Fused tricyclic compounds and methods of use thereof for the treatment of viral diseas

Abstract

The present invention relates to novel Fused Tricyclic Compounds, compositions comprising at least one Fused Tricyclic Compound, and methods of using Fused Tricyclic Compounds for treating or preventing a viral infection or a virus-related disorder in a patient.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein each dotted line represents an optional and additional bond, such that only one optional and additional bond can be attached to each of Y 1  and Y 2 , and wherein:
 A is -alkylene-N(R 7 )(R 11 ) or heterocycloalkyl, wherein said heterocycloalkyl group can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R 12 , and wherein said heterocycloalkyl group can be optionally fused to a cycloalkyl group or an aryl group; 
 B is monocyclic heteroarylene or bicyclic heteroarylene, wherein said monocyclic heteroarylene group or said bicyclic heteroarylene group can be optionally and independently substituted on one or more ring nitrogen atoms with R 6 , and on one or more ring carbon atoms with R 12 ; 
 C is a bond, monocyclic heteroarylene or bicyclic heteroarylene, wherein said monocyclic heteroarylene group or said bicyclic heteroarylene group can be can be optionally and independently substituted on one or more ring nitrogen atoms with R 6  and on one or more ring carbon atoms with R 12 ; 
 D is -alkylene-N(R 7 )(R 11 ) or heterocycloalkyl, wherein said heterocycloalkyl group can be can be optionally and independently substituted on one or more ring nitrogen atoms with R 4 , and on one or more ring carbon atoms with R 12 , and wherein a heterocycloalkyl can be optionally fused to a cycloalkyl group or an aryl group; 
 M 1  is a bond, —[C(R 7 ) 2 ] q —, —[C(R 7 ) 2 ] m —C(R 2 )═C(R 2 )—[C(R 7 ) 2 ] m —, —C(R 7 )═N—, —N═C(R 7 )—, —[C(R 7 ) 2 ] m —O—[C(R 7 ) 2 ] m , —O—[C(R 7 ) 2 ] q —O—, —[C(R 7 ) 2 ] m —N(R 6 )—[C(R 7 ) 2 ] m —, —S—, —[C(R 7 ) 2 ]-S(O) m —[C(R 7 ) 2 ] m —, —[C(R 7 ) 2 ] m —OC(O)N(R 6 )—[C(R 7 ) 2 ] m , —[C(R 7 ) 2 ] m —N(R 6 )C(O)N(R 6 )—[C(R 7 ) 2 ] m —, —[C(R 7 ) 2 ] m —S(O) 2 N(R 6 )—[C(R 7 ) 2 ] m — or —[C(R 7 ) 2 ] m —N(R 6 )S(O) 2 N(R 6 )—[C(R 7 ) 2 ] m —; 
 M 2  is a bond, —[C(R 7 ) 2 ] q —, —[C(R 7 ) 2 ] m —C(R 2 )═C(R 2 )—[C(R 7 ) 2 ] m —, —C(R 7 )═N—, —N═C(R 7 )—, —[C(R 7 ) 2 ] m —O—[C(R 7 ) 2 ] m , —O—[C(R 7 ) 2 ] q —O—, —[C(R 7 ) 2 ] m —N(R 6 )—[C(R 7 ) 2 ] m —, —S—, —[C(R 7 ) 2 ] m —S(O) m —[C(R 7 ) 2 ] m —, —[C(R 7 ) 2 ] m —OC(O)N(R 6 )—[C(R 7 ) 2 ] m —, —[C(R 7 ) 2 ] m —N(R 6 )C(O)N(R 6 )—[C(R 7 ) 2 ] m —, —[C(R 7 ) 2 ] m —S(O) 2 N(R 6 )—[C(R 7 ) 2 ] m — or —[C(R 7 ) 2 ] m —N(R 6 )S(O) 2 N(R 6 )—[C(R 7 ) 2 ] m —, such that at least one of M 1  and M 2  is other than a bond, and such that the central ring of formula (I) that contains M 1  and M 2  has from 5 to 10 total ring atoms, and wherein two vicinal R 7  groups of M 1  or M 2  together with the carbon atoms to which they are attached, can optionally join to form a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocycloalkyl group, or a 5- to 6-membered heteroaryl group; 
