Heteroaryl sulfonamides and ccr2/ccr9

Abstract

Compounds are provided that act as potent antagonists of the CCR2 receptor. Animal testing demonstrates that these compounds are useful for treating inflammation, a hallmark disease for CCR2. The compounds are generally aryl sulfonamide derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR2-mediated diseases, and as controls in assays for the identification of CCR2 antagonists.

1 . A compound of the formula (I), or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 Ar is selected from the group consisting of substituted or unsubstituted C 6-10  aryl and substituted or unsubstituted 5- to 10-membered heteroaryl; 
 R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 Y 1  is selected from the group consisting of —CR 2a —, —N—, and —N + (O) − —; 
 Y 2  is selected from the group consisting of —CR 2b —, —N—, and —N + (O) − —; 
 Y 3  is selected from the group consisting of —CR 2c —, —N—, and —N + (O) − —;
 R 2a , R 2b , and R 2  are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 3 , —CO 2 R 3 , —C(O)NR 3 R 4 , —OR 3 , —OC(O)R 3 , —OC(O)NR 3 R 4 , —SR 3 , —S(O)R 3 , —S(O) 2 R 3 , —S(O) 2 NR 3 R 4 , —NO 2 , —NR 3 R 4 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 R 4 , —NR 3 C(O)NR 4 R 5 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
 R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 R 3  and R 4 , R 4  and R 5  or R 3  and R 5  may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; 
 
 
 L is selected from the group consisting of a bond, —O—, —S—, —S(O)—, S(O) 2 —, —CR 6 R 7 —, —NR 8 —, —C(O)— and —NR 8 C(O)—;
 R 6  and R 7  are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —CN, —OR 9 , —NR 10 R 11 , —S(O)R 9 , and —S(O) 2 R 9 ; 
 R 6  and R 7  may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8  cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
 R 9  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 R 10  and R 11  are each independently selected from the group consisting of substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 2-8  alkenyl, and substituted or unsubstituted C 2-8  alkynyl; 
 R 10  and R 11  of —NR 10 R 11  may, together with the nitrogen, form a substituted or unsubstituted C 3-8  cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 
 R 8  is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6  alkenyl, and substituted or unsubstituted C 2-6  alkynyl;
 R 12  is selected from the group consisting of substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; 
 
 
 Z 1  is selected from the group consisting of substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —NR 13 R 14 ;
 R 13  and R 14  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C 1-4  alkyl)-(C 6-10  aryl), and substituted or unsubstituted (C 1-4  alkyl)-(5- to 10-membered heteroaryl); 
 R 13  and R 14  may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl; 
 
 Y 4  is selected from the group consisting of —N— and —N + (O) − —;
  with the proviso that compounds of formula CC are excluded from formula (I): 
 
 
       
         
           
           
               
               
           
         
       
       where
 X 14  is selected from the group consisting of —Cl, —NO 2 , —OCH 3 , —CH 3 , —NHC(O)CH 3 , and —CH 2 CH 2 — (phenyl); 
 R 65  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-4  alkyl, and substituted or unsubstituted —SO 2 (phenyl); and 
 R 60  is selected from the group consisting of —NR 61 CH 2 CH 2 OR 62 , —NR 61 CH 2 CH 2 NR 63 R 64 , —NR 61 CH 2 CH 2 SR 62 , 
 
       
         
           
           
               
               
           
         
         
           where R 61  is selected from the group consisting of hydrogen and substituted or unsubstituted phenyl; 
           R 62  is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted C 1-4  alkyl; and 
           R 63  and R 64  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted —SO 2 (phenyl), —C(O)CH 3 , —C(O)C(O)OH, and —C(O) 2 C(CH 3 ) 3 . 
         
