# US 10,500,209 B2 · Quinazolinones as bromodomain inhibitors

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- Number: US 10,500,209 B2
- Document ID: US10500209B2
- Status: Granted
- Kind: B2
- Application number: 15/821,454
- Filed: 2017-11-22
- Published: 2018-04-05
- Granted: 2019-12-10
- Earliest claimed: 2013-07-31
- Assignees: Zenith Epigenetics Ltd.
- Applicants: Zenith Epigenetics Ltd.
- Inventors: John Frederick Quinn; Vladimir Khlebnikov
- Web page: https://patentgrep.com/patent/US10500209B2

## CPC

- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/16: Masculine contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 239/91: with aryl or aralkyl radicals attached in position 2 or 3
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

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

## Claims

### Claim 1

A method for inhibiting BET protein function in a mammal, comprising administering a therapeutically effective amount of a compound of Formula I:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt 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;
X is selected from N and CH;
Y is selected from —S(O)—, —NH—, —NHCH2—, —NHCH2CH2—, and —NHCH2CH2CH2—,
wherein if Y is —NH—, —NHCH2—, —NHCH2CH2—, or —NHCH2CH2CH2—, then the nitrogen is attached to the B ring, and one or more hydrogens may be optionally substituted with alkyl(C1-C3), halogen, hydroxyl, or amino;
R1, R2, R3, and R4 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, aryloxy, aryl, hydroxyl, and halogen,
wherein each alkyl and alkoxy may be optionally substituted with hydroxyl, amino, or halogen,
wherein each aryl and aryloxy may be optionally substituted with halogen, alkoxy, or amino, and
wherein 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;
R5 is selected from amino and 5- and 6-membered carbocycles and heterocycles;
R6 is selected from hydrogen, alkoxy, alkyl, halogen, aminoalkyl, and thioalkyl;
R7 is selected from hydrogen, alkyl, alkoxy, thioalkyl, aminoalkyl, and halogen;
and wherein said mammal is afflicted with a cancer 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, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal 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, diffuse large B cell lymphoma with germinal center phenotype, Hodgkin's lymphoma, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barrett's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is a compound of Formula Ia:
or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof,
wherein:
X is selected from N and CH;
Y is selected from —S(O)—, —NH—, —NHCH2—, —NHCH2CH2—, and —NHCH2CH2CH2—,
wherein if Y is —NH—, —NHCH2—, —NHCH2CH2—, or —NHCH2CH2CH2—, then the nitrogen is attached to the B ring, and one or more hydrogens may be optionally substituted with alkyl(C1-C3), halogen, hydroxyl, or amino;
R1 and R3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, amino, aryloxy, aryl, hydroxyl, and halogen,
wherein each alkyl and alkoxy may be optionally substituted with hydroxyl, amino, or halogen,
wherein each aryl and aryloxy may be optionally substituted with halogen, alkoxy, or amino;
R5 is selected from amino and 5- and 6-membered carbocycles and heterocycles;
wherein the 5- and 6-membered carbocycles and heterocycles are selected from:
wherein the 5- and 6-membered carbocycles and heterocycles may be optionally substituted with halogen, amino, amide, alkyl(C1-C6), or alkoxy(C1-C6);
and wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, —C(O)Me, —C(O)Pr, —C(O)iPr, benzyl, —C(O)CF3, —C(O)-tBu, —C(O)NHiPr, —C(O)NMe2, —C(O)NHEt, —C(O)NH2, —C(O)CH(OH)CH3, —C(O)C(O)OMe, —CF3, —CH2CH2OH, —CH2CH2—, amino, and —CH2CH2C(Me)2OH;
R6 is selected from hydrogen, alkoxy, alkyl, halogen, aminoalkyl, and thioalkyl; and
R7 is selected from hydrogen, alkyl, alkoxy, thioalkyl, aminoalkyl, and halogen.

### Claim 3 (depends on 2)

The method of claim 2, wherein X is N.

### Claim 4 (depends on 2)

The method of claim 2, wherein R1 and R3 are each independently an alkoxy group.

### Claim 5 (depends on 4)

The method of claim 4, wherein R1 and R3 are each independently selected from methoxy, ethoxy, isopropoxy, and propoxy.

