Heterocyclic compounds as bromodomain inhibitors
The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.
1. A method for inhibiting BET proteins in a mammal, comprising administering an effective amount of a compound of Formula II:
or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,
wherein:
W 1 is selected from N and CR 5 ;
W 2 is CR 4 ;
W 3 is CR 3 ;
each W may be the same or different from each other;
R 1 is a carbocycle or heterocycle,
wherein the carbocycle is a saturated or unsaturated cycloalkyl optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;
wherein the heterocycle is optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, and
wherein the cycloalkyl or heterocycle may be fused to other cycloalkyl, aryl, or heterocyclyl groups;
V is an optionally substituted isoxazole;
wherein V is optionally substituted with alkyl (C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, —NHC(O)NHalkyl), 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, ester, each of which may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo;
R 3 , R 4 , and R 5 are each independently selected from hydrogen, alkyl, —OH, —NH 2 , thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, carbonate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN,
R 3 and R 4 may be connected to form an optionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;
X is selected from O and S;
A is selected from —CR x R y —, C═O, —C(O)CR x R y —, —CR x R y CR z R v —, —SO 2 —, —CR x R y CR z R v O—, —CR x R y CR z R v N—, —CR x R y CR z R v S—, and —CR x R y CR z R v CR Q R R —,
with the proviso that R x and R y cannot both be an unsubstituted phenyl ring,
and with the proviso that if A is —CH 2 CH 2 O— then R 1 is not
R x , R y , R z , R v , R Q and R R are each independently selected from hydrogen, alkyl(C 1 -C 8 ), halogen, —OH, —CF 3 , amino, alkoxy (C 1 -C 8 ), carboxyl, —CN, sulfone, sulfoxide, carbocycle, and heterocycle, or two substituents selected from R x , R y , R z , R v , R Q and R R may form an oxo or thio-oxo group, or
two substituents selected from R x , R y , R z , R v , R 5 , and R 1 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;
B is selected from —(CR a R b ) n —, —(CR a R b CR c R d )—, —O—, —OCR a R b —, —CR a R b O—, —NH—, —NHCR a R b —, —CR a R b NH—, —S—, —SCR a R b —, —CR a R b S—, —S(O)—, —S(O)CR a R b —, —CR a R b S(O)—, —SO 2 —, —SO 2 CR a R b —, and —CR a R b SO 2 —;
n is selected from 0 and 1, meaning if n=0 then B is absent; and wherein
R a , R b , R c , and R d are each independently selected from hydrogen, alkyl(C 1 -C 3 ), and alkoxy(C 1 -C 3 ).
2. The method according to claim 1 , wherein V is
3. The method according to claim 1 , wherein A is selected from C═O and —CR x R y —.
4. The method according to claim 1 , wherein R 1 is selected from an optionally substituted 3-, 4-, 5-, and 6-membered carbocycle or heterocycle.
5. The method according to claim 4 , wherein the carbocycle or heterocycle is selected from cyclopropyl, phenyl, pyridyl, thiophene, cyclobutyl, piperidine, piperazine, cyclopentyl, and cyclohexyl.
6. The method according to claim 4 , wherein R 1 is selected from an optionally substituted 5- and 6-membered carbocycle or heterocycle.
7. The method according to claim 6 , wherein the carbocycle or heterocycle is selected from phenyl, pyridyl, thiophene, and cyclopentyl.
8. The method according to claim 7 , wherein R 1 is selected from an optionally substituted phenyl or pyridyl ring.
9. The method according to claim 1 , wherein B is selected from —(CR a R b ) n —, —O—, —NH—, —S—, —S(O)—, —SO 2 —, where n is 0 or 1, meaning if n=0 then B is absent.
