Back to results
US 9,790,198 B2Granted
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.
Claims22
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O— or —OCH2—;
- Z is CH;
- 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 hydrogen, chloro, or a substituent selected from the group consisting of C1-3akyl, hydroxy C1-3alkylsulfonyl, C1-3alkylsulfonylamino, and —OR4 ;
- wherein R4 is
- i) C1-8alkyl optionally independently substituted with one or two C1-3alkoxy or hydroxy sub stituents;
- ii) C3-7cycloalkyl;
- iii) C1-3alkylsulfonylpropyl;
- iv) 2-(1-hydroxycyclopropyl)ethyl;
- v) (1 -C3-6cycloalkyl-1-ol) methyl;
- or
- vi) 2-(C3-7cycloalkyl)-2-hydroxyethyl;
- R5 is methyl, methoxy, bromo, chloro, C1-6alkoxy-C1-6alkoxyl, C1-6alkylsulfonyl, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
16 more elements
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2 O— or —OCH2—;
- Z is CH;
- 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 hydrogen, chloro, or a substituent selected from the group consisting of C1-3alkyl, hydroxy, C1-3alkylsulfonyl, C1-3alkylsulfonylamino, and —OR4;
- wherein R4 is
- i) C1-8alkyl optionally independently substituted with one or two C1-3alkoxy or hydroxy substituents;
- ii) C3-7cycloalkyl;
- iii) C1-3alkylsulfonylpropyl;
- or
- iv) 2-(1-hydroxycyclopropyl)ethyl;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
14 more elements
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O— or —OCH2—;
- Z is CH;
- R6 is hydrogen;
- R1 is (S)-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 —OR4;
- wherein R4 is
- i) C1-4alkyl optionally independently substituted with one or two hydroxy or C1-3 alkoxy substituents;
- or
- ii) C1-3alkylsulfonylpropyl;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
12 more elements
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2—;
- Z is CH;
- R6 is hydrogen;
- R1 is (S)-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
- i) C1-4alkyl optionally independently substituted with one or two hydroxyl or C1-3 alkoxy substituents;
- or
- ii) C1-3alkylsulfonylpropyl;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
12 more elements
A compound of Formula (I)
- wherein
- ring W is phenyl;
- A is —CH2O— or —OCH2—;
- Z is CH;
- 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 selected from the group consisting of hydrogen;
- methyl;
- methoxy;
- hydroxy;
- chloro;
- -4-(3-methylsulfonylpropoxy;
- -(1-hydroxycycl opropyl)ethoxy;
- 3 -hydroxy-3 -methylbutoxy;
- 2,3-dihydroxypropoxy;
- -methoxyethoxy;
- methyl sulfonyl;
- methyl sul fonami do;
- and 3-hydroxy-3-methylbutoxy;
- R5 is methyl, methoxy, 2-methoxyethoxy, methanesulfonyl, chloro, or trifluoromethyl;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
20 more elements
A compound selected from the group consisting of
- Cpd 1, 3-[4-[[3- (2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]propanoic acid;
- Cpd 2, (3S)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 4, (3S)-3-[4-[[3-[2-Methyl-4-(3-methylsulfonylpropoxy)phenyl]benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 7, (3S)-3-[4-[[3-(4-Hydroxy-2-methyl-phenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 10, (3S)-3-[4-[[3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- Cpd 11, (3S)-3-(4-((3-(4-(2-(1-Hydroxycyclopropyl)ethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 12, (3S)-3-(4((3-(4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 13, (3S)-3-(4((3-(4-(2,3-Dihydroxypropoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 16, (3S)-3-(4-((3-(4-(2-Methoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 19, (3S)-3-(4((3-(2-Chlorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 20, (3S)-3-(4((3-(2-Bromophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 21, (3S)-3-(4((3-(2-(Trifluoromethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 23, (3S)-3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
- Cpd 24, (3S)-3-(4-(((3-(2-Methyl-4-(3-(methylsulfonyl)propoxy)phenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
- Cpd 27, (3S)-3-(4-(((3-(2,6-Dimethylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)hex-4-ynoic acid;
- Cpd 30, 2-(3-Oxo-1-(4((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic acid;
- Cpd 31, 2-((1r,30-3-Hydroxy-1-(4-((3-(2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic acid;
- Cpd 32, 2-(1-(4-((3-(4-(2-Ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)-3-oxocyclobutyl)acetic acid;
- Cpd 35, 2-((1r,3r)-3-Hydroxy-1-(4-((3-(4-(2-ethoxyethoxy)-2-methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)cyclobutyl)acetic acid;
- Cpd 41, (3S)-3-(4((3-(2-Methyl-5-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 42, (3S)-3-(4((3-(2-Methyl-4-(methylsulfonyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 43, (3S)-3-(4((3-(2-Methyl-5-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 44, (3S)-3-(4((3-(2-Methyl-6-(methylsulfonamido)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 53, 3-(4-(((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)oxy)methyl)phenyl)propanoic acid;
- Cpd 54, (3S)-3-[4-[([3-[4-(3-Hydroxy-3-methylbutoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic acid;
- Cpd 55, (3S)-3-[4-[([3-[4-(2,3-Dihydroxypropoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic acid;
- Cpd 58, (3S)-3-[4-[([3-[4-( 2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]oxy)methyl]phenyl]hex-4-ynoic acid;
- Cpd 65, (3S)-3-[4-([3-[5-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic acid;
- Cpd 66, (3S)-3-[4-([3-[2-(2-Methoxyethoxy)-6-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic acid;
- Cpd 67, (3S)-3-[4-([3-[3-(2-Methoxyethoxy)-2-methylphenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic acid;
- Cpd 68, (3S)-3-[4-([3-[2-(2-Methoxyethoxy)phenyl]-1-benzothiophen-5-yl]methoxy)phenyl]hex-4-ynoic acid;
- Cpd 69, (3S)-3-(4-[[3-(2-Methanesulfonylphenyl)-1-benzothiophen-6-yl]methoxy]phenyl)hex-4-ynoic acid;
- Cpd 79, (3S)-3-(4-((3-(2-Methoxyphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 97, 3-(4-((3-(2-Methylphenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)hex-4-ynoic acid;
- Cpd 98, (3R)-3-[4-[[3-(2-Methylphenyl)benzo[b]thiophen-5-yl]methoxy]phenyl]hex-4-ynoic acid;
- or a pharmaceutically acceptable salt form thereof.
33 more elements
A compound that is
- or a pharmaceutically acceptable salt form thereof.
A compound that is
- or a pharmaceutically acceptable salt form thereof.
Dependencies are inferred from the claim text.