Benzimidazole derivatives

Abstract

Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of inflammatory and immune-related conditions or disorders. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, immune response regulation and cell proliferation. The subject compounds are 2-amino-imidazole derivatives.

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt or prodrug thereof, wherein
 R 1  is selected from the group consisting of H, (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 8 )alkyl, heterocyclo(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 8 )alkyl, arylhetero(C 1 -C 8 )alkyl and heteroaryl; 
 R 2  is selected from the group consisting of (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, perfluoro(C 1 -C 4 )alkyl, aryl and heteroaryl; 
 Y is selected from the group consisting of C(O), S(O) m , S(O) 2 NR′, C(O)NR′, CR 3 R 4 , C(NR′), C(═CR 3 R 4 ), CR 3 (OR′) and CR 3 (NR′R″), wherein the subscript m is an integer selected from 1 to 2; 
 Z 1  and Z 2  are independently selected from the group consisting of H, halogen, CN, CO 2 R′, CONR′R″, (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, perfluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, NR′R″ and OR′, or Z 1  and Z 2  may be combined to an additional fused 5-, 6-, 7- or 8-membered cycloalkane, heterocycloalkane, aromatic or heteroaromatic ring; 
 R 3  and R 4  are independently selected from the group consisting of H, CN, CO 2 R′, CONR′R″, (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, heteroaryl, NR′R″ and OR′; 
 R′ and R″ are independently selected from the group consisting of H, (C 1 -C 4 )alkyl, hetero(C 1 -C 4 )alkyl, aryl and aryl(C 1 -C 4 )alkyl; 
 alternatively, when R′ and R″ are attached to nitrogen, R′ and R″ may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring; and 
 alternatively, when Y is CR 3 R 4 , C(NR′), C(═CR 3 R 4 ), CR 3 (OR′) or CR 3 (NR′R″), then R 3 , R 4  or R′ may be combined with R 2  to form a 5-, 6-, 7- or 8-membered ring containing from 0 to 3 heteroatoms selected from the group consisting of O, N, Si and S; 
 with the proviso that R 1  is not 3-(dialkylamino)propyl when Y is C(O) and Z 1  and Z 2  are combined to form an additional fused benzene ring. 
 
   
   
       2 .- 12 . (canceled) 
   
   
       13 . The compound of  claim 1 , wherein Z 1  and Z 2  are combined to form an additional fused 6-membered cycloalkane, heteroaromatic or heterocycloalkane ring. 
   
   
       14 . The compound of  claim 13 , wherein Z 1  and Z 2  are combined to form an additional fused benzene ring. 
   
   
       15 . The compound of  claim 13 , wherein Z 1  and Z 2  are combined to form an additional fused cyclohexane ring. 
   
   
       16 . The compound of  claim 13 , wherein Z 1  and Z 2  are combined to form an additional fused pyridine ring. 
   
   
       17 . The compound of  claim 13 , wherein Z 1  and Z 2  are combined to form an additional fused tetrahydropyran ring. 
   
   
       18 . The compound of  claim 1 , having the formula (II): 
     
       
         
         
             
             
         
       
     
     wherein
 D, E, F and G are independently selected from the group consisting of CR′″ and N, wherein each R′″ is independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R 1  and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2, or R′″ may be combined with R 1  to form an additional 5-, 6-, 7- or 8-membered ring or an adjacent R′″ to form an additional fused 5-,6-, 7- or 8-membered ring. 
 
   
   
       19 . The compound of  claim 18 , having the formula (IIa): 
     
       
         
         
             
             
         
       
     
     wherein
 R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
 alternatively, R 5 , R 6  or R 7  may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7  and R 8  to form an additional fused 5-, 6-, 7- or 8-membered ring; and R 8  may be combined with R 7  to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1  to form an additional 5-, 6-, 7- or 8-membered ring. 
 
