US2009029995A1PendingUtilityA1

Hetero biaryl derivatives as matrix metalloproteinase inhibitors

Assignee: WARNER LAMBERT COPriority: Aug 13, 2002Filed: Nov 29, 2006Published: Jan 29, 2009
Est. expiryAug 13, 2022(expired)· nominal 20-yr term from priority
A61P 9/10A61P 35/00A61P 9/04A61P 9/00A61P 43/00A61P 27/02A61P 25/00A61P 29/00A61P 17/06A61P 19/00A61P 11/00A61P 1/04A61P 19/10A61P 19/02A61P 11/06C07D 401/12C07D 409/06C07D 413/10C07D 271/107C07D 233/56C07D 417/10C07D 405/12C07D 401/14C07D 231/12C07D 401/04C07D 401/06C07D 249/08C07D 271/10C07D 403/06C07D 285/12C07D 257/04C07D 417/12
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Claims

Abstract

This invention provides compounds defined by Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , Q, S, T, U, V, and R 2 are as defined in the specification. The invention also provides pharmaceutical compositions and methods of treating diseases.

Claims

exact text as granted — not AI-modified
1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  and R 2  independently are selected from:
 H; 
 C 1 -C 6  alkyl; 
 Substituted C 1 -C 6  alkyl; 
 C 2 -C 6  alkenyl; 
 Substituted C 2 -C 6  alkenyl; 
 C 2 -C 6  alkynyl; 
 Substituted C 2 -C 6  alkynyl; 
 C 3 -C 6  cycloalkyl; 
 Substituted C 3 -C 6  cycloalkyl; 
 C 3 -C 6  cycloalkyl-(C 1 -C 6  alkylenyl); 
 Substituted C 3 -C 6  cycloalkyl-(C 1 -C 6  alkylenyl); 
 3- to 6-membered heterocycloalkyl; 
 Substituted 3- to 6-membered heterocycloalkyl; 
 3- to 6-membered heterocycloalkyl-(C 1 -C 6  alkylenyl); 
 Substituted 3- to 6-membered heterocycloalkyl-(C 1 -C 6  alkylenyl); 
 Phenyl-(C 1 -C 6  alkylenyl); 
 Substituted phenyl-(C 1 -C 6  alkylenyl); 
 Naphthyl-(C 1 -C 6  alkylenyl); 
 Substituted naphthyl-(C 1 -C 6  alkylenyl); 
 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 Phenyl; 
 Substituted phenyl; 
 Naphthyl; 
 Substituted naphthyl; 
 5-, 6-, 9-, and 10-membered heteroaryl; 
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl; 
 R 3 O—(C 1 -C 6  alkylenyl); 
 Substituted R 3 O—(C 1 -C 6  alkylenyl); 
 5- or 6-membered heteroaryl; 
 Substituted 5- or 6-membered heteroaryl; 
 8- to 10-membered heterobiaryl; 
 Substituted 8- to 10-membered heterobiaryl; 
 Phenyl-O—(C 1 -C 8  alkylenyl); 
 Substituted phenyl-O—(C 1 -C 8  alkylenyl); 
 Phenyl-S—(C 1 -C 8  alkylenyl); 
 Substituted phenyl-S—(C 1 -C 8  alkylenyl); 
 Phenyl-S(O)—(C 1 -C 8  alkylenyl); 
 Substituted phenyl-S(O)—(C 1 -C 8  alkylenyl); 
 Phenyl-S(O) 2 —(C 1 -C 8  alkylenyl); and 
 Substituted phenyl-S(O) 2 —(C 1 -C 8  alkylenyl); 
 
         wherein R 1  and R 2  are not both selected from:
 H; 
 C 1 -C 6  alkyl; 
 C 2 -C 6  alkenyl; 
 C 2 -C 6  alkynyl; and 
 C 3 -C 6  cycloalkyl; 
 
         Each R 3  independently is selected from:
 H; 
 C 1 -C 6  alkyl; 
 Substituted C 1 -C 6  alkyl; 
 C 3 -C 6  cycloalkyl; 
 Substituted C 3 -C 6  cycloalkyl; 
 Phenyl-(C 1 -C 6  alkylenyl); 
 Substituted phenyl-(C 1 -C 6  alkylenyl); 
 Naphthyl-(C 1 -C 6  alkylenyl); 
 Substituted naphthyl-(C 1 -C 6  alkylenyl); 
 
