Thiazole sulfonamide compounds for the treatment of neurodegenerative disorders

Abstract

The present invention relates to compounds of the Formula: wherein R 1 to R 6 , X, Z and A are as defined. These compounds have activity inhibiting production of Aβ-peptide. The invention also relates to pharmaceutical compositions and methods for treating diseases, for example, neurodegenerative diseases, e.g., Alzheimer's disease, in a mammal comprising compounds of the present Formula.

1 - 22 . (canceled)  
     
     
         23 . A compound of the Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is (C 6 -C 14 ) aryl, or -(5-14 membered) heteroaryl, wherein said aryl and heteroaryl are each optionally substituted with one or more (C 0 -C 4  alkylene)-R 13 ;  
 R 2  and R 3  are independently selected from the group consisting of: —H, a straight or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8  cycloalkyl, C 6 -C 14  aryl and (5-14 membered) heteroaryl, wherein said alkyl, alkenyl and alkynyl are each optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —Br, —OH, C 1 -C 4  alkoxy, and —S—(C 1 -C 4 )alkyl, and wherein said aryl and heteroaryl are each optionally substituted with one or more (C 0 -C 4  alkylene)-R 13 ; or R 2  and R 3  taken together form a C 3 -C 8  cycloalkyl;  
 R 4  is C 6 -C 14  aryl or (5-14 membered) heteroaryl substituted with one or more (C 0 -C 4  alkylene)-R 13 ;  
 R 5  and R 6  are independently selected from the group consisting of: —H, —F, —Cl, —Br, —CN, —CHO, —NO 2 , —C(═O)NR 9 R 10 , —C(═O)OR 10 , —NR 9 R 10 , —NR 9 C(═O)R 10 , —NR 9 C(═O)OR 1 , and NR 9 C(═O)NR 9 R 10 ;  
 or R 5  and R 6  are independently a straight or branched C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, (C 0 -C 6  alkylene)-(C 3 -C 12  cycloalkyl), or (C 0 -C 6  alkylene)-(C 3 -C 12  heterocycloalkyl), wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl and heteroalkyl are each optionally substituted with one or more (C 0 -C 6  alkylene)-R 7 ; or R 5  and R 6  are independently (C 0 -C 6  alkylene)-(C 6 -C 14  aryl) or (C 0 -C 6  alkylene)-(5-14 membered heteroaryl), wherein said aryl and heteroaryl are each optionally substituted with one or more R 7  and wherein said alkylene is optionally substituted with one or more (C 0 -C 6  alkylene)-R 8 ; or R 5  and R 6 , when attached to the adjacent carbon atoms of the thiazole ring, together form a (4-8 membered) cycloalkyl, (4-8 membered)-heterocycloalkyl, or C 6 -C 10  aryl wherein said cycloalkyl and heteroalkyl are each substituted with one or more (C 0 -C 6  alkylene)-R 8 , (C 0 -C 6  alkylene)-(C 6 -C 14  aryl), and (C 0 -C 6 -alkylene)-(5-14 membered heteroaryl), wherein said aryl or heteroaryl are each optionally substituted with one or more R 7 ;  
 Z is a bond or a straight or branched C 1 -C 6  alkylene, wherein each hydrogen atom of said alkylene is optionally independently replaced with a fluorine;  
 X is O or S;  
 R 7  is —F, —Cl, —Br, —OH, —CN, —CHO, —NO 2 , —NR 9 R 10 , —NR 9 C(═O)R 10 , —NR 9 C(═O)NR 9 R 10 , —NR 9 C(═O)OR 10 , —OC(═O)—R 9 , —OC(═O)NR 9 R 10 , —C(═O)NR 9 R 10 , —C(═O)OR 10 , —SO 2 NR 9 R 10 , —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl-C 3 -C 8 cycloalkyl, —C 3 -C 8  heterocycloalkyl, —C 1 -C 6  alkoxy, —(C 6 -C 14 ) aryloxy, -(5-14 membered) heteroaryloxy, —(C 0 -C 4  alkylene)-(C 6 -C 14 ) aryl, or —(C 0 -C 4  alkylene)-(5-14 membered) heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are each optionally substituted with one or more R 8 , and wherein each hydrogen atom of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl and alkoxy is optionally independently replaced with a fluorine;  
 R 8  is —F, —Cl, —Br, —CN, —CHO, —OR 9 , —OC(═O)—R 9 , —OC(═O)NR 9 R 10 , —NO 2 , —NR 9 R 10 , —NR 9 C(═O)R 10 —NR 9 C(═O)NR 9 R 10 , —NR 9 C(═O)OR 10 —C(═O)NR 9 R 10 , —SO 2 NR 9 R 10 , —C(═O)R 10  or —C(═O)OR 10 ;  
 R 9  and R 10  are —H, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —(C 0 -C 4  alkylene)-(C 3 -C 8  cycloalkyl), —(C 0 -C 4 alkylene)-(C 6 -C 14  aryl), —(C 0 -C 4  alkylene)-(3-8 membered heterocycloalkyl), or —(C 0 -C 4  alkylene)-(5-14 membered heteroaryl), wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl are each optionally independently substituted with one or more substituents independently selected from the group consisting of —F, —Cl, —Br, —CN, —CHO, —OH, —NO 2 , —NR 11 R 12 , —C(═)ONR 11 R 12 , —C(═O)R 11 , —C(═O)OR 12 , —SO 2 NR 11 R 12 , —C 1 -C 6  alkyl, —C 1 -C 6  alkoxy, —C 1 -C 6  hydroxyalkyl, —(C 0 -C 4 )—(C 6 -C 14 ) aryl), and —(C 0 -C 4 )-(5-14 membered heteroaryl);  
 or R 9  and R 10  with nitrogen forms a 4-8 membered heterocycloalkyl moiety, wherein said heterocycloalkyl is optionally substituted with one or more substitutents selected from the group consisting of —F, —Cl, —Br, —CN, —CHO, —OH, —NO 2 , —NR 11 R 12 , —C(═)ONR 11 R 12 , —C(═O)R 11 —C(═O)OR 12 —SO 2 NR 11 R 12 , —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 1 -C 6  alkoxy, —C 3 -C 8  cycloalkyl, C 3 -C 8  heterocycloalkyl, C 6 -C 10  aryl, and 5-14 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are each optionally substituted with F, —Cl, —Br, —CN, —OR 11 , —OC(═O)—R 11 , —OC(═O)NR 11 R 12 , —NO 2 , —NR 11 R 12 , —NR 11 C(═O)R 12 —NR 11 C(═O)NR 11 R 12 , —NR 11 C(═O)OR 12 , —C(═O)NR 11 R 12 , —SO 2 NR 11 R 12 , —C(═O)R 11 , or —C(═O)OR 11 ;  
 R 11  and R 12  are hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 14  aryl or 5-14 membered heteroaryl, wherein said alkyl, alkenyl, alkynyl, aryl and heteroaryl are each optionally independently substituted with from one to three substituents independently selected from the group consisting of —OH, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 1 -C 6  alkoxy, —C 2 -C 6  alkenoxy, —C 2 -C 6  alkynoxy, —C 1 -C 6  hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1 -C 6  alkyl), —C(═O)N(C 1 -C 6  alkyl) 2 , —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —C(═O)H, —C(═O)OH and —C(═O)O(C 1 -C 6  alkyl), wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms;  
 or R 11  and R 12  with nitrogen taken together form a 4-8 membered heterocycloalkyl, wherein said heterocycloalkyl is optionally independently substituted with from one to three substituents independently selected from the group consisting of —OH, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 1 -C 6  alkoxy, —C 2 -C 6  alkenoxy, —C 2 -C 6  alkynoxy, —C 1 -C 6  hydroxyalkyl, —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2 , —C(═O)NH 2 , —C(═O)NH(C 1 -C 6  alkyl), —C(═O)N(C 1 -C 6  alkyl) 2 , —SO 2 NH 2 , —SO 2 NH(C 1 -C 6  alkyl), —SO 2 N(C 1 -C 6  alkyl) 2 , —C(═O)H, —C(═O)OH and —C(═O)O(C 1 -C 6  alkyl), wherein said alkyl, alkenyl and alkynyl substituents are each optionally independently further substituted with from one to six fluorine atoms; and  
 R 13  is —F, —Cl, —Br, —CN, —CHO, —OH, —NO 2 , —NR 11 R 12 , —C(═)ONR 11 R 12 , —C(═O)R 11 —C(═O)OR 12 —SO 2 NR 11 R 12 , —C 1 -C 6  alkyl, —C 1 -C 6  alkoxy, —C 3 -C 8  cycloalkyl, 4-8 membered heterocycloalkyl, C 6 -C 10  aryl or 5-14 membered heteroaryl, wherein each hydrogen atom of said alkyl, alkoxy, cycloalkyl and heterocycloalkyl is optionally independently replaced with a fluorine; or  
 a pharmaceutically acceptable salt thereof.  
 