 X 1  is a bond, —C(R 2 )═C(R 2 )—, —N═C(R 5 )—, —C(R 5 )═NC—, —C(R 5 )═N—, —O—, —N(R 6 )—, —S— or —S(O) 2 — when the optional and additional bond to X 1  is not present, and X 1  is —C(R 5 )—, is —C(R 5 )(C(R 5 )=(C(R 5 )—, —N—, —N—C(R 5 )═C(R 5 )—, —C(R 5 )N═C(R 5 )—, —C(R 5 )C(R 5 )═N—, —C(R 5 )O—, —C(R 5 )N(R 6 )—, —N—N(R 6 )—, —C(R 5 )S— or —C(R 5 )S(O) 2 — when the optional and additional bond to X 1  is present, such that X 1  and Z 1  cannot each be a bond, and such that when X 1  is —C(R 5 )—, —N(R 6 )—, —N—, or —O—, then Z 1  is other than a bond; 
 X 2  is a bond, —C(R 2 )═C(R 2 )—, —N═C(R 5 )—, —C(R 5 )N═C—, —C(R 5 )═N—, —O—, —N(R 6 )—, —S— or —S(O) 2 — when the optional and additional bond to X 2  is not present, and X 2  is —C(R 5 )—, is —(C(R 5 )=(C(R 5 )C(R 5 —, —C(R 5 )═C(R 5 )N—, —C(R 5 )═NC(R 5 )—, —N═C(R 5 )C(R 5 )—, —OC(R 5 )—, —N(R 6 )C(R 5 )—, —N(R 6 )—N—, —S—C(R 5 )— or —S(O) 2 C(R 5 )— when the optional and additional bond to X 2  is present, such that X 2  and Z 2  cannot each be a bond, and such that when X 2  is —C(R 5 )— —N(R 6 )—, —N—, or —O—, then Z 2  is other than a bond; 
 Y 1  is —C—, when an optional and additional bond to Y 1  is present, and Y 1  is —CH— when an optional and additional bond to Y 1  is absent; 
 Y 2  is —C—, when an optional and additional bond to Y 2  is present, and Y 2  is —CH— when an optional and additional bond to Y 2  is absent; 
 Z 1  is a bond, —C(R 5 )═C(R 5 )—, —N═C(R 5 )—, —C(R 5 )═NC—, —C(R 5 )═N—, —O—, —N(R 6 )—, —S— or —S(O) 2 — when the optional and additional bond to Z 1  is not present, and Z 1  is —C(R 5 )—, —C(R 5 )(CH(R 5 )) m —, —N—, —NCH(R 5 )CH(R 5 )—, —C(R 5 )NHCH(R 5 )—, —C(R 5 )CH(R 5 )NH—, —C(R 5 )O—, —C(R 5 )N(R 6 )—, —N—N(R 6 )—, —C(R 5 )S— or —C(R 5 )S(O) 2 — when the optional and additional bond to Z 1  is present, such that the ring in formula (I) containing X 1 , Y 1  and Z 1  has 5 or 6 total ring atoms; 
 Z 2  is a bond, —C(R 5 )═C(R 5 )—, —N═C(R 5 )—, —C(R 5 )N═C—, —C(R 5 )═N—, —O—, —N(R 6 )—, —S— or —S(O) 2 — when the optional and additional bond to Z 2  is not present, and Z 2  is —C(R 5 )—, —(CH(R 5 ) m C(R 5 )—, —CH(R 5 )CH(R 5 )N—, —CH(R 5 )NHC(R 5 )—, —NHCH(R 5 )C(R 5 )—, —OC(R 5 )—, —N(R 6 )C(R 5 )—, —N(R 6 )—N—, —S—C(R 5 )— or —S(O) 2 C(R 5 )— when the optional and additional bond to Z 2  is present, such that the ring in formula (I) containing X 2 , Y 2  and Z 2  has 5 or 6 total ring atoms; 
 each occurrence of R 1  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, 3 to 7 membered cycloalkyl, 4 to 7 membered heterocycloalkyl or heteroaryl, wherein said aryl group, said cycloalkyl group, said heterocycloalkyl group or said heteroaryl group can be optionally and independently substituted with up to three R 2  groups; 
 each occurrence of R 2  is independently C 1 -C 6  alkyl, aryl, 3 to 7 membered cycloalkyl, 4 to 7 membered heterocycloalkyl, heteroaryl, halo, C 1 -C 6  haloalkyl, —CN, —OR 3 , —N(R 3 ) 2 , —C(O)R 10 , —C(O)OR 3 , —C(O)N(R 3 ) 2 , —NHC(O)R 10 , —NHC(O)NHR 3 , —NHC(O)OR 3 , —OC(O)R 10 , —SR 3  or —S(O) 2 R 1 ; 
 each occurrence of R 3  is independently H, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, 3 to 7 membered cycloalkyl, 4 to 7 membered heterocycloalkyl or heteroaryl, wherein said aryl group, said cycloalkyl group, said heterocycloalkyl group or said heteroaryl group can be optionally and independently substituted with up to three groups independently selected from hydroxy, halo, alkyl, aminoalkyl, and haloalkyl. 
