US 2023/0047296 A1Published application

Nrf2 REGULATORS

AssigneesGlaxoSmithKline Intellectual Property Development Limited, Astex Therapeutics Limited

InventorsJeffrey K. KERNS, James Callahan, Hongxing Yan, Thomas Daniel Heightman, Charlotte Mary Griffiths-Jones, Alison Jo-Anne Woolford, Tindy Li, Ami Lakdawala Shah, Roderick S. Davis, David Norton, Jeffrey Charles Boehm, Paris L. Hamilton, Nicole Cathleen Goodwin, Yun Jin

Life of this patent

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Abstract

The present invention relates to aryl analogs, pharmaceutical compositions containing them and their use as NRF2 regulators.

Claims10

Dependent claims

A compound of Formula (I)

wherein,
B is benzotriazolyl, phenyl or triazolopyridinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —O—C1-3alkyl, CN, —(CH2)2—O—(CH2)2—OR4 and halo;
D is —C(O)OH, —C(O)NHSO2CH3, —SO2NHC(O)CH3, 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
R1 is independently hydrogen, C1-3alkyl, F, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
R2 is hydrogen, methyl, CF3, or halo;
R4 is hydrogen or —C1-3alkyl;
Linker is —CH2—, —CH2—N(-cyclopropyl)-CH2—, —CH2—N(CH3)—CH2— or —N—(CH3)—CH2—;
A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl;
each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, C3-6spirocycloalkyl, halo, CN, —O—C1-3alkyl, —CH2—O—CH3, and OH;
and the piperidinyl is unsubstituted or additionally substituted by one or two substituents independently selected from pyrazolyl, —CH2pyrazolyl, and oxadiazolyl, each of which is unsubstituted or further substituted by one or two —C1-3alkyl, or, when A is piperidinyl, it is unsubstituted or substituted by —SO2R, wherein R is —C1-3alkyl, phenyl or C3-7cycloalkyl;
and the oxazepane is unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3alkyl and —C3-7cycloalkyl;
and the morpholinyl is unsubstituted or substituted by a phenyl which itself is unsubstituted or substituted by one or two substituents independently selected from C1-3 alkyl and —O—C1-3alkyl;
and the pyrrolidinyl is unsubstituted or substituted by a triazolyl group which itself is unsubstituted or substituted by —C1-3alkyl;
and the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups are each unsubstituted or substituted by one or two substituents independently selected from —CH2—C4-7cycloalkyl, —CH2-05_7 heterocycloalkyl, —CH2-azabicycloheptanyl, —CH2-oxepane and —CH2-azabicyclohexanyl, each of which, including the —CH2—, is unsubstituted or further substituted by 1 or 2 substituents independently selected from —C1-3 alkyl and F;
and
X is independently CH or N;
or a pharmaceutically acceptable salt thereof.

14 more elements

A compound which is:

(S)-Methyl 3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;
(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;
(2R,3S)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2.3-dihydropyrido[2,3-f][1,4]oxazepin-4(51-)-yl)methyl)-4-methylphenyhpropionic acid;
rel-(R)-3-(1,4-dimethyl-1H-benzo[d]-[1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyl)-propanoic acid;
rel-(R)-3-(4-chloro-3-((2,2-dimethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid;
(S)-3-(4-chloro-3-(((R)-2-ethyl-2,3-dihydropyrido[2,3-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)propanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-9-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(S)-3-(3-(((R)-8-Chloro-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;
(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)propanoic acid;
3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)propanoic acid;
(S)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;
(R)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;
3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2,2-dimethylpropanoic acid;
(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;
(2S,3R)-3-(3-(((R)-2-Ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;
(2S,3R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;
(2R,3S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;
(R)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(2R,3S)-3-(7-Chloro-1-ethyl-4-methyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(6-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-5-methylpyridin-2-yl)-2,2-dimethylpropanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(5-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-6-methylpyridin-3-yl)-2,2-dimethylpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-6-fluoro-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;
3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-methyl-3-((2,2,8-trimethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)phenyl)pronoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid;
(2R,3S)-3-(4-Chloro-1-ethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2-methylpropanoic acid;
(2R,3S)-3-(3-((2,2-Dimethyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-3-(1-ethyl-4-fluoro-1H-benzo[d][1,2,3]triazol-5-yl)-2-methylpropanoic acid;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[3,4-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethyl-N-(methylsulfonyl)propenamide;
(S)-3-(1,4-Dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid;
(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyl) propanoic acid;
(S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-fluorophenyhpropanoic acid;
or (S)-3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-((2,2-dimethyl-2,3-dihydropyrido[4,3-f][1,4]oxazepin-4(5H)-yl)methyl)-4-methylphenyhpropanoic acid, or a pharmaceutically acceptable salt thereof.

