Anti-pcsk9 compounds and methods for the treatment and/or prevention of cardiovascular diseases

Abstract

Disclosed are compounds that modulate the physiological action of the proprotein convertase subtilisin kexin type 9 (PCSK9), and methods of using these modulators to reduce LDL-cholesterol levels and/or for the treatment and/or prevention of cardiovascular disease (CVD), including treatment of hypercholesterolemia.

What is claimed is: 
     
         1 . A method for treating or preventing hypercholesterolemia, and/or at least one symptom of dyslipidemia, atherosclerosis, CVD or coronary heart disease in a patient in need of said treatment, the method comprising administering to said patient a therapeutically effective amount of at least one compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1 , R 2  and R 3  are independently selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         X is O or NR 4 ; wherein R 4  is H, lower alkyl, or optionally taken together with Q or R 1  and the atoms to which each is attached forms an optionally substituted 5- or 6-membered heterocycle ring; 
         A is CO, CONR 5 , SO 2 , C(═O)—O or a valence bond to R 1 ; wherein R 5  is H or lower alkyl; 
         M is CO or CR 6 R 7 ; wherein R 6  and R 7  are independently H, lower alkyl, a bond to Q, or optionally taken together with R 3  and the atoms to which each is attached forms an optionally substituted aryl, heteroaryl, or heterocycle ring; and 
         Q is O or NR 8 ; wherein R 8  is H, lower alkyl, or optionally when X is NR 4  and Q is NR 8 , R 4  and R 8  and the nitrogen atom to which each of R 4  and R 8  is attached complete an optionally substituted 5- or 6-membered heterocycle ring, as represented by —(CR a ) n —, wherein R a  represents H or lower alkyl and n=1 or 2; and 
         the pharmaceutically acceptable salts and all stereoisomers of the compound. 
       
     
     
         2 . The method of  claim 1 , wherein said patient is administered at least one compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are the same or different and each represents hydrogen or a substituent selected from the group consisting of hydroxyl, halogen, amino, alkoxy, carboxy, amido, formamido, alkylamido, arylamido, aminocarbonyl amino, monoalkylaminocarbonylamino, dialkylaminocarbonylamino, carbamato, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, di alkylaminosulfonyl, alkyl sulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkyl sulfonyl alkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         X is O or NR 4 ; wherein R 4  is selected from the group consisting of H and lower alkyl; and 
         A is CO, CONR 5 , SO 2 , C(═O)—O or a valence bond to R 1 ; wherein R 5  is H or lower alkyl. 
       
     
     
         3 . The method of  claim 2 , wherein said patient is administered at least one compound of formula (III): 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are the same or different and each represents hydrogen or a substituent selected from the group consisting of hydroxy, halogen, amino, alkoxy, carboxy, amido, formamido, alkylamido, arylamido, aminocarbonyl amino, monoalkylaminocarbonylamino, dialkylaminocarbonylamino, carbamato, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, di alkylaminosulfonyl, alkyl sulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkyl sulfonyl alkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; and 
         R 9  is selected from the group consisting of H, OR 10 , and NR 10 R 11 ; wherein R 10  and R 11  are independently selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, aryl, heteroaryl, or heterocycle, or taken together form an optionally substituted heterocycle. 
       
     
     
         4 . The method of  claim 2 , wherein said patient is administered at least one compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are the same or different and each represent hydrogen or a substituent selected from the group consisting of hydroxy, halogen, amino, alkoxy, carboxy, amido, formamido, alkylamido, arylamido, aminocarbonyl amino, monoalkylaminocarbonylamino, dialkylaminocarbonylamino, carbamato, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, di alkylaminosulfonyl, alkyl sulfonylamino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkyl sulfonyl alkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; and 
         R 9  is selected from the group consisting of H, OR 10 , and NR 10 R 11 ; wherein R 10  and R 11  are independently selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, aryl, heteroaryl, or heterocycle, or taken together form an optionally substituted heterocycle. 
       
     
     
         5 . The method of  claim 2 , wherein said patient is administered at least one compound of formula (V): 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are the same or different and each represents hydrogen or a substituent selected from the group consisting of hydroxy, halogen, amino, alkoxy, carboxy, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkyl sulfonyl amino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; and 
         R 9  is selected from the group consisting of H, OR 10 , and NR 10 R 11 ; wherein R 10  and R 11  are independently selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, aryl, heteroaryl, or heterocycle, or taken together form an optionally substituted heterocycle. 
       
     
     
         6 . The method of  claim 1 , wherein said patient is administered at least one compound of formula (VI): 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are the same or different and each represents hydrogen or a substituent selected from the group consisting of hydroxy, halogen, amino, alkoxy, carboxy, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkyl sulfonyl amino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         R 12  is selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         A is CO or SO 2 ; and 
         Y is H 2  or O. 
       
     
     
         7 . The method of  claim 6 , wherein said patient is administered at least one compound of e formula (VII): 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , Y 1  and Z 1  are the same or different and each represents hydrogen or a substituent selected from the group consisting of hydroxy, halogen, amino, alkoxy, carboxy, carboxamido, monoalkylaminosulfinyl, dialkylaminosulfinyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, alkyl sulfonyl amino, hydroxysulfonyloxy, alkoxysulfonyloxy, alkylsulfonyloxy, hydroxysulfonyl, alkoxysulfonyl, alkylsulfonylalkyl, monoalkylaminosulfonylalkyl, dialkylaminosulfonylalkyl, monoalkylaminosulfinylalkyl, dialkylaminosulfinyl and, optionally substituted, lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         R 12  is selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl; 
         R 13  is selected from the groups consisting of H, OR 14 , and NR 14 R 15 ; wherein R 14  and R 15  are independently selected from the group consisting of H and optionally substituted lower alkyl, alkenyl, aryl, heteroaryl, or heterocycle, or taken together when attached to a nitrogen atom form an optionally substituted heterocycle; 
         A is CO or SO 2 ; and 
         Y is H 2  or O. 
       
     
     
         8 . The method of  claim 2 , wherein the compound is selected from the group consisting of [(3-chloro-4-methylphenyl)carbamoyl](phenyl)methyl 4-(carbamoylamino)benzoate (SBC-110,686); N-(3-chloro-4-methylphenyl)-2-[(4-acetamidophenyl)formamido]-2-phenylacetamide (SBC-110,720); and [(3-chloro-4-methylphenyl)carbamoyl](phenyl)methyl 4-acetamidobenzoate (SBC-110,721). 
     
     
         9 . The method of  claim 2 , wherein the compound is N-{4-[4-(4-methylphenyl)-2-phenylpiperazine-1-carbonyl]phenyl}acetamide (SBC-110,736) or {4-[4-(3-chloro-4-methylphenyl)-2-phenylpiperazine-1-carbonyl]phenyl}urea (SBC-110,733). 
     
     
         10 . The method of  claim 2 , further comprising administering to said patient a therapeutically effective amount of a low density lipoprotein (LDL) lowering drug. 
     
     
         11 . The method of  claim 10 , wherein said LDL lowering drug is a statin. 
     
     
         12 . The method of  claim 6 , further comprising administering to said patient a therapeutically effective amount of a low density lipoprotein (LDL) lowering drug. 
     
     
         13 . The method of  claim 12 , wherein said LDL lowering drug is a statin.