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US 9,067,898 B1Granted
Isothiazole derivatives as GPR120 agonists for the treatment of type II diabetes
AssigneeJanssen Pharmaceutica NV
InventorsCarl R. Illig, Mark R. Player, Xuqing 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 GPR120 receptor. Such compounds are represented by Formula (I) as follows: wherein R1, G, and Q are defined herein.
Claims20
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of cyclopropyl, 4-methylcyclohex-1-en-1-yl, trifluoromethyl, and phenyl;
- wherein phenyl is optionally independently substituted with one or two substituents that are C1-2alkyl, methoxy, chloro, fluoro, or trifluoromethyl;
- Q is selected from the group consisting of q1 to q3
- wherein
- RB is absent, or RB is one to four substituents independently selected from the group consisting of methyl, ethyl, methoxy, fluoro, 1-fluoroethyl, 1,1-difluoroethyl, difluoromethyl, trifluoromethyl, and trifluoromethoxy;
- provided that RB is no more than one of ethyl, methoxy, 1-fluoroethyl, 1,1-difluoroethyl, difluoromethyl, trifluoromethyl, or trifluoromethoxy;
- RC is
- R2 is hydroxymethyl or carboxy;
- R4 is hydrogen or methyl;
- G is
- i) chloro;
- ii) pyridinyl optionally independently substituted with one or two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, chloro, and fluoro;
- iii) thiophenyl optionally substituted with one chloro substituent;
- iv) 4-(RA)phenyl, wherein RA is selected from the group consisting of hydrogen, C1-3alkyl, C1-2alkoxy, fluoro, chloro, cyano, trifluoromethyl, methylcarbonyl, and cyclopropyl;
- wherein said phenyl of group iv) is optionally independently further substituted with one or two additional fluoro or methoxy substituents;
- v) thiazolyl optionally substituted with one trifluoromethyl, chloro, methyl, or methoxy substituent;
- or
- vi) isothiazolyl optionally substituted with one trifluoromethyl, chloro, methyl, or methoxy substituent;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
17 more elements
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of cyclopropyl, trifluoromethyl, and phenyl;
- wherein phenyl is optionally independently substituted with one or two substituents that are C1-2alkyl, methoxy, chloro, or fluoro;
- Q is selected from the group consisting of q1 and q3
- wherein
- RB is absent or RB is one to four substituents independently selected from the group consisting of methyl, methoxy, fluoro, and trifluoromethyl;
- provided that RB is no more than one of trifluoromethyl;
- RC is
- R2 is hydroxymethyl or carboxy;
- R4 is hydrogen or methyl;
- G is
- i) chloro;
- ii) pyridinyl optionally independently substituted with one or two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, chloro, and fluoro;
- iii) 4-(RA)phenyl, wherein RA is selected from the group consisting of C1-3alkyl, C1-2alkoxy, fluoro, chloro, cyano, and trifluoromethyl;
- wherein said phenyl of group iii) is optionally independently further substituted with one or two additional fluoro or methoxy substituents;
- or
- iv) thiazolyl optionally substituted with one chloro or methoxy substituent;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
15 more elements
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of trifluoromethyl and phenyl;
- wherein phenyl is optionally independently substituted with one or two substituents that are methyl, methoxy, chloro, or fluoro;
- Q is q1
- wherein
- RB is absent or RB is one to four substituents independently selected from the group consisting of methyl, methoxy, fluoro, and trifluoromethyl;
- provided that RB is no more than one of trifluoromethyl substituent;
- RC is
- R2 is hydroxymethyl or carboxy;
- R4 is hydrogen or methyl;
- G is
- i) chloro;
- ii) pyridinyl optionally independently substituted with one or two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, chloro, and fluoro;
- iii) 4-(RA)phenyl, wherein RA is selected from the group consisting of C1-3alkyl, C1-2alkoxy, fluoro, chloro, cyano, and trifluoromethyl;
- wherein said phenyl of group iii) is optionally independently further substituted with one or two additional fluoro or methoxy substituents;
- or
- iv) thiazolyl optionally substituted with one chloro or methoxy substituent;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
15 more elements
A compound of Formula (I)
- wherein
- R1 is selected from the group consisting of trifluoromethyl and phenyl;
- wherein phenyl is optionally independently substituted with one or two substituents that are methyl, methoxy, chloro, or fluoro;
- Q is q1
- wherein
- RB is one to two substituents independently selected from the group consisting of methyl and fluoro;
- RC is
- R2 is hydroxymethyl or carboxy;
- R4 is hydrogen or methyl;
- G is
- i) chloro;
- ii) pyridinyl optionally independently substituted with one or two substituents selected from the group consisting of methyl, methoxy, chloro, and fluoro;
- or
- iii) 4-(RA)phenyl, wherein RA is selected from the group consisting of methyl, methoxy, fluoro, chloro, and trifluoromethyl;
- wherein said phenyl of group iii) is optionally independently further substituted with one or two additional fluoro or methoxy substituents;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