10. The method according to claim 1 , wherein W 1 is N.
11. The method according to claim 1 wherein W 1 is CR 5 .
12. A method for treating a cancer that is sensitive to a BET inhibitor, said method comprising administering a therapeutically effective amount of a compound of Formula II:
or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,
wherein:
W 1 is selected from N and CR 5 ;
W 2 is CR 4 ;
W 3 is CR 3 ;
each W may be the same or different from each other;
R 1 is a carbocycle or heterocycle,
wherein the carbocycle is a saturated or unsaturated cycloalkyl optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;
wherein the heterocycle is optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, and
wherein the cycloalkyl or heterocycle may be fused to other cycloalkyl, aryl, or heterocyclyl groups;
V is an optionally substituted isoxazole;
wherein V is optionally substituted with alkyl (C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, —NHC(O)NHalkyl), 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, ester, each of which may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo;
R 3 , R 4 , and R 5 are each independently selected from hydrogen, alkyl, —OH, —NH 2 , thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, carbonate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN,
R 3 and R 4 may be connected to form an optionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;
X is selected from O and S;
A is selected from —CR x R y —, C═O, —C(O)CR x R y —, —CR x R y CR z R v —, —SO 2 —, —CR x R y CR z R v O—, —CR x R y CR z R v N—, —CR x R y CR z R v S—, and —CR x R y CR z R v CR Q R R —,
with the proviso that R x and R y cannot both be an unsubstituted phenyl ring,
and with the proviso that if A is —CH 2 CH 2 O— then R 1 is not
R x , R y , R z , R v , R Q and R R are each independently selected from hydrogen, alkyl(C 1 -C 8 ), halogen, —OH, —CF 3 , amino, alkoxy (C 1 -C 8 ), carboxyl, —CN, sulfone, sulfoxide, carbocycle, and heterocycle, or two substituents selected from R x , R y , R z , R y , R Q and R R may form an oxo or thio-oxo group, or
two substituents selected from R x , R y , R z , R v , R 5 , and R 1 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;
B is selected from —(CR a R b ) n —, —(CR a R b CR c R d )—, —O—, —OCR a R b —, —CR a R b O—, —NH—, —NHCR a R b —, —CR a R b NH—, —S—, —SCR a R b —, —CR a R b S—, —S(O)—, —S(O)CR a R b —, —CR a R b S(O)—, —SO 2 —, —SO 2 CR a R b —, and —CR a R b SO 2 —;
n is selected from 0 and 1, meaning if n=0 then B is absent; and wherein
R a , R b , R c , and R d are each independently selected from hydrogen, alkyl(C 1 -C 3 ), and alkoxy(C 1 -C 3 ); and
wherein said cancer is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.
13. A method for treating a cancer that is sensitive to a BET inhibitor, said method comprising administering a therapeutically effective amount of a compound of Formula II:
or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof,
wherein:
W 1 is selected from N and CR 5 ;
W 2 is CR 4 ;
W 3 is CR 3 ;
each W may be the same or different from each other;
R 1 is a carbocycle or heterocycle,
wherein the carbocycle is a saturated or unsaturated cycloalkyl optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;
wherein the heterocycle is optionally substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, and
wherein the cycloalkyl or heterocycle may be fused to other cycloalkyl, aryl, or heterocyclyl groups;
V is an optionally substituted isoxazole:
wherein V is optionally substituted with alkyl (C 1 -C 4 ), alkoxy(C 1 -C 4 ), amino, —NHC(O)NHalkyl), 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, ester, each of which may be optionally substituted with hydrogen, F, Cl, Br, —OH, —NH 2 , —NHMe, —OMe, —SMe, oxo, and thio-oxo;
R 3 , R 4 , and R 5 are each independently selected from hydrogen, alkyl, —OH, —NH 2 , thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, carbonate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN,
R 3 and R 4 may be connected to form an optionally substituted 5-, 6-, or 7-membered carbocycle or heterocycle;
X is selected from O and S:
A is selected from —CR x R y —, C═O, —C(O)CR x R y —, —CR x R y CR z R v —, —SO 2 —, —CR x R y CR z R v O—, —CR x R y CR z R v N—, —CR x R y CR z R v S—, and —CR x R y CR z R v CR Q R R —,
with the proviso that R x and R y cannot both be an unsubstituted phenyl ring,
and with the proviso that if A is —CH 2 CH 2 O— then R 1 is not
R x , R y , R z , R v , R Q and R R are each independently selected from hydrogen, alkyl(C_—Ca), halogen, —OH, —CF 3 , amino, alkoxy (C 1 -C 8 ), carboxyl, —CN, sulfone, sulfoxide, carbocycle, and heterocycle, or two substituents selected from R x , R y , R z , R v , R Q and R R may form an oxo or thio-oxo group, or
two substituents selected from R x , R y , R z , R y , R 5 , and R 1 may be connected in a 5- or 6-membered ring to form a bicyclic carbocycle or bicyclic heterocycle;
B is selected from —(CR a R b ) n —, —(CR a R b CR c R d )—, —O—, —OCR a R b —, —CR a R b O—, —NH—, —NHCR a R b —, —CR a R b NH—, —S—, —SCR a R b —, —CR a R b S—, —S(O)—, —S(O)CR a R b —, —CR a R b S(O)—, —SO 2 —, —SO 2 CR a R b —, and —CR a R b SO 2 —;
n is selected from 0 and 1, meaning if n=0 then B is absent; and wherein R a , R b , R c , and R d are each independently selected from hydrogen, alkyl(C 1 -C 3 ), and alkoxy(C 1 -C 3 ); and
wherein said cancer:
(a) exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein and is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, Diffuse large cell lymphoma, Multiple myeloma, Primary plasma cell leukemia, Atypical carcinoid lung cancer, Bladder cancer, Breast cancer, Cervix cancer, Colon cancer, Gastric cancer, Glioblastoma, Hepatocellular carcinoma, Large cell neuroendocrine carcinoma, Medulloblastoma, Melanoma, Nodular melanoma, Neuroblastoma, esophageal cancer, Osteosarcoma, Ovarian cancer, Prostate cancer, Renal clear cell carcinoma, Retinoblastoma, Rhabdomyosarcoma, and Small cell lung carcinoma;
(b) results from aberrant regulation of BET proteins and is selected from NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, esophageal cancer, head and neck squamous cell carcinoma, and colon cancer;
(c) relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes and is selected from chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma, diffuse large cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma, primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer;
