Sulfamide derivatives as cyclin-dependent kinase 2 inhibitors

A compound of Formula (I):

• wherein:
• W is N, CH, or C when W is attached to R6;
• X and Z are independently CR8, NR8A, N, O, or S;
• and Y is CR9, NR10, or N;
• provided that both of X and Z are not simultaneously O or S;
• and at least one of X, Y, and Z is not carbon;
• R8 is hydrogen, alkyl, halo, hydroxyalkyl, or cyano;
• R8A is hydrogen or alkyl;
• R9 and R10 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, amino, alkylamino, dialkylamino, substituted amino, aminoalkyl, cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, spiro cycloalkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein:
• (A) cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, and spiro cycloalkyl of R9 and R10 are substituted with one or two Ra independently selected from hydrogen, deuterium, alkyl, deuteroalkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, and dialkylamino;
• (B) heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, and spiro heterocyclyl of R9 and R10 are substituted with Rb, Rc, and Rd independently selected from hydrogen, alkyl, deuteroalkyl, cycloalkyl, bridged cycloalkyl, spiro cycloalkyl (wherein cycloalkyl, bridged cycloalkyl, and spiro cycloalkyl are substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, hydroxy, cyano, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, heteroaryl, or heteroaralkyl (wherein aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, bridged heterocyclyl, and spiro heterocyclyl are substituted with Re, Rf, and Rg independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino);
• and
• (C) aryl, by itself or as part of aralkyl, and heteroaryl, by itself or as part of heteroaralkyl, of R9 and R10 are substituted with Rh, Rj, and Rk independently selected from hydrogen, alkyl, deuteroalkyl, cycloalkyl (wherein cycloalkyl is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, hydroxy, cyano, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, heteroaryl, or heteroaralkyl (wherein aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, bridged heterocyclyl, and spiro heterocyclyl are substituted with Rm, Rn, and Ro independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino);
• ring RA is phenyl or heteroaryl;
• R1, R2, and R3 are independently hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or cyano;
• R4 and R5 are independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiro heterocyclyl, and spiro heterocyclylalkyl (wherein cycloalkyl, by itself or as part of cycloalkylalkyl, fused cycloalkyl, aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl, by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl, by itself or as part of fused heterocyclylalkyl, and spiro heterocyclyl, by itself or as part of spiro heterocyclylalkyl, are substituted with Rp, Rq, and Rr independently from hydrogen, alkyl, alkoxy, alkylsulfonyl, alkyloxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkyloxy (wherein aryl, by itself or as part of aralkyl and aryloxy, heteroaryl, by itself or as part of heteroaryloxy and heteroaralkyl, and heterocyclyl, by itself or as part of heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkyloxy, are substituted with one, two, or three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano));
• or
• R4 and R5 together with the nitrogen atom to which they are attached form cyclylaminyl, bicyclylaminyl, fused cyclylaminyl, bridged cyclylaminyl, fused bridged cyclylaminyl, spiroaminyl, or fused spiroaminyl, wherein each of the aforementioned rings is substituted with Rs, Rt, and Ru independently selected from hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, alkoxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy, and unsaturated heterocyclyl (wherein aryl, by itself or as part of aryloxy and aralkyl, heteroaryl, by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkyloxy, and unsaturated heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano);
• R6 is hydrogen, alkyl, cycloalkyl, cyano, halo, or haloalkyl;
• R7 is -Q-(alk1)n1-SO2R11, -Q1-(alk2)n2-SO(═NR12)R13, -Q2-(alk3)n3-SO2NR14R15, -Q3-(alk4)n4-COR16, -Q4-(alk5)n5-CONR17R18, -Q5-(alk6)n6-NR19COR20, -Q6-(alk7)n7-NR21SO2R22, heterocyclyl, bicyclic heterocyclyl, fused heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, cyclylsulfoximinyl, bicyclylsulfoximinyl, spiro sulfoximinyl, aryl, heteroaryl, or fused heteroaryl wherein:
• each of Q, Q1, Q2, Q3, Q4, Q5, and Q6 is a bond, cycloalkyl, bridged cycloalkyl, spiro cycloalkyl, heterocyclylA, bicyclic heterocyclylA, bridged heterocyclylA, fused heterocyclylA, spiro heterocyclylA, aryl, or heteroaryl, wherein each of the aforementioned rings is substituted with Rv and Rw independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano;
• each of n1, n2, n3, n4, n5, n6, and n7 is 0 or 1, provided that, when Q is a bond, then each of n1, m2, n3, n4, n5, n6, and n7 is 1;
• each alk1, alk2, alk3, alk4, alk5, alk6, and alk7 is alkylene;
• R12, R19, and R21 are hydrogen or alkyl;
• R11, R13, R16, R20, and R22 are independently selected from hydrogen, alkyl, fluoro, chloro, bromo, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, spiro heterocyclyl, heterocyclylalkyl, or —CR23═CR24R25 [where R23 is hydrogen, alkyl, or cyano, R24 is hydrogen or alkyl, and R25 is hydrogen, alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, or -(alkylene)-NR26R27 (where R26 and R27 are independently hydrogen, or alkyl), or heterocyclylalkyl], wherein cycloalkyl, by itself or as part of cycloalkylalkyl, aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, heterocyclyl, by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiro heterocyclyl of R11, R13, R16, R20), and R22 and heterocyclyl of heterocyclylalkyl of R25 are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyano, and heterocyclyl;
• provided R11, R16, R20, and R22 are not hydrogen;
• R14, R15, R17, and R18 are independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, wherein cycloalkyl, by itself or as part of cycloalkylalkyl, aryl, by itself or as part of aralkyl, heteroaryl, by itself or as part of heteroaralkyl, and heterocyclyl, by itself or as part heterocyclylalkyl, are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano;
• and
• the heterocyclyl, bicyclic heterocyclyl, fused heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, cyclylsulfoximinyl, spiro cyclylsulfoximinyl, aryl, heteroaryl, and fused heteroaryl of R7 are substituted with Rx, Ry, and Ry1 independently selected from hydrogen, deuterium, alkyl, alkoxy, alkoxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy (wherein aryl, by itself or as part of aralkyl and aryloxy, heteroaryl, by itself or as part, of heteroaryloxy and heteroaralkyl, and heterocyclyl, by itself or as part of, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkyloxy, are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl);
• or
• a pharmaceutically acceptable salt thereof, provided that the compound of Formula (I) is not:
• N-(3-(2-isopropyl-S-(2-((2-(methylsulfonyl)ethyl)amino)pyrimidin-4-yl)thiazol-4-yl)-phenyl)morpholine-4-sulfonamide.