6,11-4C-bicyclic 9a-azalide derivatives

Abstract

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

1 . A compound of formula I, or a pharmaceutically acceptable salt, ester, or prodrug thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 W is 
 (a) —CH 2 —C(A)═C(B)—CH 2 —, wherein, A and B are independently selected from: 
 1. hydrogen;  
 2. deuterium;  
 3. halogen;  
 4. R 1 , wherein R 1  is selected from: 
 a. —C 1 -C 6  alkyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 b. —C 2 -C 6  alkenyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or  
 c. —C 2 -C 6  alkynyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 
 5. R 2 , wherein R 2  is selected from: 
 a. aryl;  
 b. heteroaryl;  
 c. substituted aryl;  
 d. substituted heteroaryl;  
 e. heterocycloalkyl; or  
 f. substituted heterocycloalkyl;  
 
 6. —(C 1 -C 3 -alkyl)-M—(C 1 -C 3 -alkyl)-R 2 , wherein M=—O—, —NH—, —N(CH 3 )—, —NHC(O)— or —S(O) n —, wherein n=0, 1 or 2, and R 2  is as previously defined;  
 7. —(C 1 -C 3 -alkyl)-M—R 2 , wherein M and R 2  are as previously defined;  
 8. —C(O)—V—R 3 , wherein V is absent, O or S, and R 3  is H, R 1  or R 2 ; where R 1  and R 2  are as previously defined; or  
 9. —C(O)—NR 11 R 12 , wherein R 11  and R 12  are each independently selected from: 
 a. hydrogen;  
 b. —C 1 -C 6 -alkyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 c. —C 2 -C 6 -alkenyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 d. —C 2 -C 6 -alkynyl, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or  
 in the alternative, R 11  and R 12  taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more double bonds and one or more heterofunctions selected from —O—, —NH—, —N(C 1 -C 6 -alkyl)-, —N(R 2 )—, —S(O) n —, wherein n and R 2  are as previously defined;  
 
 
 (b) —CH 2 —CH(A)—C(B)═CH—, wherein A and B are as previously defined;  
 (c) —CH 2 —CH(E)—CH(G)—CH 2 —, wherein E and G are independently selected from 
 1. A, wherein A is as previously defined;  
 2. —OH;  
 3. —OR p , wherein R p  is a hydroxy protecting group;  
 4. —O—R 9 , wherein R 9  is R 1  or R 2 , and wherein R 1  and R 2  are as previously defined;  
 5. —S(O) n R 9 , wherein n and R 9  are as previously defined;  
 6. —NHC(O)R 3 , wherein R 3  is as previously defined;  
 7. —NHC(O)NR 11 R 3 , wherein R 11  and R 3  are as previously defined;  
 8. —NHS(O) 2 R 9 , wherein R 9  is as previously defined;  
 9. —NHR 13 , wherein R 13  is an amino protecting group; or  
 10. —NR 11 R 12 , wherein R 11  and R 12  are as previously defined;  
                     
 
 wherein -J- is selected from —O—; —O—C(O)—CH(R 7 )—; —N(R 7 )—; —O—C(O)—N(R 7 )—; —O—C(O)—O—; —N(R 7 )—N═N—; —C(R 7 )═N—O—; or —CH(R 7 )—N(R 8 )—O—; wherein R 7  and R 8  are independently selected from R 3 , wherein R 3  is as previously defined; or, in the alternative, -J- is taken with the two carbon atoms to which it is attached to form a cyclic moiety selected from 
 a. C 3 -C 12  cycloalkyl;  
 b. C 3 -C 12  cycloalkenyl; or  
 c. heterocycloalkyl; or  
 
 (e) —CH 2 —C(R 4 )(R 5 )—CH 2 —CH 2 —, wherein R 4  and R 5  taken together with the carbon atom to which they are attached are selected from: 
 1. C═O;  
 2. C(OR 1 ) 2 , wherein R 1  is as previously defined;  
 3. C(SR 1 ) 2 , wherein R 1  is as previously defined;  
 4. C(OR 12 )(OR 13 ), where R 12  and R 13  taken together are —(CH 2 ) m —, and where m is 2 or 3;  
 5. C(SR 12 )(SR 13 ), where R 12  and R 13  taken together are —(CH 2 ) m —, where m is as previously defined;  
 6. C═CHR 3 , wherein R 3  is as previously defined;  
 7. C═N—O—R 3 , wherein R 3  is as previously defined;  
 8. C═NNHR 3 , wherein R 3  is as previously defined;  
 9. C═NNHC(O)R 3 , wherein R 3  is as previously defined;  
 10. C═NNHC(O)NR 11 R 3 , wherein R 11  and R 3  are as previously defined;  
 11. C═NNHS(O) 2 R 9 , wherein R 9  is as previously defined;  
 12. C═NNHR 13 , wherein R 13  is as previously defined; or  
 13. C═NR 9 , wherein R 9  is as previously defined;  
 