         5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl);
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 Phenyl; 
 Substituted phenyl; 
 Naphthyl; 
 Substituted naphthyl; 
 
         5-, 6-, 9-, and 10-membered heteroaryl;
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl; 
 
         S, T, U, and W each are C—R 4 ; or 
         One of S, T, U, and W is N and the other three of S, T, U, and W are C—R 4 ; or 
         Two of S, T, U, and W are N and the other two of S, T, U, and W are C—R 4 ; or 
         T is C—R 4  and S, U, and W are each N; or 
         U is C—R 4  and S, T, and W are each N; or 
         S is C—R 4  and T, U, and W are each N; 
         Each R 4  independently is selected from:
 H; 
 F; 
 CH 3 ; 
 CF 3 ; 
 C(O)H; 
 CN; 
 HO; 
 CH 3 O; 
 C(F)H 2 O; 
 C(H)F 2 O; and 
 CF 3 O; 
 V is a 5-membered heteroarylenyl; and Q is selected from: 
 OCH 2 ; 
 N(R 6 )CH 2 ; 
 OC(O); 
 CH(R 6 )C(O); 
 OC(NR 6 ); 
 CH(R 6 )C(NR 6 ); 
 N(R 6 )C(O); 
 N(R 6 )C(S); 
 N(R 6 )C(NR 6 ); 
 N(R 6 )CH 2 ; 
 SC(O); 
 CH(R 6 )C(S); 
 SC(NR 6 ); 
 trans-(H)C═C(H); 
 cis-(H)C═C(H); 
 C≡C; 
 CH 2 C≡C; 
 C≡CCH 2 ; 
 CF 2 C≡C; 
 C≡CCF 2 ; 
 
       
       
         
           
           
               
               
           
         
         
           or V is C(O)O, C(S)O, C(O)N(R 5 ), or C(S)N(R 5 ); and Q is selected from: 
           OCH 2 ; 
           N(R 6 )CH 2 ; 
           CH(R 6 )C(O); 
           OC(NR 6 ); 
           CH(R 6 )C(NR 6 ); 
           N(R 6 )C(NR 6 ); 
           N(R 6 )CH 2 ; 
           CH(R 6 )C(S); 
           SC(NR 6 ); 
           trans-(H)C═C(H); 
           cis-(H)C═C(H); 
           C≡CCH 2 ; 
           C≡CCF 2 ; 
         
       
       
         
           
           
               
               
           
         
         R 5  is H or C 1 -C 6  alkyl; 
         R 6  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl; 3- to 6-membered heterocycloalkyl; phenyl; benzyl; or 5- or 6-membered heteroaryl; 
         X is O, S, N(H), or N(C 1 -C 6  alkyl); 
         Each V 1  is independently C(H) or N; 
         Each “substituted” group contains from 1 to 4 substituents, each independently on a carbon or nitrogen atom, independently selected from:
 C 1 -C 6  alkyl; 
 C 2 -C 6  alkenyl; 
 C 2 -C 6  alkynyl; 
 C 3 -C 6  cycloalkyl; 
 C 3 -C 6  cycloalkylmethyl; 
 Phenyl; 
 Phenylmethyl; 
 3- to 6-membered heterocycloalkyl; 
 3- to 6-membered heterocycloalkylmethyl; 
 cyano; 
 CF 3 ; 
 (C 1 -C 6  alkyl)-OC(O); 
 HOCH 2 ; 
 (C 1 -C 6  alkyl)-OCH 2 ; 
 H 2 NCH 2 ; 
 (C 1 -C 6  alkyl)-N(H)CH 2 ; 
 (C 1 -C 6  alkyl) 2 -NCH 2 ; 
 N(H) 2 C(O); 
 (C 1 -C 6  alkyl)-N(H)C(O); 
 (C 1 -C 6  alkyl) 2 -NC(O); 
 N(H) 2 C(O)N(H); 
 (C 1 -C 6  alkyl)-N(H)C(O)N(H); 
 N(H) 2 C(O)N(C 1 -C 6  alkyl); 
 (C 1 -C 6  alkyl)-N(H)C(O)N(C 1 -C 6  alkyl); 
 (C 1 -C 6  alkyl) 2 -NC(O)N(H); 
 (C 1 -C 6  alkyl) 2 -NC(O)N(C 1 -C 6  alkyl); 
 N(H) 2 C(O)O; 
 (C 1 -C 6  alkyl)-N(H)C(O)O; 
 (C 1 -C 6  alkyl) 2 -NC(O)O; 
 HO; 
 (C 1 -C 6  alkyl)-O; 
 CF 3 O; 
 CF 2 (H)O; 
 CF(H) 2 O; 
 H 2 N; 
 (C 1 -C 6  alkyl)-N(H); 
 (C 1 -C 6  alkyl) 2 -N; 
 O 2 N; 
 (C 1 -C 6  alkyl)-S; 
 (C 1 -C 6  alkyl)-S(O); 
 (C 1 -C 6  alkyl)-S(O) 2 ; 
 (C 1 -C 6  alkyl) 2 -NS(O) 2 ; 
 (C 1 -C 6  alkyl)-S(O) 2 —N(H)—C(O)—(C 1 -C 8  alkylenyl) m ; and 
 (C 1 -C 6  alkyl)-C(O)—N(H)—S(O) 2 —(C 1 -C 8  alkylenyl) m ; 
 
