Compounds and compositions for the inhibition of NAMPT
Inventors
Bair, Kenneth W. • Baumeister, Timm R. • Buckmelter, Alexandre J. • Clodfelter, Karl H. • Dragovich, Peter • Gosselin, Francis • Han, Bingsong • Lin, Jian • Reynolds, Dominic J. • Roth, Bruce • Smith, Chase C. • Wang, Zhongguo • Yuen, Po-Wai • Zheng, Xiaozhang
Assignees
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Publication Number
US-12336981-B2
Publication Date
2025-06-24
Expiration Date
Abstract
The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications, and antidotes. An illustrative compound of the invention is shown below:
Core Innovation
The invention relates to compounds of Formula IIA, or pharmaceutically acceptable salts thereof, defined by a heteroaryl group R comprising 1, 2, 3 or 4 heteroatom(s) independently selected from N, S or O. The heteroaryl R may be substituted by amino, oxo, and halo, and may comprise one or more N-oxide(s) formed with a N atom member of the heteroaryl. The structure further includes an aryl group Ar and an aryl group R1.
R1 is aryl and is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from a broad set including deuterium, halo, hydroxy, hydroxyalkyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkoxyalkyl-, alkenyl, alkynyl, alkynylalkoxy, carbonyl- and sulfonyl-related groups, heteroaryl, cycloalkyl, heterocycloalkyl, and methylenedioxy. The aryl may optionally be fused with independently selected aryl, heteroaryl, heterocycloalkyl or cycloalkyl to form a bicyclic or tricyclic group that may be substituted by halo, cyano, alkyl, or alkoxy.
The Formula IIA framework further defines R2 and R3 as independently selected from H and deuterium, R5 as H, alkyl, or arylalkyl-, z as 0, 1, or 2, Ra and Rb as independently selected from H, alkyl, alkoxy, alkoxyalkyl and haloalkyl, and m as 0, 1, 2, 3, 4, 5 or 6. The provided examples describe sulfonyl-linked heteroaryl carboxamide and sulfonamide compounds with fused heteroaromatic cores including imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine, thieno[2,3-c]pyridine, furo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrazolo[3,4-b]pyridine, tetrazolo[1,5-a]pyridine, and benzo[d]thiazole.
Claims Coverage
The consolidated claim coverage centers on compounds of Formula IIA, or pharmaceutically acceptable salts thereof, with one independent compound claim and a pharmaceutical composition claim. The inventive features combine a heteroaryl R with 1, 2, 3 or 4 heteroatom(s) independently selected from N, S or O and optional N-oxides, an aryl R1 with broad substitution and optional fusion, and explicit constraints on R2, R3, R5, z, Ra, Rb, and m.
Formula IIA compound definition
A compound of Formula IIA, or a pharmaceutically acceptable salt thereof, wherein R is heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from N, S or O, Ar is aryl, and R1 is aryl with defined optional substitution and fusion patterns.
Heteroaryl R with optional N-oxides
R is heteroaryl comprising 1, 2, 3 or 4 heteroatom(s) independently selected from N, S or O, optionally substituted by amino, oxo, and halo, and optionally comprising one or more N-oxide(s) formed with a N atom member of said heteroaryl.
Aryl R1 with broad substitution and optional fusion
R1 is aryl, unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents independently selected from a broad set of substituent classes, and the aryl may optionally be fused with independently selected aryl, heteroaryl, heterocycloalkyl or cycloalkyl to form a bicyclic or tricyclic group.
Variable constraints for R2, R3, R5, z, Ra, Rb, and m
R2 and R3 are independently selected from H and deuterium; R5 is H, alkyl, or arylalkyl-; z is 0, 1, or 2; Ra and Rb are independently selected from H, alkyl, alkoxy, alkoxyalkyl and haloalkyl; and m is 0, 1, 2, 3, 4, 5 or 6.
Pharmaceutical composition with carrier
A pharmaceutical composition comprising the compound of Formula IIA, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claims cover a Formula IIA compound family defined by heteroaryl R with 1–4 N/S/O heteroatoms and optional N-oxides, an aryl R1 with broad substitution and optional bicyclic or tricyclic fusion, and the stated variable limits for R2, R3, R5, z, Ra, Rb, and m. The claims also include a pharmaceutical composition embodiment with a pharmaceutically acceptable carrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
NAMPT inhibition context.
Biochemical inhibition assay context using recombinant NAMPT with mass-spec quantification of NMN and determination of IC50 values.
Cell viability/proliferation assay context in A2780 cells for the NAMPT-targeting small molecules.
Specificity considerations via reversal with NAM/NMN in the provided testing context.
In vitro U251 cell proliferation/survival SRB assay under NMN and NAM conditions, with % inhibition and IC50 determination.
U251 IC50 activity reporting for selected substituted heteroaryl carboxamide/sulfonamide-containing compounds.
A2780 xenograft studies in which certain compounds produced tumor stasis or tumor regression.
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