Alpha helix mimetics and methods relating thereto

Abstract

Alpha-helix mimetic structures and compounds represented by the formula (I) wherein the general formula and the definition of each symbol are as defined in the specification, a chemical library relating thereto, and methods relating thereto, are disclosed. Applications of these compounds in the treatment of medical conditions, e.g., cancer diseases, fibrotic diseases, and pharmaceutical compositions comprising the mimetics are further disclosed.

1 . A compound having the following general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
            is single bond or double bond; 
         A is —CHR 7 —,
 wherein 
 R 7  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
 
         E is bond, —CHR 5 —, —O— or —NR 8 —,
 wherein 
 R 5  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 R 8  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
 
         B is void or optionally substituted monocyclic ring formed together with G and Y; 
         D is void or optionally substituted spiro ring formed together with Y; 
         with the proviso that 
         B and D are not both present, 
         when B is present, then G and Y are independently carbon atom or nitrogen atom, 
         when D is present, then Y is carbon atom and G is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —, 
         when both B and D are void, then G and Y are the same or different and each is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —,
 wherein 
 each R 6  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 
         when E is bond, then D is void, B is optionally substituted monocyclic ring, and G and Y are independently carbon atom or nitrogen atom; 
         R 1  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
         R 2  is —W 21 —W 22 —Rb—R 20 ,
 wherein 
 W 21  is —(CO)— or —(SO 2 )—, 
 W 22  is bond, —O—, —NH— or optionally substituted lower alkylene, 
 Rb is bond or optionally substituted alkylene, and 
 R 20  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and 
 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
         with the proviso that 
         when D is void, E is bond, B is benzene, and R 2  is —W 21 —W 22 —Rb—R 20 , wherein W 21  is —(CO)—, W 22  is —NH—, and Rb is bond, then R 20  should not be optionally substituted phenyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound of  claim 1 ,
 wherein      is single bond or double bond;   A is —CHR 7 —,
 wherein 
 R 7  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
   E is —CHR 5 —, —O— or —NR 8 —,
 wherein 
 R 5  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 R 8  is hydrogen or optionally substituted alkyl; 
   B is void or optionally substituted monocyclic ring formed together with G and Y;   D is void or optionally substituted spiro ring formed together with Y;   with the proviso that   B and D are not both present,   when B is present, then G and Y are independently carbon atom or nitrogen atom,   when D is present, then Y is carbon atom and G is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —, and   when both B and D are void, then G and Y are the same or different and each is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —,
 wherein 
 each R 6  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; 
   R 1  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl;   R 2  is —W 21 —W 22 —Rb—R 20 ,
 wherein 
 W 21  is —(CO)— or —(SO 2 )—, 
 W 22  is bond, —O—, —NH— or optionally substituted lower alkylene, 
 Rb is bond or optionally substituted alkylene, and 
 R 20  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and 
   R 3  is hydrogen or optionally substituted alkyl.   
     
     
         3 . The compound of  claim 1 , which has the following general formula (I-d): 
       
         
           
           
               
               
           
         
         wherein 
            is single bond or double bond; 
         A is —(CHR 7 )—;
 wherein 
 R 7  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
 
         B is optionally substituted monocyclic ring; 
         G is carbon atom or nitrogen atom; 
         R 1  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
         R 2  is —W 21 —W 22 —Rb—R 20 ,
 wherein 
 W 21  is —(CO)— or —(SO 2 )—, 
 W 22  is bond, —O—, —NH— or optionally substituted lower alkylene, 
 Rb is bond or optionally substituted lower alkylene, and 
 R 20  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and 
 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
         with the proviso that 
         when B is benzene, and R 2  is —W 21 —W 22 —Rb—R 20 , wherein W 21  is —(CO)—, W 22  is —NH—, and Rb is bond, then R 20  should not be optionally substituted phenyl. 
       
     
     
         4 . The compound of  claim 1 ,
 wherein   D is void; and   B is optionally substituted 3-, 4-, 5-, 6- or 7-membered saturated or unsaturated mono cyclic ring formed together with G and Y.   
     
     
         5 . The compound of  claim 1 ,
 wherein   D is void; and   B is optionally substituted 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y and the hetero atom is selected from S, N and O and the number of hetero atoms is an integer of 1-3.   
     
     
         6 . The compound of  claim 1 ,
 wherein   both B and D are void; and   at least one of G and Y is —NR 6′ —, —CHR 6′ — or —C(R 6′ ) 2 —,
 wherein 
 each R 6′  is independently hydrogen, optionally substituted cyclic or noncyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl. 
   
     
     
         7 - 21 . (canceled) 
     
     
         22 . The compound of  claim 1 ,
 wherein   E is bond, —CHR 5 —, —O— or —NR 8 —,
 wherein 
 R 5  is lower alkyl, lower alkenyl, lower alkynyl or lower arylalkyl; and 
 R 8  is hydrogen or alkyl. 
   
