US 11,447,493 B2Granted

Inhibitors of cyclin-dependent kinases

OwnerToufike Kanouni, Lee Arnold +2inventors

InventorsToufike Kanouni, Lee Arnold, Stephen W. Kaldor, Eric A. Murphy

Life of this patent

Estimating the term…

Abstract

Provided herein are inhibitors of cyclin-dependent kinases (CDKs), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

Claims19

Dependent claims

A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

wherein,
E is selected from —C(O)—;
G is selected from a group having the structure:
wherein,
L is O, NH, or N (optionally substituted C1-C4 alkyl);
t is 0, 1, or 2;
u is 1, or 2;
p is 0, 1, or 2;
r is 0, 1, or 2;
R1 is selected from hydrogen, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclylalkyl;
R2 is selected from hydrogen, or optionally substituted C1-C4 alkyl;
R3 is selected from hydrogen, —CN, or optionally substituted C1-C4 alkyl;
each R4 is independently selected from optionally substituted C1-C4 alkyl, or optionally substituted heterocyclylalkyl;
R5 is optionally substituted C1-C4 alkyl, or optionally substituted heterocyclylalkyl;
each R11 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, or both R11 groups form an oxo;
q is 0, 1, 2, or 3;
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
X is halogen, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
Y is a group selected from:
wherein,
R15 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R21, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
R16 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R21, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
R17 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R2′, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
R18 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R2′, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
each R21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
and
each R22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

25 more elements

A compound, or pharmaceutically acceptable salt or solvate thereof, selected from:

(R)—N-(4-(3-(quinazolin-2-ylamino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-(isoquinolin-3-ylamino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-chloroquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-fluoroquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-fluoroquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-methoxyquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-methoxyquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-methylquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-methylquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-chloroquinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-(methyl sulfonyl)quinazolin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)-2-((1-(4-acrylamidobenzoyl)piperidin-3-yl)amino)-N,N-dimethylquinazoline-7-carboxamide,
(R)-2-((1-(4-acrylamidobenzoyl)piperidin-3-yl)amino)quinazoline-7-carboxamide,
(R)-2-((1-(4-acrylamidobenzoyl)piperidin-3-yl)amino)quinazoline-7-carboxylic acid,
(R)—N-(4-(3-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-chloroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-(isoquinolin-3-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-methoxyquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-methylquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-(pyrido[3,4-d]pyrimidin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-methylquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-(methylsulfonyl)quinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-methoxyquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-chloroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((7-cyanoquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)-2-((1-(4-acrylamidobenzoyl)pyrrolidin-3-yl)amino)quinazoline-7-carboxylic acid,
(R)-2-((1-(4-acrylamidobenzoyl)pyrrolidin-3-yl)amino)quinazoline-7-carboxamide,
(R)-2-((1-(4-acrylamidobenzoyl)pyrrolidin-3-yl)amino)-N-methylquinazoline-7-carboxamide,
(R)-2-((1-(4-acrylamidobenzoyl)pyrrolidin-3-yl)amino)-N,N-dimethylquinazoline-7-carboxamide,
(R)—N-(4-(3-((7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((8-isopropyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)-2-((1-(4-acrylamidobenzoyl)pyrrolidin-3-yl)amino)-N-methylquinazoline-7-carboxamide, (R)—N-(2-fluoro-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
N-(4-((3 S,4S)-3-fluoro-4-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
N-(4-(3-(quinazolin-2-ylamino)azetidine-1-carbonyl)phenyl)acrylamide, (R,E)-4-(dimethylamino)-N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)but-2-enamide,
(R,E)-4-(dimethylamino)-N-(4-(3-(quinazolin-2-ylamino)piperidine-1-carbonyl)phenyl)but-2-enamide,
(R)—N-(5-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)pyridin-2-yl)acrylamide,
(R,E)-4-(dimethylamino)-N-(2-fluoro-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)but-2-enamide,
(R)—N-(2-fluoro-4-(3-((6-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)propiolamide,
(R)—N-(2-methoxy-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(2-methyl-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
N-{3-Methoxy-4-[3-(quinazolin-2-yl amino)-pyrrolidine-1-carbonyl]-phenyl}-acrylamide,
(R)—N-methyl-N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(2-fluoro-6-methyl-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R,E)-4-(dimethylamino)-N-(4-(3-((6-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)but-2-enamide,
(R)—N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)but-2-ynamide,
(R)—N-(3-methyl-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)-1-(6-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one,
(R)-1-(7-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)prop-2-en-1-one,
(R,E)-4-(dimethylamino)-N-(2-methoxy-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)but-2-enamide,
(R,E)-N-(2-chloro-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)-4-(dimethylamino)but-2-enamide,
(R,E)-4-(dimethylamino)-N-(2-methyl-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)but-2-enamide,
(R,E)-4-(dimethylamino)-1-(7-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)but-2-en-1-one,
4-Dimethylamino-but-2-enoic acid {3-methoxy-4-[3-(quinazolin-2-ylamino)-pyrrolidine-1-carbonyl]-phenyl}-amide,
(R,E)-4-(dimethylamino)-N-methyl-N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)but-2-enamide,
(R)—N-(3-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(2-chloro-4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R,E)-4-(dimethylamino)-1-(6-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)-3,4-dihydroquinolin-1(2H)-yl)but-2-en-1-one,
(R)—N-(4-(3-((8-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((5-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)—N-(4-(3-((6-fluoroquinazolin-2-yl)amino)pyrrolidine-1-carbonyl)-2-methylphenyl)acrylamide,
(R)—N-(2-methyl-4-(3-((7-(methylsulfonyl)quinazolin-2-yl)amino)pyrrolidine-1-carbonyl)phenyl)acrylamide,
(R)-2-methylene-N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)butanamide,
(R)—N-(4-(3-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)ethenesulfonamide, or
N-(4-((3 S,4R)-3-methyl-4-(quinazolin-2-ylamino)pyrrolidine-1-carbonyl)phenyl)acrylamide.