 each occurrence of R 4  is independently H, —C(O)—[C(R 7 ) 2 ] q N(R 6 ) 2 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)—R 1 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)O—R 1 , —C(O)—[C(R 7 ) 2 ] q C(O)O—R 1 , —C(O)[C(R 7 ) 2 ] q N(R 6 )SO 2 —R 1  or -alkylene-N(R 6 )—[C(R 7 ) 2 ] q —N(R 6 )—C(O)O—R 1 ; 
 each occurrence of R 5  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, aryl or heteroaryl; 
 each occurrence of R 6  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, or heteroaryl, wherein said aryl group, said cycloalkyl group, said heterocycloalkyl group or said heteroaryl group can be optionally and independently substituted with up to two R 8  groups, and wherein two R 6  groups that are attached to a common nitrogen atom, together with the nitrogen atom to which they are attached, can optionally join to form a 4 to 7-membered heterocycloalkyl group; 
 each occurrence of R 7  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, heteroaryl, wherein said aryl group, said cycloalkyl group, said heterocycloalkyl group or said heteroaryl group can be optionally and independently substituted with up to 3 substituents, which can be the same or different, and are selected from C 1 -C 6  alkyl, halo, —C 1 -C 6 haloalkyl, C 1 -C 6  hydroxyalkyl, —OH, —C(O)NH—(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —O—(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2  and —NHC(O)—(C 1 -C 6  alkyl), and wherein two geminal R 7  groups, together with the common carbon atom to which they are attached, can optionally join to form —C(O)—, —C(S)—, —C(═NR 9 )—, —C(═NOR 9 )—, a 3 to 7-membered cycloalkyl group or a 4 to 7-membered heterocycloalkyl group, such that no two adjacent —C(R 7 ) 2 — groups can join to form a —C(O)—C(O)—, —C(S)—C(S)—, —C(O)—C(S)— or —C(S)—C(O)— group; 
 each occurrence of R 8  is independently H or C 1 -C 6  alkyl; 
 each occurrence of R 9  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl or 4 to 7-membered heterocycloalkyl; 
 each occurrence of R 10  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl or heteroaryl; 
 each occurrence of R 11  is independently —C(O)—[C(R 7 ) 2 ] q N(R 6 ) 2 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)—R 1 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)O—R 1 , —C(O)—[C(R 7 ) 2 ] q C(O)O—R 1 , —C(O)[C(R 7 ) 2 ] q N(R 6 )SO 2 —R 1  or -alkylene-N(R 6 )—[C(R 7 ) 2 ] q —N(R 6 )—C(O)O—R 1 ; 
 each occurrence of R 12  is H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, heteroaryl, halo, C 1 -C 6  haloalkyl, —CN, —OR 3 , —N(R 3 ) 2 , —C(O)R 10 , —C(O)OR 3 , —C(O)N(R 3 ) 2 , —NHC(O)R 10 , —NHC(O)NHR 3 , —NHC(O)OR 3 , —OC(O)R 10 , —SR 3  or —S(O) 2 R 1 ; and wherein two R 12  groups together with the carbon atoms to which they are attached, can optionally join to form a 5 to 7-membered cycloalkyl or 4 to 7-membered heterocycloalkyl group; 
 each occurrence of m is independently an integer ranging from 0 to 2; and 
 each occurrence of q is independently an integer ranging from 1 to 4. 
 
