3-Phenyl-7-Hydroxy-Isocoumarins as Macrophage Migration Inhibitory Factor (MIF) Inhibitors

Abstract

Provided herein are 3-phenyl-7-hydroxy-isocoumarin compounds which are MIF inhibitors; compositions comprising said inhibitors and methods for treating or preventing diseases associated with MIF.

1 - 46 . (canceled) 
     
     
         47 . A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein p is 4; z is 0 to 4;
 R 1  is C 1 -C 12  aliphatic; 
 
         wherein R 1  can be unsubstituted or substituted with at least one of a halogen, a hydroxyl, an amino group, a sulfonyl group, a sulphonamide group, a thiol, a C 1 -C 6  alkyl, a C 1 -C 6  alkoxy, a C 1 -C 6  ether, a C 1 -C 6  thioether, a C 1 -C 6  ester, a C 1 -C 6  ketone, a C 1 -C 6  ketimine, a C 1 -C 6  sulfone, a C 1 -C 6  sulfoxide, a C 1 -C 6  primary amide, a C 1 -C 6  secondary amide, a halo C 1 -C 6  alkyl, a carboxyl group, a cyano group, a nitro group, a nitroso group, —C(O)O—C 1 -C 6  alkyl, —OC(O)O—C 1 -C 6  alkyl, —OC(O)NR′R′, —N(R′)C(O)NR′R′, —N(R′)C(O)O—C 1 -C 6  alkyl, or oxo; wherein R′ is independently selected for each occurrence, from the group consisting of hydrogen and C 1 -C 6  alkyl;
 R 2  is independently selected from the group consisting of hydrogen, an amino group, a halogen, a cyano group, a nitro group, a nitroso group, and C 1 -C 12  aliphatic; 
 R 3  is hydrogen; 
 
         wherein independently any R 2  can be unsubstituted or substituted with at least one of a halogen, a hydroxyl, an amino group, a sulfonyl group, a sulphonamide group, a thiol, a C 1 -C 6  alkyl, a C 1 -C 6  alkoxy, a C 1 -C 6  ether, a C 1 -C 6  thioether, a C 1 -C 6  ester, a C 1 -C 6  ketone, a C 1 -C 6  ketimine, a C 1 -C 6  sulfone, a C 1 -C 6  sulfoxide, a C 1 -C 6  primary amide, a C 1 -C 6  secondary amide, a halo C 1 -C 6  alkyl, a carboxyl group, a cyano group, a nitro group, a nitroso group, —C(O)O—C 1 -C 6  alkyl, —OC(O)O—C 1 -C 6  alkyl, —OC(O)NR′R′, —N(R′)C(O)NR′R′, —N(R′)C(O)O—C 1 -C 6  alkyl, or oxo; wherein each R′ is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; or a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate thereof. 
       
     
     
         48 . The method of treating cancer as claimed in  claim 47 , wherein R 1  is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl and octyl. 
     
     
         49 . The method of treating cancer as claimed in  claim 47 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         50 . The method of treating cancer as claimed in  claim 47 , wherein the cancer is selected from the group consisting of: lung cancer, ovarian cancer, breast cancer, hepatocellular cancer, oesophageal squamous-cell cancer, bladder cancer, cervical squamous-cell cancer, pancreatic cancer, glioblastomas, prostate cancer, osteosarcoma, colorectal cancer, head and neck cancer and malignant melanoma, gastric cancer, glioma, and nasopharyngeal cancer. 
     
     
         51 . The method of treating cancer as claimed in  claim 47 , wherein the cancer is lung cancer, ovarian cancer or breast cancer. 
     
     
         52 . A method of treating cancer comprising administering to a patient in need thereof a pharmaceutical composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein p is 4; z is 0 to 4;
 R 1  is C 1 -C 12  aliphatic; 
 
         wherein R 1  can be unsubstituted or substituted with at least one of a halogen, a hydroxyl, an amino group, a sulfonyl group, a sulphonamide group, a thiol, a C 1 -C 6  alkyl, a C 1 -C 6  alkoxy, a C 1 -C 6  ether, a C 1 -C 6  thioether, a C 1 -C 6  ester, a C 1 -C 6  ketone, a C 1 -C 6  ketimine, a C 1 -C 6  sulfone, a C 1 -C 6  sulfoxide, a C 1 -C 6  primary amide, a C 1 -C 6  secondary amide, a halo C 1 -C 6  alkyl, a carboxyl group, a cyano group, a nitro group, a nitroso group, —C(O)O—C 1 -C 6  alkyl, —OC(O)O—C 1 -C 6  alkyl, —OC(O)NR′R′, —N(R′)C(O)NR′R′, —N(R′)C(O)O—C 1 -C 6  alkyl, or oxo; wherein R′ is independently selected for each occurrence, from the group consisting of hydrogen and C 1 -C 6  alkyl;
 R 2  is independently selected from the group consisting of hydrogen, an amino group, a halogen, a cyano group, a nitro group, a nitroso group, and C 1 -C 12  aliphatic; 
 R 3  is hydrogen; 
 
         wherein independently any R 2  can be unsubstituted or substituted with at least one of a halogen, a hydroxyl, an amino group, a sulfonyl group, a sulphonamide group, a thiol, a C 1 -C 6  alkyl, a C 1 -C 6  alkoxy, a C 1 -C 6  ether, a C 1 -C 6  thioether, a C 1 -C 6  ester, a C 1 -C 6  ketone, a C 1 -C 6  ketimine, a C 1 -C 6  sulfone, a C 1 -C 6  sulfoxide, a C 1 -C 6  primary amide, a C 1 -C 6  secondary amide, a halo C 1 -C 6  alkyl, a carboxyl group, a cyano group, a nitro group, a nitroso group, —C(O)O—C 1 -C 6  alkyl, —OC(O)O—C 1 -C 6  alkyl, —OC(O)NR′R′, —N(R′)C(O)NR′R′, —N(R′)C(O)O—C 1 -C 6  alkyl, or oxo; wherein each R′ is independently selected from the group consisting of hydrogen and C 1 -C 6  alkyl; or a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrate thereof. 
       
     
     
         53 . The method of treating cancer as claimed in  claim 52 , wherein R 1  is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, hexyl, heptyl and octyl. 
     
     
         54 . The method of treating cancer as claimed in  claim 52 , wherein the compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         55 . The method of treating cancer as claimed in  claim 52 , wherein the cancer is selected from the group consisting of: lung cancer, ovarian cancer, breast cancer, hepatocellular cancer, oesophageal squamous-cell cancer, bladder cancer, cervical squamous-cell cancer, pancreatic cancer, glioblastomas, prostate cancer, osteosarcoma, colorectal cancer, head and neck cancer and malignant melanoma, gastric cancer, glioma, and nasopharyngeal cancer. 
     
     
         56 . The method of treating cancer as claimed in  claim 52 , wherein the cancer is lung cancer, ovarian cancer or breast cancer.