       
     
     
         2 . The compound of  claim 1 , which is represented by formula (II) or a salt thereof: 
       
         
           
           
               
               
           
         
         Y 5 , Y 6  and Y 7  are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 15 , —CO 2 R 15 , —C(O)NR 15 R 16 , —OR 15 , —OC(O)R 15 , —OC(O)NR 15 R 16 , —SR 15 , —S(O)R 15 , —S(O) 2 R 15 , —S(O) 2 NR 15 R 16 , —NO 2 , —NR 15 R 16 , —NR 15 C(O)R 16 , —NR 15 C(O)OR 16 , —NR 15 S(O) 2 R 16 , —NR 15 C(O)NR 16 R 17 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
 R 15 , R 16  and R 17  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 R 15  and R 16 , R 16  and R 17  or R 15  and R 17  may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring. 
 
       
     
     
         3 . The compound of  claim 1 , which is represented by formula (CLI) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 X b  is selected from the group consisting of —OR 24a , and substituted or unsubstituted C 1-8  alkyl;
 R 24a  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and 
 
 Y b  is selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 27a , —CO 2 R 27a , —C(O)NR 27a R 28a , —OR 27a , —OC(O)R 27a , —OC(O)NR 27a R 28a , —SR 27a , —S(O)R 27a , —S(O) 2 R 27a , —S(O) 2 NR 27a R 28a , —NO 2 , —NR 27a R 28a , —NR 27a C(O)R 28a , —NR 27a C(O) 2 R 28a , —NR 27a S(O) 2 R 28a , —NR 27a C(O)NR 28a R 29a , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
 R 27a , R 28a  and R 29a  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 R 27a  and R 28a , R 28a  and R 29a  or R 27a  and R 29a  may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; and 
 
 Z b  is substituted or unsubstituted C 1-8  alkyl. 
 
     
     
         4 . The compound of  claim 1 , which is represented by formula (CLII) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 X b  is selected from the group consisting of —OR 24a , and substituted or unsubstituted C 1-8  alkyl;
 R 24a  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and 
 
 Z b  is —OR 30a ;
 R 30a  is selected from the group consisting of hydrogen and substituted or unsubstituted C 1-8  alkyl. 
 
 
     
     
         5 . The compound of  claim 1 , which is represented by formula (CLIII) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 X b  is selected from the group consisting of —OR 24a , and substituted or unsubstituted C 1-8  alkyl;
 R 24a  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; and 
 
 Z b  is halogen. 
 
     
     
         6 . (canceled) 
     
     
         7 . A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of a compound of formula (I), or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 Ar is selected from the group consisting of substituted or unsubstituted C 6-10  aryl and substituted or unsubstituted 5- to 10-membered heteroaryl; 
 R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 Y 1  is selected from the group consisting of —CR 2a —, —N—, and —N + (O) − —; 
 Y 2  is selected from the group consisting of —CR 2b —, —N—, and —N + (O) − —; 
 Y 3  is selected from the group consisting of —CR 2c —, —N—, and —N + (O) − —;
 R 2a , R 2b , and R 2  are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 3 , —CO 2 R 3 , —C(O)NR 3 R 4 , —OR 3 , —OC(O)R 3 , —OC(O)NR 3 R 4 , —SR 3 , —S(O)R 3 , —S(O) 2 R 3 , —S(O) 2 NR 3 R 4 , —NO 2 , —NR 3 R 4 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 R 4 , —NR 3 C(O)NR 4 R 5 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl;
 R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 R 3  and R 4 , R 4  and R 5  or R 3  and R 5  may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; 
 
 
 Y 4  is selected from the group consisting of —N— and —N + (O) − —; 
 L is selected from the group consisting of a bond, —O—, —S—, —S(O)—, S(O) 2 —, —CR 6 R 7 —, —NR 8 —, —C(O)— and —NR 8 C(O)—;
 R 6  and R 7  are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —CN, —OR 9 , —NR 10 R 11 , —S(O)R 9 , and —S(O) 2 R 9 ; 
 R 6  and R 7  may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8  cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring;
 R 9  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 R 10  and R 11  are each independently selected from the group consisting of substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 2-8  alkenyl, and substituted or unsubstituted C 2-8  alkynyl; 
 R 10  and R 11  of —NR 10 R 11  may, together with the nitrogen, form a substituted or unsubstituted C 3-8  cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclyl; 
 
 R 8  is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6  alkenyl, and substituted or unsubstituted C 2-6  alkynyl;
 R 12  is selected from the group consisting of substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; 
 
 
 Z 1  is selected from the group consisting of substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —NR 13 R 14 ;
 R 13  and R 14  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C 1-4  alkyl)-(C 6-10  aryl), and substituted or unsubstituted (C 1-4  alkyl)-(5- to 10-membered heteroaryl); 
 R 13  and R 14  may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl. 
 
