Receptor-interacting protein 1 inhibitors including piperazine heterocyclic amide ureas

A compound of formula Ia:

• or a salt, hydrate or stereoisomer thereof;
• R1 is a 6-membered aryl that is unsubstituted or substituted at C3 and/or C5 with halogen or CN, or a 6-membered heteroaryl that comprises 1 nitrogen heteroatom and that is unsubstituted or substituted at C3 and/or C5 with halogen or CN;
• R2 is a 6-membered aryl that is unsubstituted or substituted with halogen or C1-C3 alkoxy, or a 6-membered heteroaryl that comprises 1 or 2 nitrogen heteroatoms and that is unsubstituted or substituted with halogen or C1-C3 alkoxy;
• Y is O or N;
• when Y is N, m is 2, and
• R3 and R4 are independently H or alkyl or cycloalkyl or —ORs, wherein Rs is C1-C6 alkyl optionally substituted with halogen and/or C3-C6 cycloalkyl;
• wherein the alkyl and cycloalkyl are each independently substituted with 0-3 substituents selected from halogen, —R′—OR′, ═O, ,═N—OR′, —NR′R″, —SR′—SiR′R″R″, —OC(O)R′, —C(O)R′—CO2R′—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO2NR′″, —NR″CO2R′, —NH—C(NH2)=NH, —NR′C(NH2)=NH, —NH—C(NH2)=NR′, —S(O)R′—SO2R′, —SO2NR′R″, —NR″SO2R, —CN and —NO2, —CH(Ph)2 perfluoro (C1-C4) alkoxy and perfluoro (C1-C4)alkyl, wherein R3 and R4 may be joined in a heterocycle;
• when Y is O, m is 1, and
• R3 is H or alkyl or cycloalkyl, wherein the alkyl and cycloalkyl are each independently substituted with 0-3 substituents selected from halogen, —R′, —OR′, ═O, ,═N—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO2R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′SO2NR′″, —NR″CO2R′, —NH—C(NH2)=NH, —NR′C(NH2)=NH, —NH—C(NH2)=NR′, —S(O)R′, —SO2R′, —SO2NR′R″—NR″SO2R, —CN and —NO2, ,—CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro (C1-C4)alkyl;
• wherein R′, R″ and R′″ each independently refer to hydrogen, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 heteroalkyl, C1-C8 alkyl substituted with one to three halogens, C1-C8 heteroalkyl substituted with one to three halogens, unsubstituted C6-C14 aryl, C6-C14 aryl substituted with one to three halogens, unsubstituted C1-C8 alkoxy, unsubstituted C1-C8 thioalkoxy groups, or C6-C14 aryl-(C1-C4) alkyl groups, and wherein when R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring.