Heterocyclic aspartyl protease inhibitors

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

wherein

R 1 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,—OR 15 , —CN, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 11 )(R 12 ), —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —NO 2 , —N═C(R 8 ) 2 and —N(R 8 ) 2 ;

R 3 and R 4 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, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —CN, —C(O)R 8 , —C(O)OR 9 or —C(O)N(R 11 )(R 12 );

or optionally, R 3 and R 4 , together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl ring optionally substituted by 1 to 4 R 14 moieties; wherein 1-5 of the atoms in the ring are optionally replaced by —O—; —S—; —N(R 5 )—; —C(O)—; —S(O)— or —S(O) 2 —;

each R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;

R 9 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl;

R 10 is independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —N(R 15 )(R 16 );

R 11 and R 12 are each independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —C(O)R 8 , —C(O)OR 9 , —S(O)R 10 , —S(O) 2 R 10 , —C(O)N(R 15 )(R 16 ), —S(O)N(R 15 )(R 16 ) and —S(O) 2 N(R 15 )(R 16 );

R 14 (when present) is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) and —N(R 15 )C(O)OR 16 ;

R 15 , R 16 and R 17 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, arylheterocycloalkyl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -cycloalkylalkyl, R 18 -heterocycloalkyl, R 18 -heterocycloalkylalkyl, R 18 -aryl, R 18 -arylalkyl, R 18 -heteroaryl and R 18 -heteroarylalkyl; or

R 15 , R 16 and R 17 are

wherein R 23 numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;

R 18 is 1-5 substituents independently selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, —NO 2 , halo, heteroaryl, HO—alkyoxyalkyl, —CF 3 , —CN, alkyl-CN, —C(O)R 19 , —C(O)OH, —C(O)OR 19 , —C(O)NHR 20 , —C(O)NH 2 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 19 , —S(O) 2 R 20 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 19 , —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OCF 3 , —OH, —OR 20 , —O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH 2 , —NHR 20 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)-(heteroarylalkyl), —NHC(O)R 20 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 20 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

or two R 18 moieties on adjacent carbons can be linked together to form

R 19 is alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl;

R 20 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups;

each R 21 group is independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , —C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —CH(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —R 15 ; —N(R 15 )S(O)R 16 ,—N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —S(O)R 15 , ═NOR 15 , —N 3 , —NO 2 and —S(O) 2 R 15 and wherein each of the alkyl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 21 are independently unsubstituted or substituted by 1 to 5 R 22 groups independently selected from the group consisting of alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 15 , —C(O)R 15 , —C(O)OR 15 , -alkyl-C(O)OR 15 , C(O)N(R 15 )(R 16 ), —SR 15 , —S(O)N(R 15 )(R 16 ), —S(O) 2 N(R 15 )(R 16 ), —C(═NOR 15 )R 16 , —P(O)(OR 15 )(OR 16 ), —N(R 15 )(R 16 ), -alkyl-N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ), —N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 , —CH 2 —N(R 15 )C(O)OR 16 , —N 3 , ═NOR 15 , —NO 2 , —S(O)R 15 and —S(O) 2 R 15 ;

or two R 21 or two R 22 moieties on adjacent carbons can be linked together to form

and when R 21 or R 22 are selected from the group consisting of -—C(═NOR 15 )R 16 , —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —N(R 15 )S(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )S(O) 2 R 16 , —N(R 15 )S(O) 2 N(R 16 )(R 17 ),—N(R 15 )S(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)OR 16 and —CH 2 —N(R 15 )C(O)OR 16 , R 15 and R 16 together can be a C 2 to C 4 chain wherein, optionally, one, two or three ring carbons can be replaced by —C(O)— or —N(H)— and R 15 and R 16 , together with the atoms to which they are attached, form a 5 to 7 membered ring, optionally substituted by R 23 ;

R 23 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, —OR 24 , —C(O)R 24 , —C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ; and wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups in R 23 are independently unsubstituted or substituted by 1 to 5 R 27 groups independently selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, —CF 3 , —CN, —OR 24 , —C(O)R 24 , —C(O)OR 24 , -alkyl-C(O)OR 24 , —C(O)N(R 24 )(R 25 ), —SR 24 , —S(O)N(R 24 )(R 25 ), —S(O) 2 N(R 24 )(R 25 ), —C(═NOR 24 )R 25 , —P(O)(OR 24 )(OR 25 ), —N(R 24 )(R 25 ), -alkyl-N(R 24 )(R 25 ), —N(R 24 )C(O)R 25 , —CH 2 —N(R 24 )C(O)R 25 , —N(R 24 )S(O)R 25 , —N(R 24 )S(O) 2 R 25 , —CH 2 —N(R 24 )S(O) 2 R 25 , —N(R 24 )S(O) 2 N(R 25 )(R 26 ), —N(R 24 )S(O)N(R 25 )(R 26 ), —N(R 24 )C(O)N(R 25 )(R 26 ), —CH 2 —N(R 24 )C(O)N(R 25 )(R 26 ), —N(R 24 )C(O)OR 25 , —CH 2 —N(R 24 )C(O)OR 25 , —S(O)R 24 and —S(O) 2 R 24 ;

