The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.
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1. A compound of Formula I: or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof, wherein: W1 is selected from N and CR1;W2 is selected from N and CR2;W3 is selected from N and CR3;W4 is selected from N and CR4;each W may be the same or different from each other;A is selec
1. A compound of Formula I: or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof, wherein: W1 is selected from N and CR1;W2 is selected from N and CR2;W3 is selected from N and CR3;W4 is selected from N and CR4;each W may be the same or different from each other;A is selected from N and CH;R1, and R4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, amino, hydroxyl, and halogen;R2 and R3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;two adjacent substituents selected from R1, R2, R3, and R4 may be connected in a 5- or 6- membered ring to form a bicyclic carbocycle or bicyclic heterocycle;AR1 is a group selected from the following: B is a group selected from the following: each ring system may be substituted with one or more substituents independently selected from R10 and R11;R5 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;R6 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, and halogen;R7 is selected from hydrogen, alkyl, —SO2R12, —C(O)NR12R13, and —C(O)R12;R8 and R9 are independently selected from hydrogen, aryl, alkenyl, alkyl, —SO2R12, —C(O)NR12R13, and —C(O)R12;R10 and R11 are independently selected from hydrogen, halogen, alkyl, alkoxy, aryl, and hydroxyl;R12 and R13 are independently selected from hydrogen, aryl, and alkyl;Y is selected from NH, O, and S;andtwo adjacent substituents selected from R5, R6, R6, R9, R10, and R11 may be connected in a 5- or 6-membered ring to form a carbocycle or heterocycle. 2. The compound according to claim 1wherein R1, and R4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino and R2 and R3 are independently from hydrogen, alkyl, alkoxy, and halogen;wherein at least one of R1-R4 is not hydrogen;wherein R5 is selected from hydrogen, alkyl, alkoxy, and halogen;wherein R6 is selected from hydrogen and alkoxy optionally substituted with a hydroxyl or amino; and/or wherein Y is N. 3. The compound according to claim 2, wherein AR1 is selected from wherein B is selected from wherein R7 is selected from hydrogen and alkyl;wherein R8 and R9 are independently selected from hydrogen and alkyl;wherein R10 and R11 are independently selected from hydrogen and halogen;wherein R12 and R13 are independently selected from hydrogen and alkyl. 4. A compound according to claim 1 selected from: 2-(3-(4-Isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(3-(4-Isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-Dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(6-(4-Isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-Dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate;2-(6-(4-(1-Hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide;2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid;3-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoic acid;2-(5-(2-(Isopropylamino)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one bis(trifluoroacetate);2-(5-(2-Hydroxyethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one acetate;2-(6-(4-Isopropylpiperazin-1-yl)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-Dimethoxy-2-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;5,7-Dimethoxy-2-(6-morpholinopyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;5,7-Dimethoxy-2-(6-(4-propionylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one dihydrochloride;2-(3-(4-Isopropylpiperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;7-Fluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Hydrochloride;7-(Benzyloxy)-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3-H)-one Hydrochloride;2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxy-7-phenylquinazolin-4(3H)-one;8-(Benzyloxy)-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-5-methoxyquinazolin-4(3H)-one;4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N-isopropylpiperazine-1-carboxamide Hydrochloride;2-(6-(4-Isopropyl-2-oxopiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;2-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;5,7-Dimethoxy-2-(6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;2-(3-Chloro-5-(piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one, and2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one. 5. A compound according to claim 1, wherein R6 is selected from the group represented by Formula II: wherein: D is selected from O and S;E is selected from O, N, and S;R14 and R15 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein if E is O or S, only one of R14 and R15 is present; andn is selected from 1, 2, and 3. 6. The compound according to claim 5wherein D is oxygenwherein n=1;wherein R14 and R15 are independently selected from hydrogen, and alkyl; and/or wherein R6 is selected from hydrogen, methoxy, 7. A pharmaceutical composition comprising a compound according to any one of claims 1-6 and a pharmaceutically acceptable carrier. 8. The compound of claim 2, wherein R1 is independently selected from alkoxy, halogen, and amino, and R3 is independently selected from alkoxy, and halogen. 9. The compound of claim 8, wherein R1 is independently selected from methoxy, fluoride, and a substituted piperazine, and R3 is independently selected from methoxy and fluoride. 10. The compound of claim 9, wherein R1 and R3 are independently selected from alkoxy. 11. The compound of claim 2, wherein R1 and R3 are methoxy and R2 and R4 are hydrogen. 12. The compound of claim 2, wherein R5 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —OCF3, fluoride, and chloride. 13. The compound of claim 12, wherein R5 is selected from hydrogen, methoxy, ethoxy, —OCF3, fluoride, chloride, methyl, and ethyl. 14. The compound of claim 2, wherein R6 is selected from hydrogen, methoxy, and ethoxy. 15. The compound of claim 2, wherein R6 is selected from hydrogen, methoxy; 16. The compound of claim 3, wherein B is selected from 17. The compound of claim 3, wherein R8 and R9 are independently selected from hydrogen, methyl, and ethyl. 18. The compound of claim 3, wherein R12 and R13 are independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. 19. The compound of claim 6, wherein R14 and R15 are independently selected from hydrogen and C1-C5 alkyl.
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