Compounds and methods for development of Ret Modulators
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Abstract
Compounds active on Ret are described, as well as methods of using such compounds. Also described are crystal structures of Ret surrogates that were determined using X-ray crystallography. The use of such Ret surrogate crystals and structural information can, for example, be used for identifying molecular scaffolds and for developing ligands that bind to and modulate Ret and for identifying improved ligands based on known ligands.
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Citations
108 Claims
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1-9. -9. (canceled)
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10. A method for treating a patient suffering from or at risk of a disease or condition for which Ret modulation provides a therapeutic benefit, comprising administering to said patient a Ret modulator having a chemical structure of Formula I,
- View Dependent Claims (11, 12, 13, 14, 15, 103, 104, 105, 106, 107, 108)
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11. The method of claim 10, wherein said Ret modulator is selected from the group consisting of
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12. The method of claim 10, wherein said compound is selected from the group consisting of:
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3-(6-Chloro-pyridin-3-ylmethyl)-4-phenyl-1H-pyrrolo[2,3-b]pyridine, 3-(3-Methoxy-benzyl)-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, {3-[3-(Thiophen-2-ylsulfanyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanol, [3-(3-p-Tolylsulfanyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-phenyl]-methanol, 4-(3-Fluoro-phenyl)-3-(thiophen-2-ylsulfanyl)-1H-pyrrolo[2,3-b]pyridine, 5-Bromo-3-(3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methanone, 3-{3-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-benzyl}-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, 3-(3-Methoxy-benzyl)-5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridine, Phenyl-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 4-[3-(3-Methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenylamine, 4-[3-(3-Methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, 3-(6-Chloro-pyridin-3-ylmethyl)-5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-methoxy-phenyl)-methanone, 4-Bromo-3-(3-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine, 3-(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol, (4-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)-phenyl-methanone, (3-Methoxy-phenyl)-[5-(1H-pyrrol-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (3-Methoxy-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 4-(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-benzene-1,2-diol, 3-Methoxy-5-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenol, 5-(5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-benzene-1,3-diol, [4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-phenyl-methanone, [4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone, (2,5-Difluoro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2,5-Difluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-phenyl)-methanone, (2-Fluoro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(4-chloro-phenyl)-methanone, (4-Chloro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (4-Chloro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone, [4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-fluoro-phenyl)-methanone, 3-(6-Methoxy-pyridin-2-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, 3-(6-Methoxy-pyridin-3-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, 4-Bromo-3-(6-methoxy-pyridin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine, (3-Hydroxy-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-fluoro-phenyl)-methanone, (2,5-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (2,3-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (2,4-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (2,6-Difluoro-phenyl)-[4-(3,5-difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, [4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone, 3-(6-Chloro-pyridin-3-ylmethyl)-4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridine, (3-Methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (3-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [4-(3,5-Difluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-hydroxy-phenyl)-methanone, (5-Methyl-isoxazol-3-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Methyl-isoxazol-3-yl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 4-[3-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (1,5-Dimethyl-1H-pyrazol-3-yl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, N-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide, 4-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (5-Fluoro-2-methyl-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone, (5-Fluoro-2-methyl-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3-dichloro-phenyl)-methanone, (2,3-Dichloro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2,3-Dichloro-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 3-[3-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (5-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone, 3-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1,1-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, N-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide, (5-Thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-phenyl)-methanone, (3-Methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone, (E)-3-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone, (E)-3-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(4-chloro-phenyl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(1,5-dimethyl-1H-pyrazol-3-yl)-methanone, N-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide, N-{3-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-dimethyl-2H-pyrazol-3-yl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzo[1,2,5]thiadiazol-5-yl-methanone, N-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide, (3-Fluoro-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-3-methoxy-phenyl)-methanone, (2-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-3-methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-5-methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-3-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-5-hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 4-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (2,5-Dimethyl-2H-pyrazol-3-yl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 4-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, 4-[3(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, 4-[3-(Benzo[1,2,5]thiadiazole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (E)-3-{3-[3-(Benzo[1,2,5]thiadiazole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid, N-{3-[3-(Benzo[1,2,5]thiadiazole-5-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-methanesulfonamide, 4-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, 4-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (E)-3-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acrylic acid, 4-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, (4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-phenyl)-methanone, (5-Chloro-2-fluoro-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (4-Methoxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (4-Hydroxy-phenyl)-(5-thiophen-2-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (3-Methoxy-phenyl)-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 4-[3-(3-Hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-hydroxy-phenyl)-methanone, (5-Ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-(3-hydroxy-phenyl)-methanone, (2-Fluoro-phenyl)-[4-(2-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, N-{3-[3-(2-Fluoro-5-methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide, N-{3-[3-(2-Fluoro-5-hydroxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-acetamide, (2-Fluoro-5-methoxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-O-(2,3-dichloro-phenyl)-methanone, (3-Methoxy-phenyl)-(5-pyridin-3-O-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-5-hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzamide, 3-Benzenesulfinyl-5-bromo-1H-pyrrolo[2,3-b]pyridine, (2-Fluoro-5-hydroxy-phenyl)-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone, (3-Hydroxy-phenyl)-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-O-(2-fluoro-5-hydroxy-phenyl)-methanone, (2-Fluoro-5-hydroxy-phenyl)-(4-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [5-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-5-hydroxy-phenyl)-methanone, (4-Chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2-fluoro-5-methoxy-phenyl)-methanone, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-difluoro-phenyl)-methanone, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3-dichloro-phenyl)-methanone, (2,5-Difluoro-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (4-Chloro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(4-chloro-phenyl)-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone, 