### Claim 6 (depends on 5)

The method of claim 5, wherein R1 and R3 are each methoxy.

### Claim 7 (depends on 2)

The method of claim 2, wherein R1 is methoxy and R3 is amino.

### Claim 8 (depends on 2)

The method of claim 2, wherein Y is selected from —NH—, —NHCH2—, —NHCH2CH2—, and —NHCH2CH2CH2—, wherein the nitrogen attached to the B ring, and wherein one or more hydrogens may be optionally substituted with F, Me, or Cl.

### Claim 9 (depends on 8)

The method of claim 8, wherein Y is —NH—.

### Claim 10 (depends on 2)

The method of claim 2, wherein R5 is selected from —NHRa and 5- and 6-membered carbocycles and heterocycles;
wherein the 5- and 6-membered carbocycles and heterocycle are selected from:
wherein the 5- and 6-membered carbocycles and heterocycles may be optionally substituted with halogen, amino, amide, alkyl(C1-C6), or alkoxy(C1-C6);
and wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, —C(O)Me, —C(O)Pr, —C(O)iPr, benzyl, —C(O)CF3, —C(O)-tBu, —C(O)NHiPr, —C(O)NMe2, —C(O)NHEt, —C(O)NH2, —C(O)CH(OH)CH3, —C(O)C(O)OMe, —CF3, —CH2CH2OH, —CH2CH2-amino, and —CH2CH2C(Me)2OH.

### Claim 11 (depends on 2)

The method of claim 2, wherein R6 is selected from hydrogen, methyl, and methoxy.

### Claim 12 (depends on 2)

The method of claim 2, wherein R6 is selected from groups of Formula II:
wherein:
D is selected from O, N, and S;
E is independently selected from O and N;
R8 is selected from hydrogen and alkyl,
wherein R8 is present only if D is N;
R9 and R10 are independently selected from hydrogen, alkyl, and cycloalkyl,
wherein only one of R9 and R10 is present if E is O;
R9 and R10 may be connected to form a heterocycle containing one or more heteroatoms; and
n is selected from 1, 2, and 3.

### Claim 13 (depends on 12)

The method of claim 12, wherein R6 is selected from:

### Claim 14 (depends on 2)

The method of claim 2, wherein:
R1 and R3 are each alkoxy;
Y is selected from —NH—, —NHCH2—, —NHCH2CH2—, and —NHCH2CH2CH2—,
wherein the nitrogen is attached to the B ring;
R5 is selected from —NHRa and 5- and 6-membered carbocycles and heterocycles,
wherein the 5- and 6-membered carbocycles and heterocycles are selected from:
wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, —C(O)Me, —C(O)Pr, —C(O)iPr, benzyl, —C(O)CF3, —C(O)-tBu, —C(O)NHiPr, —C(O)NMe2, —C(O)NHEt, —C(O)NH2, —C(O)CH(OH)CH3, —C(O)C(O)OMe, —CF3, —CH2CH2OH, —CH2CH2 amino, and —CH2CH2C(Me)2OH; and
R6 is selected from hydrogen, methyl, and alkoxy,
wherein the alkoxy is optionally substituted with hydroxyl or amino.

### Claim 15 (depends on 2)

The method of claim 2, wherein:
R1 is alkoxy;
R3 is amino;
Y is selected from —NH—, —NHCH2—, —NHCH2CH2—, and —NHCH2CH2CH2—,
wherein the nitrogen is attached to the B ring;
R5 is selected from —NHRa and 5- and 6-membered carbocycles and heterocycles,
wherein the 5- and 6-membered carbocycles and heterocycles are selected from:
wherein Ra is selected from hydrogen, methyl, ethyl, propyl, isopropyl, t-butyl, —C(O)Me, —C(O)Pr, —C(O)iPr, benzyl, —C(O)CF3, —C(O)-tBu, —C(O)NHiPr, —C(O)NMe2, —C(O)NHEt, —C(O)NH2, —C(O)CH(OH)CH3, —C(O)C(O)OMe, —CF3, —CH2CH2OH, —CH2CH2 amino, and —CH2CH2C(Me)2OH; and
R6 is selected from hydrogen, methyl, and alkoxy,
wherein the alkoxy is optionally substituted with hydroxyl or amino.

