Pyrazole derivatives useful as NAMPT modulators
Inventors
SHEN, Minxing • Romero, Antonio • Lu, Pu-Ping
Assignees
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Publication Number
US-12649729-B2
Publication Date
2026-06-09
Expiration Date
Abstract
Provided herein are compounds of formula (A): or a pharmaceutically acceptable salt thereof, wherein X, R1, R2, R3, R4, Ry, and Rz are as defined herein. Also provided herein is a pharmaceutically acceptable composition comprising a compound of formula (A), or a pharmaceutically acceptable salt thereof, as well as methods of using a compound of formula (A), or a pharmaceutically acceptable salt thereof, to treat various diseases and conditions mediated by nicotinamide phosphoribosyltransferase (NAMPT).
Core Innovation
The disclosure provides compounds of formula (A) and pharmaceutically acceptable salts thereof, including a heteroaromatic carboxamide or pyrimidine-2-carboxamide scaffold with defined substituent variables X, R1, R2, R3, R4, Ry, and Rz. The structural definition includes X as N or CH, R1 and R2 as independent substituents or taken together with the nitrogen to form an optionally substituted 3-15 membered heterocyclyl, and a defined relationship between R3 and R4.
Ry and Rz are H, halo, or optionally substituted C1-6 alkyl, or taken together with the carbon atoms to which they are attached to form an optionally substituted non-aromatic cyclic ring containing 3 to 10 carbon atoms. The disclosure identifies named sub-forms within the scaffold family, including formula (I) and formula (II), together with dependent refinements that constrain ring formation and substitution.
The patent text also describes NAMPT-activating and NAMPT-modulating compounds built on pyrimidine-2-carboxamide based scaffolds, including stereochemical variants, tautomers, deuterated compounds, hydrates, solvates, racemates, polymorphic forms, and pharmaceutically acceptable salts. It also presents specific example compounds, reported characterization data, and stated NAMPT-pathway association.
Claims Coverage
The consolidated claim coverage centers on one broad independent claim to a compound of formula (A), with dependent refinements that map the scaffold to formula (I) and formula (II), refine ring formation, and include a treatment method directed to NAMPT activity. Across the inputs, the claim family consistently defines the same core structural variables and ring-forming relationships.
Formula (A) compound scaffold with defined substituent constraints
A compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein X is N or CH, R1 and R2 are each independently H or optionally substituted C1-6 alkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C6-20 aryl, optionally substituted 3-15 membered heterocyclyl, or optionally substituted 5-20 membered heteroaryl, or R1 and R2 are taken together with the nitrogen to which they are attached to form an optionally substituted 3-15 membered heterocyclyl; R3 is H or optionally substituted C1-6 alkyl and R4 is H, or R3 and R4 taken together are —CH2CH2—; and Ry and Rz are each independently H, halo, or optionally substituted C1-6 alkyl, or Ry and Rz taken together with the carbon atoms to which they are attached to form an optionally substituted non-aromatic cyclic ring containing 3 to 10 carbon atoms.
Named scaffold sub-forms via X selection
The compound of formula (A), or a pharmaceutically acceptable salt thereof, is specified by setting X to N so that the compound corresponds to a compound of formula (I), or by setting X to CH so that the compound corresponds to a compound of formula (II).
R1 and R2 taken together form an optionally substituted 3-15 membered heterocyclyl
R1 and R2 together with the nitrogen to which they are attached form an optionally substituted 3-15 membered heterocyclyl, including embodiments where the heterocyclyl is unsubstituted or substituted with one or more specified substituents Rs.
Ry and Rz taken together form an optionally substituted non-aromatic cyclic ring
Ry and Rz are taken together with the carbon atoms to which they are attached to form an optionally substituted non-aromatic cyclic ring containing 3 to 10 carbon atoms.
Treatment method mediated by NAMPT activity
A method of treating a disease or condition mediated by NAMPT activity by administering the compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need.
Selected listed NAMPT-activating structures
A compound selected from the group consisting of the listed structures and/or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is anchored in a broad formula (A) genus with explicit constraints on X, R1/R2, R3/R4, and Ry/Rz, including ring-forming alternatives. The claim family also includes X-based mapping to formula (I) and formula (II), ring substitution refinements for the R1/R2-derived heterocyclyl, a treatment method tied to NAMPT activity, and listed-structure coverage in some inputs.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Methods of treatment of a disease or condition mediated by NAMPT activity by administering the compound, or a pharmaceutically acceptable salt, to a subject in need.
Pharmaceutical compositions, including medicaments for NAMPT-mediated diseases.
NAMPT-mediated diseases and conditions, including cancer, hyperproliferative disease, inflammatory disease, metabolic disorder, cardiac disease, chemotherapy induced tissue damage, renal disease, neurological disease or injury, neurodegenerative disorder, DNA damage, primary mitochondrial disorders, and muscle disease or muscle wasting disorder.
Packaged pharmaceutical compositions and kits.
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