Wee1 degradation inhibitors
The invention provides compounds that inhibit the degradation of Wee1. The compounds of the present invention are generally N-((1H-benzo[d]imidazol-2-yl)methyl)-9H-purin-6-amines. Compounds of the invention can be used for treatment of malconditions in patients for which inhibition of Wee1 is medically indicated, for example cancer, Alzheimer's, neurological disorders, psychiatric disorders, or inflammation-related disorders.
1. A compound of formula (I),
wherein
R 1 and R 1a are each independently selected from the group consisting of hydrogen, deuterium, (CH 2 ) 0-4 N(R) 2 , (CH 2 ) 0-4 SO 3 R, (CH 2 ) 0-4 C(O)R, (CH 2 ) 0-4 C(O)C(O)R, (CH 2 ) 0-4 C(O)CH 2 C(O)R, (CH 2 ) 0-4 C(S)R, (CH 2 ) 0-4 C(O)OR, (CH 2 ) 0-4 OC(O)R, (CH 2 ) 0-4 OC(O)OR, (CH 2 ) 0-4 C(O)N(R) 2 , OC(O)N(R) 2 , (CH 2 ) 0-4 C(S)N(R) 2 , (CH 2 ) 0-4 NHC(O)R, (CH 2 ) 0-4 N(R)SO 2 R, (CH 2 ) 0-4 N(R)SO 2 N(R) 2 , (CH 2 ) 0-4 N(R)C(O)OR, (CH 2 ) 0-4 N(R)C(O)R, (CH 2 ) 0-4 N(R)C(S)R, (CH 2 ) 0-4 N(R)C(O)N(R) 2 , (CH 2 ) 0-4 N(R)C(S)N(R) 2 , (CH 2 ) 0-4 N(COR)COR, (CH 2 ) 0-4 N(OR)R, (CH 2 ) 0-4 C(═NH)N(R 2 ), (CH 2 ) 0-4 C(O)N(OR)R, (CH 2 ) 0-4 C(═NOR)R, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )acyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein any alkyl, alkoxy, acyloxy, cycloalkyl, heterocyclyl, aryl, heteroaryl can be mono- or independently multi-substituted with J, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, (C 1-6 )haloalkoxy, cycloalkyl(C 0-6 )alkyl, heterocyclyl(C 0-6 )alkyl, aryl(C 0-6 )alkyl, or heteroaryl(C 0-6 )alkyl, of which any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be further substituted with J;
wherein R 2 is morpholino which can be mono- or independently multi-substituted with J, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, (C 1-6 )haloalkoxy, cycloalkyl(C 0-6 )alkyl, heterocyclyl(C 0-6 )alkyl, aryl(C 0-6 )alkyl, or heteroaryl(C 0-6 )alkyl;
R 3 , R 4 , R 5 , and R 6 each are independently selected from the group consisting of F, Cl, Br, I, OR, CN, CF 3 , OCF 3 , NO 2 , R, (CH 2 ) 0-4 N(R) 2 , (CH 2 ) 0-4 SR, (CH 2 ) 0-4 SOR, (CH 2 ) 0-4 SO 2 R, (CH 2 ) 0-4 SO 2 N(R) 2 , (CH 2 ) 0-4 SO 3 R, (CH 2 ) 0-4 C(O)R, (CH 2 ) 0-4 C(O)C(O)R, (CH 2 ) 0-4 C(O)CH 2 C(O)R, (CH 2 ) 0-4 C(S)R, (CH 2 ) 0-4 C(O)OR, (CH 2 ) 0-4 OC(O)R, (CH 2 ) 0-4 OC(O)OR, (CH 2 ) 0-4 C(O)N(R) 2 , (CH 2 ) 0-4 OC(O)N(R) 2 , (CH 2 ) 0-4 C(S)N(R) 2 , (CH 2 ) 0-4 NHC(O)R, (CH 2 ) 0-4 N(R)N(R)C(O)R, (CH 2 ) 0-4 N(R)N(R)C(O)OR, (CH 2 ) 0-4 N(R)N(R)CON(R 2 ), (CH 2 ) 0-4 N(R)SO 2 R, (CH 2 ) 0-4 N(R)SO 2 N(R) 2 , (CH 2 ) 0-4 N(R)C(O)OR, (CH 2 ) 0-4 N(R)C(O)R, (CH 2 ) 0-4 N(R)C(S)R, (CH 2 ) 0-4 N(R)C(O)N(R) 2 , (CH 2 ) 0-4 N(R)C(S)N(R) 2 , (CH 2 ) 0-4 N(COR)COR, (CH 2 ) 0-4 N(OR)R, (CH 2 ) 0-4 C(═NH)N(R 2 ), (CH 2 ) 0-4 C(O)N(OR)R, (CH 2 ) 0-4 C(═NOR)R, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )acyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein any alkyl, alkoxy, acyloxy, cycloalkyl, heterocyclyl, aryl, heteroaryl can be mono- or independently multi-substituted with J, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, (C 1-6 )haloalkoxy, cycloalkyl(C 0-6 )alkyl, heterocyclyl(C 0-6 )alkyl, aryl(C 0-6 )alkyl, or heteroaryl(C 0-6 )alkyl; wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be further substituted with J;