### Claim 16 (depends on 1)

The method of claim 1, wherein the cancer:
(a) exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein;
(b) results from aberrant regulation of BET proteins;
(c) relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes;
(d) is associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB and/or hTERT; and/or
(e) is associated with a viral infection.

### Claim 17 (depends on 16)

The method of claim 16, wherein:
(a) the cancer exhibiting overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein 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, Nodular melanoma, Superficial spreading melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, and small cell lung carcinoma;
(b) the cancer resulting from aberrant regulation of BET proteins 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) the cancer relying on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes is selected from chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma, primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer;
(d) the cancer associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB, and hTERT 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, Barrett'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) the 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.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound of Formula I is administered in combination with another anticancer agent.

### Claim 19 (depends on 18)

The method of claim 18, 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).

### Claim 20

A method for inhibiting BET protein function in a mammal, comprising administering a therapeutically effective amount of a compound selected from:
5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpiperidin-4-yl)amino)phenyl)-quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-(4-methylpiperazine-1-carbonyl)phenyl) quinazolin-4(3H)-one;
2-(2-((1-isopropylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((1-methylpyrrolidin-3-yl)amino)phenyl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-(methyl(1-methylpiperidin-4-yl)amino)phenyl) quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpiperidin-4-yl)methyl)amino)phenyl) quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-(((1-methylpyrrolidin-3-yl)methyl)amino)phenyl)-quinazolin-4(3H)-one;
2-(2-((2-(Isopropylamino)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-dim ethoxy-2-(4-Methoxy-2-((tetrahydro-2H-pyran-4-yl)amino)-phenyl)quinazolin-4(3H)-one;
2-(2-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((2-(pyrrolidin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperidin-1-yl)ethyl)amino)-phenyl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((3-morpholinopropyl)amino)-phenyl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((2-morpholinoethyl)amino)phenyl)-quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((3-(pyrrolidin-1-yl)propyl)amino)phenyl)quinazolin-4(3H)-one;
2-(2-(((1-Isopropylpyrrolidin-3-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(2-(((1-Isopropylpyrrolidin-2-yl)methyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(2-((1-Isobutyrylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(2-((3-(Isopropylamino)propyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-j(3-(4-methylpiperazin-1-yl)propyl)amino)-phenyl)quinazolin-4(3H)-one;
2-(2-((2-(4-Isopropylpiperazin-1-yl)ethyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-[4-methoxy-2-(1-methylpiperidin-4-ylsulfinyl)phenyl]quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((2-(piperazin-1-yl)ethyl)amino)phenyl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-((2-(4-methylpiperazin-1-yl)ethyl)amino)phenyl)-quinazolin-4(3H)-one;
2-(2-((1-Isopropylpiperidin-4-yl)amino)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-Isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(4-methoxy-2-[3-(piperazin-1-yl)propylamino]phenyl)quinazolin-4(3H)-one;
2-(2-((4,4-Dimethylcyclohexyl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(2-((trans-4-(2-Hydroxypropan-2-yl)cyclohexyl)amino)-4-m ethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-Isobutyrylpiperidin-4-yl)amino)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-Chloro-2-((1-isopropylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-Chloro-2-((1-isobutyrylpiperidin-4-yl)amino)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(2-((1-Benzylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(-((1-Isobutyrylpiperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-Acetylpiperidin-4-yl)amino)pyridine-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
N-(cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)cyclohexyl)isobutyramide;
2-(2-((1-Acetylpiperidin-4-yl)amino)-4-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(5-methoxy-3-((1-methylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(3-(((1-methylpyrrolidin-3-yl)methyl)amino)pyridin-2-yl)quinazolin-4(3H)-one;