(d) is associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB and/or hTERT and is selected from pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barret's adenocarcinoma, hepatoma, prostate cancer, pro-myelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal carcinoma; and/or
(e) is associated with a viral infection, wherein said viral infection is selected from Epstein-Barr Virus, hepatitis B virus, hepatitis C virus, Kaposi's sarcoma associated virus, human papilloma virus, Merkel cell polyomavirus, and human cytomegalovirus.
14. The method of claim 12 , wherein the compound of Formula II is administered in combination with another anticancer agent.
15. The method of claim 14 , 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, Revilmid (Lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Nexavar), SU11248 (Sunitinib), SU11274, Vinblastine, Vincristine (Oncovin), Vinorelbine (Navelbine), Vorinostat (SAHA), and WP1130 (Degrasyn).
16. A method for inhibiting BET proteins in a mammal, comprising administering an effective amount of a compound selected from:
6-(3,5-Dimethylisoxazol-4-yl)-2-phenethylpyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(pyridin-2-ylmethyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(pyrimidin-2-ylmethyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
1-(4-((Dimethylamino)methyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-((3,5-dimethylisoxazol-4-yl)methyl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methylpyridin-2(1H)-one;
4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzamide;
2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(quinoxalin-6-ylmethyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;
2-Benzyl-4-methyl-6-(5-methylisoxazol-4-yl)pyridazin-3(2H)-one;
2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluorobenzyl)pyridazin-3(2H)-one;
2-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
2-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)benzonitrile;
2-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
2-(2-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluoro-5-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methoxybenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methoxybenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methylbenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluorobenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylpropyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;
2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(quinolin-8-ylmethyl)pyridin-2(1H)-one;
1-(Cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-Y)pyridin-2(1H)-one;
1-(Cyclobutylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(3-(Difluoromethyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenoxyethyl)pyridin-2(1H)-one;
1-((5-Chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(isoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(isothiazol-4-yl)pyridin-2(1H)-one;
2-Benzyl-6-((3,5-dimethylisoxazol-4-yl)amino)pyridazin-3(2H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2(1H)-one;
1-Benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methylpyridin-2(1H)-one;
1-Benzyl-3-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzoyl)pyridin-2(1H)-one;
1-(4-Chlorobenzoyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorophenyl)pyridin-2(1H)-one;
N-(1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one;
3-Amino-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-3-(benzylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(methylamino)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(naphthalen-2-ylmethyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methoxybenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one;
1-Benzyl-5-(thiazol-5-yl)pyridin-2(1H)-one;
1-Benzyl-5-(5-methyl-1H-imidazol-4-yl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)-4-methylpyridazin-3(2H)-one;
2-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one;
2-Benzyl-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-4-methyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one;
2-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
4-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)-N-methylbenzamide;
2-(2,6-Difluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2,4,6-trifluorobenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-fluorophenyl)ethyl)pyridazin-3(2H)-one;
2-(2-Chloro-6-fluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(isoxazol-4-ylmethyl)pyridazin-3(2H)-one;
5-(5-Amino-3-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(quinolin-8-ylmethyl)pyridazin-3(2H)-one;
1-(1-(2-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one;
1-(1-(4-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenylpropan-2-yl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(thiophen-3-ylmethyl)pyridazin-3(2H)-one;
(R)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;
(S)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;
(S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;
(R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)pyridin-2(1H)-one;
1-(1-(3-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-6-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-6-methylpyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methylbenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methylbenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-fluorophenyl)ethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
1-(3-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(2-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one;
1-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;
(S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
(R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
2-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile;
1-(2,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile;
1-(2,4-Difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(2-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3,4,5-trifluorobenzyl)pyridin-2(1H)-one;
2-((1H-Benzo[d]imidazol-5-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3,4,5-trifluorobenzyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(methylsulfonyl)benzyl)pyridin-2(1H)-one;
