US 10,500,209 B2Granted

Quinazolinones as bromodomain inhibitors

AssigneeZenith Epigenetics Ltd.

InventorsJohn Frederick Quinn, Vladimir Khlebnikov

Life of this patent

Estimating the term…

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.

Claims24

Dependent claims

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.

14 more elements

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.

70 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/821,454Filed 22 Nov 2017 · division
Priority: 31 Jul 2013
Published: US 2018/0092924 A15 Apr 2018
Granted: 10 Dec 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification54 codes

A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Family

Application61/860,403Us provisional application · filed 31 Jul 2013
PCT/IB2014/002510Parent of this division · filed 30 Jul 2014
US 2018/0092924 A1Pre-grant publication · published 5 Apr 2018
Application14/908,898Parent of this division
US 9,855,271 B2Parent of this division
US 2016/0193218 A1Published application
US 10,500,209 B2This patent

From the US filing history. Foreign family members aren’t listed.

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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.

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.

14 more elements

Facts

Application

15/821,454Filed 22 Nov 2017 · division

Priority

31 Jul 2013

Published

US 2018/0092924 A15 Apr 2018

Granted

10 Dec 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification54 codes

A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol
A61K 31/517
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Family

Application61/860,403Us provisional application · filed 31 Jul 2013

PCT/IB2014/002510Parent of this division · filed 30 Jul 2014

US 2018/0092924 A1Pre-grant publication · published 5 Apr 2018

Application14/908,898Parent of this division

US 9,855,271 B2Parent of this division

US 2016/0193218 A1Published application

US 10,500,209 B2This patent

From the US filing history. Foreign family members aren’t listed.