Compositions and methods of modulating the immune response by activating alpha protein kinase 1

A method for treating a disease or disorder amendable to treatment by activation of NFkB, p38, and JNK cell signaling pathways in cells of a subject, the method comprising administering to the subject an effective amount of a compound represented by formula (I), or a stereoisomer, a stable isotope, prodrug or a pharmaceutically acceptable salt thereof:

• and/or a stereoisomer, tautomer, stable isotopes, prodrug or pharmaceutically acceptable salt thereof, wherein:
• A1 and A2 are independently selected from O, S and —C(R8R9)—, wherein R8 and R9 are independently selected from H, D, —OH, N3, —CN, halogen, C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 haloalkyl, C1-C4 haloalkoxyl, C1-C4 alkanoyloxyl, C1-C4 alkenyloxyl and substituted or unsubstituted aralkyloxyl, wherein the optional substituents are 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy;
• at least one of A1 or A2 is —C(R8R9);
• wherein R8 or R9 in A1 can cyclize with R8 or R9 in A2 to form C3-C6 cycloalkyl and cycloheteroalkyl containing 3 to 9 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, each optionally substituted by 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy;
• L1 and L2 are independently selected from O, CH2, CHF and CF2;
• L3 is O, S or CH2;
• Z1 and Z2 are independently selected from O and S;
• W1 is —C(R10R11)—, wherein R10 and R11 are independently selected from H, D, —OH, halogen, and optionally substituted groups selected from C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 haloalkyl, C1-C4-haloalkoxyl, C1-C4 alkenyloxyl, aralkyloxyl and R12CO2—, wherein R12 is selected from C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 alkenyloxyl, C1-C4 alkylamino, C3-C6 cycloalkyl, cycloheteroalkyl containing 3 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members;, wherein the optional substituents for R10 and R11 are 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy;
• W2 is H or C1-C3 alkyl optionally substituted with 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C3 alkoxyl, C1-C3 haloalkyl, C1-C3 haloalkoxyl, C1-C3 alkenyloxyl and R12CO2—, wherein R12 is C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C3-C6 cycloalkyl, cycloheteroalkyl containing 3 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members;
• R1 is C6-C10 aryl or heteroaryl containing 5 to 10 ring atoms and having 1-4 heteroatoms selected from N, O and S as ring members, wherein R1 is optionally substituted with 1-3 substituents selected from of D, halogen, —OH, ═O, CN, NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamine, C1-C4 dialkylamine and (R13R14)NCO—, wherein R13 and R14 are independently
• selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, cycloheteroalkyl containing 3 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members;
• R2, R3 and R4 are independently selected from H, D, halogen, C1-C4 alkyl and C1-C4 haloalkyl;
• R5, R6 and R7 are selected from H, D, halogen and —OH, R12CO2—, wherein R12 is selected from C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 alkenyloxyl, C1-C4 alkylamino, C3-C6 cycloalkyl, cycloheteroalkyl containing 3 to 6 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, C6-C10 aryl, and heteroaryl containing 5 to 10 ring atoms and having 1-3 heteroatoms selected from N, O and S as ring members;
• wherein any two of the adjacent groups of R5, R6 and R7 can cyclize to form cycloheteroalkyl containing 5 to 9 ring members and having 1-3 heteroatoms selected from N, O and S as ring members, each optionally substituted by 1-3 substituents independently selected from D, halogen, —OH, ═O, C1-C4 alkyl and C1-C4 alkoxy.