1-((1H-Benzo[d]imidazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(3-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-((1H-Indazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-((1H-Indol-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-((4-Chlorophenyl)sulfonyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3-Amino-5-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one;
3-Amino-1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-methylpiperazin-1-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methoxypyridin-2(1H)-one;
1-(3,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((4-fluorophenyl)amino)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3-fluorophenyl)amino)pyridin-2(1H)-one;
1-Benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3-methylisothiazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(piperazin-1-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methoxybenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(pyrimidin-2-ylmethyl)pyridin-2(1H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2H-phthalazin-1-one;
6-Benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one;
7-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one; and
stereoisomers, tautomers, pharmaceutical acceptable salts, or hydrates thereof.
17. A method for inhibiting BET proteins in a mammal, comprising administering an effective amount of a compound selected from:
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;
3-chloro-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;
5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-(phenylamino)pyridin-2(1H)-one;
3-(azetidin-1-yl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((1-methyl-1H-pyrazol-3-yl)amino)pyridin-2(1H)-one;
3-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(ethylamino)pyridin-2(1H)-one;
1-benzyl-5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one;
3-amino-1-benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-morpholinopyridin-2(1H)-one;
1-benzyl-3-(benzyloxyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(isopropylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-3-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-4-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisothiazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile;
methyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylate;
N-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methanesulfonamide;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxamide;
3-amino-1-(4-chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(1H-imidazol-1-yl)pyridin-2(1H)-one;
3-amino-1-(4-chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(4-chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(2-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-3-(cyclopentylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-hydroxypyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methoxypyrid in-2(1H)-one;
3-amino-1-(3,4-difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(3-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(3,4-dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-2-ylmethyl)pyridin-2(1H)-one;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3,5-dimethylisoxazol-4-yl)amino)pyridin-2(1H)-one;
5-(3,5-dimethylisoxazol-4-yl)-1-(4-vinylbenzyl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridazin-3-ylamino)pyridin-2(1H)-one;
3-amino-1-((5-chlorothiophen-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-fluoropyridin-3-yl)amino)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-methylpyridin-2(1H)-one;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylic acid;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;
3-amino-1-(2-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methoxypyridin-3-yl)amino)pyridin-2(1H)-one;
5-((1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)picolinonitrile;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methoxypyridin-3-yl)amino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrazin-2-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrimidin-5-ylamino)pyridin-2(1H)-one;
3-amino-1-(4-(azetidin-1-yl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-morpholinobenzyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrrolidin-3-ylamino)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)pyridin-2(1H)-one;
3-amino-1-(4-bromobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-isopropylbenzyl)pyridin-2(1H)-one;
1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-((2,2,2-trifluoroethyl)amino)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methylpyridin-3-yl)amino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methylpyridin-3-yl)amino)pyridin-2(1H)-one;
1-((1H-indol-4-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
4-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methoxy-N,5-dimethylisoxazole-3-carboxamide;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((2,5-dimethylthiophen-3-yl)methyl)pyridin-2(1H)-one;
3-amino-1-((5-chloropyridin-3-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-((3-chloropyridin-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-((3-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-((5-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(benzo[d][1,3]dioxol-4-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-3-yl)methyl)pyridin-2(1H)-one;
methyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylate;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylic acid:
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-fluorobenzonitrile;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-fluorobenzonitrile;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)thiophene-2-carbonitrile;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-N,3-dimethylisoxazole-5-carboxamide;
3-(aminomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-iodobenzyl)pyridin-2(1H)-one;
1-benzyl-5-(5-oxopyrrolidin-3-yl)pyridin-2(1H)-one;
4-(1-(3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile;
1-((1H-indol-3-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methyl-1H-indol-4-yl)methyl)pyridin-2(1H)-one;
5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(quinolin-5-ylmethyl)pyridin-2(1H)-one;
2-benzyl-6-(((3,5-dimethylisoxazol-4-yl)methyl)amino)pyridazin-3(2H)-one;
4-amino-2-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
2-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;
4-amino-2-benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one; and
stereoisomers, tautomers, pharmaceutical acceptable salts, or hydrates thereof.
