, with one or more, the same or different, R10; R3 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl; R4 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R10; R5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10; or R4 and R5 and the attached atoms come together to form a cyclic or heterocyclic ring optionally substituted with one or more, the same or different, R10. R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 0 is optionally substituted with one or more, the same or different, R11; and R11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 2. The compound of claim 1 having the following formula or salt thereof wherein R1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10; R2 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R10; or R1 and R2 and the attached nitrogen come together to form a carbocyclyl, aryl, or heterocyclyl optionally substituted, with one or more, the same or different, R10; R10 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11; R is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; R12 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl; and R13 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl. 3. The compound of claim 1 having the following formula or salt thereof wherein R2 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R10; or R3 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl; R is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R10; R5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10; R6 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10; R7 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10; R8 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10; R9 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10; R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11; and R11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 4. The compound of claim 1 having the following formula or salt thereof wherein R2 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R10; or R3 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl; R6 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R10; R7 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R10; R8 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R10; R9 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R10; R10 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11; and R11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; R12 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl; and R13 is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl. 5. The compound of claim 4, which is 2-(3-(5-chloro-2-methoxyphenyl)ureido)-N,N- dimethyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-sulfonamide (SCAS2_01) or salt thereof. 6. The compound of claim 4, which is 1-(5-chloro-2-methoxyphenyl)-3-(5- (cyclopropylsulfonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)urea (SCAS2_05) or salt thereof. 7. A compound 6-(piperidin-1-ylsulfonyl)benzo[d]thiazol-2-amine (SCAS-02) or salt thereof. 8. A pharmaceutical composition comprising a compound as in any of claims 1-7 and a pharmaceutically acceptable excipient. 9. A method of treating or preventing sickle cell disease or related condition comprising administering an effective amount of a compound as provided in any of claims 1-6 to a subject in need thereof. 10. A compound having the following formula or salts thereof, wherein X is S or O; Y is O or S; R1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R20; or R is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R20; R3 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R20; R4 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R20; or R1 and R4 and the attached atoms come together to form a heterocyclic ring, optionally substituted with one or more, the same or different, R20; R5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R20; R6 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R20; R7 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R20; R8 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R8 is optionally substituted with one or more, the same or different, R20; R9 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R9 is optionally substituted with one or more, the same or different, R20; or R8 and R9 and the attached atoms come together to form a heterocyclic ring, optionally substituted with one or more, the same or different, R20; R20 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R20 is optionally substituted with one or more, the same or different, R21; and R21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 11. The compound of claim 10 wherein X is S and Y is O, or wherein X is S and Y is S. 12. The compound of claim 10 having the following formula or salts thereof, wherein X is S, NH, or O; Y is O or S; R1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R20; or R2 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R20; R3 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R3 is optionally substituted with one or more, the same or different, R20; R4 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R20; or R1 and R4 and the attached atoms come together to form a heterocyclic ring, optionally substituted with one or more, the same or different, R20; R5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R20; R6 