66 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/052,162Filed 2 May 2019 · us provisional application
Priority: 2 May 2018
Published: US 2021/0053969 A125 Feb 2021
Granted: 20 Sep 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification12 codes

A61P 35/00
Antineoplastic agents
C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/08
Medicinal preparations characterised by special physical form: solutions

Family

Application62/666,024Us provisional application · filed 2 May 2018
US 2021/0053969 A1Pre-grant publication · published 25 Feb 2021
US 11,447,493 B2This patent

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

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Abstract

Provided herein are inhibitors of cyclin-dependent kinases (CDKs), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.

A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I):

wherein,
E is selected from —C(O)—;
G is selected from a group having the structure:
wherein,
L is O, NH, or N (optionally substituted C1-C4 alkyl);
t is 0, 1, or 2;
u is 1, or 2;
p is 0, 1, or 2;
r is 0, 1, or 2;
R1 is selected from hydrogen, optionally substituted C1-C4 alkyl, or optionally substituted heterocyclylalkyl;
R2 is selected from hydrogen, or optionally substituted C1-C4 alkyl;
R3 is selected from hydrogen, —CN, or optionally substituted C1-C4 alkyl;
each R4 is independently selected from optionally substituted C1-C4 alkyl, or optionally substituted heterocyclylalkyl;
R5 is optionally substituted C1-C4 alkyl, or optionally substituted heterocyclylalkyl;
each R11 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, or both R11 groups form an oxo;
q is 0, 1, 2, or 3;
n is 0, 1, 2, or 3;
m is 0, 1, 2, or 3;
X is halogen, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy;
Y is a group selected from:
wherein,
R15 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R21, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
R16 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R21, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
R17 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R2′, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
R18 is selected from hydrogen, halogen, —CN, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkyl-O—, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted aryloxy, optionally substituted aralkyloxy, optionally substituted heteroaryloxy, optionally substituted heteroaralkyloxy, —N(R22)2, —SO2R21, —N(R22)SO2R21, —SO2N(R22)2, —N(R22)SO2N(R22)2, —CON(R22)2, —N(R22)CO2R2′, —N(R22)CON(R22)2, —N(R22)COR21, —OC(O)N(R22)2, —OSO2N(R22)2, or —N(R22)SO3R21;
each R21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
and
each R22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

25 more elements

Facts

Application

17/052,162Filed 2 May 2019 · us provisional application

Priority

2 May 2018

Published

US 2021/0053969 A125 Feb 2021

Granted

20 Sep 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification12 codes

A61P 35/00
Antineoplastic agents
C07D 471/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 9/0019
Galenical forms characterised by the site of application: injectable compositions; Intramuscular, intravenous, arterial, subcutaneous…
A61K 9/08
Medicinal preparations characterised by special physical form: solutions