2-oxindole compounds

Abstract

Oxindole compounds useful for the treatment of CCR(9) mediated conditions or diseases are provided.

1 . A compound having formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Ar is a 5- to 10-membered aromatic or heteroaromatic ring, optionally substituted with from one to three R; 
         L 1  is selected from the group consisting of a bond, C 1-6  alkylene, and C 1-6  heteroalkylene, 
         L 2  is selected from the group consisting of a bond, C 1-6  alkylene, and C 1-6  heteroalkylene, 
         Y is CO 2 H or a carboxylic acid bioisostere; 
         each R 1  and each R 2a  is independently selected from the group consisting of halogen, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, and C 2-6  alkenyl, wherein the alkyl, cycloalkyl and alkenyl portions are optionally substituted with from one to three members selected from fluoro, OH, CN, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy; 
         R 2b  is selected from the group consisting of H, halogen, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 3-6  cycloalkyl, and C 2-6  alkenyl, wherein the alkyl, cycloalkyl and alkenyl portions are optionally substituted with from one to three members selected from fluoro, CN, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy;
 or optionally one R 2a  and R 2b  when on adjacent vertices of a phenyl ring, may be joined together to form a 5- or 6-membered heterocycloalkyl ring having one or two ring vertices independently selected from O, N and S, wherein said heterocycloalkyl ring is optionally substituted with from one to three members selected from fluoro and C 1-3  alkyl; 
 
         each R 3  is independently selected from the group consisting of halogen, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, and C 2-6  alkenyl; 
         the subscript m is an integer of from 0 to 4; and 
         the subscript n is an integer of from 0 to 3. 
       
     
     
         2 . The compound of  claim 1 , having formula (I′): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         Ar is a 5- to 10-membered aromatic or heteroaromatic ring, optionally substituted with from one to three R 3 ; 
         L 1  is selected from the group consisting of a bond, C 1-6  alkylene, and C 1-6  heteroalkylene, 
         L 2  is selected from the group consisting of a bond, C 1-6  alkylene, and C 1-6  heteroalkylene, 
         each R 1  and each R 2a  is independently selected from the group consisting of halogen, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, and C 2-6  alkenyl, wherein the alkyl, cycloalkyl and alkenyl portions are optionally substituted with from one to three members selected from fluoro, CN, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy; 
         R 2b  is selected from the group consisting of H, halogen, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 3-6  cycloalkyl, and C 2-6  alkenyl, wherein the alkyl, cycloalkyl and alkenyl portions are optionally substituted with from one to three members selected from fluoro, CN, C 1-3  alkyl, C 1-3  haloalkyl, and C 1-3  alkoxy;
 or optionally one R 2a  and R 2b  when on adjacent vertices of a phenyl ring, may be joined together to form a 5- or 6-membered heterocycloalkyl ring having one or two ring vertices independently selected from O, N and S, wherein said heterocycloalkyl ring is optionally substituted with from one to three members selected from fluoro and C 1-3  alkyl; 
 
         each R 3  is independently selected from the group consisting of halogen, cyano, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl, C 1-6  haloalkoxy, C 3-6  cycloalkyl, and C 2-6  alkenyl; 
         the subscript m is an integer of from 0 to 4; and 
         the subscript n is an integer of from 0 to 3. 
       
     
     
         3 . A compound of  claim 1 , wherein Y is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         tetrazolyl and tetrazolonyl, wherein the tetrazolyl or tetrazolonyl is optionally substituted with R, wherein p is 0, 1 or 2 and wherein each R group is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  alkoxy, or C 1 -C 4  alkyl-O—C 1 -C 4  alkyl. 
       
     
     
         4 . A compound of  claim 1 , wherein Y is selected from the group consisting of: tetrazolyl and tetrazolonyl, wherein the tetrazolyl or tetrazolonyl is optionally substituted with C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, —C 1-6  alkoxy or C 1-4 alkyl-O—C 1-4 alkyl. 
     
     
         5 . A compound of  claim 1 , having the formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein said compound is substantially free of other isomers. 
       
     
     
         6 . A compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein L 2  is C 1-3  alkylene and wherein said compound is substantially free of other isomers. 
       
     
     
         7 . A compound of  claim 1 , wherein Ar is selected from benzene, pyridine and quinoline, each of which is optionally substituted with from one to two R 3 . 
     
     
         8 . A compound of  claim 1 , wherein L 1  is selected from the group consisting of a bond, —CH 2 — and —CH(CH 3 )—. 
     
     
         9 . A compound of  claim 1 , wherein L 2  is selected from the group consisting of a
 bond, —O—CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 —, and —CH 2 CH 2 CH 2 —.   
     
     
         10 . A compound of  claim 1 , wherein n is 1 or 2. 
     
     
         11 . A compound of  claim 1 , wherein m is 1, 2 or 3. 
     
     
         12 . A compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . A compound of  claim 12 , wherein Ar is selected from benzene, pyridine and quinoline, each of which is optionally substituted with from one to two R 3 . 
     