R 24 , R 25 and R 26 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, R 27 -alkyl, R 27 -cycloalkyl, R 27 -cycloalkylalkyl, R 27 -heterocycloalkyl, R 27 -heterocycloalkylalkyl, R 27 -aryl, R 27 -arylalkyl, R 27 -heteroaryl and R 27 -heteroarylalkyl;

R 27 is 1-5 substituents independently selected from the group consisting of alkyl, aryl, arylalkyl, —NO 2 , halo, —CF 3 , —CN, alkyl-CN, —C(O)R 28 , —C(O)OH, —C(O)OR 28 , —C(O)NHR 29 , —C(O)N(alkyl) 2 , —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR 28 , —S(O) 2 R 29 , —S(O)NH 2 , —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O) 2 NH 2 , —S(O) 2 NHR 28 , —S(O) 2 NH(aryl), —S(O) 2 NH(heterocycloalkyl), —S(O) 2 N(alkyl) 2 , —S(O) 2 N(alkyl)(aryl), —OH, —OR 29 , —O-heterocycloalkyl, —O-cycloalkylalkyl,—O-heterocycloalkylalkyl, —NH 2 , —NHR 29 , —N(alkyl) 2 , —N(arylalkyl) 2 , —N(arylalkyl)(heteroarylalkyl), —NHC(O)R 29 , —NHC(O)NH 2 , —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O) 2 R 29 , —NHS(O) 2 NH(alkyl), —NHS(O) 2 N(alkyl)(alkyl), —N(alkyl)S(O) 2 NH(alkyl) and —N(alkyl)S(O) 2 N(alkyl)(alkyl);

R 28 is alkyl, cycloalkyl, arylalkyl or heteroarylalkyl; and

R 29 is alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.

2. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure:

3. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure selected from the group consisting of:

4. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure:

5. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure:

6. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure:

7. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, said compound having a structure:

8. A compound of any one of claims 1 - 7 , wherein R 1 is alkyl, heterocycloalkyl or heterocycloalkylalkyl.

9. A compound of any one of claims 1 - 7 , wherein R 3 is aryl, heteroaryl, alkyl, cycloalkyl or cycloalkylalkyl.

10. A compound of any one of claims 1 - 7 , wherein R 4 is alkyl.

11. A compound of any one of claim 1 , 2 , 5 , or 6 , wherein R 14 is aryl, heteroaryl, alkyl, cycloalkyl or cycloalkylalkyl.

12. A compound of any one of claims 1 - 7 , wherein R 3 is aryl-substituted aryl, heteroaryl-substituted aryl, aryl-substituted heteroaryl or heteroaryl-substituted heteroaryl, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl, aryl-substituted alkyl, heteroaryl-substituted alkyl, or heteroaryl-substituted cycloalkylalkyl.

13. A compound of any one of claims 1 - 7 , wherein R 3 is selected from the group consisting of:

14. A compound of any one of claims 1 - 7 , wherein

R 1 is alkyl, heterocycloalkyl or heterocycloalkylalkyl;

R 3 is aryl, heteroaryl, alkyl, cycloalkyl or cycloalkylalkyl; and

R 4 is alkyl.

15. A compound of any one of claims 1 , 2 , 4 , and 5 , wherein:

R 1 is alkyl, heterocycloalkyl or heterocycloalkylalkyl;

R 3 is aryl, heteroaryl, alkyl, cycloalkyl or cycloalkylalkyl;

R 4 is alkyl; and

R 14 is aryl, heteroaryl, alkyl, cycloalkyl or cycloalkylalkyl.

16. A compound of claim 14 wherein R 3 is aryl-substituted aryl, heteroaryl-substituted aryl, aryl-substituted heteroaryl or heteroaryl-substituted heteroaryl, aryl-substituted cycloalkyl, heteroaryl-substituted cycloalkyl, aryl-substituted alkyl, heteroaryl-substituted alkyl, or heteroaryl-substituted cycloalkylalkyl.

17. A compound of claim 14 wherein R 3 is selected from the group consisting of:

18. A compound of claim 1 selected from the group consisting of:

19. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 - 7 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier.