IP Library Patent Application 13832484
Patent Application
App. No. 13/832,484

TREATMENT OF DISEASES BY EPIGENETIC REGULATION

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Patent No.
US None
App. No.
13/832,484
Abstract

The present disclosure provides non-naturally occurring polyphenol compounds that inhibit the bromodomain and extra terminal domain (BET) proteins. The disclosed compositions and methods can be used for treatment and prevention of cancer, including NUT midline carcinoma, Burkitt's Lymphoma, Acute Myelogenous Leukemia, and Multiple Myeloma; autoimmune or inflammatory diseases or conditions, and sepsis.

Claims (194)

1 . A method for inhibiting BET proteins comprising administering to a mammal, such as a human, a therapeutically effective amount of a compound of Formula I:

wherein:

X is selected from CR 11 and N;

Y is selected from CO and SO 2 ;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 , are each independently selected from alkoxy, aryloxy, alkyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone; and

each W is independently selected from C and N, wherein if W is N, then p is 0 and if W is C, then p is 1;

or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof.

2 . A method of inhibiting BET proteins in a mammal, such as a human, comprising administering a therapeutically effective amount of a compound of Formula II:

wherein:

X is selected from CH and N;

R 1 and R 3 are each independently selected from alkoxy, alkyl, and halogen;

R 4 is H;

R 6 and R 8 are each independently selected from alkoxy, alkyl, halogen, and hydrogen;

R 7 is selected from alkoxy, alkyl, amino, ether, hydrogen, and hydroxyl; and

W is selected from C and N, wherein if W is N, then p is 0 or 1, and if W is C, then p is 1;

or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof.

3 . The method according to claim 1 , wherein X is selected from CH and N.

4 . The method according to claim 1 , wherein the compound of Formula I is selected from:

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-7-(morpholinomethyl)isoquinolin-1(2H)-one;

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-6,7-dimethoxyquinazolin-4(3H)-one;

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6,7-dimethoxyquinazolin-4(3H)-one;

2-(2-chloro-6-methylpyridin-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one;

4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5-guanidino-pentanoate trihydrochloride;

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methylisoquinolin-1(2H)-one;

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2,7-dimethylisoquinolin-1(2H)-one;

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxy-2-methyl-7-(morpholino-methyl)isoquinolin-1(2H)-one;

5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(pyridin-3-yl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(pyridin-4-yl)quinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one;

2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;

2-(4-(dimethylamino)pyridinon-1-yl)quinazolin-4(3H)-one;

2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;

2-(4-(dimethylamino)pyridinon-1-yl)-6,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one;

2-(4-hydroxy-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;

N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide;

2-(4-(6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)acetamide;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,7-dimethoxyquinazolin-4(3H)-one;

2-(4-hydroxy-3,5-dimethylphenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one;

N-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-4-oxo-3,4-dihydro-quinazolin-6-yl)acetamide;

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxy-6-(morpholino-methyl)quinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6-methoxyquinazolin-4(3H)-one;

2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5-methoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-o-tolylquinazolin-4(3H)-one;

5,7-dimethoxy-2-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(6-methylpyridin-2-yl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(6-(4-(methylthio)phenyl)pyridin-2-yl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(1-phenyl-5-propyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one;

2-(3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

6-bromo-2-(4-hydroxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;

6-bromo-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

6-bromo-2-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)-3,5-dimethyl-phenyl)quinazolin-4(3H)-one; and

5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one;

and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.

5 . The method according to claim 2 , wherein R 1 and R 3 are each independently an alkoxy.

6 . The method according to claim 5 , wherein R 6 and R 8 are independently selected from alkyl and hydrogen; R 7 is selected from amino and alkoxy, and X is N.

7 . The method according to claim 2 , wherein at least two of R 6 , R 7 , and R 8 are not hydrogen.

8 . The method according to claim 7 , wherein R 6 and R 8 are each independently selected from alkyl and hydrogen; R 7 is selected from amino, alkoxy; and X is N.

9 . The method according to claim 2 , wherein R 7 is an alkoxy group substituted with an amine.

10 . The method according to claim 2 , wherein R 7 is an alkoxy substituted with a cyclic amine.

11 . The method according to claim 10 , wherein the compound of Formula II is 2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one.

12 . The method according to claim 2 , wherein R 7 is an amino or an alkoxy selected from the group represented by Formula

wherein:

A is selected from O and N;

n is selected from 0, 1, 2, and 3;

B is selected from —C(O)N(R h ) 2 —, —S(O) 2 N(R h ) 2 —, —C(O)—, —S(O) 2 —, and —C(O)O—, wherein each R h is independently selected from alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen; and

R 20 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen.

13 . The method according to claim 2 , wherein R 7 is selected from alkoxy, alkyl, amino, and hydroxyl.

14 . The method according to claim 13 , wherein:

X is N;

R 1 and R 3 are each independently selected from alkoxy;

R 6 and R 8 are each independently selected from alkyl, alkoxy, and hydrogen;

R 7 is selected from amino, alkoxy, and alkyl substituted with a heterocyclyl;

with the proviso that if R 7 is selected from alkoxy, then at least one of R 6 and R 8 is alkyl or alkoxy.