         wherein each substituent on a carbon atom may further be independently selected from: 
         Halo; 
         HO 2 C; and 
         OCH 2 O, wherein each 0 is bonded to adjacent carbon atoms to form a 5-membered ring; 
         wherein 2 substituents may be taken together with a carbon atom to which they are both bonded to form the group C═O; 
         wherein two adjacent, substantially sp 2  carbon atoms may be taken together with a diradical substituent to form a cyclic diradical selected from: 
       
       
         
           
           
               
               
           
         
         R is H or C 1 -C 6  alkyl; 
         m is an integer of 0 or 1; 
       
       wherein each 5-membered heteroarylenyl independently is a 5-membered ring containing carbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 NH, 1 N(C 1 -C 6  alkyl), and 4 N, wherein the O and S atoms are not both present, and wherein the heteroarylenyl may optionally be unsubstituted or substituted with 1 substituent selected from fluoro, methyl, hydroxy, trifluoromethyl, cyano, and acetyl; 
       wherein each heterocycloalkyl is a ring that contains carbon atoms and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O), 1 S(O) 2 , 1 N, 2 N(H), and 2 N(C 1 -C 6  alkyl), and wherein when two O atoms or one O atom and one S atom are present, the two O atoms or one O atom and one S atom are not bonded to each other, and wherein the ring is saturated or optionally contains one carbon-carbon or carbon-nitrogen double bond; 
       wherein each 5-membered heteroaryl contains carbon atoms and from 1 to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C 1 -C 6  alkyl), and 4 N, and each 6-membered heteroaryl contains carbon atoms and 1 or 2 heteroatoms independently selected from N,N(H), and N(C 1 -C 6  alkyl), and 5- and 6-membered heteroaryl are monocyclic rings; and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused bicyclic rings, respectively, wherein at least 1 of the 2 fused rings of a bicyclic ring is aromatic, and wherein when the O and S atoms both are present, the O and S atoms are not bonded to each other; 
       wherein with any (C 1 -C 6  alkyl) 2 -N group, the C 1 -C 6  alkyl groups may be optionally taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycloalkyl; and 
       wherein each group and each substituent recited above is independently selected. 
     
     
         2 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein V is a 5-membered heteroarylenyl; and Q is N(H)C(O). 
     
     
         3 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein S is N and T, U, and W each are C—R 4 ; V is a 5-membered heteroarylenyl; and Q is N(H)C(O). 
     
     
         4 . The compound according to  claims 2  or  3 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 1  and R 2  is independently selected from:
 Phenyl-(C 1 -C 6  alkylenyl); and   Substituted phenyl-(C 1 -C 6  alkylenyl);   wherein each group and each substituent is independently selected.   
     
     
         5 . The compound according to  claims 2  or  3 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 1  and R 2  is independently selected from:
 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); and   Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl);   wherein each heteroaryl contains carbon atoms and from 1 to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C 1 -C 6  alkyl), and 4 N, and 5- and 6-membered heteroaryl are monocyclic rings and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused bicyclic rings, respectively, wherein at least 1 of the 2 fused rings of a bicyclic ring is aromatic, and wherein when the O and S atoms both are present, the O and S atoms are not bonded to each other; and   wherein each group and each substituent is independently selected.   
     
