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US 2017/0362196 A1Published application
Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
AssigneeJanssen Pharmaceutica NV
InventorsHui Huang, Gee-Hong Kuo, Mark R. Player, Shyh-Ming Yang, Yue-Mei Zhang
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR40 receptor. Such compounds are represented by Formula (I) as follows: wherein R1, R2, R3, R5, R6, W, and A are defined herein.
Claims27
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O— or —OCH2—;
- Z is CH or N;
- R6 is hydrogen;
- R1 is selected from hydrogen or methylacetylenyl;
- or R1 and R6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
- R2 is selected from hydrogen or methyl;
- R3 is a substituent selected from the group consisting of 1,1-dioxothian-4-yl, 1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl, 1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, 1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl, piperidin-4-yl, piperidin-4-ylmethyl, and —OR4;
- wherein R4 is
- iii) 4-hydroxy-1,1-dioxo-thian-4-ylmethyl;
- iv) 1,1-dioxothian-4-yl;
- v) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;
- vi) tetrahydro-2H-pyran-4-yl;
- ix) 3-methyloxetan-3-yl-methyl;
- x) (3-methyl-1,1-dioxidothietan-3-yl)methyl;
- xii) 4-hydroxy-tetrahydropyran-4-ylmethyl;
- xiv) tetrahydro-2H-pyran-4-ylmethyl;
- or
- xv) tetrahydrofuran-3-yl;
- R5 is methyl, methoxy, bromo, chloro, C1-6alkoxy-C1-6alkoxyl, C1-6alkylsulfonyl, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt forms thereof.
19 more elements
(canceled)
(canceled)
(canceled)
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O— or —OCH2—;
- Z is CH or N;
- R6 is hydrogen;
- R1 is selected from hydrogen or methylacetylenyl;
- or R1 and R6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
- R2 is hydrogen;
- R3 is a substituent selected from the group consisting 1,1-dioxothian-4-yl, 1,1-dioxido-3,6-dihydro-2H-thiopyran-4-yl, 1,1-dioxo-1,4-thiazinane-4-ylcarbonyl, 1,1-dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl, piperidin-4-yl, piperidin-4-ylmethyl, and —OR4;
- wherein R4 is
- iii) 4-hydroxy-1,1-dioxo-thian-4-ylmethyl;
- iv) 1,1-dioxothian-4-yl;
- v) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;
- vi) tetrahydro-2H-pyran-4-yl;
- ix) 3-methyloxetan-3-yl-methyl;
- x) (3-methyl-1,1-dioxidothietan-3-yl)methyl;
- xi) tetrahydro-2H-pyran-4-ylmethyl;
- or
- xii) tetrahydrofuran-3-yl;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt forms thereof.
18 more elements
(canceled)
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O— or —OCH2—;
- when Z is CH, R6 is hydrogen and R1 is (S)-methylacetylenyl;
- or R1 and R6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
- or
- when Z is N, R6 is hydrogen and R1 is (R)-methylacetylenyl;
- or R1 and R6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
- R2 is hydrogen;
- R3 is piperidin-4-yl, piperidin-4-ylmethyl, or —OR4;
- wherein R4 is
- ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;
- iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;
- iv) tetrahydro-2H-pyran-4-yl;
- vi) tetrahydro-2H-pyran-4-ylmethyl;
- or
- vii) tetrahydrofuran-3-yl;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt forms thereof.
16 more elements
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O—;
- when Z is CH, R6 is hydrogen and R1 is (S)-methylacetylenyl;
- or R1 and R6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
- or
- when Z is N, R6 is hydrogen and R1 is (R)-methylacetylenyl;
- or R1 and R6 are taken together to form a spirofused 3-hydroxycyclobutyl or a spirofused 3-oxocyclobutyl;
- R2 is hydrogen;
- R3 is hydrogen or a substituent that is —OR4;
- wherein R4 is
- ii) (4-hydroxy-1,1-dioxo-thian-4-yl)methyl;
- iii) 1,1-dioxidotetrahydro-2H-thiopyran-4-ylmethyl;
- iv) tetrahydro-2H-pyran-4-yl;
- vi) tetrahydro-2H-pyran-4-ylmethyl;
- or
- vii) tetrahydrofuran-3-yl;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt forms thereof.
16 more elements
(canceled)
(canceled)
A compound
- selected from the group consisting of
- Cpd 3, (3S)-3-[4-[[3-[4-[(4-Hydroxy-1,1-dioxo-thian-4-yl)methoxy]-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 5, (3S)-3-[4-[[3-[4-(1,1-Dioxo-1,4-thiazinane-4-carbonyl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 6, (3S)-3-[4-[[3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 8, (3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)-2-methyl-phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 9, (3S)-3-[4-[[3-[4-(1,1-Dioxothian-4-yl)oxy-2-methyl-phenyl]-2-methyl-benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 14, (3S)-3-(4-((3-(2-Methyl-4-((3-methyloxetan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 15, (3S)-3-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 17, (3S)-3-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 18, (3S)-3-(4-((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 25, (3S)-3-(4-(((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
- Cpd 26, (3S)-3-(4-(((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
- Cpd 28, 2-(1-(4-((3-(4-(1,1-Dioxido-3,6-dihydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid;
- Cpd 29, 2-(1-(4-((3-(4-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid;
- Cpd 33, 2-(1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid;
- Cpd 34, 2-(1-(4-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid;
- Cpd 36, 2-((1r,3r)-1-(4-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)oxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-hydroxycyclobutyl)acetic acid;
- Cpd 37, 2-((1r,3r)-3-Hydroxy-1-(4-((3-(2-methyl-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic acid;
- Cpd 40, 2-(1-(4-((3-(4-(1,1-Dioxido-1-thia-6-azaspiro[3.3]heptan-6-yl)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid;
- Cpd 46, 3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)oxy) phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 47, 3-(6-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 56, (3S)-3-(4-[[(3-[2-Methyl-4-[(3-methyloxetan-3-yl)methoxy]phenyl]-1-benzothiophen-5-yl)oxy]methyl]phenyl)hex-4-ynoic acid;
- Cpd 57, (3S)-3-[4-[([3-[2-Methyl-4-(oxan-4-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic acid;
- Cpd 59, (3S)-3-{4-[((3-{4-[(1,1-Dioxo-tetrahydro-2H-thiopyran-4-yl)methoxy]-2-methylphenyl}-1-benzothiophen-5-yl)oxy)methyl]phenyl}hex-4-ynoic acid;
- Cpd 60, (3S)-3-(4-(((3-(2-Methyl-4-((3-methyl-1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
- Cpd 63, 3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 64, 3-(6-((3-(2-Methyl-4-((3-methyl -1,1-dioxidothietan-3-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 72, (3S)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 73, (3R)-3-(6-((3-(2-Methyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)phenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 74, (3S)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 75, (3R)-3-(6-((3-(4-((1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)pyridin-3-yl)hex-4-ynoic acid;
- Cpd 86, (3S)-3-[4-[([3-[2-Methyl-4-(tetrahydrofuran-3-yloxy)phenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic acid;
- Cpd 95, (3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-ylmethyl)phenyl)benzo[b]-thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- and
- Cpd 96, (3S)-3-(4-((3-(2-Methyl-4-(piperidin-4-yl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- or a pharmaceutically acceptable salt forms thereof.
33 more elements
(canceled)
(canceled)
27-35. (canceled)
Dependencies are inferred from the claim text.