     
     
         2 . The compound of  claim 1 , wherein A and D are each independently selected from: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , wherein B is: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein C is a bond, 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 1 , wherein each occurrence of R 4  is independently selected from: 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 1 , wherein each occurrence of R 4  is independently: 
       
         
           
           
               
               
           
         
       
       wherein R a  is H, alkyl, haloalkyl, cycloalkyl or aryl, and R b  is alkyl. 
     
     
         7 . The compound of  claim 1 , wherein the group: 
       
         
           
           
               
               
           
         
       
       has the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       the group: 
       
         
           
           
               
               
           
         
       
       has the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         each occurrence of R 1  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, 3 to 7 membered cycloalkyl, 4 to 7 membered heterocycloalkyl or heteroaryl, wherein an aryl, cycloalkyl, heterocycloalkyl or heteroaryl group can be optionally and independently substituted with up to three R 2  groups; 
         each occurrence of R 2  is independently C 1 -C 6  alkyl, aryl, 3 to 7 membered cycloalkyl, 4 to 7 membered heterocycloalkyl, heteroaryl, halo, C 1 -C 6  haloalkyl, —CN, —OR 3 , —N(R 3 ) 2 , —C(O)R 10 , —C(O)OR 3 , —C(O)N(R 3 ) 2 , —NHC(O)R 10 , —NHC(O)NHR 3 , —NHC(O)OR 3 , —OC(O)R 10 , —SR 3  or —S(O) 2 R 1 ; 
         each occurrence of R 3  is independently H, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, 3 to 7 membered cycloalkyl, 4 to 7 membered heterocycloalkyl or heteroaryl wherein an aryl, cycloalkyl, heterocycloalkyl or heteroaryl group can be optionally and independently substituted with up to three groups independently selected from hydroxy, halo, alkyl, aminoalkyl, and haloalkyl. 
         each occurrence of R 4  is independently H, —C(O)—[C(R 7 ) 2 ] q N(R 6 ) 2 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)—R 1 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)O—R 1 , —C(O)—[C(R 7 ) 2 ] q C(O)O—R 1 , —C(O)[C(R 7 ) 2 ] q N(R 6 )SO 2 —R 1  or -alkylene-N(R 6 )—[C(R 7 ) 2 ] q —N(R 6 )—C(O)O—R 1 ; 
         each occurrence of R 5  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, aryl or heteroaryl; 
         each occurrence of R 6  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, or heteroaryl, wherein a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can be optionally and independently substituted with up to two R 8  groups, and wherein two R 6  groups that are attached to a common nitrogen atom, together with the nitrogen atom to which they are attached, can optionally join to form a 4 to 7-membered heterocycloalkyl group; 
         each occurrence of R 7  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, heteroaryl, wherein a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group can be optionally and independently substituted with up to 3 substituents, which can be the same or different, and are selected from C 1 -C 6  alkyl, halo, —C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, —OH, —C(O)NH—(C 1 -C 6  alkyl), —C(O)N(C 1 -C 6  alkyl) 2 , —O—(C 1 -C 6  alkyl), —NH 2 , —NH(C 1 -C 6  alkyl), —N(C 1 -C 6  alkyl) 2  and —NHC(O)—(C 1 -C 6  alkyl), and wherein two geminal R 7  groups, together with the common carbon atom to which they are attached, can optionally join to form —C(O)—, —C(S)—, —C(═NR 9 )—, —C(═NOR 9 )—, a 3 to 7-membered cycloalkyl group or a 4 to 7-membered heterocycloalkyl group, such that no two adjacent —C(R 7 ) 2 — groups can join to form a —C(O)—C(O)—, —C(S)—C(S)—, —C(O)—C(S)— or —C(S)—C(O)— group; 
         each occurrence of R 8  is independently H or C 1 -C 6  alkyl; 
         each occurrence of R 9  is independently H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl or 4 to 7-membered heterocycloalkyl; 
         each occurrence of R 10  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, aryl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl or heteroaryl; 
         each occurrence of R 11  is independently —C(O)—[C(R 7 ) 2 ] q N(R 6 ) 2 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)—R 1 , —C(O)—[C(R 7 ) 2 ] q N(R 6 )C(O)O—R 1 , —C(O)—[C(R 7 ) 2 ] q C(O)O—R 1 , —C(O)[C(R 7 ) 2 ] q N(R 6 )SO 2 —R 1  or -alkylene-N(R 6 )—[C(R 7 ) 2 ] q —N(R 6 )—C(O)O—R 1 ; 
         each occurrence of R 12  is H, C 1 -C 6  alkyl, 3 to 7-membered cycloalkyl, 4 to 7-membered heterocycloalkyl, aryl, heteroaryl, halo, C 1 -C 6  haloalkyl, —CN, —OR 3 , —N(R 3 ) 2 , —C(O)R 10 , —C(O)OR 3 , —C(O)N(R 3 ) 2 , —NHC(O)R 10 , —NHC(O)NHR 3 , —NHC(O)OR 3 , —OC(O)R 10 , —SR 3  or —S(O) 2 R 10 ; and wherein two R 12  groups together with the carbon atoms to which they are attached, can optionally join to form a 5 to 7-membered cycloalkyl or 4 to 7-membered heterocycloalkyl group; 
         each occurrence of m is independently an integer ranging from 0 to 2; and 
         each occurrence of q is independently an integer ranging from 1 to 4. 
       
     
     
         9 . The compound of  claim 8 , wherein A and D are each: 
       
         
           
           
               
               
           
         
       
       and each occurrence of R 4  is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein the group: 
       
         
           
           
               
               
           
         
       
       has the structure: 
       
         
           
           
               
               
           
         
       
       and 
       C is a bond or: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound having the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A pharmaceutical composition comprising an effective amount of one or more compounds of  claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         13 . The pharmaceutical composition of  claim 12 , further comprising at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is not a compound of  claim 1  and wherein the at least one additional therapeutic agent is selected from an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, and an antibody therapy (monoclonal or polyclonal). 
     
     
         14 . A method for treating HCV infection in a patient, the method comprising administering to the patient an effective amount of one or more compounds of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method of  claim 14 , further comprising administering to the patient an effective amount of at least one additional therapeutic agent, wherein the at least one additional therapeutic agent is not a compound of  claim 1  and wherein the at least one additional therapeutic agent is selected from an interferon, an immunomodulator, a viral replication inhibitor, an antisense agent, a therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral helicase inhibitor, a virion production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, and an antibody therapy (monoclonal or polyclonal).