wherein m and n are each independently 0, 1, 2, or 3, provided m plus n is less than or equal to 4;
wherein J independently at each occurrence is selected from the group consisting of F, Cl, Br, I, OR, CN, CF 3 , OCF 3 , NO 2 , R, O, S, C(O), C(S), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, OC(O)OR, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 0-4 NHC(O)R, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R 2 ), N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(═NH)N(R 2 ), C(O)N(OR)R, C(═NOR)R, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )acyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein any alkyl, alkoxy, acyloxy, cycloalkyl, heterocyclyl, aryl, hetero aryl can be mono- or independently multi-substituted with R, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 2-6 )alkynyl, (C 1-6 )haloalkyl, (C 1-6 )alkoxy, (C 1-6 )haloalkoxy, cycloalkyl(C 0-6 )alkyl, heterocyclyl(C 0-6 )alkyl, aryl(C 0-6 )alkyl, or heteroaryl(C 0-6 )alkyl; wherein any alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocyclyl, or heteroaryl can be further mono- or independently multi-substituted with R; or wherein two R groups together with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3-8 )heterocyclyl mono- or multi-substituted with R; optionally further including 1-3 additional hetero atoms selected from the group consisting of O, N, S, S(O) and S(O) 2 ;
wherein R is independently at each occurrence is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, OH, CN, CF 3 , OCF 3 , NO 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl; wherein any alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J R ; or wherein two R groups with a nitrogen atom or with two adjacent nitrogen atoms to which they are bonded can together form a (C 3-8 )heterocyclyl substituted with 0-3 J R ; optionally further comprising 1-3 additional heteroatoms selected from the group consisting of O, N, S, S(O) and S(O) 2 ;
wherein any cycloalkyl, aryl, heterocyclyl, or heteroaryl can be fused, bridged, or in a spiro configuration with one or more additional optionally mono- or independently multi-J R substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl, monocyclic, bicyclic, bicyclic or polycyclic, saturated, partially unsaturated, or aromatic rings;
wherein J R is independently at each occurrence is selected from the group consisting of F, Cl, Br, I, OR, CN, CF 3 , OCF 3 , NO 2 , O, S, C(O), C(S), S(O), methylenedioxy, ethylenedioxy, N(R) 2 , SR, SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R, C(O)OR, OC(O)R, OC(O)OR, C(O)N(R) 2 , OC(O)N(R) 2 , C(S)N(R) 2 , (CH 2 ) 0-4 NHC(O)R, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R 2 ), N(R)SO 2 R, N(R)SO 2 N(R) 2 , N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R) 2 , N(R)C(S)N(R) 2 , N(COR)COR, N(OR)R, C(═NH)N(R 2 ), C(O)N(OR)R, C(═NOR)R, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-4 )acyloxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
wherein the compound of formula (I) can be any stereoisomer thereof, or any salt or tautomer thereof.
2. The compound of claim 1 wherein the compound is selected from the group consisting of