Sulfonamido derivatives as cyclin-dependent kinase 2 inhibitors
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Publication Number
US-12331026-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The present disclosure provides certain sulfonamido derivatives that are Cyclin-dependent kinase 2 (CDK2) inhibitors of Formula (I): for the treatment of diseases treatable by inhibition of CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Core Innovation
The invention provides compounds of Formula (I) that maintain a thiazolyl-pyrimidinyl-benzene sulfonamide framework and define variable substituent patterns through ring R_A and ring R_B substitution definitions. Ring R_A is a ring of formula (i), (ii), (iii), or (iv) substituted with R4 and R5, and R2 and R3 are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy.
Ring R_B is selected from cycloalkyl, bridged cycloalkyl, heterocyclyl, or bridged heterocyclyl with defined substitution regimes for Ra, Rb/Rc/Rd, and Re/Rf/Rg. The disclosed examples and embodiments maintain the same sulfonamide core while varying ring R_B scaffolds and their substituents, and the document also provides pharmaceutically acceptable salts.
The partial content further lists specific scaffold exemplars and named structures, including bicyclo[1.1.1]pentan-1-yl, adamantyl, bicyclo[2.2.1]heptan-1-yl, bicyclo[2.2.2]octan-1-yl, and dioxido-thiaspiro motifs within the same Formula (I) framework. The provided content also shows multiple named compounds and structure images, including fluorinated and trifluoromethyl substituted variants.
Claims Coverage
The independent claim coverage centers on one Formula (I) compound claim with defined options for R1, ring R_A, R2/R3, and ring R_B, and it also expressly covers pharmaceutically acceptable salts. A further claim set includes a cancer-treatment method using a therapeutically effective amount of the claimed compound in a pharmaceutical composition. There are six inventive feature groups in the consolidated claim coverage.
Formula (I) sulfonamide compound with thiazolyl-pyrimidinyl-benzene sulfonamide framework
A compound of Formula (I) wherein R1 is hydrogen or halo, ring R_A is a ring of formula (i), (ii), (iii), or (iv) with R4 and R5 independently selected from hydrogen, alkyl, and halo, R2 and R3 are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy, and ring R_B is cycloalkyl, bridged cycloalkyl, heterocyclyl, or bridged heterocyclyl with defined substitution regimes for Ra, Rb/Rc/Rd, and Re/Rf/Rg.
Cycloalkyl or bridged cycloalkyl ring R_B substitution pattern
Ring R_B cycloalkyl or bridged cycloalkyl is substituted with Ra selected from hydrogen, halo, haloalkyl, and hydroxalkyl.
Heterocyclyl ring R_B substitution pattern
Ring R_B heterocyclyl is substituted with Rb, Rc, and Rd, where Rb and Rc are independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy and Rd is selected from hydrogen, alkyl, deuteroalkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl.
Bridged heterocyclyl ring R_B substitution pattern
Ring R_B bridged heterocyclyl is substituted with Re, Rf, and Rg, where Re and Rf are independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy and Rg is selected from hydrogen, alkyl, deuteroalkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, oxo, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl.
Coverage of pharmaceutically acceptable salts
The compound of Formula (I) is also claimed together with a pharmaceutically acceptable salt thereof.
Cancer treatment by administering a Formula (I) compound
A method for treating cancer by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt in a pharmaceutical composition of claim 22.
Independent claim clm-00001 covers a Formula (I) compound defined by the thiazolyl-pyrimidinyl-benzene sulfonamide scaffold with variable ring R_A and R2/R3 substituents, and a ring R_B selected among cycloalkyl, bridged cycloalkyl, heterocyclyl, and bridged heterocyclyl with defined substitution patterns for Ra, Rb/Rc/Rd, and Re/Rf/Rg; it also covers pharmaceutically acceptable salts and a cancer-treatment method.
Stated Advantages
Inhibition of CDK2 activity is evaluated via phospho-RB (S807/811) TR-FRET in OVCAR3 cells, with CDK2 pRb IC50 values reported for example compounds.
Documented Applications
Cancer treatment by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt in a pharmaceutical composition.
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