18. A method for treating a cancer that is sensitive to a BET inhibitor, said method comprising administering a therapeutically effective amount of a compound selected from:
6-(3,5-Dimethylisoxazol-4-yl)-2-phenethylpyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(pyridin-2-ylmethyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(pyrimidin-2-yl methyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
1-(4-((Dimethylamino)methyl)benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(piperidin-4-ylmethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-((3,5-dimethylisoxazol-4-yl)methyl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methylpyridin-2(1H)-one;
4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzamide;
2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(quinoxalin-6-ylmethyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;
2-Benzyl-4-methyl-6-(5-methylisoxazol-4-yl)pyridazin-3(2H)-one;
2-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluorobenzyl)pyridazin-3(2H)-one;
2-(3-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
2-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)benzonitrile;
2-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
2-(2-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-fluorobenzyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-fluoro-5-methylbenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-methoxybenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-methoxybenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-((tetrahydro-2H-pyran-4-yl)methyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-(trifluoromethyl)phenyl)ethyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethoxy)benzylpyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methylbenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-fluorobenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylpropyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-3-ylmethyl)pyridin-2(1H)-one;
2-(Cyclopropylmethyl-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(quinolin-8-ylmethyl)pyridin-2(1H)-one;
1-(Cyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(Cyclobutylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(3-(Difluoromethyl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenoxyethyl)pyridin-2(1H)-one;
1-((5-Chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(isoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(isothiazol-4-yl)pyridin-2(1H)-one;
2-Benzyl-6-((3,5-dimethylisoxazol-4-yl)amino)pyridazin-3(2H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-fluoropyridin-2(1H)-one;
1-Benzyl-3-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methylpyridin-2(1H)-one;
1-Benzyl-3-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzoyl)pyridin-2(1H)-one;
1-(4-Chlorobenzoyl)-5-(3,5-dimethyloxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-fluorphenyl)pyridin-2(1H)-one;
N-(1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)acetamide;
1-Benzyl-5-(3,5-dimethyloxazol-4-yl-3-(phenylamino)pyridin-2(1H)-one;
3-Amino-1-benzyl-5-(3,5-dimethyloxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-3-(benzylamino)-5-(3,5-dimethyloxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(methylamino)pyridin-2(1H)-one;
6-(3,5-dimethylisoxazol-4-yl)-2-(4-(trifluoromethoxy)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(naphthalene-2-ylmethyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methoxybenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one;
1-Benzyl-5-(thiazol-5-yl)pyridin-2(1H)-one;
1-Benzyl-5-(5-methyl-1H-imidazol-4-yl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)-4-methylpyridazin-3(2H)-one;
2-(Cyclopropylmethyl)-6-(3,5-di methylisoxazol-4-yl)-4-methylpyridazin-3(2H)-one;
2-Benzyl-6-(3,5-dimethyl-1H-pyrazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-4-methyl-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one;
2-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
4-((3-(3,5-Dimethylisoxazol-4-yl)-6-oxopyridazin-1(6H)-yl)methyl)-N-methylbenzamide;
