Macrophage Migration Inhibitory Factor Inhibitors, and Methods of Making and Using Same

Abstract

The present invention provides novel inhibitors of MIF tautomerase activity. In certain embodiments, the compounds of the invention are useful in treating or preventing inflammatory and/or auto-immune diseases. In other embodiments, the compounds of the invention are useful in reversing, ameliorating, and/or preventing tumor growth. In yet other embodiments, the compounds of the invention are useful in reversing, ameliorating, and/or preventing angiogenesis.

1 - 14 . (canceled) 
     
     
         15 . A method of inhibiting macrophage migration inhibitory factor (MIF) activity in a subject, the method comprising
 administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:   
       
         
           
           
               
               
           
         
       
       wherein:
 A is CR 5  or N; 
 R 1  is: 
 (a) methyl substituted with at least one selected from the group consisting of —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, and —OC(═O)NRR; or 
 (b) selected from the group consisting of propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, cyclopropylmethyl, and C 1 -C 6  heteroalkyl; or 
 (c) selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl, and C 1 -C 6  heteroalkyl, wherein the ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, cyclopropylmethyl or heteroalkyl group is substituted with at least one selected from the group consisting of —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, 
 R 2  and R 3  are independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, (C 3 -C 7  cycloalkyl)-C 1 -C 4  alkylene, (C 6 -C 10  aryl)-C 1 -C 4  alkylene, (5-10 membered heteroaryl)-C 1 -C 4  alkylene, (4-10 membered heterocyclyl)-C 1 -C 4  alkylene, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, 
 or one of R 2  and R 3  is -L-R 11 , wherein:
 L is selected from the group consisting of a bond, —O—, —N(R)—, C 1 -C 4  alkylene, —C(═O)—, —N(R)C(═O)—, and —C(═O)N(R)—; and 
 R 11  is optionally substituted phenyl, pyridinyl, or pyrimidinyl; 
 
 R 4 , R 5 , R 6 , and R 10  are each independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; 
 R 7 , R 8 , and R 9  are independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, (C 3 -C 7  cycloalkyl)-C 1 -C 4  alkylene, (C 6 -C 10  aryl)-C 1 -C 4  alkylene, (5-10 membered heteroaryl)-C 1 -C 4  alkylene, (4-10 membered heterocyclyl)-C 1 -C 4  alkylene, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, 
 each occurrence of R is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heterocyclyl, or the two R bound to the same N optionally form a C 3 -C 8  heterocyclyl group; 
 each occurrence of R′ is independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heterocyclyl; 
 each alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl group is optionally substituted with at least one substituent selected from the group consisting of halogen, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, and 
 each phenyl or heteroaryl group is optionally substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 3 -C 7  cycloalkyl-C 1 -C 4  alkylene, C 6 -C 10  aryl-C 1 -C 4  alkylene, 5-10 membered heteroaryl-C 1 -C 4  alkylene, 4-10 membered heterocyclyl-C 1 -C 4  alkylene, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR. 
 
     
     
         16 . A method of treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is selected from the group consisting of an inflammatory disease or condition, an autoimmune disease, cancer, a disease or condition that is associated with high MIF expression, and anemia of chronic disease, the method comprising
 administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:   
       
         
           
           
               
               
           
         
       
       wherein:
 A is CR 5  or N; 
 R 1  is: 
 (a) methyl substituted with at least one selected from the group consisting of —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, and —OC(═O)NRR, or 
 (b) selected from the group consisting of propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, cyclopropylmethyl, and C 1 -C 6  heteroalkyl; or 
 (c) selected from the group consisting of ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl, and C 1 -C 6  heteroalkyl, wherein the ethyl, propyl, isopropyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, cyclopropylmethyl or heteroalkyl group is substituted with at least one selected from the group consisting of —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, 
 R 2  and R 3  are independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, (C 3 -C 7  cycloalkyl)-C 1 -C 4  alkylene, (C 6 -C 10  aryl)-C 1 -C 4  alkylene, (5-10 membered heteroaryl)-C 1 -C 4  alkylene, (4-10 membered heterocyclyl)-C 1 -C 4  alkylene, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, 
 or one of R 2  and R 3  is -L-R 11 , wherein:
 L is selected from the group consisting of a bond, —O—, —N(R)—, C 1 -C 4  alkylene, —C(═O)—, —N(R)C(═O)—, and —C(═O)N(R)—; and 
 R 11  is optionally substituted phenyl, pyridinyl, or pyrimidinyl; 
 
 R 4 , R 5 , R 6 , and R 10  are each independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; 
 R 7 , R 8 , and R 9  are independently selected from the group consisting of H, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, (C 3 -C 7  cycloalkyl)-C 1 -C 4  alkylene, (C 6 -C 10  aryl)-C 1 -C 4  alkylene, (5-10 membered heteroaryl)-C 1 -C 4  alkylene, (4-10 membered heterocyclyl)-C 1 -C 4  alkylene, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, 
 each occurrence of R is independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heterocyclyl, or the two R bound to the same N optionally form a C 3 -C 8  heterocyclyl group; 
 each occurrence of R′ is independently selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl, or C 3 -C 8  heterocyclyl; 
 each alkyl, alkenyl, alkynyl, cycloalkyl, or heterocyclyl group is optionally substituted with at least one substituent selected from the group consisting of halogen, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR, and 
 
       each phenyl or heteroaryl group is optionally substituted with at least one substituent selected from the group consisting of halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, C 3 -C 7  cycloalkyl-C 1 -C 4  alkylene, C 6 -C 10  aryl-C 1 -C 4  alkylene, 5-10 membered heteroaryl-C 1 -C 4  alkylene, 4-10 membered heterocyclyl-C 1 -C 4  alkylene, nitro, —CN, —OR, —NRR, —C(═O)R, —C(═O)OR, —C(═O)NRR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR, —N(R)C(═O)R, —N(R)C(═O)OR, —N(R)C(═O)NRR, —SR, —S(═O)R′, —S(═O) 2 R′, and —S(═O) 2 NRR. 
     