     
         6 . The compound according to  claim 4 , or a pharmaceutically acceptable salt thereof, wherein each C 1 -C 6  alkylenyl is CH 2 , C(CH 3 ) 2 , C(═O), or CF 2 . 
     
     
         7 . The compound according to  claim 6 , or a pharmaceutically acceptable salt thereof, wherein each C 1 -C 6  alkylenyl is CH 2 . 
     
     
         8 . The compound according to  claim 5 , or a pharmaceutically acceptable salt thereof, wherein each C 1 -C 6  alkylenyl is CH 2 , C(CH 3 ) 2 , C(═O), or CF 2 . 
     
     
         9 . The compound according to  claim 8 , or a pharmaceutically acceptable salt thereof, wherein each C 1 -C 6  alkylenyl is CH 2 . 
     
     
         10 . The compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Ia 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1  and R 2  independently are selected from:
 Substituted C 1 -C 6  alkyl; 
 Substituted C 2 -C 6  alkenyl; 
 Substituted C 2 -C 6  alkynyl; 
 Substituted C 3 -C 6  cycloalkyl; 
 Substituted C 3 -C 6  cycloalkyl-(C 1 -C 6  alkylenyl); 
 Substituted 3- to 6-membered heterocycloalkyl; 
 Substituted 3- to 6-membered heterocycloalkyl-(C 1 -C 6  alkylenyl); 
 Phenyl-(C 1 -C 6  alkylenyl); 
 Substituted phenyl-(C 1 -C 6  alkylenyl); 
 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 Phenyl; 
 Substituted phenyl; 
 5-, 6-, 9-, and 10-membered heteroaryl; 
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl; 
 R 3 O—(C 1 -C 6  alkylenyl); 
 Substituted R 3 O—(C 1 -C 6  alkylenyl); 
 Naphthyl; 
 Substituted naphthyl; 
 5- or 6-membered heteroaryl; 
 Substituted 5- or 6-membered heteroaryl; 
 8- to 10-membered heterobiaryl; 
 Substituted 8- to 10-membered heterobiaryl; 
 Phenyl-O—(C 1 -C 8  alkylenyl); 
 Substituted phenyl-O—(C 1 -C 8  alkylenyl); 
 Phenyl-S—(C 1 -C 8  alkylenyl); 
 Substituted phenyl-S—(C 1 -C 8  alkylenyl); 
 Phenyl-S(O)—(C 1 -C 8  alkylenyl); 
 Substituted phenyl-S(O)—(C 1 -C 8  alkylenyl); 
 Phenyl-S(O) 2 —(C 1 -C 8  alkylenyl); and 
 Substituted phenyl-S(O) 2 —(C 1 -C 8  alkylenyl); 
 
         Each R 3  independently is selected from:
 Substituted C 1 -C 6  alkyl; 
 Substituted C 3 -C 6  cycloalkyl; 
 Phenyl-(C 1 -C 6  alkylenyl); 
 Substituted phenyl-(C 1 -C 6  alkylenyl); 
 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl-(C 1 -C 6  alkylenyl); 
 5-, 6-, 9-, and 10-membered heteroaryl; 
 Substituted 5-, 6-, 9-, and 10-membered heteroaryl; 
 
         S, T, U, and W each are C—R 4 ; or 
         One of S, T, U, and W is N and the other three of S, T, U, and W are C—R 4 ; or 
         Two of S, T, U, and W are N and the other two of S, T, U, and W are C—R 4 ; or 
         T is C—R 4  and S, U, and W are each N; or 
         U is C—R 4  and S, T, and W are each N; or 
         S is C—R 4  and T, U, and W are each N; 
         Each R 4  independently is selected from: H, F, CH 3 , CF 3 , C(O)H, CN, HO, CH 3 O, C(F)H 2 O, C(H)F 2 O, and CF 3 O; 
         V is a 5-membered heteroarylenyl; and Q is selected from: OCH 2 , N(R 6 )CH 2 , OC(O), CH(R 6 )C(O), OC(NR 6 ), CH(R 6 )C(NR 6 ), N(R 6 )C(O), N(R 6 )C(S), N(R 6 )C(NR 6 ), N(R 6 )CH 2 , SC(O), CH(R 6 )C(S), SC(NR 6 ), trans-(H)C═C(H), cis-(H)C═C(H), C≡C, CH 2 C≡C, C≡CCH 2 , CF 2 C≡C, C≡CCF 2 , 
       