 
 L is 
 (a) —CH 3 ;  
 (b) —CH 2 CH 3 ;  
 (c) —CH(OH)CH 3 ;  
 (d) —C 1 -C 6  alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 (e) —C 2 -C 6  alkenyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl; or  
 (f) —C 2 -C 6  alkynyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 
 D is —N(Q)CH 2 —, —N(R′)C(O)—, or —N═C(OR′)—, wherein R′ is R 11  as previously defined;  
 Q is 
 (a) hydrogen;  
 (b) —C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, or C 2 -C 12 -alkynyl, all optionally substituted with one, two or three substituents independently selected from: 
 1. halogen;  
 2. —OR 6 , wherein R 6  is selected from: 
 a. hydrogen;  
 b. —C 1 -C 12 -alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 c. aryl;  
 d. substituted aryl;  
 e. heteroaryl;  
 f. substituted heteroaryl;  
 g. heterocycloalkyl; or  
 h. substituted heterocycloalkyl;  
 
 3. —NR 4 R 5 , where R 4  and R 5  are each independently R 6 , where R 6  is as previously defined, or in the alternative R 4  and R 5 , together with the atom to which they are attached, form a heterocycloalkyl or substituted heterocycloalkyl moiety;  
 4. ═N—O—R 6 , where R 6  is as previously defined;  
 5. —R 1 , where R 1  is as previously defined;  
 6. —C 3 -C 8 -cycloalkyl;  
 7. substituted —C 3 -C 8 -cycloalkyl;  
 8. heterocycloalkyl;  
 9. substituted heterocycloalkyl;  
 10. —NHC(O)R 6 , where R 6  is as previously defined;  
 11. —NHC(O)OR 7 , where R 7  is selected from: 
 a. —C 1 -C 12 -alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
 b. aryl;  
 c. substituted aryl;  
 d. heteroaryl;  
 e. substituted heteroaryl;  
 f. heterocycloalkyl; or  
 g. substituted heterocycloalkyl;  
 
 12. —NHC(O)NR 4 R 5 , where R 4  and R 5  are as previously defined;  
 13. —OC(O)NR 4 R 5 , where R 4  and R 5  are as previously defined;  
 14. —OC(O)R 7 , where R 7  is as previously defined;  
 15. —OC(O)OR 7 , where R 7  is as previously defined;  
 16. —OC(O)NR 4 R 5 , where R 4  and R 5  are as previously defined,  
 17. —C(O)R 6 , where R 6  is as previously defined,  
 18. —CO 2 R 6 , where R 6  is as previously defined, or  
 19. —C(O)NR 4 R 5 , where R 4  and R 5  are as previously defined;  
 
 
 X is hydrogen;  
 Y is 
 (a) hydrogen;  
 (b) —OH;  
 (c) —OR p , where R p  is as previously defined;  
 (d) —OR y , where R y  is R 1  and R 2  as previously defined;  
 (e) —OC(O)R y , where R y  is R 1  and R 2  as previously defined;  
 (f) —OC(O)NHR y , where R y  is R 1  and R 2  as previously defined;  
 (g) —S(O) n R y , where n is previously defined and R y  is R 1  and R 2  as previously defined;  
                     where R 3 ″ is hydrogen or methyl; R 4 ″ is hydrogen or R p , where R p  is as previously defined; or    
 (i) in the alternative, X and Y combined together are oxo;  
 
 Z is 
 (a) hydrogen;  
 (b) methyl; or  
 (c) halogen; and  
 
 R 2 ′ is hydrogen or R p , where R p , is as previously defined.  
 
     
     
         2 . A compound according to  claim 1  represented by formula II:  
       
         
           
           
               
               
           
         
       
       wherein Q, W, X, Y, Z, and R 2 ′ are as defined in  claim 1 .  
     
     
         3 . A compound according to  claim 1  represented by formula III:  
       
         
           
           
               
               
           
         
       
       wherein Q, W, and R 2 ′ are as defined in  claim 1 .  
     
     
         4 . A compound according to  claim 1  represented by formula IV:  
       
         
           
           
               
               
           
         
       
       wherein Q, W, Z, and R 2 ′ are as defined in  claim 1 .  
     
