Bifunctional compounds containing 2,5-substituted pyrimidine derivatives for degrading cyclin-dependent kinase 2 via ubiquitin proteasome pathway

A compound of Formula (Ia):

• wherein:
• R1 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, aryloxy, cyano, cycloalkyl where the cycloalkyl is substituted with one to three halo;
• R2 and R2a are independently hydrogen or deuterium;
• Hy is cycloalkylene, arylene, heteroarylene, heterocyclylene, bicyclic heterocyclylene, spiro heterocyclylene, bridged heterocyclylene, or fused heterocyclylene, where each of the aforementioned rings is substituted with Ra, Rb, and Rc independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxy, and cyano;
• Degron is an E3 ubiquitin ligase ligand selected from:
• (a) a group of formula (i):
• (b) a group of formula (ii):
• (c) a group of formula (iii):
• (d) a group of formula (iv):
• (e) a group of formula (v):
• and
• (f) a group of formula (vi):
• where:
• Rx and Rx1 are each hydrogen;
• Ya is CH or N;
• Za is a bond, —CH2—, —NH—, —O—, or —NHC(O)— where NH of —NHC(O)— is attached to Ya:
• ring A is a group of formula (a), (b), or (c):
• where:
• Raa, Rbb, Rcc, and Rdd are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;
• R4 and R5 are independently hydrogen or alkyl;
• or R4 and R5 together with the carbon to which they are attached form >C═O;
• and
• R6 is hydrogen or alkyl;
• ring B is phenylene, cyclylaminylene, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms and further wherein the phenylene, cyclylaminylene, and each heteroarylene are independently substituted with Ree and Rff independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, haloalkoxy, and cyano;
• and
• X1, X2, X3, and X4 are independently a bond, -alkylene-, —O—, —(O-alkylene)-, (alkylene-O)—, —(NRgg-alkylene)-, -(alkylene-NRhh)—,
• —NH—, —N(alkyl)-, —C(═O)—, —NRjjC(═O)—, or —C(═O)NRkk— where Rgg, Rhh, Rjj, and Rkk are independently hydrogen, alkyl, or cycloalkyl and each alkylene, itself or as part of another group, is optionally substituted with one or two fluoro;
• Ry, Ry1, and Ry2 are independently alkyl, hydroxyalkyl, cycloalkyl or heterocyclyl wherein cycloalkyl and heterocyclyl are substituted with Rd and Rf selected from hydrogen, halo, cyano, alkylcarbonyl, and alkylcarbonylamino;
• and
• Wa is bond, O, S, or alkylene;
• and
• L is —Z1—Z2—Z3—Z4—Z5—Z6— where:
• Z1 is a bond, alkylene, —C(O)NR—, —NR′(CO)—, —S(O)2NR—, —NR′S(O)2—, —(O-alkylene)a-, -(alkylene-O)a—, phenylene, monocyclic heteroarylene, or heterocyclylene, where each ring is substituted with Rh and Ri independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
• Z2 is a bond, alkylene, alkynylene, —C(O)—, —C(O)N(R)—, —NR′(CO)—, —(O-alkylene)-, -(alkylene-O)b—, —O(CH2)7—, —O(CH2)8—, cycloalkylene, or -heterocyclylene, where each ring is substituted with Rj and Rk independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
• Z3 is a bond, alkylene, alkynylene, —C(O)NR—, —NR′(CO)—, —O—, —NR″-, —(O-alkylene)c-, -(alkylene-O)c—, cycloalkylene, spiro cyclolalkylene, phenylene, -(alkylene)-phenylene-, -phenylene-(alkylene)-, monocyclic heteroarylene, -(alkylene)-monocyclic heteroarylene-, -monocyclic heteroarylene-(alkylene)-, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, bicyclic heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, fused heterocyclylene, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene-, -spiro heterocyclylene-(alkylene)-, or 11 to 13 membered spiro heterocyclylene, where each ring, by itself or as part of another group, is substituted with Rm and Rn independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
• Z4 is a bond, alkylene, alkynylene, -(alkylene-NR″)—, —(NR″-alkylene)-, —O—, —C(O)—, —NR″—, —(O-alkylene)d-, -(alkylene-O)d—, cycloalkylene, -(alkylene)-cycloalkylene-, -cycloalkylene-(alkylene)-, spiro cyclolalkylene, phenylene, heteroarylene, heterocyclylene, -(alkylene)-heterocyclylene-, -heterocyclylene-(alkylene)-, fused heterocyclylene, bridged heterocyclylene, -(alkylene)-bridged heterocyclylene-, -bridged heterocyclylene-(alkylene)-, spiro heterocyclylene, -(alkylene)-spiro heterocyclylene, or -spiro heterocyclylene-(alkylene)-, where each ring, by itself or as part of another group, is substituted with Ro and Rp independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
• Z5 is a bond, -alkylene, —NR″—, —O—, —C(O)—, —S(O)2—, —NR′(CO)—, —C(O)NR—, phenylene, monocyclic heteroarylene, or heterocycylene, where each ring is substituted with Rq and Rr independently selected from hydrogen, deuterium, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, alkylamino, and dialkylamino;
• and
• Z6 is a bond, alkylene, —NR″—, —O—, -(alkylene-O)—, —C(O)—, —S(O)2—, —NR′(CO)—, or —C(O)NR—;
• where each R, R′ and R″ is independently hydrogen or alkyl, each a, b, c, and d is independently an integer selected from 1 to 6, and each alkylene of —Z1—, —Z2—, —Z3—, —Z4—, —Z5— and —Z6—, by itself or as part of another group, is independently substituted with Rs and Rt where Rs is hydrogen or deuterium and Rt is hydrogen, deuterium, haloalkyl, hydroxy, alkoxy, cyano, cycloalkyl, heterocyclyl, aryl, or monocyclic heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, monocyclic heteroaryl are substituted with one or two substituents independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, haloalkoxy, or cyano;
• provided that at least one of —Z1—Z2—Z3—Z4—Z5—Z6— is not a bond;
• or
• a pharmaceutically acceptable salt thereof.