13 more elements
A compound of Formula (I)
- selected from the group consisting of
- Cpd 252, 3-(4-{[3-Chloro-5-(2-fluoro-4-methylphenyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)propanoic acid;
- Cpd 253, 3-[4-{[3-Chloro-5-(2-methylphenyl)isothiazol-4-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoic acid;
- Cpd 254, 3-(4-{[3-Chloro-5-(2-methylphenyl)isothiazol-4-yl]methoxy}phenyl)propanoic acid;
- Cpd 255, 3-(4-{[3-Chloro-5-(2,4-dimethylphenyl)isothiazol-4-yl]methoxy}phenyl)propanoic acid;
- Cpd 256, 3-[4-{[3-Chloro-5-(2,4-dimethylphenyl)isothiazol-4-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoic acid;
- Cpd 257, 3-(4-{[3-Chloro-5-(2-methylphenyl)isothiazol-4-yl]methoxy}-2-methylphenyl)propanoic acid;
- Cpd 258, 3-(4-{[3-Chloro-5-(2-fluoro-4-methylphenyl)isothiazol-4-yl]methoxy}-2-methoxyphenyl)propanoic acid;
- Cpd 259, 3-[4-{[3-Chloro-5-(2-chlorophenyl)isothiazol-4-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoic acid;
- Cpd 260, 3-[4-{[3-Chloro-5-(2-methoxyphenyl)isothiazol-4-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoic acid;
- Cpd 261, 3-(4-{[3-(4-Cyanophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)propanoic acid;
- Cpd 262, 3-(4-{[3-(4-Chloro-2-fluorophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)propan-1-ol;
- Cpd 263, Methyl 3-(4-{[3-(4-chloro-2-fluorophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)propanoate;
- Cpd 264, 3-(4-{[3-(4-Cyanophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoic acid;
- Cpd 265, 3-(4-{[3-(5-Chloro-3-fluoropyridin-2-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)-2-methylpropanoic acid;
- Cpd 266, 3-(4-{[3-(5-Chloro-3-fluoropyridin-2-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3-fluorophenyl)-2-methylpropanoic acid;
- Cpd 267, 3-(3,5-Difluoro-4-{[3-(2-methoxy-1,3-thiazol-5-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}phenyl)propanoic acid;
- Cpd 268, 3-(4-{[3-(2-Methoxy-1,3-thiazol-5-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoic acid;
- Cpd 269, 3-(4-{[3-(2-Chloro-1,3-thiazol-5-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-2,3-dimethylphenyl)propanoic acid;
- Cpd 270, 3-(4-{[3-(5-Chloropyridin-2-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)propanoic acid;
- Cpd 271, 3-(3,5-Difluoro-4-{[3-(5-methoxypyridin-2-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}phenyl)propanoic acid;
- Cpd 272, 3-(3,5-Difluoro-4-{[5-(trifluoromethyl)-3,5′-biisothiazol-4-yl]methoxy}phenyl)propanoic acid;
- Cpd 273, 3-(4-{[3-(5-Ethylpyridin-2-yl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-3,5-difluorophenyl)propanoic acid;
- Cpd 274, 3-[4-{[3-(4-Chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-2-(difluoromethyl)phenyl]propanoic acid;
- Cpd 275, 3-(4-{[3-(4-Chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl]methoxy}-2-methylphenyl)propanoic acid;
- Cpd 276, 3-[4-{[3-Chloro-5-(4-methylcyclohex-1-en-1-yl)isothiazol-4-yl]methoxy}-2-(trifluoromethyl)phenyl]propanoic acid;
- Cpd 277, 3-(7-{[3-Chloro-5-(4-methylphenyl)isothiazol-4-yl]methoxy}-3,3-difluoro-2,3-dihydro-1H-inden-4-yl)propanoic acid;
- Cpd 278, 3-[4-{[3-Chloro-5-(4-methylphenyl)isothiazol-4-yl]methoxy}-2-(1,1-difluoroethyl)phenyl]propanoic acid;
- Cpd 279, 3-[4-{[3-Chloro-5-(4-methylphenyl)isothiazol-4-yl]methoxy}-2-(1-fluoroethyl)phenyl]propanoic acid;
- or a pharmaceutically acceptable salt form thereof.
27 more elements
A compound of Formula (II)
- wherein
- R11 is selected from the group consisting of cyclopropyl, 4-methylcyclohex-1-en-1-yl, trifluoromethyl, and phenyl;
- wherein phenyl is optionally independently substituted with one or two substituents that are C1-2alkyl, methoxy, chloro, fluoro, or trifluoromethyl;
- Q1 is selected from the group consisting of q11 to q13
- wherein
- RB1 is absent, or RB1 is one to four substituents independently selected from the group consisting of methyl, ethyl, methoxy, fluoro, chloro, 1-fluoroethyl, 1,1-difluoroethyl, difluoromethyl, trifluoromethyl, and trifluoromethoxy;
- provided that RB1 is no more than one of ethyl, methoxy, 1-fluoroethyl, 1,1-difluoroethyl, difluoromethyl, trifluoromethyl, or trifluoromethoxy;
- RE is C1-4alkyl;
- RC1 is
- R2 is C1-4alkoxycarbonyl;
- R4 is hydrogen or methyl;
- G1 is
- i) chloro;
- ii) pyridinyl optionally independently substituted with one or two substituents selected from the group consisting of C1-2alkyl, C1-2alkoxy, chloro, and fluoro;
- iii) thiophenyl optionally substituted with one chloro substituent;
- iv) 4-(RA)phenyl, wherein RA is selected from the group consisting of hydrogen, C1-3alkyl, C1-2alkoxy, fluoro, chloro, cyano, trifluoromethyl, methylcarbonyl, and cyclopropyl;
- wherein said phenyl of group iv) is optionally independently further substituted with one or two additional fluoro or methoxy substituents;
- v) thiazolyl optionally substituted with one trifluoromethyl, chloro, methyl, or methoxy substituent;
- or
- vi) isothiazolyl optionally substituted with one trifluoromethyl, chloro, methyl, or methoxy substituent;
- or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.
18 more elements
Dependencies are inferred from the claim text.