2-(2,6-Difluorobenzyl-6-(3,5-dimethyloxazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(4-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2,4,6-trifluorobenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-fluorobenzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(2-(trifluoromethyl)benzyl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(1-(2-fluorophenyl)ethyl)pyridazin-3(2H)-one;
2-(2-Chloro-6-fluorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(isoxazol-4-ylmethyl)pyridazin-3(2H)-one;
5-(5-Amino-3-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(quinolin-8-ylmethyl)pyridazin-3(2H)-one;
1-(1-(2-Chlorophenyl)ethyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(3-fluorophenyl)ethyl)pyridin-2(1H)-one;
1-(1-(4-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-phenylpropan-2-yl)pyridin-2(1H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(thiophen-3-ylmethyl)pyridazin-3(2H)-one;
(R)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;
(S)-6-(3,5-Dimethylisoxazol-4-yl)-2-(1-phenylethyl)pyridazin-3(2H)-one;
(S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;
(R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(4-fluorophenyl)ethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl pyridin-2(1H)-one;
1-(1-(3-Chlorophenyl)ethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-6-chloro-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-6-methylpyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methylbenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3-methylbenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-(2-fluorophenyl)ethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
1-(3-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(2-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one;
1-(3,4-Dimethoxybenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;
(S)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
(R)-5-(3,5-Dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
2-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile:
1-(2,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
4-((5-(3,5-Dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile:
1-(2,4-Difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(2-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(3,4,5-trifluorobenzyl)pyridin-2(1H)-one;
2-((1H-Benzo[d]imidazol-5-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)pyridazin-3(2H)-one;
6-(3,5-Dimethylisoxazol-4-yl)-2-(3,4,5-trifluorobenzyl)pyridazin-3(2H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(4-(methylsulfonyl)benzyl)pyridin-2(1H)-one;
1-((1H-Benzo[d]imidazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-(3-Chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-((1H-Indazol-5-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-((1H-Indol-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-((4-Chlorophenyl)sulfonyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
5-(3-Amino-5-methylisoxazol-4-yl)-1-benzylpyridin-2(1H)-one;
3-Amino-1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(4-methylpiperazin-1-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-4-methoxypyridin-2(1H)-one;
1-(3,4-Dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((4-fluorophenyl)amino)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3-fluorophenyl)amino)pyridin-2(1H)-one;
1-Benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-Chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3-methylisothiazol-4-yl)pyridin-2(1H)-one;
1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(piperazin-1-yl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(2-methoxybenzyl)pyridin-2(1H)-one;
5-(3,5-Dimethylisoxazol-4-yl)-1-(pyrimidin-2-ylmethyl)pyridin-2(1H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)isoquinolin-1(2H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2H-phthalazin-1-one;
6-Benzyl-8-(3,5-dimethylisoxazol-4-yl)-1,6-naphthyridin-5(6H)-one;
7-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1,7-naphthyridin-8(7H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one;
2-Benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,6-naphthyridin-1(2H)-one; and
stereoisomers, tautomers, pharmaceutical acceptable salts, or hydrates thereof;
wherein said cancer is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.