4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylpiperidine-1-carboxamide;
2-(3-((3-(Isopropylamino)propyl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
5,7-Dimethoxy-2-(3-((1-methylpiperidin-4-yl)amino)pyridine-2-yl)quinazolin-4(3H)-one;
cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-5-methoxypyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide;
5,7-Dimethoxy-2-(3-((1-(2,2,2-trifluoroacetyl)piperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one;
4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylpiperidine-1-carboxamide;
5,7-Dimethoxy-2-(3-((1-pivaloylpiperidin-4-yl)amino)pyridin-2-yl)quinazolin-4(3H)-one;
5,7-Dimethoxy-2-(3-((2-morpholinoethyl)amino)pyridine-2-yl)quinazolin-4(3H)-one;
2-(3-((1-Isopropylpiperidin-4-yl)amino)-5-(2-((1-isopropylpiperidin-4-yl)amino)ethoxy)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-N,N-dimethyl-2-oxoacetamide;
4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-ethylpiperidine-1-carboxamide;
cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N,N-dimethylcyclohexane-1-carboxamide;
4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidine-1-carboxamide;
Methyl-2-(4-((2-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)piperidin-1-yl)-2-oxoacetate;
N-(2-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)ethyl)isobutyramide;
N-(3-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)propyl)isobutyramide;
2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxypyrido[3,4-d]pyrimidin-4(3H)-one;
2-(3-((1-(2-Hydroxy-2-methylpropyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-(2-hydroxypropanoyl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxy-7-((4-methoxybenzyl)amino)quinazolin-4(3H)-one;
2-[5-(2-Hydroxyethoxy)-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one;
cis-4-((2-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-3-yl)amino)-N-isopropylcyclohexane-1-carboxamide;
2-[5-(2-Hydroxyethoxy)-3-(1-isobutyroylpiperidin-4-ylamino)pyridin-2-yl]-5,7-dimethoxyquinazolin-4(3H)-one;
7-amino-2-(3-((1-Isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one;
2-{3-(1-Isopropylpiperidin-4-ylamino)-5-[2-(pyrrolidin-1-yl)ethoxy]pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one;
2-{5-[2-(Isopropylamino)ethoxy]-3-(1-isopropylpiperidin-4-ylamino)pyridin-2-yl}-5,7-dimethoxyquinazolin-4(3H)-one;
2-(3-((1-(1-Hydroxy-2-methylpropan-2-yl)piperidin-4-yl)amino)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one; and
7-(Ethylamino)-2-(3-((1-isopropylpiperidin-4-yl)amino)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one; and
stereoisomers, tautomers, and pharmaceutically acceptable salts thereof;
wherein said mammal is afflicted with a cancer 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, neuroblastoma, esophageal cancer, osteosarcoma, ovarian cancer, prostate cancer, renal 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, diffuse large B cell lymphoma with germinal center phenotype, Hodgkin's lymphoma, activated anaplastic large cell lymphoma, primary neuroectodermal tumor, pancreatic cancer, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, malignant glioma, thyroid cancer, Barrett's adenocarcinoma, hepatoma, pro-myelocytic leukemia, and mantle cell lymphoma.

### Claim 21 (depends on 20)

The method of claim 20, wherein the cancer:
(a) exhibits overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein;
(b) results from aberrant regulation of BET proteins;
(c) relies on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes;
(d) is associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB and/or hTERT; and/or
(e) is associated with a viral infection.

### Claim 22 (depends on 21)

The method of claim 21, wherein:
(a) the cancer exhibiting overexpression, translocation, amplification, or rearrangement of a myc family oncoprotein 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, Nodular melanoma, Superficial spreading melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, and small cell lung carcinoma;
(b) the cancer resulting from aberrant regulation of BET proteins 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) the cancer relying on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes is selected from chronic lymphocytic leukemia, multiple myeloma, follicular lymphoma, diffuse large B cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, anaplastic large cell lymphoma, neuroblastoma, primary neuroectodermal tumor, rhabdomyosarcoma, prostate cancer, and breast cancer;
(d) the cancer associated with upregulation of BET responsive genes CDK6, Bcl2, TYRO3, MYB, and hTERT 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, Barrett'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) the 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.

### Claim 23 (depends on 20)

The method of claim 20, wherein the compound of Formula I is administered in combination with another anticancer agent.

### Claim 24 (depends on 23)

The method of claim 23, 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).