15 . The method according to claim 2 , wherein the compound of Formula II is selected from:

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)methanesulfonamide;

2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one;

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl cyclohexylcarbamate;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)acetamide;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)isobutyramide;

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-3-phenylurea;

3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-1,1-dimethylurea;

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one;

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one);

3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethyl phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;

5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-amino-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-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

4-chloro-N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethyl)benzenesulfonamide;

3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

3-(4-hydroxy-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

7-(4-hydroxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;

3-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

3-(4-(2-(dimethylamino)ethoxy)-3,5-dimethylphenyl)-6,8-dimethoxy-isoquinolin-1(2H)-one;

3-(4-hydroxy-3,5-dimethylphenyl)-7-(morpholinomethyl)isoquinolin-1(2H)-one;

2-hydroxy-7-(4-hydroxy-3,5-dimethylphenyl)-4-methoxy-1,6-naphthyridin-5(6H)-one;

2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

3-(4-(2-hydroxy-2-methylpropoxy)-3,5-dimethylphenyl)-6,8-dimethoxy-isoquinolin-1(2H)-one;

6,8-dimethoxy-3-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2-benzothiazine-1,1-dioxide;

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

3-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-6,8-dimethoxyisoquinolin-1(2H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one);

2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

3-(3,5-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6,8-dimethoxy-isoquinolin-1(2H)-one;

2-(4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetic acid;

2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-methoxyphenyl)quinazolin-4(3H)-one;

2-(4-hydroxy-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3-chloro-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(dimethylamino)naphthalen-1-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenoxy)acetamide;

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)quinazolin-4(3H)-one;

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-morpholinophenyl)quinazolin-4(3H)-one;

7-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

3-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propanoic acid;

2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)quinazolin-4(3H)-one;

N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide;

7-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-2,4-dimethoxy-1,6-naphthyridin-5(6H)-one;

2,4-dimethoxy-7-(4-methoxy-3,5-dimethylphenyl)-1,6-naphthyridin-5(6H)-one;

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)phenyl)-2-hydroxyacetamide;

5,7-dimethoxy-2-(4-(morpholinomethyl)phenyl)quinazolin-4(3H)-one;

2-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-hydroxy-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-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;

2-(3,5-dimethyl-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5,7-dimethoxy-quinazolin-4(3H)-one;

7-(4-hydroxy-3,5-dimethylphenyl)-2,4-diisopropoxy-1,6-naphthyridin-5(6H)-one;

2-(4-hydroxy-3-(2-hydroxyethyl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one;

2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one;

5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

5,7-dichloro-2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one;

5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one;

2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

(E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenyl)-N,N-dimethylformimidamide;

2-(4-(benzyloxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(2-hydroxyethoxy)-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

N1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-N2-methylphthalamide;

2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-4-methoxybenzenesulfonamide;

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-dimethyl-phenoxy)ethyl)methanesulfonamide;

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxy-phenoxy)acetic acid;

2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl propylcarbamate;

2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl methylcarbamate;

N-(2-(4-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-4-methylbenzamide;

2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl cyclohexylcarbamate;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)benzenesulfonamide;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-4-methylbenzenesulfonamide;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-4-methoxybenzamide;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)acetamide;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)benzamide;

N-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)isobutyramide;

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-3-methyl urea;

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-3-(4-methoxyphenyl)urea;

1-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-3-phenylurea;

3-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethyl-phenoxy)ethyl)-1,1-dimethylurea;

and stereoisomers, tautomers, pharmaceutically acceptable salts, and hydrates thereof.

16 . The method of claim 1 , wherein the therapeutically effective amount of the compound of Formula I or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

17 . The method of claim 2 , wherein the therapeutically effective amount of the compound of Formula II or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof is administered with a pharmaceutically acceptable carrier in a pharmaceutically acceptable composition.

18 . The method of claim 1 , wherein the compound of Formula I is administered to treat or prevent a disease or disorder that responds to a BET inhibitor, wherein the disease or disorder is selected from cancer, autoimmune or inflammatory diseases or conditions, diseases or disorders caused by bacterial or viral infection.

19 . The method of claim 2 , wherein the compound of Formula II is administered to treat or prevent a disease or disorder that responds to a BET inhibitor, wherein the disease or disorder is selected from cancer, autoimmune or inflammatory diseases or conditions, diseases or disorders caused by bacterial or viral infection.

20 . The method of claim 18 , wherein the disease or disorder is a cancer selected from cancers that exhibit c-myc overexpression, cancers that overexpress n-myc, cancers that that rely on the recruitment of p-TEFb to regulate activated oncogenes, Burkitt's lymphoma, acute myelogenous leukemia, multiple myeloma, aggressive human medulloblastoma, hematological, epithelial cancers, lung cancers, breast cancers, colon carcinomas, midline carcinomas, mesenchymal tumors, hepatic tumors, renal tumors, and neurological tumors.

21 . The method of claim 1 , wherein, the compound of Formula I or tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof induces apoptosis in cancer cells by decreasing expression of the anti-apoptosis gene Bcl2.

22 . The method of claim 1 , wherein the compound of Formula I is administered in combination with another anti-cancer agent selected from the group consisting of bortezomib, thalidomide, dexamethasone, 5-azacitidine, decitabine, vorinostat, cyclophosphamide, a PI3K or mTOR inhibitor, rapamycin or a rapamycin analog, a gamma secretase inhibitor, an AMPK inducer, metformin, phenformin, an ornithine decarboxylase inhibitor, and difluoromethylornithine.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 23, 2016
From: ZENITH CAPITAL CORP.
To: ZENITH EPIGENETICS LTD.
Reel/Frame 041182/0891 →
CHANGE OF NAME Recorded Dec 21, 2016
From: ZENITH EPIGENETICS CORP.
To: ZENITH CAPITAL CORP.
Reel/Frame 041120/0548 →
GENERAL CONVEYANCE AND ASSUMPTION AGREEMENT Recorded Jul 14, 2014
From: RVX THERAPEUTICS INC.
To: ZENITH EPIGENETICS CORP.
Reel/Frame 033312/0422 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 27, 2013
From: MCLURE, KEVIN G.; YOUNG, PETER RONALD
To: RVX THERAPEUTICS INC.
Reel/Frame 030097/0108 →