Heterocyclic aspartyl protease inhibitors
View Patent ↗Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O) 2 —, —C(═O)—, —O—, —C(R 6 )(R 7 )—, —N(R 5 )— or —C(═N(R 5 ))—; X is —O—, —N(R 5 )— or —C(R 6 )(R 7 )—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O) 2 —, —C(═O)— or —C(═NR 5 )—; U is a bond, —S(O)—, —S(O) 2 —, —C(O)—, —O—, —P(O)(OR 15 )—, —C(═NR 5 )—, —(C(R 6 )(R 7 )) b — or —N(R 5 )—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, U is not —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—; provided that when X is —N(R 5 )— and W is —S(O)—, —S(O) 2 —, —O—, or —N(R 5 )—, then U is not a bond; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic antagonist.
1. A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having the structural formula
wherein
W is —C(═S)—,—C(═O)—, —C(R 6 )(R 7 )—, or —C(═N(R 5 ))—;
X is —N(R 5 )—
U is —C(═NR 5 )— or —(C(R 6 )(R 7 )) b —, wherein b is 1;
R 1 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —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 2 is selected from the group consisting of H and alkyl;
R 5 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —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 , provided that R 1 and R 5 are not both selected from —NO 2 , —N═C(R 8 ) 2 and —N(R 8 ) 2 ;
R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9 and —C(═NOH)R 8 ;
or R 3 and R 4 , or R 6 and R 7 (when present), or R 3 and R 6 (when R 6 is present), together with the carbon to which they are attached, form a 3-7 membered cycloalkyl group optionally substituted by R 14 or a 3-7 membered cycloalkylether optionally substituted by R 14 ;
or non-adjacent groups R 3 and R 4 or R 6 and R 7 (when R 6 and R 7 are present) together with the carbon to which they attached, are combined to form a multicyclic group selected from
wherein M is —CH 2 —, S, —N(R 19 )— or O, A and B are independently aryl or heteroaryl and q is 0, 1 or 2, provided that when q is 2, one M must be a carbon atom, and when q is 2, M is optionally a double bond;
R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyf, 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 , R 12 and R 13 are 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 ), —S(O) 2 N(R 15 )(R 16 ) and —CN;
R 14 is 1-5 substituents 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 ), —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)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 (when present) in R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups 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 15 ), —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(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 , —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, heterocycroalkyl, heterocycloalkylalkyl, aryl, arylal kyl, heteroaryl, heteroarylalkyt, 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 ), —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)NH R 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 NH R 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 , —NH R 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;
provided that when X is —N(R 5 )—, U is —O— and W is a bond or —C(R 6 )(R 7 )—, (R 3 ,R 4 ) is not (H, —NHC(O)-alkyl-heteroaryl) or (H, alkyl-NHC(O)-alkyl-heteroaryl); and
provided that when X is —N(R 5 )—, R 1 and R 5 are not alkylaryl-aryl-SO 2 —N(R 15 )(R 16 ) wherein R 15 is H and R 16 is heteroaryl;
and provided that when R 1 is R 21 -aryl or R 21 -arylalkyl, wherein R 21 is —OCF 3 , —S(O)CF 3 , —S(O) 2 CF 3 , —S(O)alkyl, —S(O) 2 alkyl, —S(O) 2 CHF 2 , —S(O) 2 CF 2 CF 3 , —OCF 2 CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —SF 5 or —S(O) 2 NR 15 R 16 ; wherein R 15 and R 16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -heterocycloalkyl, R 18 -aryl and R 18 -heteroaryl; U is a bond or —CH 2 ; and X is —N(R 5 )—; then R 5 is H.
2. A compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having the structure IB:
3. A compound of claim 2 of the structure lB wherein U is —C(R 6 )(R 7 )—.
4. A compound of claim 1 wherein R 2 is H.
5. A compound of claim 1 wherein R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —CH 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), —S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9 and —C(═NOH)R 8 .
6. A compound of claim 1 wherein R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of aryl, heteroaryl, heteroarylalkyl, arylalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, alkyl and cycloalkylalkyl.