19. A method for treating a cancer that is sensitive to a BET inhibitor, said method corn rising administering a therapeutically effective amount of a compound selected from:
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;
3-chloro-5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)pyridin-2(1H)-one;
5-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-(phenylamino)pyridin-2(1H)-one;
3-(azetidin-1-yl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((1-methyl-1H-pyrazol-3-yl)amino)pyridin-2(1H)-one;
3-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)benzamide;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(ethylamino)pyridin-2(1H)-one;
1-benzyl-5-(3-(methoxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-(phenylamino)pyridin-2(1H)-one;
3-amino-1-benzyl-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-morpholinopyridin-2(1H)-one;
1-benzyl-3-(benzyloxyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(isopropylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-3-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-4-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisothiazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile;
methyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylate;
N-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)methanesulfonamide;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxamide;
3-amino-1-(4-chloro-3-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(1H-imidazol-1-yl)pyridin-2(1H)-one;
3-amino-1-(4-chlorobenzyl)-5-(3-(hydroxymethyl)-5-methylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(4-chloro-2-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(2-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-3-(cyclopentylamino)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-hydroxypyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-methoxypyridin-2(1H)-one;
3-amino-1-(3,4-difluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(3-chloro-4-fluorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(3,4-dichlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiazol-2-ylmethyl)pyridin-2(1H)-one;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)benzonitrile;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((3,5-dimethylisoxazol-4-yl)amino)pyridin-2(1H)-one;
5-(3,5-dimethylisoxazol-4-yl)-1-(4-vinylbenzyl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(thiophen-3-ylmethyl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyridazin-3-ylamino)pyridin-2(1H)-one;
3-amino-1-((5-chlorothiophen-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl-3-((5-fluoropyridin-3-yl)amino)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-methylpyridin-2(1H)-one;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-5-methylisoxazole-3-carboxylic acid;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethoxy)benzyl)pyridin-2(1H)-one;
3-amino-1-(2-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-(trifluoromethyl)benzyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methoxypyridin-3-yl)amino)pyridin-2(1H)-one;
5-((1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydropyridin-3-yl)amino)picolinonitrile;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((6-methoxypyridin-3-yl)amino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrazin-2-ylamino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrimidin-5-ylamino)pyridin-2(1H)-one;
3-amino-1-(4-(azetidin-1-yl)benzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-morpholinobenzyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-(pyrrolidin-3-ylamino)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methylisoxazol-5-yl)methyl)pyridin-2(1H)-one;
3-amino-1-(4-bromobenzyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-isopropylbenzyl)pyridin-2(1H)-one;
1-(4-chlorobenzyl)-5-(3,5-dimethylisoxazol-4-yl)-3-((2,2,2-trifluoroethyl)amino)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-2-yl)methyl)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl-3-((6-methylpyridin-3-yl)amino)pyridin-2(1H)-one;
1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-3-((5-methylpyridin-3-yl)amino)pyridin-2(1H)-one;
1-((1H-indol-4-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
4-(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)-N-methoxy-N,5-dimethylisoxazole-3-carboxamide;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((2,5-dimethylthiophen-3-yl)methyl)pyridin-2(1H)-one;
3-amino-1-((5-chloropyridin-3-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-((3-chloropyridin-4-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-((3-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-((5-chloropyridin-2-yl)methyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-1-(benzo[d][1,3]dioxol-4-ylmethyl)-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((6-methylpyridin-3-yl)methyl)pyridin-2(1H)-one;
methyl 4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylate;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-3-methylisoxazole-5-carboxylic acid;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-3-fluorobenzonitrile;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-fluorobenzonitrile;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)pyridin-2(1H)-one;
5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)thiophene-2-carbonitrile;
4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)-N,3-dimethylisoxazole-5-carboxamide;
3-(aminomethyl)-1-benzyl-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(4-iodobenzyl)pyridin-2(1H)-one;
1-benzyl-5-(5-oxopyrrolidin-3-yl)pyridin-2(1H)-one;
4-(1-(3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)ethyl)benzonitrile;
1-((1H-indol-3-yl)methyl)-3-amino-5-(3,5-dimethylisoxazol-4-yl)pyridin-2(1H)-one;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-((3-methyl-1H-indol-4-yl)methyl)pyridin-2(1H)-one;
5-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile;
4-((3-amino-5-(3,5-dimethylisoxazol-4-yl)-2-oxopyridin-1(2H)-yl)methyl)-2-bromobenzonitrile;
3-amino-5-(3,5-dimethylisoxazol-4-yl)-1-(quinolin-5-ylmethyl)pyridin-2(1H)-one;
2-benzyl-6-(((3,5-dimethylisoxazol-4-yl)methyl)amino)pyridazin-3(2H)-one;
4-amino-2-(4-chlorobenzyl)-6-(3,5-di methylisoxazol-4-yl)pyridazin-3 (2H)-one;
2-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-(pyridin-3-ylamino)pyridazin-3(2H)-one;
4-amino-2-benzyl-6-(3,5-di methylisoxazol-4-yl)pyridazin-3(2H)-one; and
stereoisomers, tautomers, pharmaceutical acceptable salts, or hydrates thereof:
wherein said cancer is selected from B-acute lymphocytic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervix cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, small cell lung carcinoma, NUT midline carcinoma, B-cell lymphoma, non-small cell lung cancer, head and neck squamous cell carcinoma, chronic lymphocitic leukemia, follicular lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barret's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.