Mnk inhibitors and methods related thereto

Abstract

The present invention relates to compounds according to Formula (I): or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , W 1 , W 2 , Y and n are as defined herein. Also described are pharmaceutically acceptable compositions of Formula I compounds as well as methods for utilizing the compounds of Formula I and the pharmaceutically acceptable compositions of Formula I compounds as inhibitors of Mnk as well as therapeutics for the treatment of diseases such as cancer.

1 . A method for treating a disease or condition in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of at least one MAP kinase interacting kinase (Mnk) inhibitor and at least one other therapeutic agent, wherein the at least one other therapeutic agent is other than the at least one Mnk inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         3 . The method of  claim 1 , wherein the at least one other therapeutic agent is an anti-cancer agent. 
     
     
         4 . The method of  claim 3 , wherein the anti-cancer agent is a chemo-therapeutic drug. 
     
     
         5 . The method of  claim 3 , wherein the anti-cancer agent is selected from folate antagonists, antiproliferative agents, antimitotic agents, microtubule inhibiting agents, DNA damaging agents, DNA synthesis inhibitors, DNA interactive agents, DNA repair inhibitors, antiplatelet agents, antimetabolites, hormones, hormone analogs, aromatase inhibitors, fibrinolytic agents, antimigratory agents, antisecretory agents, immunosuppressives, anti-angiogenic compounds, growth factor inhibitors, angiotensin receptor blocker, nitric oxide donors, anti-sense oligonucleotides, antibodies, chimeric antigen receptors, cell cycle inhibitors, differentiation inducers, mTOR inhibitors, topoisomerase inhibitors, corticosteroids, growth factor signal transduction kinase inhibitors, mitochondrial dysfunction inducers, caspase activators, and inhibitors of chromatin function. 
     
     
         6 . The method of  claim 1 , wherein the Mnk inhibitor is a compound according to Formula (I): 
       
         
           
           
               
               
           
         
         or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, wherein:
 W 1  and W 2  are independently O, S or N—OR′, wherein R′ is lower alkyl; 
 Y is —N(R 5 )—, —O—, —S—, —C(O)—, —S═O, —S(O) 2 —, or —CHR 9 —, wherein R 5  is hydrogen, cyano, or lower alkyl; 
 R 1  is hydrogen, lower alkyl, cycloalkyl or heterocyclyl, wherein any lower alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; 
 n is 1, 2 or 3; 
 R 2  and R 3  are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene is optionally substituted with 1, 2 or 3 J groups; 
 or R 2  and R 3  taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; 
 R 4a  and R 4b  are each independently hydrogen, halogen, hydroxyl, thiol, hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl; 
 R 6 , R 7  and R 8  are each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups; 
 or R 5  and R 8  taken together with the atoms to which they are attached form a fused heterocyclyl optionally substituted with 1, 2 or 3 J groups; 
 or R 7  and R 8  taken together with the atoms to which they are attached form a fused heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J groups; 
 wherein each J group is independently —SH, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —S(O)NH 2 , —S(O)NR 9 R 9 , —NH 2 , —NR 9 R 9 , —COOH, —C(O)OR 9 , —C(O)R 9 , —C(O)—NH 2 , —C(O)—NR 9 R 9 , hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH 2 —C(O)-alkylene, NR 9 R 9 —C(O)-alkylene, —CHR 9 —C(O)-lower alkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkyl alkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, —CHR 9 —C(O)-cycloalkyl, —C(O)— cycloalkyl, —CHR 9 —C(O)-aryl, —CHR 9 -aryl, —C(O)-aryl, —CHR 9 —C(O)-heterocycloalkyl, —C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl; or any two J groups bound to the same carbon or hetero atom may be taken together to form oxo; and 
 R 9  is hydrogen, lower alkyl or —OH. 
 
       
     
     
         7 . The method of  claim 6 , wherein n is 1. 
     
     
         8 . The method of  claim 6 , wherein R 2  and R 3  taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups selected from the group consisting of halogen, —CN, methyl, difluoroethylene, trifluoroethylene, and methylenenitrile. 
     
     
         9 . The method of  claim 8 , wherein R 2  and R 3  taken together with the carbon atom to which they are attached form a cyclohexyl or piperidine ring. 
     
     
         10 . The method of  claim 6 , wherein:
 R 4a  and R 4b  are each independently hydrogen, halogen, or alkyl;   R 6  and R 8  are hydrogen; and   R 7  is amino, cycloalkyl carbonylaminyl, heterocyclylaminyl, or cycloalkylalkylene.   
     
     
         11 . The method of  claim 6 , wherein and W is O or S, and Y is —N(R 5 )—, wherein R 5  is hydrogen. 
     
     
         12 . The method of  claim 6 , wherein the compound according to Formula (I) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof. 
       
     
     
         13 . The method of  claim 1 , wherein the disease or condition is associated with over-expression or hyperactivation of eukaryotic initiation factor 4E (eIF4E). 
     
     
         14 . The method of  claim 1 , wherein the disease or condition is cancer. 
     
     
         15 . The method of  claim 14 , wherein the cancer is selected from a solid tumor and a hematological cancer. 
     
     
         16 . The method of  claim 14 , wherein the cancer is selected from colorectal cancer, bladder cancer, gastric cancer, esophageal cancer, head and neck cancer, CNS cancer, malignant glioma, glioblastoma, hepatocellular cancers, thyroid cancer, lung cancer, non-small cell cancer, small cell lung cancer, melanoma, myeloma, pancreatic cancer, pancreatic carcinoma, renal cell carcinoma, cervical cancer, urothelial cancer, prostate cancer, castration-resistant prostate cancer, ovarian cancer, breast cancer, triple-negative breast cancer, leukemia, Hodgkins lymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuse large B-cell lymphoma, Burkitts lymphoma, multiple myeloma, and myelodysplastic syndrome. 
     
     
         17 . The method of  claim 14 , wherein the mammal exhibits resistance to cancer therapy with an mTOR inhibitor. 
     
     
         18 . The method of  claim 1 , wherein the disease or condition is selected from an inflammatory disease. 
     
     
         19 . The method of  claim 18 , wherein the disease or condition is an inflammatory disease selected from inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis, rubella arthritis, acute synovitis and gouty arthritis; sunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema, dermatitis, acute or chronic graft formation, atopic dermatitis, contact dermatitis, urticaria and scleroderma; inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis, and diverticulitis; nephritis, urethritis, salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupus erythematosus, multiple sclerosis, asthma, meningitis, myelitis, encephalomyelitis, encephalitis, phlebitis, thrombophlebitis, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory lung disease, adult respiratory distress syndrome, allergic rhinitis; endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valve disease, rheumatic aortic valve disease, prostatitis, prostatocystitis, spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis, myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis or bursitis, gout, pseudo gout, vasculitides, granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon, Sjogren's syndrome, neuroinflammatory disease, sepsis, conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis, lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis, laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis, gingivitis, oesophagitis, gastritis, peritonitis, hepatitis, cholelithiasis, cholecystitis, glomerulonephritis, goodpasture's disease, crescentic glomerulonephritis, pancreatitis, endomyometritis, myometritis, metritis, cervicitis, endocervicitis, exocervicitis, parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis, pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatric arthropathies, intestinal fibrosis, bronchiectasis and enteropathic arthropathies.