7. A compound of claim 1 wherein
U is —(C(R 6 )(R 7 )) b —, wherein b is 1;
W is —C(O)—;
X is —N(R 5 )—;
R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,
R 2 is H;
R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl;
R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl;
R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyt, R 21 -aryl or R 21 -arylalkyl:
R 15 , R 16 and R 17 is H, R 18 -alkyl, alkyl or
R 21 is alkyl, aryl, halo, —OR 15 , —NO 2 , —C(O)R 15 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ) or —CH(R 15 )(R 16 );
n is 1;
m is 1;
is —OR 20
R 20 is aryl; and
R 23 is alkyl.
8. A compound of claim 7 wherein
R 3 , R 4 , R 6 and R 7 are
and
R 1 and R 5 is H, CH 3 ,
9. A compound of claim 1 wherein
U is —C(R 6 )(R 7 )—;
W is —C(O)—;
X is —N(R 5 )—;
R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl,
R 2 is H;
R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;
R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;
R 5 is H;
R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;
R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl, R 21 -arylalkyl, heteroarylalkyl, heteroaryl, heterocycloalkyl, heterocydoalkylalkyl, R 21 -heteroarylalkyl, R 21 -heteroaryl, R 21 -heterocycloalkyl or R 21 -heterocycloalkylalkyl;
R 15 , R 16 and R 17 is H, cycloalkyl, cycloalkylalkyl, R 18 -alkyl, alkyl, aryl, R 18 -aryl, R 18 -arylalkyl, arylalkyl,
n is 1 or 2;
m is 0 or 1;
R 18 is —OR 20 or halo;
R 20 is aryl or halo substituted aryl;
R 21 is alkyl, aryl, heteroaryl, R 22 -alkyl, R 22 -aryl, R 22 -heteroaryl, halo, heterocycloalkyl, —N(R 15 )(R 16 ), —OR 15 , —NO 2 , —C(O)R 15 , —N(R 15 )C(O)R 16 , —N(R 15 )S(O) 2 R 16 , —CH 2 —N(R 15 )C(O)N(R 16 )(R 17 ), —N(R 15 )C(O)N(R 16 )(R 17 ) or —CH(R 15 )(R 16 );
R 22 is —OR 15 or halo; and
R 23 is H or alkyl.
10. A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, selected from the group consisting of:
11. A compound of claim 3 , wherein R 6 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl.
12. A compound of claim 3 , wherein R 6 is alkyl.
13. A compound of claim 3 , wherein R 7 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cyctoalkyl, R 21 -aryl or R 21 -arylalkyl.
14. A compound of claim 3 , wherein R 7 is alkyl, aryl, R 21 -alkyl, R 21 -aryl or R 21 -arylalkyl.
15. A compound of claim 3 , wherein R 7 is alkyl.
16. A compound of claim 3 , wherein R 7 is aryl or R 21 -aryl.
17. A compound of claim 3 ,-wherein R 7 is aryl substituted with from 1-5 R 21 groups.
18. A compound of claim 17 , wherein R 7 is aryl substituted with from 1-3 R 21 groups.
19. A compound of claim 16 , wherein each R 21 is independently selected from halo, alkyl, aryl, aryl-R 22 , heteroaryl, or heteroaryl-R 22 .
20. A compound of claim 16 , wherein R 21 is alkyl substituted with from 1-5 R 22 groups.
21. A compound of claim 20 , wherein each said R 22 group is independently selected from halo.
22. A compound of claim 3 , wherein R 1 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl.
23. A compound of claim 3 , wherein R 1 is H, alkyl, or R 21 -alkyl.
24. A compound of claim 3 , wherein R 1 is alkyl.
25. A compound of claim 3 , wherein R 1 is methyl.
26. A compound of claim 3 , wherein R 2 is H.
27. A compound of claim 3 , wherein R 3 is H.
28. A compound of claim 3 , wherein R 3 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl.
29. A compound of claim 3 , wherein R 4 is H.
30. A compound of claim 3 , wherein R 4 is alkyl, cycloalkylalkyl, cycloalkyl, aryl, arylalkyl, R 21 -alkyl, R 21 -cycloalkylalkyl, R 21 -cycloalkyl, R 21 -aryl or R 21 -arylalkyl.
31. A compound of claim 3 , wherein R 5 is H, alkyl, R 21 -alkyl, arylalkyl, R 21 -arylalkyl, cycloalkylalkyl, R 21 -cycloalkylalkyl, heterocycloalkyalkyl or R 21 -heterocycloalkylalkyl.
