Compounds which inhibit beta-secretase activity and methods of use thereof

Abstract

The present invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating Alzheimer's disease.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is halogen, —OH, —CF 3 , —NO 2 , —N(R 8 )R 9 , —OR 10 , —S(O) n R 11 , —C(O)R 12 , hydrogen, substituted or unsubstituted C 3 -C 20  alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L 4 -Y; 
 R 5  is halogen, —OH, —CF 3 , —NO 2 , —N(R 8 )R 9 , —OR 10 , —S(O) n R 11 , —C(O)R 12 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 2  and R 3  are independently halogen, —CF 3 , —NO 2 , —N(R 8 )R 9 , —OR 10 , —S(O) n R 11 , —C(O)R 12 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L 4 -Y; 
 R 4  is halogen, —OH, —CF 3 , —NO 2 , —N(R 8 )R 9 , —OR 10 , —S(O) n R 11 , —C(O)R 12 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L 4 -Y; 
 R 6  and R 7  are independently —S(O) 2 R 11 , —C(O)R 12 , —N(R 8 )R 9 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L 4 -Y; 
 n is independently 0, 1, or 2; 
 R 8  is independently —C(O)R 13 , —S(O) 2 R 14 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 9  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 10  is independently —C(O)R 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 11  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein if n is 2, then R 11  is optionally —N(R 15 )R 16 , and wherein if n is 1 or 2, then R 11  is not hydrogen; 
 R 12  is independently —N(R 18 )R 19 , —OR 19 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 13  is independently —OR 19 , —N(R 18 )R 19 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, 
 R 14  is independently —N(R 18 )R 19 , hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein 
 R 18  and R 19  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 R 15  and R 16  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 L 1  is —N(R 17 )—, —S(O) q —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; 
 L 2  is substituted or unsubstituted alkylene, —N(R 17 )—, —S(O) q —, or substituted or unsubstituted heteroalkylene; 
 L 3  is a bond, —N(R 17 )—, —S(O) q —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; 
 R 17  is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 q is independently 0, 1, or 2; 
 A 1  is substituted or unsubstituted C 5 -C 7  cycloalkyl, substituted or unsubstituted 5-7 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 A 2  is substituted or unsubstituted C 5 -C 7  cycloalkyl, or substituted or unsubstituted 5-7 membered heterocycloalkyl; 
 Y is a carrier moiety; and 
 L 4  is a bond, —OP(OH) 2 O—, —C(O)OR 20 —, —C(O)NHR 21 —, —S(O) 2 NHR 22 —, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or a peptidyl linker, wherein
 R 20 , R 21 , and R 22  are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
 
 
       or a pharmaceutically acceptable salt, prodrug, hydrate, racemate, diastereomer, tautomer, isotope, or crystalline form thereof. 
     
     
         2 - 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein A 1  is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 
     
     
         27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein A 1  is substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted thianaphthenyl, substituted or unsubstituted carbazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzooxazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted acridinyl, substituted or unsubstituted benzoisazolyl, or substituted or unsubstituted indolyl. 
     
     
         29 - 71 . (canceled) 
     
     
         72 . The compound of  claim 1 , wherein R 1  is hydrogen, halogen, —NR 8 R 9 , —OR 10 , or —S(O) n R 11    
     
     
         73 . The compound of  claim 1 , wherein R 1  is hydrogen, —NR 9 S(O) n R 14 , —OR 10 , or —S(O) n R 11    
     
     
         74 . The compound of  claim 1 , wherein R 1  is hydrogen or —N(R 9 )S(O) n R 14 . 
     
     
         75 . The compound of  claim 1 , wherein R 5 , R 8 , R 9 , and R 11  are independently hydrogen, substituted or unsubstituted C 1 -C 20  alkyl, substituted or unsubstituted 2 to 20 membered heteroalkyl, substituted or unsubstituted C 5 -C 7  cycloalkyl, substituted or unsubstituted 5 to 7 membered heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L 4 -Y. 
     