     
         5 . A compound of  claim 1  selected from: 
 Compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N═CH(OMe)—, X═Z ═H,                           L=CH 2 CH 3 , and R 2 ′=Bz;    Compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—NHCH 2 —, X═Z═H,                           L=CH 2 CH 3 , and R 2 ′=Bz;    Compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—NHCH 2 —, X═Z═H,                           L=CH 2 CH 3 , and R 2 ′═H;    Compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—NHCH 2 —, X═Z═H, Y═OH, L=CH 2 CH 3 , and R 2 ′═H;    Compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—NHCH 2 —, X and Y are taken together with the carbon to which they are attached are C═O, L=CH 2 CH 3 , and R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—NHC(O)—, X═Z═H, L=—CH 2 CH 3 ,                           R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 3 , X═Z═H, Y═OH, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 3 , Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 Ph, Z═X═H, Y═OH, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 Ph, Z═H, X and Y are taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 (2-pyridyl), Z═X═H, Y═OH, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 (2-pyridyl), Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 (3-quinolyl), Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 (3-quinolyl), Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 (CH═CH)Ph, Z═X═H, Y═OH, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 (CH═CH)Ph, Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 CH═CH(2-pyridyl), Z═X═H, Y═OH, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein A and B taken together with the carbon atom to which they are attached ═C═CH 2 , D=—N(Q)CH 2 —, Q=CH 2 CH═CH(2-pyridyl), Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H;    A compound of formula I, wherein W is —CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 C≡C(3-quinolyl), Z═X═H, Y═OH, L=CH 2 CH 3 , R 2 ′═H; or    A compound of formula I, wherein W=—CH 2 CH═CHCH 2 —, D=—N(Q)CH 2 —, Q=CH 2 C≡C(3-quinolyl), Z═H, X and Y taken together are oxo, L=CH 2 CH 3 , R 2 ′═H.    
     
     
         6 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with a pharmaceutically acceptable carrier.  
     
     
         7 . A method for controlling a bacterial infection in a subject, comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to  claim 6 .  
     
     
         8 . A process for the preparation of a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein L, Q, W, X, Y, Z and R 2 ′ are as defined in  claim 1 , comprising the steps of: 
 (1) reacting a compound of the formula:  
                     
 wherein 
 R 8  is 
 a. Hydrogen;  
 b. —CH 2 O(CH 2 ) 2 OCH 3 ;  
 c. —CH 2 O(CH 2 O) n CH 3 , where n is as previously defined;  
 d. —C 1 -C 12  alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl;  
 e. —C 3 -C 12  cycloalkyl;  
 f. —C(O)—C 1 -C 12  alkyl;  
 g. —C(O)—C 3 -C 12  cycloalkyl;  
 h. —C(O)—R 1 , where R 1  is as previously defined; or  
 i. —Si(R a )(R b )(R c ), wherein R a , R b  and R c  are each independently selected from C 1 -C 12  alkyl, aryl, or substituted aryl; and  
 
 L, R 2 ′, and R 4 ″ are as defined in  claim 1;   
 with  
                     
  wherein A and B are as defined in  claim 1 , in the presence of a phosphine ligand and Pd(0) catalyst under reflux conditions to prepare a compound of the formula:  
                     
 wherein A, B, L, R 8 , R 2 ′, and R 4 ″ are as defined in  claim 1;   
 
 (2) reacting the compound prepared in step (1) with a mild acid to prepare a compound of the formula:  
                     wherein A, B, L, R 8 , and R 2 ′ are as defined in  claim 1;     
 (3) reacting the compound prepared in step (2) with an oxime activating agent and quenching with methanol to prepare a compound of the formula:  
                     wherein A, B, L, R′, and R 2 ′ are as defined  claim 1;     
 (4) reacting the compound prepared in step (3) with a reducing agent to prepare compound of the formula:  
                     wherein A, B, L, and R 2 ′ are as defined  claim 1;     
 (5) reacting the compound prepared in step (4) with an alkylating agent, preferably an alykyl halide in the presence of a base, or with an aldehyde via reductive amination in the presence of NaCNBH 3  to prepare a compound of the formula:  
                     wherein A, B, L, Q, and R 2 ′ is as defined  claim 1;  and    
 (6) oxidizing the hydroxyl in the 3 position of the compound prepared in step (5) via Dess-Martin oxidation, Corey-Kim.oxidation, or a Moffat oxidation to prepare a compound of the formula:  
                     wherein A, B, L, Q, and R 2 ′ are as defined  claim 1.