Substituted bicyclic compounds as bromodomain inhibitors

1. A method for treating prostate cancer in a mammal, comprising administering a therapeutically effective amount of a compound of formula:

or a tautomer, pharmaceutically acceptable salt, or hydrate thereof,

wherein:

D 1 is selected from isoxazole, optionally substituted with one or more groups independently selected from deuterium, alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, halogen, amide, —C(O)cycloamino, —CF 3 , CN, —N 3 , ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), —COOH, and ester, wherein said alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, amide, ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), and ester are optionally substituted with one or more groups independently selected from hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo;

X is present and selected from —(NH)—, —O—, —NHCR x R y —, —NHSO 2 —, and —CR x R y NH—;

Z 1 is —NR a ;

R a is selected from hydrogen, deuterium, and alkyl (C 1-3 );

R 3 is selected from isoxazole, pyrazole, pyridyl, thiazole, isothiazole, pyrimidine, phenyl, cyclohexene, benzo[d]oxazolyl, naphthyl, and quinolyl, optionally substituted with one or more groups independently selected from deuterium, alkyl(C 1 -C 4 ), —OH, alkoxy(C 1 -C 4 ), amino, halogen, amide, —CF 3 , CN, —N 3 , ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), carboxyl, and ester,

wherein said alkyl(C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, amide, ketone (C 1 -C 4 ), —S(O)Alkyl(C 1 -C 4 ), —SO 2 alkyl(C 1 -C 4 ), -thioalkyl(C 1 -C 4 ), and ester are optionally substituted with one or more groups independently selected from hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and/or thio-oxo;

R 1 and R 2 are independently selected from hydrogen, deuterium, alkyl, —OH, —NH 2 , -thioalkyl, and alkoxy; and

R x and R y are each independently selected from hydrogen, alkyl(C 1-5 ), halogen, —OH, —CF 3 , deuterium, amino, and alkoxy(C 1-5 ), or two substituents selected from R x , R y and R 1 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle.

2. The method of claim 1 , wherein D 1 is

3. A method for treating prostate cancer in a mammal, comprising administering a therapeutically effective amount of a compound selected from:

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(2-(trifluoromethyl)pyridin-3-yl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(4-methylisothiazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(2-methoxy-5-methyl phenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(2-methoxypyridin-3-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-methylbenzonitrile;

4,6-bis(3,5-dimethylisoxazol-4-yl)-1,3-dimethyl-1H-benzo[d]imidazol-2(3H)-one;

3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile;

5-(3,5-dimethylisoxazol-4-yl)-7-(4-methoxypyridin-3-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(5-fluoro-2-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(5-chloro-2-methylphenyl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(6-amino-2-methylpyridin-3-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(3,5-dimethyl-1H-pyrazol-4-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

6-(3,5-dimethylisoxazol-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

6-(3,5-dimethylisoxazol-4-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione;

6-(3,5-dimethylisoxazol-4-yl)-4-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-2-thiol;

3-(6-(3,5-dimethylisoxazol-4-yl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methylbenzonitrile;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-((1,3,5-trimethyl-1H-pyrazol-4-yl)amino)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-((2-methylpyridin-3-yl)amino)-1H-benzo[d]imidazol-2(3H)-one;

5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-4-methylbenzamide;

3-(6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-2-methylbenzamide;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-((2-methylpyridin-3-yl)oxy)-1H-benzo[d]imidazol-2(3H)-one;

7-(3,5-dimethyl-1H-pyrazol-4-yl)-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-((3,5-dimethylisoxazol-4-yl)amino)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(3,5-dichloropyridin-4-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(2-chlorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(3-methylpyridin-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-1-methyl-7-(o-tolyl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(2-fluoro-5-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(5-chloro-2-methoxyphenyl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(2-fluoro-3-methoxyphenyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(2,4-dimethylthiazol-5-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

5-(3,5-dimethylisoxazol-4-yl)-7-(2-methoxy-6-methyl pyridin-3-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(benzo[d]oxazol-5-yl)-5-(3,5-dimethyl isoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one;

7-(cyclohex-1-en-1-yl)-5-(3,5-dimethylisoxazol-4-yl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; and

tautomers, pharmaceutically acceptable salts, and hydrates thereof.

4. The method of claim 1 , 2 , or 3 , wherein the compound is administered in combination with another anticancer agent.

5. The method of claim 4 , wherein the anticancer agent is selected from ABT-737, Azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin Sulfate, Bortezomib (Velcade), Busulfan (Myleran), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa), Idarubicin, Ifosfamide (Mitoxana), IFNa2a (Roferon A), Melphalan (Alkeran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (Midostaurin), PLX4032 (Vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Revlimid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).