Substituted aromatic compounds for inflammation and immune-related uses

Abstract

The invention relates to compounds of structural formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Y, L, A, W 1 , W 2 , and R′ 1 are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

1 - 21 . (canceled) 
     
     
         22 . A compound represented by formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         Y′ is an optionally substituted monocyclic aryl or an optionally substituted monocyclic heteroaryl; 
         X 3  and X 4  are each, independently, CH, CZ 1  or N, provided that X 3  and X 4  are not both N; 
         L′ is —NRS(O) 2 —, —S(O) 2 NR—, —NRS(O) 2 NR—, —NRC(O)NR—, —NRC(NR)NR—, —NRC(S)NR—, —NRCH 2 NR—, —NRN═CR 6 —, —C(NR)—, —N═CH—, —CH═N—, —NR—NR—C(O)—, or —CR 6 ═NNR—; 
         Z 1  and Z 2  are each, independently, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ; 
         Z 3  is an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ; 
         R, for each occurrence, is independently —H, alkyl, —C(O)—R 7 , or —C(O)OR 7 ; 
         R 1  and R 2 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 1  and R 2  taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl; 
         R 4  and R 5 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 6 , for each occurrence, is —H or alkyl; 
         R 7 , for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and 
         p is 0, 1, or 2; 
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         23 - 32 . (canceled) 
     
     
         33 . The compound of  claim 22 , wherein L′ is —NHS(O) 2 —, —S(O) 2 NH—, —NHS(O) 2 NH—, —NHC(O)NH—, —NHC(NH)NH—, —NHC(S)NH—, —NHCH 2 NH—, —NHN═CR 6 —, —C(NH)—, or —CR 6 ═NNH—. 
     
     
         34 - 43 . (canceled) 
     
     
         44 . The compound of  claim 22 , wherein:
 Y′ is an optionally substituted phenyl, an optionally substituted pyridinyl, an optionally substituted pyridazinyl, an optionally substituted thiadiazolyl, or an optionally substituted thiophenyl;   L′ is —NHS(O) 2 —, —NHC(O)NH—, —NHC(S)NH—, or —NHN═CH—;   X 3  and X 4  are each CH;   Z 2  is halo, a lower alkyl, or a lower alkoxy; and   Z 3  is an optionally substituted phenyl, —C(O)OR 4 , an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, an optionally substituted furanyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, or an optionally substituted tetrazolyl.   
     
     
         45 . The compound of  claim 44 , wherein Z 3  is oxazol-2-yl, oxazol-5-yl, thiazol-2-yl, thiazol-5-yl, [1,3,4]oxadiazol-2-yl, —C(O)OCH 2 CH 2 CH 3 , —C(O)OCH 2 CH 3 , or —C(O)OCH 3 . 
     
     
         46 . The compound of  claim 45 , wherein L′ is —NHS(O) 2 — or —NHC(O)NH—. 
     
     
         47 . The compound of  claim 46 , wherein Y′ is an optionally substituted phenyl or an optionally substituted pyridinyl. 
     
     
         48 . The compound of  claim 47 , wherein Y′ is a difluorophenyl. 
     
     
         49 . A compound represented by formula (III): 
       
         
           
           
               
               
           
         
         wherein: 
         Y′ is an optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; 
         X′ 3  and X′ 4  are each, independently, CH or N, provided that X′ 3  and X′ 4  are not both N; 
         L″ is —NRS(O) 2 —, —S(O) 2 NR—, —NRS(O) 2 NR—, —NRC(O)NR—, —NRC(NR)NR—, —NRC(S)NR—, —NRCH 2 NR—, —NRN═CR 6 —, —C(NR)—, —CR 6 ═NNR—, —N═CH—, —CH═N—, —NR—NR—C(O)—, —CH═CH—, or —C≡C—; 
         Z 2  is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ; 
         Z′ 3  is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ; 
         R, for each occurrence, is independently —H, alkyl, —C(O)—R 7 , or —C(O)OR 7 ; 
         R 1  and R 2 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 1  and R 2  taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl; 
         R 4  and R 5 , for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 6 , for each occurrence, is —H or alkyl; 
         R 7 , for each occurrence, is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and 
         p is 0, 1, or 2; 
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         50 - 59 . (canceled) 
     
     
         60 . The compound of  claim 49 , wherein L″ is —NHS(O) 2 —, —S(O) 2 NH—, —NHS(O) 2 NH—, —NHC(O)NH—, —NHC(NH)NH—, —NHC(S)NH—, —NHCH 2 NH—, —NHN═CR 6 —, —C(NH)—, —CR 6 ═NNH—, —CH═CH—, or —C≡C—. 
     
     
         61 - 68 . (canceled) 
     
     
         69 . The compound of  claim 49 , wherein:
 Y′ is an optionally substituted phenyl, an optionally substituted pyridinyl, an optionally substituted pyridazinyl, an optionally substituted thiadiazolyl, or an optionally substituted thiophenyl;   L″ is —NHS(O) 2 —, —NHC(O)NH—, —CH═CH—, —NHC(S)NH—, or —NHN═CH—;   X 3  and X 4  are each CH;   Z 2  is halo, a lower alkyl, or a lower alkoxy; and   Z′ 3  is an optionally substituted phenyl, —C(O)OR 4 , an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, an optionally substituted furanyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, or an optionally substituted tetrazolyl.   
     
     
         70 . The compound of  claim 69 , wherein Z′ 3  is oxazol-2-yl, oxazol-5-yl, thiazol-2-yl, thiazol-5-yl, [1,3,4]oxadiazol-2-yl, —C(O)OCH 2 CH 2 CH 3 , —C(O)OCH 2 CH 3 , or —C(O)OCH 3 . 
     
     
         71 . The compound of  claim 70 , wherein L″ is —NHS(O) 2 — or —NHC(O)NH—. 
     
     
         72 - 93 . (canceled) 
     
     
         94 . A method for treating or preventing an immune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 22 . 
     
     
         95 - 96 . (canceled) 
     
     
         97 . A method for treating or preventing an inflammatory condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 22 . 
     
     
         98 - 99 . (canceled) 
     
     
         100 . A method for suppressing the immune system of a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 22 . 
     
     
         101 . (canceled) 
     
     
         102 . A method for treating or preventing an allergic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 22 . 
     
     
         103 - 104 . (canceled) 
     
     
         105 . A method for treating or preventing an immune disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 49 . 
     
     
         106 . A method for treating or preventing an inflammatory condition in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 49 . 
     
     
         107 . A method for suppressing the immune system of a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 49 . 
     
     
         108 . A method for treating or preventing an allergic disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of  claim 49 .