Imidazo[1,2-b]pyridazine derivatives as trk inhibitors
AssigneeBenevolentAI Bio Limited
InventorsAlan Brown, Angela Glen
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Abstract
The present invention relates to certain imidazo[1,2-b]pyridazine compounds and the pharmaceutically acceptable salts of such compounds. The invention also relates to the processes for the preparation of the compounds, compositions containing the compounds, and the uses of such compounds and salts in treating diseases or conditions associated with tropomyosin-related kinase (Trk), activity. More specifically the invention relates to the compounds and their salts useful as inhibitors of Trk. (I) wherein R1, R2, R3, R4 and R5 are as defined herein.
Claims26
A compound of Formula (I):
- or a pharmaceutically acceptable salt or solvate thereof;
- wherein:
- R1 is selected from H, —XR7, (C1-C6)alkyl, (C3-C8)cycloalkyl, and a C-linked 4-6 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S;
- X is selected from —CH2—;
- R2 is selected from H and —SR6;
- R3 is selected from H and halo;
- R4 is selected from H and (C1-C3)alkyl
- R5 is selected from H and halo;
- R6 is methyl;
- R7 is phenyl substituted by hydroxy wherein the hydroxyphenyl is optionally further substituted by halo;
- provided that if R2 is H then R1 is XR7.
A compound according to any preceding claim wherein R2 is —SR6.
A compound according to any preceding claim wherein R3 is H or fluoro.
A compound according to any preceding claim wherein R4 is H.
A compound according to any preceding claim wherein R5 is H or fluoro.
A compound according to any preceding claim wherein R7 is phenyl substituted by hydroxy wherein the hydroxyphenyl is optionally further substituted by fluoro.
A compound of Formula Ia:
- or a pharmaceutically salt or solvate thereof, wherein R1, R2, R3, R4 and R5 are as defined in any preceding claim.
A compound according to claim wherein said compound is selected from:
- N′-cyano-6-[2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3R)-oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- N′-cyano-6-[2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- N′-cyano-N-ethyl-6-[4-fluoro-2-[5-fluoro-3-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- N′-cyano-N-ethyl-6-[4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- N-butyl-N′-cyano-6-[4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- N′-cyano-N-cyclohexyl-6-[4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- and
- N′-cyano-6-[2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3-hydroxyphenyl)methyl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- or a pharmaceutically acceptable salt or solvate thereof.
A compound according to claim wherein said compound is selected from:
- (Z)-N′-cyano-6-[(2R)-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3R)-oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- (Z)-N′-cyano-6-[(2R)-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3S)-oxan-3-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- (Z)-N′-cyano-N-ethyl-6-[(2R,4S)-4-fluoro-2-[5-fluoro-3-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- (Z)-N′-cyano-N-ethyl-6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- (Z)-N-butyl-N′-cyano-6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- (Z)-N′-cyano-N-cyclohexyl-6-[(2R,4S)-4-fluoro-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- and
- (Z)-N′-cyano-6-[(2R)-2-[5-fluoro-2-(methylsulfanyl)phenyl]pyrrolidin-1-yl]-N-[(3-hydroxyphenyl)methyl]imidazo[1,2-b]pyridazine-3-carboximidamide;
- or a pharmaceutically acceptable salt or solvate thereof.
A compound as defined in any of the preceding claims for use in treating or preventing a condition or disorder which is mediated by Trk.
Dependencies are inferred from the claim text.