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R6 is optionally substituted with one or more, the same or different, R20; R7 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R7 is optionally substituted with one or more, the same or different, R20; R10 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R20; or R11 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R11 is optionally substituted with one or more, the same or different, R20; R12 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R12 is optionally substituted with one or more, the same or different, R20; R13 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R13 is optionally substituted with one or more, the same or different, R20; R14 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R is optionally substituted with one or more, the same or different, R20; R15 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R15 is optionally substituted with one or more, the same or different, R20; R16 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R16 is optionally substituted with one or more, the same or different, R20; R17 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R17 is optionally substituted with one or more, the same or different, R20; R20 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R20 is optionally substituted with one or more, the same or different, R21; and R21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 13. The compound of claim 12 wherein X is S and Y is O, or wherein X is S and Y is S. 14. The compound of claim 12, which is 1-(tert-butylthio)-3-(3,6-dichloro-9H-carbazol-9- yl)propan-2-ol (SCAS2_61) or salt thereof. 15. The compound of claim 12, which is 2-((3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)amino)-2- (hydroxymethyl)propane-1,3-diol (SCAS2_20); 1-(3,6-dichloro-9H-carbazol-9-yl)-3-(isopentylamino)propan-2-ol (SCAS2_A2); 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(isopentylamino)propan-2-ol (SCAS2_A13); 1-(sec-butylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol (SCAS2_A14); or salt thereof 16. A compound having the following formula or salts thereof, wherein R1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R1 is optionally substituted with one or more, the same or different, R10; R is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R2 is optionally substituted with one or more, the same or different, R10; or R3 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl; or R4 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R4 is optionally substituted with one or more, the same or different, R10; or R3 and R4 and the attached nitrogen come together to form a carbocyclyl, aryl, or heterocyclyl optionally substituted, with one or more, the same or different, R10; R5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R5 is optionally substituted with one or more, the same or different, R10; R10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R10 is optionally substituted with one or more, the same or different, R11; and R11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 17. The compound of claim 16, wherein the compound is selected from: 1-(3-chlorophenyl)-1H-pyrrole-2,5-dione (HDYB-1); 1-(3-chloro-4-methylphenyl)-1H-pyrrole-2,5-dione (HDYB-2); 1-(3-(trifluoromethyl)phenyl)-1H-pyrrole-2,5-dione (HDYB-3); 1-(3,5-dichlorophenyl)-1H-pyrrole-2,5-dione (HDYB-4); 1-phenyl-1H-pyrrole-2,5-dione (HDYB-5); 1-(4-bromo-2-chlorophenyl)-1H-pyrrole-2,5-dione (HDYB-6); 1-(4-fluoro-3-methylphenyl)-1H-pyrrole-2,5-dione (HDYB-7); 1-(5-chloro-3-methyl-[1,1'-biphenyl]-2-yl)-1H-pyrrole-2,5-dione (HDYB-8); 1-(5-chloro-2-methylphenyl)-1H-pyrrole-2,5-dione (HDYB-12); 1-(3-chloro-5-nitrophenyl)-1H-pyrrole-2,5-dione (HDYB-13); 1-(4-bromo-3-chlorophenyl)-1H-pyrrole-2,5-dione (HDYB-14); 1-(3-chloro-4-fluorophenyl)-1H-pyrrole-2,5-dione (HDYB-18); 1-(p-tolyl)-1H-pyrrole-2,5-dione (HDYB-21); 1-(4-iodophenyl)-1H-pyrrole-2,5-dione (HDYB-22); 1-([1,1'-biphenyl]-4-yl)-1H-pyrrole-2,5-dione (HDYB-23); 1-(3-fluorophenyl)-1H-pyrrole-2,5-dione (HDYB-24); 1-(2,3-dihydrobenzofuran-5-yl)-1H-pyrrole-2,5-dione (HDYB-26); 1-(3-oxo-1,3-dihydroisobenzofuran-5-yl)-1H-pyrrole-2,5-dione (HDYB-27); or salt thereof. 18. A compound 1,1'-(2,5-dichloro-1,4-phenylene)bis(1H-pyrrole-2,5-dione) (HDYB-25) or salt thereof 19 A pharmaceutical composition comprising a compound as in any of claims 11-18 and a pharmaceutically acceptable excipient. 20. A method of treating or preventing sickle cell disease or related condition comprising administering an effective amount of a compound as provided in any of claims 10-18 to a subject in need thereof. |
