Pre-organized tricyclic integrase inhibitor compounds

A compound having the structure:

• 457
• or a salt thereof;
• wherein:
• A1 and A2 are independently selected from O, S, NR, C(R2)2, CR2OR, CR2OC(═O)R, C(═O), C(═S), CR2SR, C(═NR), C(R2)2—C(R3)2, C(R2)═C(R3), NR—C(R3)2, N═C(R3), N═N, SO2—NR, C(═O)C(R3)2, C(═O)NR, C(R2)2—C(R3)2—C(R3)2, C(R2)═C(R3)—C(R3)2, C(R2)C(═O)NR, C(R2)C(═S)NR, C(R2)═N—C(R3)2, C(R2)═N—NR, and N═C(R3)—NR;
• Q is N, +NR, or CR4;
• 458
• L is selected from a bond, O, S, S—S, S(═O), S(═O)2, S(═O)2NR, NR, N—OR, C1-C12 alkylene, C1-C12 substituted alkylene, C2-C12 alkenylene, C2-C12 substituted alkenylene, C2-C12 alkynylene, C2-C12 substituted alkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH2)n, or (CH2CH2O)n, where n may be 1, 2, 3, 4, 5, or 6;
• X is selected from O, S, NH, NR, N—OR, N—NR2, N—CR2OR and N—CR2NR2;
• Ar is selected from C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl;
• R1, R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
• when taken together on a single carbon, two R2 or two R3 may form a spiro ring;
• R is independently selected from H, C1-C8 alkyl, C1-C8 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug;
• and
• P is a protecting group selected from benzyhydryl (CHPh2), trialkylsilyl (R3Si), 2-trimethylsiloxyethyl, alkoxymethyl (CH2OR), and ester (C(═O)R).

A process for preparation of a compound having the structure:

• 459
• comprising reacting a succinimide compound having the structure:
• 460
• with a heterocyclic compound having the structure:
• 461
• and reaction with an acylation reagent comprising a formula selected from:
• 462
• wherein:
• A2 is selected from O, S, NR, C(R2)2, CR2OR, CR2OC(═O)R, C(═O), C(═S), CR2SR, C(═NR), C(R2)2—C(R3)2, C(R2)═C(R3), NR—C(R3)2, N═C(R3), N═N, SO2—NR, C(═O)C(R3)2, C(═O)NR, C(R2)2—C(R3)2—C(R3)2, C(R2)═C(R3)—C(R3)2, C(R2)C(═O)NR, C(R2)C(═S)NR, C(R2)═N—C(R3)2, C(R2)═N—NR, and N═C(R3)—NR;
• Q is N, +NR, or CR4;
• L is selected from a bond, O, S, NR, N—OR, C1-C12 alkyldiyl, C1-C12 substituted alkyldiyl, C(═O)NH, C(═O), S(═O), S(═O)2, C(═O)NH(CH2)n, and (CH2CH2O)n, where n ranges from 1 to 6;
• Ar is selected from C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl;
• R1 is selected from R, OR, NR2, NHR, NHSO2R, and NRSO2R;
• E is selected from Cl, imidazole, and hydroxybenzotriazole;
• R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
• and
• R is selected from C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

A process for preparation of a compound having the structure:

• 465
• comprising reacting a compound having the structure:
• 466
• with a basic reagent comprising hydroxide, an alkoxide or an amine;
• wherein:
• A1 and A2 are independently selected from O, S, NR, C(R2)2, CR2OR, CR2OC(═O)R, C(═O), C(═S), CR2SR, C(═NR), C(R2)2—C(R3)2, C(R2)═C(R3), NR—C(R3)2, N═C(R3), N═N, SO2—NR, C(═O)C(R3)2, C(═O)NR, C(R2)2—C(R3)2—C(R3)2, C(R2)═C(R3)—C(R3)2, C(R2)C(═O)NR, C(R2)C(═S)NR, C(R2)═N—C(R3)2, C(R2)═N—NR, and N═C(R3)—NR;
• Q is N, +NR, or CR4;
• X is selected from O, S, NH, NR, N—OR, N—NR2, N—CR2OR and N—CR2NR2;
• L is selected from a bond, O, S, NR, N—OR, C1-C12 alkyldiyl, C1-C12 substituted alkyldiyl, C(═O)NH, C(═O), S(═O), S(═O)2, C(═O)NH(CH2)n, and (CH2CH2O)n, where n ranges from 1 to 6;
• Ar is selected from C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl;
• R2, R3 and R4 are each independently selected from H, F, Cl, Br, I, OH, —NH2, —NH3+, —NHR, —NR2, —NR3+, C1-C8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C1-C8 alkylsulfonate, C1-C8 alkylamino, 4-dialkylaminopyridinium, C1-C8 alkylhydroxyl, C1-C8 alkylthiol, —SO2R, —SO2Ar, —SOAr, —SAr, —SO2NR2, —SOR, —CO2R, —C(═O)NR2, 5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N3, —NO2, C1-C8 alkoxy, C1-C8 trifluoroalkyl, C1-C8 alkyl, C1-C8 substituted alkyl, C3-C12 carbocycle, C3-C12 substituted carbocycle, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, and C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety;
• and
• R is selected from C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C20 heteroaryl, C2-C20 substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrug moiety.

A process for preparation of a compound having structure 115:

• 467
• comprising reacting a compound having the structure 44:
• 468
• with tetrabutylammonium fluoride to form a desilylated intermediate;
• and
• reacting the desilylated intermediate with triphosgene (bis(trichloromethyl) carbonate), followed by dimethylhydrazine to form structure 115.