   
   
       20 . (canceled) 
   
   
       21 . The compound of  claim 19 , wherein R 6  is selected from the group consisting of 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       22 .- 23 . (canceled) 
   
   
       24 . The compound of  claim 18 , having the formula (IIb): 
     
       
         
         
             
             
         
       
     
     wherein
 R 5 , R 6  and R 8  are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
 alternatively, R 6  may be combined with R 5  to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8  may be combined with R 1  to form an additional fused 5-, 6-, 7- or 8-membered ring. 
 
   
   
       25 . The compound of  claim 18 , having the formula (IIc): 
     
       
         
         
             
             
         
       
     
     wherein
 R 5 , R 6  and R 7  are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
 alternatively, R 6  may be combined with R 5  or R 7  to form an additional fused 5-, 6-, 7- or 8-membered ring. 
 
   
   
       26 . The compound of  claim 1 , having the formula (III): 
     
       
         
         
             
             
         
       
     
     wherein
 J, K, L and M are independently selected from the group consisting of CRaRb, NRa and O, wherein Ra and Rb are independently selected from the group consisting of H, halogen, CN, CO 2 R′, CONR′R″, (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, heteroaryl, NR′R″ and OR′; 
 alternatively, J, K or L may be combined with an adjacent R group selected from R a  and le to form an additional fused 5-, 6-, 7- or 8-membered ring and M may be combined with an adjacent R group selected from R a  and R b  to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1  to form an additional fused 5-, 6-, 7- or 8-membered ring. 
 
   
   
       27 .- 39 . (canceled) 
   
   
       40 . The compound of claim  39   1 , having the formula (IV): 
     
       
         
         
             
             
         
       
     
     wherein
 R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
 alternatively, R 5 , R 6  or R 7  may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7  and R 8  to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8  may be combined with R 7  to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1  to form an additional 5-, 6-, 7- or 8-membered ring. 
 
   
   
       41 . A compound of  claim 1 , having the formula (V): 
     
       
         
         
             
             
         
       
       whereinp 
       R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
       alternatively, R 5 , R 6  or R 7  may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7  and R 8  to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8  may be combined with R 7  to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1  to form an additional 5-, 6-, 7- or 8-membered ring. 
     
   
   
       42 . A compound of  claim 1 , having the formula (VI): 
     
       
         
         
             
             
         
       
       wherein 
       R 5 , R 6 , R 7  and R 8  are independently selected from the group consisting of H, halogen, (C 1 C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
       alternatively, R 5 , R 6  or R 7  may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7  and R 8  to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8  may be combined with R 7  to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1  to form an additional 5-, 6-, 7- or 8-membered ring. 
     
   
   
       43 .- 49 . (canceled) 
   
   
       50 . A compound of  claim 40 , having the formula (VII): 
     
       
         
         
             
             
         
       
       wherein 
       R 9 , R 10 , R 11 , R 12  and R 13  are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, hetero(C 1 -C 4 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′ and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2; 
       alternatively, R 9 , R 10 , R 11 , R 12  or R 13  may be combined with an adjacent R group selected from the group consisting of R 9 , R 10 , R 11 , R 12  and R 13  to form an additional fused 5-, 6-, 7- or 8-membered ring. 
     
   
   
       51 .- 53 . (canceled) 
   
   
       54 . The compound of  claim 50 , having the formula (VIIc): 
     
       
         
         
             
             
         
       
     
   
   
       55 .- 62 . (canceled) 
   
   
       63 . The compound of  claim 50 , having the formula (VIIa): 
     
       
         
         
             
             
         
       
     
     wherein
 the subscript n is an integer from 1 to 5; and 
 X is selected from the group consisting of H, OR′, NR′R″, OC(O)R′, CO 2 R′, C(O)NR′R″, OC(O)NR′R″, NR″C(O)R′ and NR″CO 2 . 
 
   
   
       64 . (canceled) 
   
   
       65 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of any one of  claims 1 ,  13 - 19 ,  21 ,  24 - 26 ,  40 - 42 ,  50 ,  54  and  63 . 
   
   
       66 .- 78 . (canceled)