In certain embodiments, the compound has the following formula derivatives, prodrugs, or salts thereof wherein substituents are reported herein. In certain embodiments X is S or O; or S, NH, or O; Y is O or S; R 1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 20 ; or R 2 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ; R 3 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 20 ; R 4 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ; or R and R and the attached atoms come together to form a heterocyclic ring, optionally substituted with one or more, the same or different, R 20 ; R 5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ; R 6 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 20 ; R 7 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 7 is optionally substituted with one or more, the same or different, R 20 ; R 10 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ; or R 11 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ; R 12 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ; R 13 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ; R is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ; R 15 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ; R 16 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl) 2 amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 16 is optionally substituted with one or more, the same or different, R 20 ; R 17 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 17 is optionally substituted with one or more, the same or different, R 20 ; R 20 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 20 is optionally substituted with one or more, the same or different, R 21 ; and R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. In certain embodiments, X is S and Y is O, and R 12 and R 15 are halogen. In certain embodiments, X is NH and Y is O, and R 12 and R 15 are halogen. In certain embodiments, X is S or NH, and R is an alkyl or tertiary alkyl optionally substituted with a substituent and R 12 and R 15 are halogen. In certain embodiments, Y is O and R 4 is hydrogen optionally substituted with a substituent and R 12 and R 15 are halogen. In certain embodiments, R 2 , R 3 , R 5 , R 6 and R 7 are hydrogen and R 12 and R 15 are halogen. In certain embodiments, R 10 , R 11 , R 13 , R 14 , R 16 , and R 17 are hydrogen. In certain embodiments, the compound is 2-((3-(3,6-dibromo-9H-carbazol-9-yl)-2- hydroxypropyl)amino)-2-(hydroxymethyl)propane-1,3-diol (SCAS2_20), derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(tert-butylthio)-3-(3,6-dichloro-9H-carbazol- 9-yl)propan-2-ol (SCAS2_61), derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3,6-dichloro-9H-carbazol-9-yl)-3- (isopentylamino)propan-2-ol (SCAS2_A2) , derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3,6-dibromo-9H-carbazol-9-yl)-3- (isopentylamino)propan-2-ol (SCAS2_A13) , derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(sec-butylamino)-3-(3,6-dichloro-9H- carbazol-9-yl)propan-2-ol (SCAS2_A14) , derivative, prodrug, or salt thereof. In certain embodiments, the compound has the following formula derivatives, prodrugs, or salts thereof wherein substituents are reported herein. In certain embodiments R 1 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 1 is optionally substituted with one or more, the same or different, R 10 ; R 2 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 10 ; or R 3 is hydrogen, alkyl, halogenated alkyl, formyl, alkanoyl, benzyl, benzoyl, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl; or R 4 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 10 ; or R 3 and R 4 and the attached nitrogen come together to form a carbocyclyl, aryl, or heterocyclyl optionally substituted, with one or more, the same or different, R 10 ; R 5 is hydrogen, alkyl, halogenated alkyl, halogen, hydroxy, alkoxy, alkylthio, amino, alkylamino, (alkyl)2amino, cyano, formyl, alkanoyl, benzyl, benzoyl, carboxy, carbamoyl, sulfamoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 10 ; R 10 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, sulfamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, carbocyclylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkanoyl, benzyl, benzoyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 11 ; and R 11 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, propyl, tert-butyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N- ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N- diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, cyclopropylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N- methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl- N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. In certain embodiments, the compound is 1-(3-chlorophenyl)-1H-pyrrole-2,5-dione (HDYB-1) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3-chloro-4-methylphenyl)-1H-pyrrole-2,5- dione (HDYB-2) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3-(trifluoromethyl)phenyl)-1H-pyrrole-2,5- dione (HDYB-3) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3,5-dichlorophenyl)-1H-pyrrole-2,5-dione (HDYB-4) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-phenyl-1H-pyrrole-2,5-dione (HDYB-5) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(4-bromo-2-chlorophenyl)-1H-pyrrole-2,5- dione (HDYB-6) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(4-fluoro-3-methylphenyl)-1H-pyrrole-2,5- dione (HDYB-7) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(5-chloro-3-methyl-[1,1'-biphenyl]-2-yl)-1H- pyrrole-2,5-dione (HDYB-8) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(5-chloro-2-methylphenyl)-1H-pyrrole-2,5- dione (HDYB-12) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3-chloro-5-nitrophenyl)-1H-pyrrole-2,5- dione (HDYB-13) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(4-bromo-3-chlorophenyl)-1H-pyrrole-2,5- dione (HDYB-14) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3-chloro-4-fluorophenyl)-1H-pyrrole-2,5- dione (HDYB-18) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(p-tolyl)-1H-pyrrole-2,5-dione (HDYB-21) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(4-iodophenyl)-1H-pyrrole-2,5-dione (HDYB- 22) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-([1,1-biphenyl]-4-yl)-1H-pyrrole-2,5-dione (HDYB-23) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3-fluorophenyl)-1H-pyrrole-2,5-dione (HDYB-24) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(2,3-dihydrobenzofuran-5-yl)-1H-pyrrole-2,5- dione (HDYB-26) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1-(3-oxo-1,3-dihydroisobenzofuran-5-yl)-1H- pyrrole-2,5-dione (HDYB-27) derivative, prodrug, or salt thereof. In certain embodiments, the compound is 1,1'-(2,5-dichloro-1,4-phenylene)bis(1H- pyrrole-2,5-dione) (HDYB-25) derivative, prodrug, or salt thereof. Methods of managing sickle cell disease and conditions related thereto In certain embodiments, this disclosure contemplates using compounds disclosed herein as modulators of hemoglobin, e.g., treating disorders mediated by hemoglobin and disorders that would benefit from tissue and/or cellular oxygenation. Sickle cell disease is a group of disorders that affects hemoglobin. People with this disorder have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle, or crescent, shape. When red blood cells sickle, they break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children. In certain embodiments, this disclosure relates to method of treating anemia, shortness of breath, fatigue, and delayed growth and development in children by administering a compound disclosed herein to a subject in need thereof. In certain embodiments, the compound disclosed herein may be used in methods disclosed herein in combination with other agents used to treat or prevent sickle cell disease, conditions, or complications. In certain embodiments, the subject to be treated is diagnosed with a disease or condition reported herein. In certain embodiments, this disclosure relates to using a compound disclosed herein for treating sickle cell disease resulting in fewer, or less severe side effects, greater efficacy, greater response rate, or combinations thereof compared to existing therapies such as hydroxyurea or another therapeutic agent. In certain embodiments, the compound disclosed herein may be used in methods of treating sickle cell diseases including sickle cell anemia, sickle-hemoglobin C disease, sickle beta-plus- thalassemia and sickle beta-zero-thalassemia. In certain embodiments, the compound disclosed herein may be used in methods of treating hematological disorders such as sickle cell disease, pulmonary disease such as idiopathic pulmonary fibrosis, and hypoxia. In certain embodiments, the compound disclosed herein may be used in methods of increasing affinity of hemoglobin for oxygen in a patient. For purposes of treatment of sickle cell disease, beneficial or desired clinical results include, but are not limited to, multi-lineage hematologic improvement, decrease in the number of required blood transfusions, decrease in infections, decreased bleeding, and the like. For purposes of treatment of interstitial pulmonary fibrosis, beneficial or desired clinical results include, but are not limited to, reduction in hypoxia, reduction in fibrosis, and the like. Sickle cell trait or the carrier state is the heterozygous form characterized by the presence of HbS, absence of anemia, inability to concentrate urine (isosthenuria), and hematuria. Under conditions leading to hypoxia, it may become a pathologic risk factor. Accordingly, in some embodiments, the disclosed compounds disclosed herein are used to treat a subject heterozygous for an autosomal recessive mutation in the beta-chain gene of hemoglobin (i.e., heterozygous for HbS). In certain embodiments, this disclosure relates to methods of treating thalassemia, for example beta-thalassemia, in a subject in need thereof by administering to the subject an effective amount of a compound disclosed herein optionally in combination with hydroxyurea or another therapeutic agent. Beta-thalassemias are a group of inherited blood disorders caused by a variety of mutational mechanisms that result in a reduction or absence of synthesis of beta-globin and leading to accumulation of aggregates of unpaired, insoluble alpha-chains that cause ineffective erythropoiesis, accelerated red cell destruction, and severe anemia. Subjects with beta-thalassemia exhibit variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The mutations can involve a single base substitution or deletions or inserts within, near or upstream of the beta globin gene. For example, mutations occurring in the promoter regions preceding the beta-globin genes cause production of abnormal splice variants. Examples of a thalassemia contemplated for treatment with compounds disclosed herein optionally in combination with hydroxyurea or another therapeutic agent include thalassemia minor, thalassemia intermedia, and thalassemia major. Thalassemia minor refers to thalassemia where only one of beta-globin alleles bears a mutation. Individuals typically suffer from microcytic anemia. Detection usually involves lower than normal MCV value (<80 fL) plus an increase in fraction of Hemoglobin A2 (>3.5%) and a decrease in fraction of Hemoglobin A (<97.5%). Thalassemia intermedia refers to a thalassemia intermediate between the major and minor