Methylamine derivatives as lysysl oxidase inhibitors for the treatment of cancer
Inventors
Springer, Caroline • Marais, Richard • Niculescu-Duvaz, Dan • Leung, Leo • SMITHEN, Deborah • CALLENS, Cedric • TANG, Haoran
Assignees
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Publication Number
US-11608330-B2
Publication Date
2023-03-21
Expiration Date
Abstract
Provided are compounds of the Formula (I), or a pharmaceutically acceptable salt thereof: wherein W, X, Y, Z, x, R1, R2, R3, x and n are defined in the specification. The compounds are inhibitors of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family members (LOXL1, LOXL2, LOXL3, LOXL4) and are useful in therapy, particularly in the treatment of cancer. Also disclosed are LOX inhibitors for use in the treatment of a cancer associated with EGFR and biomarkers that predict responsiveness to a LOX inhibitor.
Core Innovation
The invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof. The compound is defined by X selected from S, NR, N, or O; Y selected from N and CR; W selected from N and CR; Z as carbon bonded to the residue; x as 1 or 2; and n as 0, 1, 2, 3, 4, 5, or 6, with R, R1, R2, R3, RA1/RB1, and RA5/RB5 constrained to enumerated groups and optional substitution patterns.
The Formula (I) definition further constrains R3 according to n, including an optionally substituted 3- to 15-membered ring system containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S and connected to the remainder of the compound via a carbon atom. The disclosure also includes ring-forming options in which RA1 and RB1, or RA5 and RB5, together with the nitrogen atom form a 4- to 7-membered ring system, and dependent refinements to Formula (VI), Ring E, R5, and a meta relationship of R4 to an —S(O)x— group.
The document describes compounds and examples with sulfonylated heteroaryl, thiophene, thiazole, benzenethiol, and aminomethyl derivatives, including hydrochloride salt forms. The provided material presents representative example compounds and associated characterization or activity data, and it includes treatment of LOX-mediated disease or medical condition and fibrotic disorders.
Claims Coverage
The provided material contains one independent compound claim, centered on Formula (I), with dependent claim refinements that narrow the structure through Formula (VI), Ring E, R5, and a positional constraint for R4 relative to an —S(O)x— group. The main claim coverage therefore comprises the Formula (I) genus with multiple constrained structural variables and pharmaceutically acceptable salts, together with treatment claims directed to LOX-mediated disease and fibrotic disorders.
Formula (I) compound with enumerated structural variables
A compound of Formula (I) wherein X is selected from S, NR, N, or O; Y is selected from N and CR; W is selected from N and CR; Z is carbon bonded to the residue; x is 1 or 2; and n is 0, 1, 2, 3, 4, 5, or 6, with substituent variables selected from enumerated groups, together with pharmaceutically acceptable salts thereof.
R3 ring-system selection dependent on n
R3 is an optionally substituted 3- to 15-membered ring system containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S and connected to the remainder of Formula (I) via a carbon atom, with the allowed ring-system options depending on whether n is 0 or 1 to 6.
Optional ring formation using RA1/RB1 and RA5/RB5
For the groups —NRA1RB1 and —NRA5RB5, the indicated substituents together with the nitrogen atom form a 4- to 7-membered ring system.
Formula (VI) refinement with Ring E and R5
Dependent claim content narrows the compound to Formula (VI), with Ring E and R5 selected from specified options, including R5 limited to H, —CH3, or —CH2OCH3.
Meta relationship of R4 to an —S(O)x— group
Dependent claim content requires R4 to be positioned meta to the —S(O)x— group.
Treatment of LOX-mediated disease and fibrotic disorders
Dependent claims cover a method of treating a disease or medical condition mediated by LOX by administering a therapeutically effective amount of the compound, and a method of treating fibrotic disorders involving specified organs or tissue categories.
Claim coverage centers on a broadly defined Formula (I) compound genus with enumerated heteroatom and substituent constraints, including conditional ring-system definitions for R3 and ring formation options for RA1/RB1 and RA5/RB5. The dependent claim refinements further specify Formula (VI), Ring E, R5, the meta placement of R4 relative to an —S(O)x— group, and treatment claims directed to LOX-mediated diseases and fibrotic disorders.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment of a disease or medical condition mediated by LOX by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
Treatment of fibrotic disorders involving lungs, liver, kidneys, heart or vascular system, mediastinum, bone, retroperitoneum, skin, GI tract, connective tissue, or the eye.
Therapeutic use for LOX/LOXL family-modulated conditions, including proliferative/cancer, fibrotic, and inflammatory indications.
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