4-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 4-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 4-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, (E)-3-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, N-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, N-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, 3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, N-{3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, N-{3-[3-(2-Methyl-benzoyl)-1H-pyrrolo-[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, N-{3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, (2-Fluoro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (2-Fluoro-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (4-Pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-o-tolyl-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,3-dichloro-phenyl)-methanone, (E)-3-{3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, N-{3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, N-{3-[3-(2,5-Difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, N-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, 3-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, N-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, (2,5-Difluoro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (2,3-Dichloro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, [4-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone, (2,3-Dichloro-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, (2,5-Difluoro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, 3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2-fluoro-phenyl)-methanone, (2-Fluoro-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2,3-Dichloro-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2-Fluoro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (2,3-Dichloro-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-difluoro-phenyl)-methanone, 4-[3-(4-Chloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 4-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, (E)-3-{3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(2-Fluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, 3-[3-(2-Methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, N-{3-[3-(2,3-Dichloro-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, (4-Chloro-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, [4-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-o-tolyl-methanone, (E)-3-{3-[3-(5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, N-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(2,5-dimethyl-2H-pyrazol-3-yl)-methanone, (5-Methyl-isoxazol-3-yl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, N-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, N-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, (5-Fluoro-2-methyl-phenyl)-[4-(3-methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, [4-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone, (3-Methoxy-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, [4-(6-Methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-methyl-isoxazol-3-yl)-methanone, (5-Fluoro-2-methyl-phenyl)-[4-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-methanone, [4-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone (3-Methoxy-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Fluoro-2-methyl-phenyl)-(4-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (3-Methoxy-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Fluoro-2-methyl-phenyl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, (5-Methyl-isoxazol-3-yl)-(4-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, [4-(3-Amino-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(5-fluoro-2-methyl-phenyl)-methanone, 4-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 4-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 4-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, (E)-3-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, (E)-3-{3-[3-(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acrylic acid, N-{3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, N-{3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-acetamide, 3-[3-(3-Methoxy-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, 3-[3-(5-Methyl-isoxazole-3-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-benzamide, N-{3-[3-(5-Fluoro-2-methyl-benzoyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-phenyl}-methanesulfonamide, [4-(3-Methanesulfonyl-phenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-(3-methoxy-phenyl)-methanone, (3-Hydroxy-phenyl)-(5-phenylamino-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone, and pharmaceutically acceptable salts thereof.
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13. The method of claim 10, wherein said Ret modulator is approved for administration to a human.
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14. The method of claim 10, wherein said disease or condition is a Ret-mediated disease or condition.
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15. The method of claim 10, wherein said disease or condition is selected from the group consisting of multiple endocrine neoplasia, type IIA (MEN2A), multiple endocrine neoplasia, type IIB (MEN2B), Hirschsprung disease (HSCR;
- aganglionic megacolon), or medullary thyroid carcinoma (MTC), familial medullary thyroid carcinomas (FMTC), and papillary thyroid carcinomas (PTC).
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103. The method of claim 10, wherein R2 is selected from the group consisting of —
- CH2-(optionally substituted aryl), —
CH2-(optionally substituted heteroaryl), —
C(O)-(optionally substituted aryl), —
C(O)-(optionally substituted heteroaryl), —
S-(optionally substituted aryl), —
S-(optionally substituted heteroaryl), —
S(O)-(optionally substituted aryl), —
S(O)-(optionally substituted heteroaryl), —
S(O)2-(optionally substituted aryl), and —
S(O)2-(optionally substituted heteroaryl).
- CH2-(optionally substituted aryl), —
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104. The method of claim 103, wherein R2 is selected from the group consisting of —
- CH2-(optionally substituted aryl), —
CH2-(optionally substituted heteroaryl), —
C(O)-(optionally substituted aryl), and —
C(O)-(optionally substituted heteroaryl).
- CH2-(optionally substituted aryl), —
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105. The method of claim 103, wherein R3 is hydrogen and R4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —
- O-(optionally substituted lower alkyl), —
O-(optionally substituted aryl), —
O-(optionally substituted heteroaryl), —
NH-(optionally substituted lower alkyl), —
NH-(optionally substituted aryl), and —
NH-(optionally substituted heteroaryl).
- O-(optionally substituted lower alkyl), —
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106. The method of claim 104, wherein R3 is hydrogen and R4 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, O-(optionally substituted lower alkyl), —
- O-(optionally substituted aryl), —
O-(optionally substituted heteroaryl), —
NH-(optionally substituted lower alkyl), —
NH-(optionally substituted aryl), and —
NH-(optionally substituted heteroaryl).
- O-(optionally substituted aryl), —
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107. The method of claim 103, wherein R4 is hydrogen and R3 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —
- NH-(optionally substituted lower alkyl), —
NH-(optionally substituted aryl), and —
NH-(optionally substituted heteroaryl).
- NH-(optionally substituted lower alkyl), —
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108. The method of claim 104, wherein R4 is hydrogen and R3 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, —
- NH-(optionally substituted lower alkyl), —
NH-(optionally substituted aryl), and —
NH-(optionally substituted heteroaryl).
- NH-(optionally substituted lower alkyl), —
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11. The method of claim 10, wherein said Ret modulator is selected from the group consisting of
-
16-102. -102. (canceled)
Specification
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Current AssigneePlexxikon Inc (Daiichi Sankyo Company Limited)
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Original AssigneePlexxikon Inc (Daiichi Sankyo Company Limited)
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InventorsZhu, Yong, Zhang, Jiazhong, West, Brian, Zhang, Chao, Mamo, Shumeye, Bremer, Ryan, Kumar, Abhinav, Nespi, Marika, Hurt, Clarence R., Krupka, Heike, Ibrahim, Prabha, Zuckerman, Rebecca, Artis, Dean Richard, Habets, Gaston
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/253.04
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CPC Class CodesA61P 35/00 Antineoplastic agentsC07D 471/04 Ortho-condensed systems