forms. Affected individuals can often manage a normal life but may need occasional transfusions, e.g., at times of illness or pregnancy, depending on the severity of their anemia. Thalassemia major refers to a thalassemia where both beta-globin alleles have thalassemia mutations. If left untreated, it causes anemia, splenomegaly, and severe bone deformities and typically leads to death before age 20. Treatment consists of periodic blood transfusion; splenectomy if splenomegaly is present, and treatment of transfusion-caused iron overload. Although carriers of sickle cell trait typically do not suffer from sickle cell disease, individuals with one copy of HbS and one copy of a gene that codes for another abnormal variant of hemoglobin, such as HbC or Hb beta-thalassemia, have a less severe form of the disease. For example, another specific defect in beta-globin causes another structural variant, hemoglobin C (HbC). Hemoglobin C (abbreviated as HbC) is an abnormal hemoglobin in which substitution of a glutamic acid residue with a lysine residue at the 6 th position of the beta-globin chain has occurred. A subject that is a double heterozygote for HbS and HbC (HbSC disease) is typically characterized by symptoms of moderate clinical severity. In certain embodiments, this disclosure contemplates treatment by administering effective amounts of compounds disclosed herein to subject that is a double heterozygote for HbS and HbC (HbSC disease). Another structural variant of beta-globin is hemoglobin E or hemoglobin E (HbE). HbE is an abnormal hemoglobin in which substitution of a glutamic acid residue with a lysine residue at the 26 th position of the beta-globin chain has occurred. A subject that is a double heterozygote for HbS and HbE has HbS/HbE syndrome. In certain embodiments, this disclosure contemplates treatment by administering effective amounts of a compound disclosed herein to subject that is a double heterozygote for HbS and HbE (HbS/HbE) syndrome. Some mutations in the beta-globin gene can cause other structural variations of hemoglobin or can cause a deficiency in the amount of beta-globin being produced. These types of mutations are referred to as beta-thalassemia mutations. In certain embodiments, this disclosure contemplates treatment by administering effective amounts of a compound disclosed herein to subject that is diagnosed with as beta-thalassemia mutations. The absence of beta-globin is referred to as beta-zero (beta-0) thalassemia. A subject that is a double heterozygote for HbS and beta-0 thalassemia (i.e., HbS/beta-0 thalassemia) can suffer symptoms clinically similar to sickle cell anemia. In certain embodiments, this disclosure contemplates treatment by administering effective amounts of a compound disclosed herein to subject that is diagnosed with beta-zero thalassemia. A reduced amount of beta-globin is referred to as beta-plus (beta+) thalassemia. A subject that is a double heterozygote for HbS and beta+thalassemia (i.e., HbS/beta+thalassemia) can have mild-to-moderate severity of clinical symptoms with variability among different ethnicities. In certain embodiments, this disclosure contemplates treatment by administering effective amounts of a compound disclosed herein to subject that is diagnosed with beta-plus thalassemia. In certain embodiments, this disclosure contemplates treating retinopathy complications due to sickle cell diseases or complications by administering an effective amount of a compound disclosed herein, optionally in combination with hydroxyurea or another therapeutic agent. Sickle retinopathy occurs when the retinal blood vessels get occluded by sickle red blood cells and the retina becomes ischemic. In sickle cell disease, this occurs mostly in the peripheral retina, which does not obscure vision at first. Eventually, the entire peripheral retina of the sickle cell patient becomes occluded and many neovascular formations occur. In certain embodiments, this disclosure contemplates administration of a compound disclosed herein optionally in combination with hydroxyurea or another therapeutic agent in order to reduce or inhibit the formation of occlusions in the peripheral retina of a sickle cell patient. In some embodiments, a compound disclosed herein is used to increase hemoglobin expression or activity in non-erythroid cells including, but not limited to, macrophage, retinal pigment cells, and alveolar epithelial cells such as alveolar type II (ATII) cells and Clara cells. In some embodiments, a compound disclosed herein is used to increase hemoglobin expression or activity in non-erythroid cells at interfaces where oxygen-carbon dioxide diffusion occurs, including, but not limited to the eyes and lungs. In some embodiments, a compound disclosed herein is used to induce, increase, or enhance hemoglobin synthesis or activity in retinal pigment cells in an effective amount to prevent, reduce, or alleviate one or more symptoms of age-related macular degeneration or diabetic retinopathy. In some embodiments, a compound disclosed herein is administered to a subject in an effective amount to treat or prevent one or more condition, signs, or symptom associated with sickle cell disease, a beta-thalassemia, or a related disorder as provided below. Beta-thalassemia can include symptoms such as anemia, fatigue and weakness, pale