Lysyl oxidase inhibitors
Inventors
Marais, Richard • Springer, Caroline • Niculescu-Duvaz, Dan • Miller, Natalie • Aljarah, Mohammed • Zambon, Alfonso • Leung, Leo • SMITHEN, Deborah • Brown, Michael • TANG, Haoran
Assignees
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Publication Number
US-12060360-B2
Publication Date
2024-08-13
Expiration Date
Abstract
This invention relates to compounds useful as lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family member (LOXL1, LOXL2, LOXL3, LOXL4) inhibitors. In addition there are contemplated pharmaceutical compositions comprising the compounds and the use of the compounds in the treatment of conditions mediated by LOX and LOXL, for example cancer. In particular a LOX inhibitor such as the present compounds may be for use in the treatment of a cancer associated with EGFR. The present invention also contemplates the identification of biomarkers that predict responsiveness to a LOX inhibitor.
Core Innovation
The disclosed invention describes compounds according to formula IIId, or pharmaceutically acceptable salts thereof, defined by extensive variable selections for R1, R2, L1, r, and substituent groups including RA1/RA2 and RA3/RA4. The structural scope includes halo, cyano, nitro, alkoxy, amino, thio, carbonyl-containing, ester, and sulfonyl-related motifs, together with optional substitution patterns and heterocycle formation rules.
L1 is selected from a bond and carbonyl-, thiocarbonyl-, and sulfone-containing linkers, and r is selected from 1, 2, 3 or 4. The substituent rules allow heterocyclyl, aryl, and heteroaryl options with stated heteroatom ranges, and when L1 is a bond, R2 is not H.
The compounds include synthesized and characterized examples based on bridged diazabicyclo[3.2.2]nonane scaffolds, including stereoisomeric members and downstream derivatives. The examples include reported analytical data such as 1H NMR and HRMS, and in some cases note yields, mixture products used without purification, and transformation to urea and carboxamide derivatives.
Claims Coverage
The independent claim coverage centers on a formula IIId compound, or a pharmaceutically acceptable salt thereof, with extensive structural variable definitions. The claim set combines four main inventive feature groups: R1, R2, L1, and substituent-formation rules for RA1/RA2 and RA3/RA4, with dependent refinements narrowing substituent selections and adding combination and treatment context.
Formula IIId compound with variable substituent framework
A compound according to formula IIId, or a pharmaceutically acceptable salt thereof, with defined selections for R1, R2, L1, and substituent groups, including optional substitution and heterocycle formation rules.
R1 selection with functional-group set
R1 is selected from hydrogen, halo, CN, NO2, ORA1, NRA1RA2, SR1A, carbonyl-related groups, ester-related groups, and sulfonyl-related groups, with optional substituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl options as defined.
R2 selection with bond-dependent constraint
R2 is selected from hydrogen, CN, OH, amino-substituted forms, halo, and a range of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl options, with the proviso that when L1 is a bond, R2 is not H.
L1 linker selection
L1 is selected from a bond and defined linker groups including C(O), C(O)O, C(O)NR, C(S), C(S)NR, S(O)2, S(O)2NR, and substituted carbonyl-containing alternatives, with r selected from 1, 2, 3 or 4.
RA1/RA2 and RA3/RA4 heterocycle formation rules
RA1 and RA2 are each independently selected from H and defined substituent classes, or together with the nitrogen atom form a 3- to 7-membered heterocyclyl including 1, 2 or 3 heteroatoms selected from N, O or S; RA3 and RA4 are each independently selected from defined substituent classes, or together with the nitrogen atom form a 4- to 6-membered heterocyclyl.
Combination and treatment context for cancer indications
Dependent claims include the compound together with one or more additional anti-tumour agents and/or radiotherapy, and methods for treating cancer in a subject by administering a therapeutically effective amount of the compound, with cancer selected from listed cancer types.
Overall, the claims define a broad formula IIId compound class with structured variability in R1, R2, and L1, plus heterocycle-formation rules for RA1/RA2 and RA3/RA4. The dependent material further narrows selected substituent and linker options and adds explicit anti-tumour combination and cancer treatment contexts.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A combination including the compound together with one or more additional anti-tumour agents and/or radiotherapy.
A method for treating cancer in a subject by administering a therapeutically effective amount of the compound, where the cancer is selected from lung cancer, pancreatic cancer, squamous cell carcinoma, skin cancer, thyroid cancer, colorectal cancer, prostate cancer, renal cancer, breast cancer, head & neck cancer, ovarian cancer, oesophageal cancer, cholangiocarcinoma, and hepatocellular carcinoma.
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