Spirocyclic dihydro-thiazine and dihydro-oxazine bace inhibitors, and compositions and uses thereof

Abstract

Compounds are provided having a structure according to Formula (I): wherein A 1 , A 2 , A 3 , Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n and p are defined herein. Further provided are pharmaceutical compositions including the compounds provided and methods of making and using the compounds and compositions as provided, e.g., in the treatment and prevention of various disorders, such as Alzheimer's disease.

1 : A compound having a structure according to Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically accept able salt thereof, wherein:
 Y is S; 
 L is —NR 9 —; 
 A 1  is a C 3-10  carbocyclic ring or a 3 to 10 membered heterocyclic ring; 
 A 2  is phenyl, naphthyl, or a heteroaryl ring; 
 A 3  is phenyl, naphthyl, or a heteroaryl ring; 
 R 1  is hydrogen, C 1-6  alkyl, or combines with R 2  to form a fused monocyclic C 3-7  carbocyclic ring or a 3 to 7 membered heterocyclic ring; 
 R 2  and R 3  are independently hydrogen or halogen, or R 3  is hydrogen and R 2  combines with R 1  to form a fused monocyclic C 3-7  carbocyclic ring or a 3 to 7 membered heterocyclic ring; 
 R 4  at each occurrence is independently selected from the group consisting of halogen, —CN, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, —OH, ═O, —OR 12 , —S(O) z R 12 , —C(O)R 12 , —NR 13 R 14 , and ═NR 14 , wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , or optionally fluoro substituted C 3-6  cycloalkyl; 
 R 5  and R 6  at each occurrence are independently selected from the group consisting of halogen, —CN, —OH, —NH 2 , —NO 2 , —C(O)—OH, —C(O)—NH 2 , —S(O) 2 —NH 2 , and L 1 -R 15 ; 
 R 9  is selected from the group consisting of hydrogen and C 1-6  alkyl; 
 L 1  at each occurrence is independently selected from the group consisting of a direct bond, —C(O)—, —O—, —S(O) Z , —NR 16 —, —C(O)—O—, —O—C(O)—, —C(O)—NR 16 —, —NR 16 —C(O)—, —S(O) 2 —NR 16 —, and —NR 16 —S(O) 2 —; 
 R 12  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl; 
 R 13  and R 14  at each occurrence are independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl or R 13  and R 14  combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 1-6  alkyl, optionally fluoro substituted C 2-6  alkenyl, optionally fluoro substituted C 2-6  alkynyl, and optionally fluoro substituted C 3-6  cycloalkyl; 
 R 15  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of —CN, —OH, —NO2, —C(O)—OH, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, —OR 17 , —S(O) z R 17 , —NR 18 R 19 , —C(O)R 17 , —C(O)—OR 17 , —O—C(O)R 17 , —C(O)—NR 18 R 19 , —NR 16 —C(O)R 17 , —S(O) 2 —NR 18 R 19 , and —NR 16 —S(O) 2 R 17 , and wherein C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, as R 15  or as a substituent of phenyl, naphthyl, or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO 2 , —C(O)—OH, C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, —OR 17 , —S(O) z R 17 , ═NR 17 , —NR 18 R 19 , —C(O)R 17 , —C(O)—OR 17 , —O—C(O)R 17 , —C(O)—NR 18 R 19 , —NR 16 —C(O)R 17 , —S(O) 2 —NR 18 R 19 , and —NR 16 —S(O) 2 R 17 ; 
 R 16  at each occurrence is independently selected from the group consisting of hydrogen C 1-6  alkyl; 
 R 17  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl; 
 R 18  and R 19  at each occurrence are independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl, or R 18  and R 19  combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , optionally fluoro substituted C 1-6  alkyl, optionally fluoro substituted C 2-6  alkenyl, optionally fluoro substituted C 2-6  alkynyl, and optionally fluoro substituted C 3-6  cycloalkyl; R a  and R b  at each occurrence are independently selected from the group consisting of optionally fluoro substituted C 1-6  alkyl, optionally fluoro substituted C 2-6  alkenyl, optionally fluoro substituted C 2-6  alkynyl, and optionally fluoro substituted C 3-6  cycloalkyl, or R a  and R b  combine with the nitrogen to which they are attached to form N-linked-heterocycloalkyl; 
 m is 0, 1, or 2; 
 n is 0, 1, 2, or 3; 
 p is 0, 1, 2, or 3; and 
 z is 0, 1, or 2. 
 
