CETP Inhibitors

Abstract

Compounds having the structures of Formula I, including pharmaceutically acceptable salts of the compounds, are CETP inhibitors, and are useful for raising HDL-cholesterol, reducing LDL-cholesterol, and for treating or preventing atherosclerosis: In the compounds of Formula I, B or R 2 is a phenyl group which has an ortho aryl, heterocyclic, benzoheterocyclic or benzocycloalkyl substituent, and one other position on the 5-membered ring has an aromatic, heterocyclic, cycloalkyl, benzoheterocyclic or benzocycloalkyl substituent connected directly to the ring or attached to the ring through a —CH 2 —.

1 . A compound having Formula I, or a pharmaceutically acceptable salt thereof, wherein 
       
         
           
           
               
               
           
         
         Y is selected from the group consisting of —C(═O)— and —(CRR 1 )—; 
         X is selected from the group consisting of —O—, —NH—, —N(C 1 -C 5 alkyl)-, and —(CRR 6 )—; 
         Z is selected from the group consisting of —C(═O)—, —S(O) 2 —, and —C(═N—R 9 )—, wherein R 9  is selected from the group consisting of H, —CN, and C 1 -C 5 alkyl optionally substituted with 1-11 halogens; 
         Each R is independently selected from the group consisting of H, —C 1 -C 5  alkyl, and halogen, wherein —C 1 -C 5  alkyl is optionally substituted with 1-11 halogens; 
         B is selected from the group consisting of A 1  and A 2 , wherein A 1  has the structure: 
       
       
         
           
           
               
               
           
         
         R 1  and R 6  are each selected from the group consisting of H, —C 1 -C 5  alkyl, halogen, and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5  alkyl is optionally substituted with 1-11 halogens; 
         R 2  is selected from the group consisting of H, —C 1 -C 5  alkyl, halogen, A 1 , and —(C(R) 2 ) n A 2 , wherein —C 1 -C 5  alkyl is optionally substituted with 1-11 halogens; 
         Wherein one of B and R 2  is A 1 ; and one of B, R 1 , R 2 , and R 6  is A 2  or —(C(R) 2 ) n A 2 ; so that the compound of Formula I comprises one group A 1  and one group A 2 ; 
         A 3  is selected from the group consisting of:
 (a) an aromatic ring selected from phenyl and naphthyl; 
 (b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds; 
 (c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group, wherein the point of attachment of A 3  to the phenyl ring to which A 3  is attached is a carbon atom; and 
 (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and —S(O) x — and optionally 1-2 double bonds, wherein the point of attachment of A 3  to the phenyl ring to which A 3  is attached is a carbon atom; 
 
         A 2  is selected from the group consisting of:
 (a) an aromatic ring selected from phenyl and naphthyl; 
 (b) a phenyl ring fused to a 5-7 membered non-aromatic cycloalkyl ring, which optionally comprises 1-2 double bonds; 
 (c) a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, O, and —N(O)—, and optionally also comprising 1-3 double bonds and a carbonyl group; 
 (d) a benzoheterocyclic ring comprising a phenyl ring fused to a 5-6-membered heterocyclic ring having 1-2 heteroatoms independently selected from O, N, and S and optionally 1-2 double bonds; and 
 (e) a —C 3 -C 8  cycloalkyl ring optionally having 1-3 double bonds; 
 
         wherein A 3  and A 2  are each optionally substituted with 1-5 substituent groups independently selected from R a ; 
         Each R a  is independently selected from the group consisting of —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 3 -C 8  cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —OC 3 -C 8  cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8  cycloalkyl, —C(═O)H, —CO 2 H, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —OH, —NR 3 R 4 , —C(═O)NR 3 R 4 , —NR 3 C(═O)OC 1 -C 6  alkyl, —NR 3 C(═O)NR 3 R 4 , —S(O) x C 1 -C 6  alkyl, —S(O) y NR 3 R 4 , —NR 3 S(O) y NR 3 R 4 , halogen, —CN, —NO 2 , and a 5-6-membered heterocyclic ring having 1-4 heteroatoms independently selected from N, S, and O, said heterocyclic ring optionally also comprising a carbonyl group and optionally also comprising 1-3 double bonds, wherein the point of attachment of said heterocyclic ring to the ring to which R a  is attached is a carbon atom, wherein said heterocyclic ring is optionally substituted with 1-5 substituent groups independently selected from halogen, —C 1 -C 3  alkyl, and —OC 1 -C 3  alkyl, wherein —C 1 -C 3  alkyl and —OC 1 -C 3  alkyl are optionally substituted with 1-7 halogens; 
         wherein for compounds in which R a  is selected from the group consisting of —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 3 -C 8  cycloalkyl optionally having 1-3 double bonds, —OC 1 -C 6 alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —OC 3 -C 8  cycloalkyl optionally having 1-3 double bonds, —C(═O)C 1 -C 6 alkyl, —C(═O)C 3 -C 8  cycloalkyl, —CO 2 C 1 -C 6 alkyl, —C(═O)SC 1 -C 6 alkyl, —NR 3 C(═O)OC 1 -C 6  alkyl, and —S(O) x C 1 -C 6  alkyl, then R a  is optionally substituted with 1-15 halogens and is optionally also substituted with 1-3 substituent groups independently selected from (a) —OH, (b) —CN, (c) —NR 3 R 4 , (d) —C 3 -C 8  cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (e) —OC 1 -C 4 alkyl optionally substituted with 1-9 halogens and optionally also substituted with 1-2 substituent groups independently selected from —OC 1 -C 2  alkyl and phenyl, (f) —OC 3 -C 8  cycloalkyl optionally having 1-3 double bonds and optionally substituted with 1-15 halogens, (g) —CO 2 H, (h) —C(═O)CH 3 , (i) —CO 2 C 1 -C 4 alkyl which is optionally substituted with 1-9 halogens, and (j) phenyl which is optionally substituted with 1-3 groups independently selected from halogen, —CH 3 , —CF 3 , —OCH 3 , and —OCF 3 ; 
         with the proviso that when B is A 1 , and X and Y are —CH 2 —, and Z is —C(═O)—, and R 2  is phenyl which has a substituent R a  in the 4-position, wherein R a  is —OC 1 -C 6 alkyl which is optionally substituted as described above, then there are no other R a  substitutents on R 2  in which R a  is selected from —OH, —OC 1 -C 6 alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, and —OC 3 -C 8  cycloalkyl optionally having 1-3 double bonds, optionally substituted as described above. 
         n is 0 or 1; 
         p is an integer from 0-4; 
         x is 0, 1, or 2; 
         y is 1 or 2; 
         R 3  and R 4  are each independently selected from H, —C 1 -C 5  alkyl, —C(═O)C 1 -C 5  alkyl and —S(O) y C 1 -C 5  alkyl, wherein —C 1 -C 5  alkyl in all instances is optionally substituted with 1-11 halogens; and 
         R 5  is selected from the group consisting of H, —OH, —C 1 -C 5  alkyl, and halogen, wherein —C 1 -C 5  alkyl is optionally substituted with 1-11 halogens. 
       
     
     
         2 - 21 . (canceled)