32. A compound of claim 3 , wherein R 5 is alkyl.
33. A compound of claim 3 , wherein R 5 is H.
34. A compound of claim 3 , wherein R 1 is methyl, R 2 is H, U is —C(R 6 R 7 )—, and R 5 is H.
35. A pharmaceutical composition comprising at least one compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier.
36. A pharmaceutical composition comprising at least one compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in combination with at least one additional therapeutic agent other than a compound of claim 1 , and a pharmaceutically effective carrier.
37. A pharmaceutical composition comprising at least one compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in combination with a cholinesterase inhibitor, and a pharmaceutically effective carrier.
38. A pharmaceutical composition of claim 37 , wherein said cholinesterase inhibitor is selected from an acetyl cholinesterase inhibitor and a butyrylcholinesterase inhibitor.
39. A pharmaceutical composition of claim 37 , wherein said cholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine, galantamine, pyridostigmine, and neostigmine.
40. A pharmaceutical composition comprising at least one compound of claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, in combination with an agent selected from muscarinic m, agonist and a muscarinic m 2 antagonist, and a pharmaceutically effective carrier.
41. A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, having the structural formula
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein
W is a —C(═S)—, —C(═O)—, —C(R 6 )(R 7 )—, or 13 C(═N(R 5 ))—;
X is —N(R 5 )—;
U is —C(═NR 5 )—, or —(C(R 6 )(R 7 )) b —, wherein b is 1;
R 1 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —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 2 is selected from the group consisting of H and alkyl;
R 5 is selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —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 , provided that R 1 and R 5 are not both selected from —NO 2 , —N═C(Ra) 2 and —N(R 8 ) 2 ;
R 3 , R 4 , R 6 and R 7 are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halo, —O—H 2 —O—Si(R 9 )(R 10 )(R 19 ), —SH, —CN, —OR 9 , —C(O)R 8 , —C(O)OR 9 , —C(O)N(R 11 )(R 12 ), —SR 19 , —S(O)N(R 11 )(R 12 ), S(O) 2 N(R 11 )(R 12 ), —N(R 11 )(R 12 ), N(R 11 )C(O)R 8 , —N(R 11 )S(O)R 10 , —N(R 11 )C(O)N(R 12 )(R 13 ), —N(R 11 )C(O)OR 9 and —C(═NOH)R 8 ;
R 8 is independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, a ryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 15 , —N(R 15 )(R 16 ), —N(R 15 )C(O)R 16 , —N(R 16 )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 , R 12 and R 13 are 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 ), —S(O) 2 N(R 15 )(R 16 ) and —CN;
R 14 is 1-5 substituents 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 ), —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)NH R 20 , —C(O)NH 2 , —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, heterocycloafkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, alkenyl and alkynyl groups (when present) in R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently unsubstituted or substituted by 1 to 5 R 21 groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl heteroaryl heteroarylalkyt, 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 18 ), —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 —N(R 15 )C(O)N(R 16 )(R 17 ), —CH 2 —R 15 ; —CH 2 N(R 15 )(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 , —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, cycloal kenyl, 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 , —O—H 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 15 , —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 18 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, a rylalkyl, 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(═NOR24)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;
provided that when X is —N(R 5 )—, U is —O— and W is a bond or —C(R 6 )(R 7 )—, (R 3 ,R 4 ) is not (H, —NHC(O)-alkyl-heteroaryl) or (H, alkyl-NHC(O)-alkyl-heteroaryl); and
provided that when X is —N(R 5 ), R 1 and R 5 are not alkylaryl-aryl-SO 2 —N(R 15 )(R 16 ) wherein R 15 is H and R 16 is heteroaryl;
and provided that when R 1 is R 21 -aryl or R 21 -arylalkyl, wherein R 21 is —OCF 3 , —S(O)CF 3 , —S(O) 2 CF 3 , —S(O)alkyl, —S(O) 2 alkyl , —S(O) 2 CHF 2 , —S(O) 2 CF 2 CF 3 , —OCF 2 CHF 2 , —OCHF 2 , —OCH 2 CF 3 , —SF 5 or —S(O) 2 NR 15 R 16 ; wherein R 15 and R 16 are independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R 18 -alkyl, R 18 -cycloalkyl, R 18 -heterocycloalkyl, R 18 -aryl and R 18 -heteroaryl; U is a bond or —CH 2 ; and X is —N(R 5 )—; then R 5 is H.