     
         17 . The method of  claim 16 , wherein the inflammatory disease or condition is selected from the group consisting of proliferative vascular disease, acute respiratory distress syndrome, cytokine-mediated toxicity, psoriasis, interleukin-2 toxicity, appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, ulcerative, pseudomembranous, acute and ischemic colitis, diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, inflammatory bowel disease, Crohn's disease, enteritis, Whipple's disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliac disease, congestive heart failure, meningitis, encephalitis, multiple sclerosis, cerebral infarction, cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture's syndrome, Behcets's syndrome, allograft rejection, graft-versus-host disease, ankylosing spondylitis, Berger's disease, type 1 diabetes, type 2 diabetes, Berger's disease, Retier's syndrome, and Hodgkin's disease. 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 16 , wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, graft versus host disease, autoimmune pulmonary inflammation, autoimmune encephalomyelitis, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitus, Crohn's disease, scleroderma, psoriasis, Sjögren's syndrome, and autoimmune inflammatory eye disease. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 16 , wherein the cancer is a solid tumor or a hematological cancer. 
     
     
         22 . The method of  claim 16 , wherein the cancer is selected from the group consisting of prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head or neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, lymphoma, leukemia, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 16 , wherein the disease or condition associated with high MIF expression is selected from the group consisting of protozoal infection, fungal infection, bacterial infection, viral infection, anemia of chronic disease, asthma, and autism spectrum disorder (ASD). 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 16 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 16 , wherein R 1  is selected from the group consisting of —CH 2 CH 2 OH, —CH 2 CH 2 NH 2 , —CH 2 CH 2 OCH 2 CH 2 OH, —CH 2 CH 2 OCH 2 CH 2 NH 2 , —CH 2 CH 2 OCH 2 CH 2 -4-morpholinyl, —CH 2 COOH, —CH 2 CH 2 COOH, and —CH 2 CH 2 CH 2 COOH. 
     
     
         28 . The method of  claim 16 , wherein R 2  is H or —OR. 
     
     
         29 . The method of  claim 16 , wherein R 3  is selected from the group consisting of H, C 6 -C 10  aryl, and —OR. 
     
     
         30 . The method of  claim 29 , wherein R 3  is H, unsubstituted phenyl, or phenyl substituted with 1 substituent selected from the group consisting of C 1 -C 6  alkyl, halogen, C 1 -C 6  alkoxy, and —OR″, wherein R″ is unsubstituted phenyl or phenyl substituted with 1 group independently selected from the group consisting of —OR and —C(═O)OR. 
     
     
         31 . The method of  claim 16 , wherein one of R 2  and R 3  is -L-R 11 . 
     
     
         32 . The method of  claim 16 , wherein L is O or NH. 
     
     
         33 . The method of  claim 16 , wherein R 2  and an optional substituent in R 11  are independently selected from the group consisting of H, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy-C 1 -C 6  alkyl, carboxy, carboxy-C 1 -C 6  alkyl, amino-C 1 -C 6  alkyl, C 1 -C 6  alkylamino-C 1 -C 6  alkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkyl, amino-C 1 -C 6  alkoxy-C 1 -C 6  alkyl, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy-C 1 -C 6  alkyl, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkoxy-C 1 -C 6  alkyl, 4-10 membered heterocyclyl-C 1 -C 6  alkyl, 4-10 membered heterocyclyl-C 1 -C 6  alkoxy-C 1 -C 6  alkyl, C 1 -C 6  alkoxy-C 1 -C 6  alkoxy, amino-C 1 -C 6  alkoxy, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkoxy, amino-C 1 -C 6  alkoxy-C 1 -C 6  alkoxy, C 1 -C 6  alkylamino-C 1 -C 6  alkoxy-C 1 -C 6  alkoxy, di(C 1 -C 6  alkyl)amino-C 1 -C 6  alkoxy-C 1 -C 6  alkoxy, 4-10 membered heterocyclyl-C 1 -C 6  alkoxy, 4-10 membered heterocyclyl-C 1 -C 6  alkoxy, carboxy-C 1 -C 6  alkoxy, carboxy-C 1 -C 6  alkyl-C 1 -C 6  alkoxy, and carboxy-C 1 -C 6  alkoxy-C 1 -C 6  alkoxy. 
     
     
         34 . The method of  claim 16 , wherein R 4  and R 5  are independently selected from the group consisting of H, F, and C 1 -C 6  alkyl. 
     
     
         35 . The method of  claim 16 , wherein R 6  is H; R 7  is halogen, C 1 -C 6  alkyl, or —OR; R 8  is —OH, halogen, —CN, —OR, —NRR, or —C(═O)NRR; R 9  is H or halogen; and R 10  is H. 
     
     
         36 . The method of  claim 16 , wherein R 6 , R 7 , R 9 , and R 10  are each independently selected from the group consisting of H and F. 
     
     
         37 . The method of  claim 16 , wherein R 8  is selected from the group consisting of H, F, Cl, and —OH.