     
     
         2 . The compound of  claim 1 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is O or S(O) 2 , 
 r is 0, 1, or 2; and 
 s is 0, 1, or 2. 
 
     
     
         3 . The compound of  claim 2 , wherein X is O. 
     
     
         4 . The compound of  claim 3 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein A 1  is 3 to 10 membered heterocyclic ring. 
     
     
         6 . The compound of  claim 1 , wherein A 2  is phenyl. 
     
     
         7 . The compound of  claim 1 , wherein A 3  is a heteroaryl ring. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is a C 1-6  alkyl. 
     
     
         9 . The compound of  claim 1 , wherein R 2  and R 3  are independently hydrogen or a halogen. 
     
     
         10 . The compound of  claim 1 , wherein R 4  at each occurrence is a halogen. 
     
     
         11 . The compound of  claim 1 , wherein R 6  at each occurrence L 1 -R 15 . 
     
     
         12 . The compound of  claim 11 , wherein L 1  is —O— and R 15  is a C 1-6  alkyl. 
     
     
         13 . The compound of  claim 1 , wherein R 9  is hydrogen. 
     
     
         14 . The compound of  claim 1 , wherein m is 1 or 2. 
     
     
         15 . The compound of  claim 1 , wherein n is 1 and R 5  is a halogen. 
     
     
         16 . The compound of  claim 1 , wherein p is 1 and R 6  is L 1 -R 15 , wherein L 1  is —O— and R 15  is methyl. 
     
     
         17 . The compound of  claim 2 , wherein X is O; r is 0; s is 0; A 2  is phenyl; and A 3  is pyridinyl. 
     
     
         18 . The compound of  claim 16 , wherein n is 1 and R 5  is a halogen. 
     