     
         14 . A compound of  claim 12 , wherein L 1  is selected from the group consisting of a bond, —CH 2 — and —CH(CH 3 )—. 
     
     
         15 . A compound of  claim 12 , wherein L 2  is selected from the group consisting of a
 bond, —O—CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 —, and —CH 2 CH 2 CH 2 —.   
     
     
         16 . A compound of  claim 12 , having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein said compound is substantially free of other isomers. 
       
     
     
         17 . A compound of  claim 16 , wherein Ar is selected from the group consisting of benzene, pyridine and quinoline, each of which is optionally substituted with from one to two R 3 . 
     
     
         18 . A compound of  claim 16 , wherein Ar is selected from the group consisting of 1,3-phenylene and 1,4-phenylene, each of which is optionally substituted with from one to two R 3 . 
     
     
         19 . A compound of  claim 16 , wherein L 1  is selected from the group consisting of a bond, —CH 2 — and —CH(CH 3 )—. 
     
     
         20 . A compound of  claim 16 , wherein L 2  is selected from the group consisting
 of —O—CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 — and —CH 2 CH 2 CH 2 —.   
     
     
         21 . A compound of  claim 16 , wherein R 1  is selected from the group consisting of halogen, cyano, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 3-5  cycloalkyl, and C 2-3  alkenyl. 
     
     
         22 . A compound of  claim 16 , wherein R 1  is selected from the group consisting of chloro, methyl, cyano, ethyl, cyclopropyl, 3 trifluoromethyl and trifluoromethoxy. 
     
     
         23 . A compound of  claim 16 , having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein said compound is substantially free of other isomers. 
       
     
     
         24 . A compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . A compound of  claim 24 , wherein R 2b  is hydrogen. 
     
     
         26 . A compound of  claim 24 , wherein Ar is selected from the group consisting of benzene, pyridine and quinoline, each of which is optionally substituted with from one to two R 3 . 
     
     
         27 . A compound of  claim 24 , wherein L 1  is selected from the group consisting of a bond, —CH 2 — and —CH(CH 3 )—. 
     
     
         28 . A compound of  claim 24 , wherein L 2  is selected from the group consisting of a
 bond, —O—CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 — and —CH 2 CH 2 CH 2 —.   
     
     
         29 . A compound of  claim 24 , having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein said compound is substantially free of other isomers. 
       
     
     
         30 . A compound of  claim 29 , wherein Ar is selected from the group consisting of benzene, pyridine and quinoline, each of which is optionally substituted with from one to two R 3 . 
     
     
         31 . A compound of  claim 29 , wherein Ar is selected from the group consisting of 1,3-phenylene and 1,4-phenylene, each of which is optionally substituted with from one to two R 3 . 
     
     
         32 . A compound of  claim 29 , wherein R 3  is selected from the group consisting of CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2  and CH 2 OH. 
     
     
         33 . A compound  claim 29 , wherein L 1  is selected from the group consisting of a bond, —CH 2 — and —CH(CH 3 )—. 
     
     
         34 . A compound of  claim 29 , wherein L 2  is selected from the group consisting
 of —O—CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 — and —CH 2 CH 2 CH 2 —.   
     
     
         35 . A compound of  claim 29 , wherein R 1  is selected from the group consisting of halogen, cyano, C 1-3  alkyl, C 1-3  alkoxy, C 1-3  haloalkyl, C 1-3  haloalkoxy, C 3-5  cycloalkyl, and C 2-3  alkenyl. 
     
     
         36 . A compound of  claim 29 , wherein R 1  is selected from the group consisting of chloro, methyl, cyano, ethyl, cyclopropyl, trifluoromethyl and trifluoromethoxy. 
     
     
         37 . A compound of  claim 29 , having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein said compound is substantially free of other isomers. 
       
     
     
         38 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, selected from Table 1 and having activity of ++ or +++. 
     
     
         39 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof, selected from Table 1 and having activity of +++. 
     
     
         40 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and at least one compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         41 . A method of treating a CCR(9) mediated disease or condition in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof, optionally in admixture with a pharmaceutically acceptable excipient or carrier. 
     
     
         42 . A method in accordance with  claim 41 , wherein said disease or condition is selected from the group consisting of inflammatory bowel diseases, an allergic disease, psoriasis, atopic dermatitis, asthma, fibrotic diseases, graft rejection, immune mediated food allergies, autoimmune diseases, Celiac disease, rheumatoid arthritis, thymoma, thymic carcinoma, leukemia, Sjogren syndrome, GvHD (graft versus host disease), graft rejection, solid tumor, or acute lymphocytic leukemia, melanoma, primary sclerosing cholangitis, hepatitis and inflammatory hepatic disease or post-operative ileus. 
     
     
         43 . A method in accordance with  claim 41 , wherein said disease or condition is selected from the group consisting of inflammatory bowel diseases. 
     
     
         44 . A method in accordance with  claim 41 , wherein said disease or condition is selected from the group consisting of Crohn's disease and ulcerative colitis.