 
     
     
         8 - 20 . (canceled) 
     
     
         21 . A compound of the formula (I), or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where
 Ar is substituted or unsubstituted C 6-10  aryl; 
 R 1  is selected from the group consisting of hydrogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 1  is —CR 2a —; 
 Y 2  is —CR 2b —; 
 Y 3  is —CR 2c —; 
 Y 4  is selected from the group consisting of —CR 2d —, —N— and —N + (O) − —; 
 R 2a , R 2b , R 2c  and R 2d  are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl; 
 L is —C(O)—, —C(═N—O—R 8 )—, or bond; and 
 Z 1  is substituted or unsubstituted 3- to 10-membered heterocyclic or substituted or unsubstituted 5- to 10-membered heteroaryl. 
 
     
     
         22 . The compound of  claim 21 , which is of the formula (Ia) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where:
 X 3  and X 4  are each independently hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, —ON, or C 1-8  haloalkyl, provided that at least one of X 3  or X 4  is other than hydrogen; 
 each X 2 , X 5 , and X 6  is independently hydrogen, halogen, or substituted or unsubstituted C 1-4  alkyl; 
 R 1  is hydrogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 6  is halogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 7  is hydrogen or substituted or unsubstituted C 1-4  alkyl; 
 L is selected from the group consisting of a bond, —C(O)—, and —C(═N—O—R 9 )—; 
 Z 6  and Z 7  are each independently selected from —CR 67 —, —N—, and —N + (O) − —;
 each R 67  is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, —ON, ═O, —NO 2 , —OR 68 , —OC(O)R 68 , —CO 2 R 68 , —C(O)R 68 , —C(O)NR 69 R 68 , —OC(O)NR 69 R 68 , —NR 70 C(O)R 68 , —NR 70 C(O)NR 69 R 68 , —NR 69 R 68 , —NR 70 CO 2 R 68 , —SR 68 , —S(O)R 68 , —S(O) 2 R 68 , —S(O) 2 NR 69 R 68 , —NR 70 S(O) 2 R 68 , substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocyclyl;
 each occurrence of R 68 , R 69 , and R 70  is independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, aryl, or heteroaryl; or R 69  and R 68  or R 70  and R 68 , together with the atom(s) to which they are attached, form an substituted or unsubstituted 5-, 6-, or 7-membered ring; 
 
 R 100  is selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocycle; 
 Y 4  is —CR 2a —, —N—, or —N + (O) − —; 
 Z 3  and Z 5  are —N—, or —N + (O) − —; and 
 Z 4  is —CR 67 —. 
 
 
     
     
         23 . The compound of  claim 22 , which is of the formula (Ib) or a salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 21 , which is of the formula (Ic) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where:
 where X 3  and X 4  are each independently hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, —CN, or C 1-8  haloalkyl, provided that at least one of X 3  or X 4  is other than hydrogen; 
 each X 2 , X 5 , X 6  is independently hydrogen, halogen, or substituted or unsubstituted C 1-4  alkyl; 
 R 1  is hydrogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 6  is halogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 7  is hydrogen or substituted or unsubstituted C 1-4  alkyl; 
 R 100  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocycle; 
 L is selected from the group consisting of a bond, —C(O)—, and —C(═N—O—R 9 )—; 
 Y 4  is —CR 2a —, —N—, or —N + (O) − —; 
 Z 4  is —N—, or —N + (O) − —; and 
 Z 3 , Z 5 , Z 6 , and Z 7  are each independently —CR 67 —;
 each R 67  is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, —CN, ═O, —NO 2 , —OR 68 , —OC(O)R 68 , —CO 2 R 68 , —C(O)R 68 , —C(O)NR 69 R 68 , —OC(O)NR 69 R 68 , —NR 70 C(O)R 68 , —N 70 C(O)NR 69 R 68 , —NR 69 R 68 , —NR 70 CO 2 R 68 , —SR 68 , —S(O)R 68 , —S(O) 2 R 68 , —S(O) 2 NR 69 R 68 , —NR 70 S(O) 2 R 68 , substituted or unsubstituted C 8-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocyclyl;
 each occurrence of R 68 , R 69 , and R 70  is independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, aryl, or heteroaryl; or R 69  and R 68  or R 70  and R 68 , together with the atom(s) to which they are attached, form an substituted or unsubstituted 5-, 6-, or 7-membered ring. 
 