     
         19 . A compound having a structure according to Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically accept able salt thereof, wherein:
 Y is S; 
 L is —NR 9 —C(O)—; 
 A 1  is a C 3-10  carbocyclic ring or a 3 to 10 membered heterocyclic ring; 
 A 2  is phenyl, naphthyl, or a heteroaryl ring; 
 A 3  is phenyl, naphthyl, or a heteroaryl ring; 
 R 1  is hydrogen, C 1-6  alkyl, or combines with R 2  to form a fused monocyclic C 3-7  carbocyclic ring or a 3 to 7 membered heterocyclic ring; 
 R 2  and R 3  are independently hydrogen or halogen, or R 3  is hydrogen and R 2  combines with R 1  to form a fused monocyclic C 3-7  carbocyclic ring or a 3 to 7 membered heterocyclic ring; 
 R 4  at each occurrence is independently selected from the group consisting of halogen, —CN, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-6  cycloalkyl, —OH, ═O, —OR 12 , —S(O) z R 12 , —C(O)R 12 , —NR 13 R 14 , and ═NR 14 , wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , or optionally fluoro substituted C 3-6  cycloalkyl; 
 R 5  and R 6  at each occurrence are independently selected from the group consisting of halogen, —CN, —OH, —NH 2 , —NO 2 , —C(O)—OH, —C(O)—NH 2 , —S(O) 2 —NH 2 , and L 1 -R 15 ; 
 R 9  is selected from the group consisting of hydrogen and C 1-6  alkyl; 
 L 1  at each occurrence is independently selected from the group consisting of a direct bond, —C(O)—, —O—, —S(O) Z , —NR 16 —, —C(O)—O—, —O—C(O)—, —C(O)—NR 16 —, —NR 16 —C(O)—, —S(O) 2 —NR 16 —, and —NR 16 —S(O) 2 —; 
 R 12  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl; 
 R 13  and R 14  at each occurrence are independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl or R 13  and R 14  combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteroaryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 1-6  alkyl, optionally fluoro substituted C 2-6  alkenyl, optionally fluoro substituted C 2-6  alkynyl, and optionally fluoro substituted C 3-6  cycloalkyl; 
 R 15  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, naphthyl, and heteroaryl, wherein phenyl, naphthyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of —CN, —OH, —NO2, —C(O)—OH, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5 or 6 membered heteroaryl, —OR 17 , —S(O) z R 17 , —NR 18 R 19 , —C(O)R 17 , —C(O)—OR 17 , —O—C(O)R 17 , —C(O)—NR 18 R 19 , —NR 16 —C(O)R 17 , —S(O) 2 —NR 18 R 19 , and —NR 16 —S(O) 2 R 17 , and wherein C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, as R 15  or as a substituent of phenyl, naphthyl, or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —CN, —OH, ═O, ═NH, —NO 2 , —C(O)—OH, C 3-6  cycloalkyl, 3-7 membered heterocycloalkyl, —OR 17 , —S(O) z R 17 , ═NR 17 , —NR 18 R 19 , —C(O)R 17 , —C(O)—OR 17 , —O—C(O)R 17 , —C(O)—NR 18 R 19 , —NR 16 —C(O)R 17 , —S(O) 2 —NR 18 R 19 , and —NR 16 —S(O) 2 R 17 ; 
 R 16  at each occurrence is independently selected from the group consisting of hydrogen C 1-6  alkyl; 
 R 17  at each occurrence is independently selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl; 
 R 18  and R 19  at each occurrence are independently selected from the group consisting of hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl, wherein said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, and C 3-6  cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of fluoro, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , and optionally fluoro substituted C 3-6  cycloalkyl, or R 18  and R 19  combine with the nitrogen to which they are attached to form a 4-7 membered monocyclic heterocyclic ring or a 5 or 7 membered heteraoryl ring, wherein said ring is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —CN, ═O, —OH, —NH 2 , —OR a , —S(O) z R a , —C(O)R a , —NHR a , —NR a R b , optionally fluoro substituted C 1-6  alkyl, optionally fluoro substituted C 2-6  alkenyl, optionally fluoro substituted C 2-6  alkynyl, and optionally fluoro substituted C 3-6  cycloalkyl; R a  and R b  at each occurrence are independently selected from the group consisting of optionally fluoro substituted C 1-6  alkyl, optionally fluoro substituted C 2-6  alkenyl, optionally fluoro substituted C 2-6  alkynyl, and optionally fluoro substituted C 3-6  cycloalkyl, or R a  and R b  combine with the nitrogen to which they are attached to form N-linked-heterocycloalkyl; 
 m is 0, 1, or 2; 
 n is 0, 1, 2, or 3; 
 p is 0, 1, 2, or 3; and 
 z is 0, 1, or 2. 
 
     
     
         20 . The compound of  claim 19 , wherein the compound has the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 X is O or S(O) 2 ; 
 r is 0, 1, or 2; and 
 s is 0, 1, or 2. 
 
     
     
         21 . The compound of  claim 20 , wherein X is O. 
     
     
         22 . The compound of  claim 21 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 19 , wherein A 1  is 3 to 10 membered heterocyclic ring. 
     
     
         24 . The compound of  claim 19 , wherein A 2  is phenyl. 
     
     
         25 . The compound of  claim 19 , wherein A 3  is a heteroaryl ring. 
     
     
         26 . The compound of  claim 19 , wherein R 1  is a C 1-6  alkyl. 
     
     
         27 . The compound of  claim 19 , wherein R 2  and R 3  are independently hydrogen or a halogen. 
     
     
         28 . The compound of  claim 19 , wherein R 4  at each occurrence is a halogen. 
     
     
         29 . The compound of  claim 19 , wherein R 5  at each occurrence is a halogen. 
     
     
         30 . The compound of  claim 19 , wherein R 6  at each occurrence is a halogen. 
     
     
         31 . The compound of  claim 19 , wherein R 9  is hydrogen. 
     
     
         32 . The compound of  claim 19 , wherein m is 1 or 2. 
     
     
         33 . The compound of  claim 19 , wherein n is 1 and R 5  is a halogen. 
     
     
         34 . The compound of  claim 19 , wherein p is 1 and R 6  is a halogen. 
     
     
         35 . The compound of  claim 20 , wherein X is O; r is 0; s is 0; A 2  is phenyl; and A 3  is pyridinyl. 
     
     
         36 . The compound of  claim 20 , wherein n and p are each 1, and R 5  and R 6  are each a halogen.