Heterocyclic aspartyl protease inhibitors

A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure selected from the group consisting of:

• wherein
• R1 is independently selected from the group consisting of H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl,—OR15, —CN, —C(O)R8, —C(O)OR9, —S(O)R10, —S(O)2R10, —C(O)N(R11)(R12), —S(O)N(R11)(R12), —S(O)2N(R11)(R12), —NO2, —N═C(R8)2 and —N(R8)2;
• R3 and R4 are each independently selected from the group consisting of H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl, arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl, heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylaryl, heterocycloalkenylaryl, —CH2—O—Si(R9)(R10)(R19), —CN, —C(O)R8, —C(O)OR9 or —C(O)N(R11)(R12);
• or optionally, R3 and R4, together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl ring optionally substituted by 1 to 4 R14 moieties;
• wherein 1-5 of the atoms in the ring are optionally replaced by —O—;
• —S—;
• —N(R5)—;
• —C(O)—;
• —S(O)— or —S(O)2—;
• each R8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR15, —N(R15)(R16), —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) and —N(R15)C(O)OR16;
• R9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;
• R10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R15)(R16);
• R11 and R12 are each independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R8, —C(O)OR9, —S(O)R10, —S(O)2R10, —C(O)N(R15)(R16), —S(O)N(R15)(R16) and —S(O)2N(R15)(R16);
• R14 (when present) is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), —N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17) and —N(R15)C(O)OR16;
• R15, R16 and R17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R18-alkyl, R18-cycloalkyl, R18-cycloalkylalkyl, R18-heterocycloalkyl, R18-heterocycloalkylalkyl, R18-aryl, R18-arylalkyl, R18-heteroaryl and R18-heteroarylalkyl;
• or
• R15, R16 and R17 are
• wherein R23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;
• R18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO2, halo, heteroaryl, HO—alkyoxyalkyl, —CF3, —CN, alkyl-CN, —C(O)R19, —C(O)OH, —C(O)OR19, —C(O)NHR20, —C(O)NH2, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR19, —S(O)2R20, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR19, —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OCF3, —OH, —OR20, —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH2, —NHR20, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R20, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R20, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);
• or two R18 moieties on adjacent carbons can be linked together to form
• R19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;
• R20 is alkyl, cycloalkyl, aryl, halo substituted aryl, arylalkyl, heteroaryl or heteroarylalkyl;
• and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R8, R9, R10, R11, R12, and R14 are independently unsubstituted or substituted by 1 to 5 R21 groups;
• each R21 group is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR15, —C(O)R15, —C(O)OR15, —C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —CH(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —CH2—R15;
• —N(R15)S(O)R16,—N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —S(O)R15, ═NOR15, —N3, —NO2 and —S(O)2R15and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R21 are independently unsubstituted or substituted by 1 to 5 R22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR15, —C(O)R15, —C(O)OR15, -alkyl-C(O)OR15, C(O)N(R15)(R16), —SR15, —S(O)N(R15)(R16), —S(O)2N(R15)(R16), —C(═NOR15)R16, —P(O)(OR15)(OR16), —N(R15)(R16), -alkyl-N(R15)(R16), —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17), —N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16, —CH2—N(R15)C(O)OR16, —N3, ═NOR15, —NO2, —S(O)R15 and —S(O)2R15;
• or two R21 or two R22 moieties on adjacent carbons can be linked together to form
• and when R21 or R22 are selected from the group consisting of -—C(═NOR15)R16, —N(R15)C(O)R16, —CH2—N(R15)C(O)R16, —N(R15)S(O)R16, —N(R15)S(O)2R16, —CH2—N(R15)S(O)2R16, —N(R15)S(O)2N(R16)(R17),—N(R15)S(O)N(R16)(R17), —N(R15)C(O)N(R16)(R17), —CH2—N(R15)C(O)N(R16)(R17), —N(R15)C(O)OR16 and —CH2—N(R15)C(O)OR16, R15 and R16 together can be a C2 to C4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R15 and R16, together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R23;
• R23 is 1 to 5 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR24, —C(O)R24, —C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;
• and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R23 are independently unsubstituted or substituted by 1 to 5 R27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF3, —CN, —OR24, —C(O)R24, —C(O)OR24, -alkyl-C(O)OR24, —C(O)N(R24)(R25), —SR24, —S(O)N(R24)(R25), —S(O)2N(R24)(R25), —C(═NOR24)R25, —P(O)(OR24)(OR25), —N(R24)(R25), -alkyl-N(R24)(R25), —N(R24)C(O)R25, —CH2—N(R24)C(O)R25, —N(R24)S(O)R25, —N(R24)S(O)2R25, —CH2—N(R24)S(O)2R25, —N(R24)S(O)2N(R25)(R26), —N(R24)S(O)N(R25)(R26), —N(R24)C(O)N(R25)(R26), —CH2—N(R24)C(O)N(R25)(R26), —N(R24)C(O)OR25, —CH2—N(R24)C(O)OR25, —S(O)R24 and —S(O)2R24;
• R24, R25 and R26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R27-alkyl, R27-cycloalkyl, R27-cycloalkylalkyl, R27-heterocycloalkyl, R27-heterocycloalkylalkyl, R27-aryl, R27-arylalkyl, R27-heteroaryl and R27-heteroarylalkyl;
• R27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO2, halo, —CF3, —CN, alkyl-CN, —C(O)R28, —C(O)OH, —C(O)OR28, —C(O)NHR29, —C(O)N(alkyl)2, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR28, —S(O)2R29, —S(O)NH2, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)2NH2, —S(O)2NHR28, —S(O)2NH(aryl), —S(O)2NH(heterocycloalkyl), —S(O)2N(alkyl)2, —S(O)2N(alkyl)(aryl), —OH, —OR29, —O-heterocycloalkyl, —O-cycloalkylalkyl,—O-heterocycloalkylalkyl, —NH2, —NHR29, —N(alkyl)2, —N(arylalkyl)2, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R29, —NHC(O)NH2, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)2R29, —NHS(O)2NH(alkyl), —NHS(O)2N(alkyl)(alkyl), —N(alkyl)S(O)2NH(alkyl) and —N(alkyl)S(O)2N(alkyl)(alkyl);
• R28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl;
• and
• R29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.