Mif modulators

Abstract

The invention provides novel heterocyclic compounds, pharmaceutical compositions and methods of treatment that modulate levels of MIF expression and treat disorders associated with high or low levels of MIF expression.

1 - 86 . (canceled) 
     
     
         87 . A compound, or a pharmaceutically acceptable salt or enantiomer thereof, having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are each independently H, OH, CN, NO 2 , F, Cl, Br, I, or C 1 -C 4  alkyl optionally substituted with 1 to 3 hydroxyl groups, 1 to 3 independently selected halogen groups, —(CH 2 ) j OR a , —(CH 2 ) j C(O)R a , or —(CH 2 ) j OC(O)R a ; 
 Z 1 , Z 2 , Z 3 , Z 4  and Z 5  are each independently H or C 1 -C 3  alkyl optionally substituted with 1 to 3 hydroxyl groups, 1 to 3 independently selected halogen groups, —(CH 2 ) j OR a , —(CH 2 ) j C(O)R a , or —(CH 2 ) j —OC(O)R a ; 
 R a  is H or a C 1 -C 3  alkyl optionally substituted with 1 to 3 hydroxyl groups or 1 to 3 independently selected halogen groups; 
 j is independently at each occurrence 0, 1, 2 or 3. 
 
     
     
         88 . The compound of  claim 87 , wherein Z 3  is selected from the group consisting of H, C 1 , OCH 3 , and CN. 
     
     
         89 . The compound of  claim 87 , wherein Z 2  and Z 4  are each independently selected from the group consisting of H, OCH 3 , CHO, CH 2 OAc, and CH 2 OCH 3 . 
     
     
         90 . The compound of  claim 87 , wherein R 2  is selected from the group consisting of H, NO 2 , CF 3 , F, Br, and CN. 
     
     
         91 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or enantiomer thereof. 
     
     
         92 . A pharmaceutical composition comprising the compound of  claim 87  and a pharmaceutically acceptabl carrier, additive, or excipient. 
     
     
         93 . A pharmaceutical composition comprising the compound of  claim 91  and a pharmaceutically acceptable carrier, additive, or excipient. 
     
     
         94 . The pharmaceutical composition of  claim 92 , further comprising an additional anticancer agent or antiviral agent. 
     
     
         95 . A method of treating or ameliorating in a subject a disease or disorder associated with higher than normal MIF expression, the method comprising administering to the subject a therapeutically effective amount of at least one compound of  claim 87 , wherein the disease or disorder associated with high MIF expression is an autoimmune disease, inflammatory disease, cancer, infection, anemia of chronic disease, malaria, asthma, or autism spectrum disorder. 
     
     
         96 . The method of  claim 95 , wherein:
 (a) the inflammatory disease comprises rheumatoid arthritis, costochondritis, lupus, multiple sclerosis, Perthes' disease, Lyme disease and inflammatory bowel disease, gastritis, uncontrolled skin inflammation, or pulmonary pneumonitis;   (b) the infection is caused by a flavivirus;   (c) the cancer comprises stomach cancer, colon cancer, rectal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervix uteri cancer, corpus uteri cancer, ovary cancer, prostate cancer, testis cancer, bladder cancer, renal cancer, brain/CNS cancer, head and neck cancer, throat cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, glioma, teratoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, kidney cancer, or other lymphoma.   
     
     
         97 . A method of treating or ameliorating in a subject a disease or disorder associated with lower than normal MIF expression, the method comprising administering to the subject a therapeutically effective amount of at least one compound of  claim 87 , wherein the disease or disorder associated with lower than normal MIF expression comprises an acute infection, bacterial infection, viral infection, fungal infection, sepsis, infection that leads to a respiratory disease, respiratory disease resulting from an infection, and infection caused by gram positive bacteria, gram negative bacteria, or mycobacteria. 
     
     
         98 . The method of  claim 97 , wherein at least one applies:
 (a) the disease is an infection caused by  Mycobacterium tuberculosis, Pneumocystis, Candida, Histoplasma , varicella, or corona virus; meningitis; influenza; retroviral infection; or pneumonia caused by a bacterial, viral or fungal infection;   (b) the disease is Community Acquired Pneumonia (CAP); HIV infection; or an infection caused by a virus or other pathogen that uses the CCR5 receptor for infection;   (c) the disease is HIV-1; HCV; Epstein-Barr Virus; or  Yersinia pestis.