     
     
         24 . A compound according to  claim 23 , wherein Z is a bond, or a pharmaceutically acceptable salt thereof.  
     
     
         25 . A compound according to  claim 23 , wherein Z is methylene, or a pharmaceutically acceptable salt thereof.  
     
     
         26 . A compound according to  claim 23 , wherein R 2  is hydrogen and R 3  is independently selected from the group consisting of —H, a straight or branched C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6  alkynyl, C 6 -C 14  aryl and (5-14 membered) heteroaryl, or a pharmaceutically acceptable salt thereof.  
     
     
         27 . A compound according to  claim 23 , wherein X is S or a pharmaceutically acceptable salt thereof.  
     
     
         28 . A compound according to  claim 27 , wherein  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         29 . A compound according to  claim 27 , wherein  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
     
         30 . A pharmaceutical composition for treating a disease or condition associated with the modulation of the Notch signaling pathway, comprising a compound according to  claim 23 , or a pharmaceutically acceptable salt thereof.  
     
     
         31 . The composition of  claim 30 , wherein the disease or condition is cancer.  
     
     
         32 . A method of treating a disease or condition selected from the group consisting of cancer, arteriosclerosis, diabetic retinopathy, rheumatoid arthritis, psoriasis, inflammatory bowel disease, inflammation, asthma, graft rejection, graft versus host disease, autoimmune disease and transplant rejection, comprising administering to said mammal an amount of a compound according to  claim 23  that is effective in modulating Notch signaling pathway to treat such disease or condition.  
     
     
         33 . A method according to  claim 32 , wherein said disease or condition is cancer.