US 10,065,986 B2Granted

Certain chemical entities, compositions, and methods

AssigneeNeupharma, Inc.

InventorXiangping Qian

Life of this patent

Estimating the term…

Abstract

Chemical entities that are novel compounds, pharmaceutical compositions and methods of treatment of cancer are described.

Claims14

Dependent claims

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R6, R9, R10, R11 and R12 are independently chosen from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
or
R1 and R2, or R7 and R8, or R9 and R10, or R11 and R12 mutually independently, together in each case denote an oxo group (═O);
R7 is chosen from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
R8 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
R13 is chosen from hydrogen, optionally substituted alkyl, and formyl;
R14 is chosen from hydrogen and optionally substituted lower alkyl;
and
R15 is chosen from unsubstituted alkyl, alkyl substituted with one or more substituents selected from the group consisting of cycloalkyl, heterocycloalkyl, hydroxyl, halo, cyano, oxo, optionally substituted acyl, and optionally substituted amino, —COR16, —CO2R16, —CONR17R18, and —SO2R16, where R16 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
and R17, R18 and R19 are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
or R17 and R18 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
or
R14 and R15 are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloaklyl;
W1 is chosen from the following moieties:
and
W2 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
wherein each optionally substituted group may be substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkyl-OH, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 alkylphenyl, —C(O)C1-C4 haloalkyl, —OC(O)C1-C4 alkyl, —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, —SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl).

15 more elements

A compound or a salt chosen from:

2-(pyrrolidin-1-yl)ethyl ((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate,
2-morpholinoethyl ((3S,5R,8R9S,10S,13R17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate,
2-(3-oxopiperazin-1-yl)ethyl ((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate,
N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-(pyrrolidin-1-yl)acetamide,
N-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-2-morpholinoacetamide,
(R)-2-amino-N-((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)propanamide
(S)-2-amino-N-((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)propanamide,
(R)-2-amino-N-((3 S,5R,8R, 9 S, 10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide,
(S)-2-amino-N-((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide,
(R)-2-amino-N1-((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)succinamide,
(S)-2-amino-N1-((3 S,5R8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)succinamide,
2-(3-oxopiperazin-1-yl)ethyl ((3 S,5R,8R9S, 10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate,
2-(pyrrolidin-1-yl)ethyl ((3S,5R,8R9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate,
2-morpholinoethyl ((3S,5R,8R9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)carbamate,
2-amino-N-((3 S,5R,8R9 S, 10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)acetamide,
(S)-2-amino-N-((3 S,5R,8R9S, 10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)propanamide,
(R)-2-amino-N-((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide,
(S)-2-amino-N-((3 S,5R,8R9S, 10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)-3-methylbutanamide,
(R)-2-amino-N1-((3 S,5R,8R,9S,10 S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)succinamide,
(S)-2-amino-N1-((3 S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(5-oxo-2,5-dihydrofuran-3-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl)succinamide,
and pharmaceutically acceptable salts thereof.

18 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/048,703Filed 19 Feb 2016 · continuation
Priority: 29 Apr 2012
Published: US 2016/0272671 A122 Sep 2016
Granted: 4 Sep 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07J 41/0011
The nitrogen atom being directly linked to the cyclopentahydro phenanthrene skeleton: unsubstituted amino radicals
A61P 35/00
Antineoplastic agents
C07J 19/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17
C07J 41/0005
Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring: the nitrogen atom being directly linked to the…

Family

Application61/639,930Us provisional application · filed 29 Apr 2012
Application13/873,059Parent of this continuation · filed 29 Apr 2013
US 2016/0272671 A1Pre-grant publication · published 22 Sep 2016
US 9,340,570 B2Parent of this continuation
US 2013/0345186 A1Published application
US 10,065,986 B2This patent

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

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A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1, R2, R3, R6, R9, R10, R11 and R12 are independently chosen from hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
or
R1 and R2, or R7 and R8, or R9 and R10, or R11 and R12 mutually independently, together in each case denote an oxo group (═O);
R7 is chosen from hydrogen, hydroxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, and optionally substituted amino;
R8 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
R13 is chosen from hydrogen, optionally substituted alkyl, and formyl;
R14 is chosen from hydrogen and optionally substituted lower alkyl;
and
R15 is chosen from unsubstituted alkyl, alkyl substituted with one or more substituents selected from the group consisting of cycloalkyl, heterocycloalkyl, hydroxyl, halo, cyano, oxo, optionally substituted acyl, and optionally substituted amino, —COR16, —CO2R16, —CONR17R18, and —SO2R16, where R16 is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
and R17, R18 and R19 are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
or R17 and R18 may be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
or
R14 and R15 are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloaklyl;
W1 is chosen from the following moieties:
and
W2 is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, and optionally substituted alkynyl;
wherein each optionally substituted group may be substituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkyl-OH, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo, —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 alkylphenyl, —C(O)C1-C4 haloalkyl, —OC(O)C1-C4 alkyl, —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2, —SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl).

15 more elements

Facts

Application

15/048,703Filed 19 Feb 2016 · continuation

Priority

29 Apr 2012

Published

US 2016/0272671 A122 Sep 2016

Granted

4 Sep 2018

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07J 41/0011
The nitrogen atom being directly linked to the cyclopentahydro phenanthrene skeleton: unsubstituted amino radicals
A61P 35/00
Antineoplastic agents
C07J 19/00
Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17
C07J 41/0005
Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring: the nitrogen atom being directly linked to the…

Family

Application61/639,930Us provisional application · filed 29 Apr 2012

Application13/873,059Parent of this continuation · filed 29 Apr 2013

US 2016/0272671 A1Pre-grant publication · published 22 Sep 2016

US 9,340,570 B2Parent of this continuation

US 2013/0345186 A1Published application

US 10,065,986 B2This patent

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