       
         
           
           
               
               
           
         
         
           or V is C(O)O, C(S)O, C(O)N(R 5 ), or C(S)N(R 5 ); and Q is selected from: OCH 2 , N(R 6 )CH 2 , CH(R 6 )C(O), OC(NR 6 ), CH(R 6 )C(NR 6 ), N(R 6 )C(NR 6 ), N(R 6 )CH 2 , CH(R 6 )C(S), SC(NR 6 ), trans-(H)C═C(H), cis-(H)C═C(H), C≡CCH 2 , C≡CCF 2 , 
         
       
       
         
           
           
               
               
           
         
         R 5  is H or C 1 -C 6  alkyl; 
         R 6  is H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl; 3- to 6-membered heterocycloalkyl; phenyl; benzyl; or 5- or 6-membered heteroaryl; 
         X is O, S, N(H), or N(C 1 -C 6  alkyl); 
         Each V 1  is independently C(H) or N; 
         Each “substituted” group contains from 1 to 4 substituents, each independently on a carbon or nitrogen atom, independently selected from:
 C 1 -C 6  alkyl; 
 C 2 -C 6  alkenyl; 
 C 2 -C 6  alkynyl; 
 C 3 -C 6  cycloalkyl; 
 C 3 -C 6  cycloalkylmethyl; 
 Phenyl; 
 Phenylmethyl; 
 3- to 6-membered heterocycloalkyl; 
 3- to 6-membered heterocycloalkylmethyl; 
 cyano; 
 CF 3 ; 
 (C 1 -C 6  alkyl)-OC(O); 
 HOCH 2 ; 
 (C 1 -C 6  alkyl)-OCH 2 ; 
 H 2 NCH 2 ; 
 (C 1 -C 6  alkyl)-N(H)CH 2 ; 
 (C 1 -C 6  alkyl) 2 -NCH 2 ; 
 N(H) 2 C(O); 
 (C 1 -C 6  alkyl)-N(H)C(O); 
 (C 1 -C 6  alkyl) 2 -NC(O); 
 N(H) 2 C(O)N(H); 
 (C 1 -C 6  alkyl)-N(H)C(O)N(H); 
 N(H) 2 C(O)N(C 1 -C 6  alkyl); 
 (C 1 -C 6  alkyl)-N(H)C(O)N(C 1 -C 6  alkyl); 
 (C 1 -C 6  alkyl) 2 -NC(O)N(H); 
 (C 1 -C 6  alkyl) 2 -NC(O)N(C 1 -C 6  alkyl); 
 N(H) 2 C(O)O; 
 (C 1 -C 6  alkyl)-N(H)C(O)O; 
 (C 1 -C 6  alkyl) 2 -NC(O)O; 
 HO; 
 (C 1 -C 6  alkyl)-O; 
 CF 3 O; 
 CF 2 (H)O; 
 CF(H) 2 O; 
 H 2 N; 
 (C 1 -C 6  alkyl)-N(H); 
 (C 1 -C 6  alkyl) 2 -N; 
 O 2 N; 
 (C 1 -C 6  alkyl)-S; 
 (C 1 -C 6  alkyl)-S(O); 
 (C 1 -C 6  alkyl)-S(O) 2 ; 
 (C 1 -C 6  alkyl) 2 -NS(O) 2 ; 
 (C 1 -C 6  alkyl)-S(O) 2 —N(H)—C(O)—(C 1 -C 8  alkylenyl) m ; 
 (C 1 -C 6  alkyl)-C(O)—N(H)—S(O) 2 —(C 1 -C 8  alkylenyl) m ; 
 HO—C(═O)—(C 1 -C 3  alkylenyl); 
 HO—C(═O)—(C 3 -C 6  cycloalkylen-1-yl); 
 Phenyl substituted with 1 or two substituents selected from F, Cl, OH, OCH 3 , C≡N, COOH, COOCH 3 , C(═O)CH 3 , and CF 3 ; 
 5- or 6-membered heteroaryl; 
 5- or 6-membered heteroaryl substituted with 1 substituent selected from F, Cl, OH, OCH 3 , C≡N, COOH, COOCH 3 , C(═O)CH 3 , and CF 3 ; 
 SO 3 H; 
 PO 3 H 2 ; and 
 R 7 R 7a -(J) m -N(H)CH 2 , wherein m is an integer of 0 or 1; J is N—C(═O); and R 7  and R 7a  are independently selected from hydrogen, C 1 -C 6  alkyl, (C 1 -C 6  alkyl)-C(═O), C 1 -C 6  alkyl substituted with 1 or 2 OH, C 1 -C 3  alkyl-O—(C 1 -C 3  alkylenyl), 5- or 6-membered heteroaryl-C(═O), and (C 1 -C 6  alkyl)-S(O) 2 ; or R 7  and R 7a  may be taken together with the nitrogen atom to which they are both bonded to form (i) a 3- to 6-membered heterocycloalkyl, optionally substituted with a CH 3  or oxo (i.e., ═O), containing the nitrogen atom, 0 or 10 or S atoms, and carbon atoms or (ii) a 5- or 6-membered heteroaryl containing the nitrogen atom, 0 or 1 additional N atom, and carbon atoms; 
 