40 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/495,115Filed 6 Oct 2021
Priority: 15 Jun 2015
Published: 16 Feb 2023
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 11/00
Drugs for disorders of the respiratory system
A61P 25/00
Drugs for disorders of the nervous system

Family

Application62/175,510Us provisional application · filed 15 Jun 2015
Application15/736,075Continuation · filed 13 Dec 2017
Application16/675,634Continuation · filed 6 Nov 2019
Application17/495,115Continuation
US 10,604,509 B2Related patent
US 2018/0179187 A1Published application
US 2020/0079759 A1Published application
US 2023/0047296 A1This patent

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

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Nrf2 REGULATORS

AssigneesGlaxoSmithKline Intellectual Property Development Limited, Astex Therapeutics Limited

Life of this patent

Estimating the term…

A compound of Formula (I)

wherein,
B is benzotriazolyl, phenyl or triazolopyridinyl, each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, —O—C1-3alkyl, CN, —(CH2)2—O—(CH2)2—OR4 and halo;
D is —C(O)OH, —C(O)NHSO2CH3, —SO2NHC(O)CH3, 5-(trifluoromethyl)-4H-1,2,4-triazol-2-yl, or tetrazolyl;
R1 is independently hydrogen, C1-3alkyl, F, or the two R1 groups together with the carbon to which they are attached form a cyclopropyl group;
R2 is hydrogen, methyl, CF3, or halo;
R4 is hydrogen or —C1-3alkyl;
Linker is —CH2—, —CH2—N(-cyclopropyl)-CH2—, —CH2—N(CH3)—CH2— or —N—(CH3)—CH2—;
A is tetrahydrobenzoxazepinyl, tetrahydro-pyrido-oxazepinyl, piperidinyl, tetrahydrobenzazepinyl, phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, tetrahydropyrrolopyrazinyl, imidazopyridinyl, pyridyl, benzimidazolyl, tetrahydrobenzodiazepinyl, piperidopyrimidinyl, dioxidotetrahydrothiophenyl, tetrahydroimidazodiazepinyl, pyrrolidinyl, oxazepane or morpholinyl;
each of which is unsubstituted or substituted by 1, 2, or 3 substituents independently selected from —C1-3alkyl, C3-6spirocycloalkyl, halo, CN, —O—C1-3alkyl, —CH2—O—CH3, and OH;
and the piperidinyl is unsubstituted or additionally substituted by one or two substituents independently selected from pyrazolyl, —CH2pyrazolyl, and oxadiazolyl, each of which is unsubstituted or further substituted by one or two —C1-3alkyl, or, when A is piperidinyl, it is unsubstituted or substituted by —SO2R, wherein R is —C1-3alkyl, phenyl or C3-7cycloalkyl;
and the oxazepane is unsubstituted or substituted by 1 or 2 substituents independently selected from —C1-3alkyl and —C3-7cycloalkyl;
and the morpholinyl is unsubstituted or substituted by a phenyl which itself is unsubstituted or substituted by one or two substituents independently selected from C1-3 alkyl and —O—C1-3alkyl;
and the pyrrolidinyl is unsubstituted or substituted by a triazolyl group which itself is unsubstituted or substituted by —C1-3alkyl;
and the imidazolyl, triazolyl, pyrazolyl, and tetrazolyl groups are each unsubstituted or substituted by one or two substituents independently selected from —CH2—C4-7cycloalkyl, —CH2-05_7 heterocycloalkyl, —CH2-azabicycloheptanyl, —CH2-oxepane and —CH2-azabicyclohexanyl, each of which, including the —CH2—, is unsubstituted or further substituted by 1 or 2 substituents independently selected from —C1-3 alkyl and F;
and
X is independently CH or N;
or a pharmaceutically acceptable salt thereof.

14 more elements

Facts

Application

17/495,115Filed 6 Oct 2021

Priority

15 Jun 2015

Published

16 Feb 2023

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

C07D 403/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 11/00
Drugs for disorders of the respiratory system
A61P 25/00
Drugs for disorders of the nervous system

Family

Application62/175,510Us provisional application · filed 15 Jun 2015

Application15/736,075Continuation · filed 13 Dec 2017

Application16/675,634Continuation · filed 6 Nov 2019

Application17/495,115Continuation

US 10,604,509 B2Related patent

US 2018/0179187 A1Published application

US 2020/0079759 A1Published application

US 2023/0047296 A1This patent

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