초록

The present disclosure relates to compounds, which are useful for inhibition of BET protein function by binding to bromodomains, and their use in therapy.

대표청구항 ▼

1. A method of inhibiting BET proteins in a mammal by administering a therapeutically effective amount of 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 fro

1. A method of inhibiting BET proteins in a mammal by administering a therapeutically effective amount of 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: and 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, R8, R9, R10, and R11 may be connected in a 5- or 6-membered ring to form a carbocycle or heterocycle. 2. The method according to claim 1, wherein R1 and R4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino;wherein R2 and R3 are independently selected from hydrogen, alkyl, alkoxy, and halogen;wherein at least one of R1, R2, R3, and 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; andwherein 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; andwherein R12 and R13 are independently selected from hydrogen and alkyl. 4. The method according to claim 1, wherein the compound is 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(3H)-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;2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one; andstereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof. 5. The method 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 method according to claim 5wherein D is O;wherein n=1;wherein R14 and R15 are independently selected from hydrogen, and alkyl; andwherein R6 is selected from hydrogen, methoxy, 7. The method of claim 1, further comprising treating a disease, disorder, or condition characterized by dysregulation of cell cycle control, inflammatory cytokine expression, viral transcription, hematopoietic differentiation, insulin transcription, or adipogenesis. 8. The method of claim 7, wherein the disease, disorder, or condition is an autoimmune disease. 9. The method of claim 8, wherein the autoimmune disease is selected from Acute Disseminated Encephalomyelitis, Agammaglobulinemia, Allergic Disease, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Anti-phospholipid syndrome, Autoimmune aplastic anemia, Autoimmune hepatitis, Autoimmune inner ear disease, Autoimmune myocarditis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura, Behcet's Disease, Bullous pemphigoid, Castleman's Disease, Celiac Disease, Churg-Strauss syndrome, Crohn's Disease, Cogan's syndrome, Dry eye syndrome, Essential mixed cryoglobulinemia, Dermatomyositis, Devic's Disease, Encephalitis, Eosinophlic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Giant cell arteritis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis (Wegener's), Graves' Disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, IgA nephropathy, Inclusion body myositis, Type I diabetes, Interstitial cystitis, Kawasaki's Disease, Leukocytoclastic vasculitis, Lichen planus, Lupus (SLE), Microscopic polyangitis, Multiple sclerosis, Myasthenia gravis, myositis, Optic neuritis, Pemphigus, POEMS syndrome, Polyarteritis nodosa, Primary biliary cirrhosis, Psoriasis, Psoriatic arthritis, Pyoderma gangrenosum, Relapsing polychondritis, Rheumatoid arthritis, Sarcoidosis, Scleroderma, Sjogren's syndrome, Takayasu's arteritis, Transverse myelitis, Ulcerative colitis, Uveitis, and Vitiligo. 10. The method of claim 7, wherein the disease, disorder, or condition is an inflammatory disease. 11. The method of claim 10, wherein the inflammatory disease or disorder is selected from sinusitis, pneumonitis, osteomyelitis, gastritis, enteritis, gingivitis, appendicitis, irritable bowel syndrome, tissue graft rejection, chronic obstructive pulmonary disease (COPD), septic shock, toxic shock syndrome, SIRS, bacterial sepsis, osteoarthritis, acute gout, acute lung injury, acute renal failure, burns, Herxheimer reaction, and SIRS associated with viral infections. 12. The method of claim 7, wherein the disease, disorder, or condition is a cardiovascular disease. 13. The method of claim 7, wherein the disease, disorder, or condition is insulin resistance diabetes. 14. The method of claim 7, wherein the disease, disorder, or condition is a neurological disorder. 15. The method of claim 7, wherein the disease, disorder, or condition is HIV. 16. The method of claim 7, wherein the disease, disorder, or condition is cancer. 17. The method according to claim 16, wherein R1 and R4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino;wherein R2 and R3 are independently selected from hydrogen, alkyl, alkoxy, and halogen;wherein at least one of R1, R2, R3, and 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; andwherein Y is N. 18. The compound according to claim 17, 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; andwherein R12 and R13 are independently selected from hydrogen and alkyl. 19. The method according to claim 16, wherein the compound is 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-2yl)-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-methoxyquinzolin -4(3H)-one Hydrochloride;2-(6-(4-Isopropylpiperazin-1-yl)pyrdin-2-yl)-5-methoxy-7-phenyiquinazolin-4(3H) -one;8-(Benzyloxy)-2-(3-(4-isopropylpiperazin-1 -yl)phenyl)-5-methoxyquinazolin -4(3)-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-2yl)quinazolin-4(3H)-one;2-(3-Chloro-5-(piperazin-1yl)-phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H) -one; andstereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof. 20. The method according to claim 16, 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. 21. The method according to claim 20wherein D is O;wherein n =1;wherein R14 and R15 are independently selected from hydrogen, and alkyl; andwherein R6 is selected from hydrogen, methoxy, 22. The method of claim 16, wherein the cancer is a midline carcinoma. 23. The method of claim 16, wherein the cancer exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoproteins. 24. The method of claim 23, wherein the cancer is characterized by overexpression of c-myc. 25. The method of claim 23, wherein the cancer is characterized by is characterized by overexpression n-myc. 26. The method of claim 16, wherein the cancer is characterized by recruitment of pTEFb to regulate oncogenes. 27. The method of claim 16, wherein the cancer is characterized by upregulation of at least one of CDK6, Bcl2, TYRO3, MYB and hTERT. 28. The method of claim 16, wherein the cancer is associated with a viral infection. 29. The method of claim 16, wherein the 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, oesophageal squamous cell carcinoma, 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, esophageal cancer and head and neck squamous cell carcinoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphomas, activated 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, chronic lymphocytic leukemia, and mantle cell lymphoma. 30. The method of claim 16, wherein the compound of Formula I is administered in combination with another anticancer agent. 31. The method of claim 30, 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).