     
     
         23 . The compound of  claim 22 ,
 D is void; and   B is optionally substituted 3-, 4-, 5-, 6- or 7 membered saturated or unsaturated heterocyclic ring formed together with G and Y.   
     
     
         24 . The compound of  claim 22 ,
 wherein   both B and D are void, and   at least one of G and Y is —NR 6′ —, —CHR 6′ — or —C(R 6′ ) 2 —,
 wherein 
 each R 6′  is independently hydrogen, optionally substituted, cyclic or non-cyclic lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl. 
   
     
     
         25 - 32 . (canceled) 
     
     
         33 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or diluent. 
     
     
         34 - 36 . (canceled) 
     
     
         37 . A method of treating or preventing a disease or condition selected from the group consisting of cancer, fibrosis, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, tuberous sclerosis complex (TSC), KSHV-associated tumor, hair loss, and Alzheimer's disease, comprising administering to a subject in need thereof a compound according to  claim 1  or a pharmaceutically acceptable salt thereof in an amount effective to treat or prevent said disease or condition. 
     
     
         38 - 46 . (canceled) 
     
     
         47 . A compound having the following general formula (II): 
       
         
           
           
               
               
           
         
         wherein 
            is single bond or double bond; 
         A is —CHR 7 —,
 wherein 
 R 7  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
 
         E is bond, —CHR 5 —, —O— or —NR 8 —,
 wherein 
 R 5  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 R 8  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
 
         B is void or optionally substituted monocyclic ring formed together with G and Y; 
         D is void or optionally substituted spiro ring formed together with Y; 
         with the proviso that 
         B and D are not both present, 
         when B is present, then G and Y are independently carbon atom or nitrogen atom, 
         when D is present, then Y is carbon atom and G is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —, 
         when both B and D are void, then G and Y are the same or different and each is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —,
 wherein 
 each R 6  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 
         when E is bond, then D is void, B is optionally substituted monocyclic ring, and G and Y are independently carbon atom or nitrogen atom; 
         R 1  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
         R 2  is —W 21 —W 22 —Rb—R 20 , 
         wherein 
         W 21  is —(CO)— or —(SO 2 )—, 
         W 22  is bond, —O—, —NH— or optionally substituted lower alkylene, 
         Rb is bond or optionally substituted alkylene, and 
         R 20  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
         R 91  is selected from optionally substituted alkyl, linker and solid support; and 
         R 92  is selected from optionally substituted alkyl, linker and solid support; 
         with the proviso that 
         when D is void, E is bond, B is benzene, and R 2  is —W 21 —W 22 —Rb—R 20 , wherein W 21  is —(CO)—, W 22  is —NH—, and Rb is bond, then R 20  should not be optionally substituted phenyl; 
         or a salt thereof. 
       
     
     
         48 . A process for preparing a compound having the following general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
            is single bond or double bond; 
         A is —CHR 7 —,
 wherein 
 R 7  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
 
         E is bond, —CHR 5 —, —O— or —NR 8 —,
 wherein 
 R 5  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 R 8  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
 
         B is void or optionally substituted monocyclic ring formed together with G and Y; 
         D is void or optionally substituted spiro ring formed together with Y; 
         with the proviso that 
         B and D are not both present, 
         when B is present, then G and Y are independently carbon atom or nitrogen atom, 
         when D is present, then Y is carbon atom and G is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —, 
         when both B and D are void, then G and Y are the same or different and each is —NR 6 —, —O—, —CHR 6 — or —C(R 6 ) 2 —,
 wherein 
 each R 6  is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl, and 
 
         when E is bond, then D is void, B is optionally substituted monocyclic ring, and G and Y are independently carbon atom or nitrogen atom; 
         R 1  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl; 
         R 2  is —W 21 —W 22 —Rb—R 20 ,
 wherein 
 W 21  is —(CO)— or —(SO 2 )—, 
 W 22  is bond, —O—, —NH— or optionally substituted lower alkylene, 
 Rb is bond or optionally substituted alkylene, and 
 R 20  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; and 
 
         R 3  is hydrogen, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; 
         with the proviso that 
         when D is void, E is bond, B is benzene, and R 2  is —W 21 —W 22 —Rb—R 20 , wherein W 21  is —(CO)—, W 22  is —NH—, and Rb is bond, then R 20  should not be optionally substituted phenyl; 
         or a salt thereof, which comprises reacting a compound having the following general formula (II): 
       
       
         
           
           
               
               
           
         
         wherein 
         R 91  is selected from optionally substituted alkyl, linker and solid support; 
         R 92  is selected from optionally substituted alkyl, linker and solid support; and 
         the other symbols are as defined above, or a salt thereof, with an acid.