skin, or jaundice (yellowing of the skin), protruding abdomen with enlarged spleen and liver, dark urine, abnormal facial bones and poor growth, and poor appetite. In subjects with sickle cell disease, or a related disorder, physiological changes in RBCs can result in a disease with the following signs: (1) hemolytic anemia; (2) vaso-occlusive crisis; and (3) multiple organ damage from microinfarcts, including heart, skeleton, spleen, and central nervous system. In sickle cell disease, red blood cell survival is around 10-20 days. Approximately one third of the hemolysis occurs intravascularly, releasing free hemoglobin (plasma free hemoglobin [PFH]) and arginase into plasma. PFH has been associated with endothelial injury including scavenging nitric oxide (NO), proinflammatory stress, and coagulopathy, resulting in vasomotor instability and proliferative vasculopathy. Vaso-occlusive crisis occurs when the circulation of blood vessels is obstructed by sickled red blood cells, causing ischemic injuries. The most common complaint is of pain, and recurrent episodes may cause irreversible organ damage. One of the most severe forms is the acute chest syndrome which occurs as a result of infarction of the lung parenchyma. Pain can affect any body part. It often involves the abdomen, bones, joints, and soft tissue, and it may present as dactylitis (bilateral painful and swollen hands and/or feet in children), acute joint necrosis or avascular necrosis, or acute abdomen. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vaso-occlusion, leading to isosthenuria (i.e., inability to concentrate urine). Severe deep pain can be present in the extremities, involving long bones. Abdominal pain can be severe, resembling acute abdomen; it may result from referred pain from other sites or intra- abdominal solid organ or soft tissue infarction. Bone pain and abdominal pain may be present. The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis. Skeletal manifestations include, but are not limited to, infarction of bone and bone marrow, compensatory bone marrow hyperplasia, secondary osteomyelitis, secondary growth defects, intravascular thrombosis, osteonecrosis (avascular necrosis/aseptic necrosis), degenerative bone and joint destruction, osteolysis (in acute infarction), Articular disintegration, periosteal reaction (unusual in the adult), Dystrophic medullary calcification, bone-within-bone appearance, decreased density of the skull, decreased thickness of outer table of skull due to widening of diploe, hair on-end striations of the calvaria, osteoporosis sometimes leading to biconcave vertebrae, coarsening of trabeculae in long and flat bones, and pathologic fractures, bone shortening (premature epiphyseal fusion), epiphyseal deformity with cupped metaphysis, peg-in-hole defect of distal femur, and decreased height of vertebrae (short stature and kyphoscoliosis). Renal manifestations include, but are not limited to, various functional abnormalities such as hematuria, proximal tubule dysfunction, impaired potassium excretion, and hyperkalemia; and gross anatomic alterations, for example, hypertrophied kidneys, with a characteristic smooth, capsular surface. Splenic manifestations include, but are not limited to, enlargement, including rapid and/or painful enlargement known as splenic sequestration crisis, infarction, low pH and low oxygen tension in the sinusoids and splenic cords, functional impairment, fibrosis and shrinking of the spleen, immune deficiency, and increased risk of sepsis. In certain embodiments, this disclosure relates to using a compound disclosed herein for treating subjects with sickle cell disease, beta thalassemia, or variants or related diseases or conditions thereof. In certain embodiments, this disclosure relates to using a compound disclosed herein for reducing one or more symptoms of sickle cell disease, beta thalassemia, or variants or related diseases or conditions thereof. In certain embodiments, this disclosure relates to using a compound disclosed herein for treating a sickle cell-related disorder. In certain embodiments, this disclosure relates to using a compound disclosed herein for treating sickle cell-related retinopathy. In certain embodiments, the method further comprises administering hydroxyurea or another therapeutic agent to the subject. In certain embodiments, the subject is unresponsive to treatment with hydroxyurea or another therapeutic agent alone. In certain embodiments, the compound disclosed herein is administered in combination hydroxyurea or another therapeutic agent when the subject is unresponsive or does not respond well to treatment with hydroxyurea or another therapeutic agent alone. In certain embodiments, this disclosure relates to using a compound disclosed herein for treating sickle cell disease resulting in fewer, or less severe side effects, greater efficacy, greater response rate, or combinations thereof compared to existing therapies such as hydroxyurea or another therapeutic agent. In certain embodiments, the compound disclosed herein is used in combination or alternation with another therapeutic agent to treat sickle cell disease or complications. Representative additional therapeutic agents include, but are not limited to, L-glutamine, 1- (butyryloxy)ethyl-5-amino-4-oxopentanoate (AN-233), crizanlizumab, voxelotor, i.e., chemical name 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)me thoxy)benzaldehyde, fumaric esters, pain relieving drugs, hydroxyurea, and combinations thereof. In certain embodiments, administering a compound disclosed herein may be done before, during or after red blood cell (RBC) transfusion or a hematopoietic stem cell transplantation (HSCT). In certain embodiments, any of the methods reported herein may be used in combination with providing a subject with fluids (e.g., pH balanced isotonic salt solution), oxygen, analgesics, or combinations thereof. In certain embodiments, the disclosed methods include administering to the subject an active agent, for example, vitamin supplements, nutritional supplements, anti-anxiety medication, anti-depression medication, anti-coagulants, clotting factors, anti-inflammatories, steroids such as corticosteroids, analgesic, etc. In certain embodiments, active agents may include folic acid, penicillin, or another antibiotic, preferably a quinolone or macrolide, antivirals, anti-malarial prophylactics, and analgesics to control pain. Methods of selecting a subject with a mutation in a beta-globin gene for treatment are also disclosed. The methods typically include genotyping the beta-globin gene and expression control sequence thereof in DNA isolated from a biological sample obtained from the subject; determining if the beta-globin gene or expression control sequence includes a mutation; selecting the subject for treatment if the beta-globin gene or expression control sequence includes a mutation; and treating the subject with an effective amount of a compound disclosed herein. Pharmaceutical Compositions In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound as disclosed herein or salt thereof and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, gel, gel capsule, or cream. In certain embodiments, the pharmaceutical composition is in the form of a sterilized pH buffered aqueous salt solution or a saline phosphate buffer between a pH of 5 to 9, optionally comprising a saccharide or polysaccharide. In certain embodiments, the pharmaceutical composition is in solid form surrounded by an enteric coating. In certain embodiments, the enteric coatings comprises a component such as methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hypromellose (hydroxypropyl methylcellulose), hypromellose phthalate (hydroxypropyl methyl cellulose phthalate), hypromellose acetate succinate (hydroxypropyl methyl cellulose acetate succinate), diethyl phthalate, polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, or combinations thereof. In certain embodiments, the pharmaceutically acceptable excipient is selected from lactose, sucrose, mannitol, triethyl citrate, dextrose, cellulose, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxyl propyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, croscarmellose sodium, polyvinyl N-pyrrolidone (crospovidone), ethyl cellulose, povidone, methyl and ethyl acrylate copolymer, polyethylene glycol, fatty acid esters of sorbitol, lauryl sulfate, gelatin, glycerin, glyceryl monooleate, silicon dioxide, titanium dioxide, talc, corn starch, carnauba wax, stearic acid, sorbic acid, magnesium stearate, calcium stearate, castor oil, mineral oil, calcium phosphate, starch, carboxymethyl ether of starch, iron oxide, triacetin, acacia gum, esters, or salts thereof. In certain embodiments, the pharmaceutical composition is in the form of a saline, citrate buffer or phosphate buffer, optionally comprising a saccharide or polysaccharide. In certain embodiments, this disclosure relates to pharmaceutical compositions comprising a compound disclosed herein or pharmaceutically acceptable salt, and a pharmaceutically acceptable vehicle, adjuvant, or carrier. In certain embodiments, the pharmaceutical composition comprises a compound disclosed herein and a propellant. In certain embodiments, an aerosolizing propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes or combinations thereof. In certain embodiments, the disclosure contemplates a pressurized or unpressurized container comprising a compound herein. In certain embodiments, the container is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer. In certain embodiments, the pharmaceutical compositions may additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants. The pharmaceutical compositions containing compounds reported herein may further comprise one or more additional therapeutic agent(s). In certain embodiments, the additional therapeutic agent is an antibiotic. Exemplary antibiotics useful herein include tobramycin, including tobramycin inhaled powder (TIP), azithromycin, aztreonam, including the aerosolized form of aztreonam, amikacin, including liposomal formulations thereof, ciprofloxacin, including formulations thereof suitable for administration by inhalation, levofloxacin, including aerosolized formulations thereof, and combinations of two antibiotics, e.g., fosfomycin and tobramycin. In another embodiment, the pharmaceutical compositions can be administered to a patient once daily or about every twenty-four hours. Alternatively, the pharmaceutical compositions can be administered to a patient twice daily. Alternatively, the pharmaceutical composition of the invention can be administered about every