 
 
     
     
         25 . The compound of  claim 24 , which is of the formula (Id): 
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 21 , which is of the formula (Ie) or a salt thereof: 
       
         
           
           
               
               
           
         
       
       where:
 X 3  and X 4  are each independently hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, —CN, or C 1-8  haloalkyl, provided that at least one of X 3  or X 4  is other than hydrogen; 
 each X 2 , X 5 , and X 6  is independently hydrogen, halogen, or substituted or unsubstituted C 1-4  alkyl; 
 R 1  is hydrogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 6  is halogen or substituted or unsubstituted C 1-8  alkyl; 
 Y 7  is hydrogen or substituted or unsubstituted C 1-4  alkyl; 
 R 100  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocycle; 
 L is selected from the group consisting of a bond, —C(O)—, and —C(═N—O—R 9 )—; 
 Y 4  is —CR 2a —, —N—, or —N + (O) − —; 
 Z 3  and Z 4  are each independently —CR 67 —; 
 Z 5  is —N—, or —N + (O) − —; 
 Z 6  and Z 7  are each independently —CR 67 —, —N—, or —N + (O) − —; and
 each R 67  is independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, —CN, ═O, —NO 2 , —OR 68 , —OC(O)R 68 , —CO 2 R 68 , —C(O)R 68 , —C(O)NR 69 R 68 , —OC(O)NR 69 R 68 , —NR 70 C(O)R 68 , —N 70 C(O)NR 69 R 68 , —NR 69 R 68 , —NR 70 CO 2 R 68 , —SR 68 , —S(O)R 68 , —S(O) 2 R 68 , —S(O) 2 NR 69 R 68 , —NR 70 S(O) 2 R 68 , substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl and substituted or unsubstituted 3- to 10-membered heterocyclyl;
 each occurrence of R 68 , R 69 , and R 70  is independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, aryl, or heteroaryl; or R 69  and R 68  or R 70  and R 68 , together with the atom(s) to which they are attached, form an substituted or unsubstituted 5-, 6-, or 7-membered ring. 
 
 
 
     
     
         27 . The compound of  claim 26 , which is of the formula (If): 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 26 , which is of the formula (Ig): 
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         30 . A composition comprising a pharmaceutically acceptable carrier and the compound or salt of  claim 21 . 
     
     
         31 . A method for treating a CCR2-mediated condition or disease comprising administering to a subject an effective amount of the compound or salt of  claim 21 . 
     
     
         32 . The method of  claim 31 , where the CCR2-mediated disease or condition is atherosclerosis, restenosis, multiple sclerosis, inflammatory bowel disease, renal fibrosis, rheumatoid arthritis, obesity, diabetes, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, idiopathic pneumonia syndrome, pulmonary fibrosis, transplantation rejection, graft-versus-host disease, cancer and neuropathic pain. 
     
     
         33 . The method of  claim 31 , where the administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical. 
     
     
         34 . The method of  claim 31 , further comprising administering an anti-inflammatory or analgesic agent. 
     
     
         35 . A method of modulating CCR2 function in a cell, comprising contacting the cell with a CCR2 modulating amount of the compound of  claim 21 .