     
         76 . The compound of  claim 1 , wherein each substituted or unsubstituted alkylene is an R 23 -substituted or unsubstituted C 1 -C 20  alkylene, each substituted or unsubstituted heteroalkylene is an R 23 -substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted alkyl is an R 23 -substituted or unsubstituted C 1 -C 20  alkyl, each substituted or unsubstituted heteroalkyl is an R 23 -substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is an R 23 -substituted or unsubstituted C 5 -C 7  cycloalkyl, each substituted or unsubstituted heterocycloalkyl is an R 23 -substituted or unsubstituted 5 to 7 membered heterocycloalkyl, each substituted or unsubstituted heteroaryl is an R 24 -substituted or unsubstituted heteroaryl, and each substituted or unsubstituted aryl is an R 24 -substituted or unsubstituted aryl, wherein
 R 23  is independently oxo, halogen, —CN, —CF 3 , —OCF 3 , —OR 27 , —S(O) t R 27 , —OCH 3 , —C(O)R 27 , —N(R 28 )R 29 , —N(R 28 )C(O)R 27 , —C(O)N(R 28 )R 29 , R 25 -substituted or unsubstituted C 1 -C 20  alkyl, R 25 -substituted or unsubstituted 2 to 20 membered heteroalkyl, R 25 -substituted or unsubstituted C 5 -C 7  cycloalkyl, R 25 -substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R 26 -substituted or unsubstituted heteroaryl, or R 26 -substituted or unsubstituted aryl;   R 24  is independently halogen, —CN, —CF 3 , —OCF 3 , —OCH 3 , —OR 24 , —S(O) t R 27 , —OCH 3 , —C(O)R 27 , —N(R 28 )R 29 , —N(R 28 )C(O)R 27 , —C(O)N(R 28 )R 29 , R 25 -substituted or unsubstituted C 1 -C 20  alkyl, R 25 -substituted or unsubstituted 2 to 20 membered heteroalkyl, R 25 -substituted or unsubstituted C 5 -C 7  cycloalkyl, R 25 -substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R 26 -substituted or unsubstituted heteroaryl, or R 26 -substituted or unsubstituted aryl;   t is independently 0, 1, or 2;   R 2 , R 28 , and R 29  are independently hydrogen, R 25 -substituted or unsubstituted C 1 -C 20  alkyl, R 25 -substituted or unsubstituted 2 to 20 membered heteroalkyl, R 25 -substituted or unsubstituted C 5 -C 7  cycloalkyl, R 25 -substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R 26 -substituted or unsubstituted heteroaryl, or R 26 -substituted or unsubstituted aryl, wherein if t is 1 or 2, then R 27  is not hydrogen, and wherein   R 25  is independently oxo, halogen, —CN, —OH, —CF 3 , —OCF 3 , —OCH 3 , unsubstituted C 1 -C 20  alkyl, unsubstituted 2 to 20 membered heteroalkyl, unsubstituted C 5 -C 7  cycloalkyl, unsubstituted 5 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl, and   R 26  is independently halogen, —CN, —OH, —CF 3 , —OCF 3 , —OCH 3 , unsubstituted C 1 -C 20  alkyl, unsubstituted 2 to 20 membered heteroalkyl, unsubstituted C 5 -C 7  cycloalkyl, unsubstituted 5 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.   
     
     
         77 . The compound of  claim 1 , wherein R 2  and R 3  are independently hydrogen, halogen, or unsubstituted C 1 -C 20  alkyl. 
     
     
         78 . The compound of  claim 76 , wherein R 5  is R 24 -substituted or unsubstituted heteroaryl, or R 24 -substituted or unsubstituted aryl. 
     
     
         79 . The compound of  claim 76 , wherein R 5  is R 24 -substituted or unsubstituted aryl. 
     
     
         80 . The compound of  claim 79 , wherein R 5  is phenyl. 
     
     
         81 . The compound of  claim 80 , wherein L 3  is unsubstituted C 1 -C 3  alkylene. 
     
     
         82 . The compound of  claim 1 , wherein L 1  is a branched unsubstituted C 1 -C 5  alkylene. 
     
     
         83 . The compound of  claim 1 , wherein L 2  is unsubstituted C 1 -C 5  alkylene. 
     
     
         84 . The compound of  claim 1 , wherein L 2  is methylene. 
     
     
         85 . The compound of  claim 1 , wherein if R 1  is —NR 8 R 9  and R 8  is —S(O) 2 R 14 , then R 6  is hydrogen. 
     
     
         86 . The compound of  claim 85 , wherein R 7  is unsubstituted C 1 -C 5  alkyl. 
     
     
         87 . The compound of  claim 85 , wherein R 2  and R 3  are hydrogen. 
     
     
         88 . The compound of  claim 1 , wherein if R 1  is hydrogen, then R 6  is not hydrogen. 
     
     
         89 . The compound of  claim 88 , wherein R 6  is unsubstituted C 1 -C 5  alkyl. 
     
     
         90 . The compound of  claim 89 , wherein R 7  is hydrogen. 
     
     
         91 . The compound of  claim 90 , wherein R 2  and R 3  are hydrogen. 
     
     
         92 . The compound of  claim 1  which is: 
       N1-(3-hydroxy-1-phenyl-4-((tetrahydrofuran-2-yl)methylamino)butan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-(2-morpholinoethylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(4-(1-cyclohexylethylamino)-3-hydroxy-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       benzyl 4-((2-hydroxy-3-(3-(N-methylmethylsulfonamido)-5-(1-phenylethylcarbamoyl)benzamido)-4-phenylbutylamino)methyl)piperidine-1-carboxylate; 
       N1-(3-hydroxy-1-phenyl-4-(2-(pyrrolidin-1-yl)ethylamino)butan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-1-phenyl-4-(2-(piperidin-1-yl)ethylamino)butan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-1-phenyl-4-(piperidin-4-ylmethylamino)butan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-1-phenyl-4-(piperidin-3-ylmethylamino)butan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-1-phenyl-4-(2-(pyrrolidin-1-yl)ethylamino)butan-2-yl)-N3-methyl-N3-((4-methylthiazol-2-yl)methyl)isophthalamide; 
       N1-(3-hydroxy-4-((1-methylpiperidin-3-yl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-((1-methylpyrrolidin-2-yl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-((1-isopropylpyrrolidin-2-yl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-((3-methoxycyclohexyl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-((1-isobutylpiperidin-4-yl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-((1-(2-methoxybenzyl)piperidin-4-yl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide; 
       N1-(3-hydroxy-4-((1-(3-methoxybenzyl)piperidin-4-yl)methylamino)-1-phenylbutan-2-yl)-5-(N-methylmethylsulfonamido)-N3-(1-phenylethyl)isophthalamide;
 or a pharmaceutically acceptable salt, prodrug, hydrate, racemate, diastereomer, tautomer, isotope, or crystalline form thereof. 
 
     
     
         93 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.