         wherein each substituent on a carbon atom may further be independently selected from:
 Halo; 
 HO 2 C; and 
 
         OCH 2 O, wherein each O is bonded to adjacent carbon atoms to form a 5-membered ring; 
         wherein 2 substituents may be taken together with a carbon atom to which they are both bonded to form the group C═O; 
         wherein two adjacent, substantially sp 2  carbon atoms may be taken together with a diradical substituent to form a cyclic diradical selected from: 
       
       
         
           
           
               
               
           
         
         R is H or C 1 -C 6  alkyl; 
         m is an integer of 0 or 1; 
         wherein each 5-membered heteroarylenyl independently is a 5-membered ring containing carbon atoms and from 1 to 4 heteroatoms selected from 1 O, 1 S, 1 NH, 1 N(C 1 -C 6  alkyl), and 4 N, wherein the O and S atoms are not both present, and wherein the heteroarylenyl may optionally be unsubstituted or substituted with 1 substituent selected from fluoro, methyl, hydroxy, trifluoromethyl, cyano, and acetyl; 
         wherein each heterocycloalkyl is a ring that contains carbon atoms and 1 or 2 heteroatoms independently selected from 2 O, 1 S, 1 S(O), 1 S(O) 2 , 1 N, 2 N(H), and 2 N(C 1 -C 6  alkyl), and wherein when two O atoms or one O atom and one S atom are present, the two O atoms or one O atom and one S atom are not bonded to each other, and wherein the ring is saturated or optionally contains one carbon-carbon or carbon-nitrogen double bond; 
         wherein each 5-membered heteroaryl contains carbon atoms and from 1 to 4 heteroatoms independently selected from 1 O, 1 S, 1 N(H), 1 N(C 1 -C 6  alkyl), and 4 N, and each 6-membered heteroaryl contains carbon atoms and 1 or 2 heteroatoms independently selected from N,N(H), and N(C 1 -C 6  alkyl), and 5- and 6-membered heteroaryl are monocyclic rings; and 9- and 10-membered heteroaryl are 6,5-fused and 6,6-fused bicyclic rings, respectively, wherein at least 1 of the 2 fused rings of a bicyclic ring is aromatic, and wherein when the O and S atoms both are present, the O and S atoms are not bonded to each other; 
         wherein with any (C 1 -C 6  alkyl) 2 -N group, the C 1 -C 6  alkyl groups may be optionally taken together with the nitrogen atom to which they are attached to form a 5- or 6-membered heterocycloalkyl; and 
         wherein each group and each substituent recited above is independently selected. 
       
     
     
         11 . The compound according to  claim 10 , or a pharmaceutically acceptable salt thereof, wherein S, T, U, and W are each CH or one of S, T, U, and W is N and the other three of S, T, U, and W are each CH; and Q is C≡C or N(R 6 )C(O). 
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.

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