twelve hours. These pharmaceutical compositions are administered as oral formulations containing about 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, or 400 mg of a compound disclosed herein. In this aspect, the pharmaceutical compositions further comprise a filler; a disintegrant; a surfactant; a binder; or a lubricant, or combinations thereof. Identification of anti-sickling agents by screening a compound library via an imaging-based high throughput assay An imaging assay utilizing automated microscopy and customized algorithms was used to detect sickled or normal (round shaped) RBCs. The assay is capable of discovering anti-sickling agents with physiologically relevant oxygen affinity. The assay uses native mouse or human RBCs, enabling one to identify a broader spectrum of agents and is not restricted to compounds that require direct interaction (e.g., with purified hemoglobin). Thus, in contrast to hemoglobin binding assays, this approach allows for the identification of additional classes of anti-sickling agents that modulate pathways affecting RBC sickling. Compounds resulting from the experiments are also useful for investigating SCD pathophysiology. The imaging-based protocol that can distinguish sickled vs normal (round) phenotype of intact RBCs originating from genetically engineered mice expressing human hemoglobin genes (the HbSS Townes knock-in sickle mice), or 2) SCD patients. The imaging was conducted using a BioTek Cytation TM cell imaging multimode reader and software to detect sickled or normal round-shaped phenotype of RBCs with negative control (vehicle treatment) and a positive control, 5-hydroxymethylfurfural (5-HMF). Cytotoxicity Assay To screen out anti-sickling agents that cause cell death, LDH-glo Cytotoxicity Assay Kit (Promega) was used to measure lactate dehydrogenase activity in the media which is released from the cytoplasm of cultured cells due to breach in the plasma membrane. Some of the compounds in the pilot assay show significant toxicity to HEK293 cells after 24h incubation. Others exhibited negligible cytotoxic effects. General procedure-1 for synthesis of maleimides To a 25 ml round bottom flask equipped with a magnetic stirbar and under an inert atmosphere of nitrogen/argon was added maleic anhydride 1 (2.0 equiv). Glacial Acetic Acid was then added to obtain a 0.5 M mixture that was stirred at rt until complete dissolution of the maleic anhydride. Using a syringe, the corresponding aniline 2 (1.0 equiv) was added dropwise. The reaction flask was fitted with a Findenser TM and the reaction mixture was set to stir at reflux overnight (about 16 hours). After indication by TLC (5% Ethyl Acetate/DCM) that the aniline has been consumed, the reaction mixture was allowed to cool down as it continued to stir. The slightly warm reaction mixture was then poured unto ice. The solid crude precipitate was then transferred unto Buchner filtration funnel and washed with cold DI water. The obtained solid was redissolved in hot ethanol and recrystallized overnight in the freezer. The crystalline product is then washed with hexanes and dried under high vacuum to obtain the desired HDYB maleimide. General procedure-2 for synthesis of oxindolones To a 25 ml round bottom flask equipped with a magnetic stir bar and under an inert atmosphere of nitrogen/argon was added Isatin (1H-indole-2,3-dione) 3 (1.0 equiv), the corresponding benzyl bromide 4 (1.0 equiv) and K2CO3 (3.0 equiv) were heated at reflux in acetonitrile for 1-2 hours. After completion of the reaction as indicated by TLC (2% MeOH/Hexanes), the reaction mixture was allowed to cool down to room temperature and the solvent was removed by reduced pressure before being extracted with ethyl acetate. The combined organic extract was dried over MgSO4 and concentrated to obtain the clean desired HDYB product with no further purification.
Table 1 shows data on Anti-sickling activity of maleimides derivatives
Animal Studies of Compounds for Managing of Sickle Cell Disease High throughput drug screening to identify molecules that prevent sickling of diseased RBCs. The resulting hits will be verified in dose response and a series of secondary assays. Lead compounds will be selected based on physiologically acceptable changes of hemoglobin oxygen affinity and RBC membrane deformability. Lead scaffolds will be synthesized and evaluated for anti-sickling potency, hemoglobin oxygen affinity, and improved RBC membrane deformability to identify agents best suited for animal safety and efficacy studies. Townes HbSS mice expressing human globin genes will be used to test short term lethality, efficacy of anti-sickling activity, RBC oxygen affinity, and RBC half-life in vivo. Compounds with therapeutic potential for sickle cell disease (SCD) will be intraperitoneally injected into B6/129 or C57BL/6 mice at different doses. Body weight and clinical signs of the mice will be monitored to find the short-term (3-day) maximum tolerated dose (MTD) of each test compound and pharmacokinetics (PK) will be explored. The 3-day MTD will be used as a basis in B6/129 or C57BL/6 mice to determine amore chronic MTD (e.g., 3 or 4 week administrations) for each test compound useful for conducting efficacy studies in B6/129 orC57BL/6 mice with sickle cell disease. Table 2 - Sickle Cell Disease Compounds EC50s