Eif4e-inhibiting compounds and methods

Abstract

The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.For Formula I compounds X1, X2, X3, X4, X5, X6, Q, L1, L2, Y, R1, R2, R3, R4, R5, R6, R7, R8 and rings A, B and C are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4e and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.

1 - 29 . (canceled) 
     
     
         30 . A method of treating an eIF4E dependent condition in a subject comprising:
 administering to the subject a compound of Formula III:   
       
         
           
           
               
               
           
         
       
       wherein:
 L 1  is —(CH 2 )—, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —CH((C 1 -C 8 )alkyl)(CH 2 )—, —CH((C 1 -C 8 )alkyl)(CH 2 ) 2 —, —(CH 2 ) 2 —O—, —CH 2 CH═CH—, —CH 2 C≡C— or —CH 2 (cyclopropyl)-; 
 L 2  is —C(R 6 )(R 6 )—, —C(R 6 )(R 6 )C(R 6 )(R 6 )—, —C(R 6 )═C(R 6 )—, —N(R 5 )C(R 6 )(R 6 )—, —OC(R 6 )(R 6 )—, —C(═O)—, —C(═O)N(R 5 )C(R 6 )(R 6 )— or a bond; 
 Ring C is a heteroaryl; 
 R 1  is H, OH, halo, CN, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 3 -C 6 )cycloalkyl or NR 5 R 5 ; 
 R 2  is independently H, halo, CN, NO, NO 2 , C≡CH, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, CH 2 SR 5 , OR 5 , NHR 5 , NR 5 R 5 , [(C 1 -C 8 )alkylene]heterocyclyl, [(C 1 -C 8 )alkylene]heteroaryl, [(C 1 -C 8 )alkylene]NHR 5 , [(C 1 -C 8 )alkylene]NR 5 R 5 , C(O)R 5 , C(O)OR 5 , C(O)NHR 5 , C(O)NR 5 R 5 , SR 5 , S(O)R 5 , SO 2 R 5 , SO 2 NHR 5 , SO 2 NR 5 R 5 , NH(CO)R 6 , NR 5 (CO)R 6 , aryl, heteroaryl, cycloalkyl or heterocyclyl; 
 R 3  is independently OH, halo, CN, NO 2 , (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, C≡CH, NHR 7 , NR 7 R 7 , CO 2 H, CO 2 R 7 , [(C 1 -C 3 )alkylene] (C 1 -C 3 )alkoxy, [(C 1 -C 3 )alkylene]CO 2 H, (C 3 -C 5 )cycloalkyl, ═O. ═S, SR 7 , SO 2 R 7 , NH(CO)R 7  or NR 7 (CO)R 7 ; 
 R 5  is independently H, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 3 -C 5 )cycloalkyl or heterocyclyl; 
 R 6  is independently H, OH, halo, CN, (C 1 -C 3 )alkyl, (C 1 -C 3 )haloalkyl, (C 1 -C 3 )alkoxy, NHR 7 , NR 7 R 7 , CO 2 H, [(C 1 -C 3 )alkylene]CO 2 H, (C 3 -C 5 )cycloalkyl, SR 7 , NH(CO)R 7  or NR 7 (CO)R 7 ; 
 R 7  is independently H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; 
 R 8  is H, OH, CO 2 H, CO 2 R 7 , CF 2 C(R 6 ) 2 OH, C(R 6 ) 2 OH, C(CF 3 ) 2 OH, SO 2 H, SO 3 H, CF 2 SO 2 C(R 6 ) 3 , CF 2 SO 2 N(H)R 5 , SO 2 N(H)R 5 , SO 2 N(H)C(O)R 6 , C(O)N(H)SO 2 R 5 , C(O)haloalkyl, C(O)N(H)OR 5 , C(O)N(R 5 )OH, C(O)N(H)R 5 , C(O)NR 5 C(O)N(R 5 ) 2 , P(O)(OR 5 )OH, P(O)(C(R 6 ) 3 )C(R 6 ) 3 , B(OH) 2 , heterocyclyl or heteroaryl; 
 R 9  is H, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, cycloalkyl or heterocyclyl; 
 m is 0, 1, or 2; 
 n is 0, 1, 2 or 3; 
 p is 0, 1, 2 or 3; 
 wherein any alkyl, alkylene, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2 or 3 groups selected from OH, CN, SH, SCH 3 , SO 2 CH 3 , SO 2 NH 2 , SO 2 NH(C 1 -C 4 )alkyl, halogen, NH 2 , NH(C 1 -C 4 )alkyl, N[(C 1 -C 4 )alkyl] 2 , NH(aryl), C(O)NH 2 , C(O)NH(alkyl), CH 2 C(O)NH(alkyl), COOH, COOMe, acetyl, (C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, O(C 1 -C 8 )alkyl, O(C 1 -C 8 )haloalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, thioalkyl, cyanomethylene, alkylaminyl, alkylene-C(O)NH 2 , alkylene-C(O)—NH(Me), NHC(O)alkyl, CH 2 —C(O)—(C 1 -C 8 )alkyl, C(O)—(C 1 -C 8 )alkyl, and alkylcarbonylaminyl, and 
 one or more other therapeutic agents. 
 
     
     
         31 . The method of  claim 30 , wherein L 2  is a bond. 
     
     
         32 . The method of  claim 30 , wherein Ring C is 
       
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 30 , wherein the compound of Formula (III) is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 30 , wherein the eIF4E dependent condition is selected from the group consisting of cell proliferative disorders, inflammatory diseases, and fibrotic diseases. 
     
     
         35 . The method of  claim 34 , wherein the cell proliferative disorder is cancer, wherein the cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, pancreatic cancer, melanoma, brain cancer, CNS cancer, renal cancer, prostate cancer, ovarian cancer, or breast cancer. 
     
     
         36 . The method of  claim 35 , wherein the cancer is breast cancer, prostate cancer, or lung cancer. 
     
     
         37 . The method of  claim 35 , wherein the cancer is a metastatic cancer. 
     
     
         38 . The method of  claim 35 , wherein the other therapeutic agent is an anti-cancer agent. 
     
     
         39 . The method of  claim 38 , wherein the compound of formula (III) is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         40 . The method of  claim 38 , wherein the anticancer agent is a chemotherapeutic agent, radiation, or an immune checkpoint molecule. 
     
     
         41 . The method of  claim 39 , wherein the chemotherapeutic agent is selected from the group consisting of pyrimidine analogs, purine analogs, folate antagonists, antiproliferative agents, antimitotic agents, microtubule disruptors, DNA damaging agents, antibiotics, enzymes, antiplatelet agents, antiproliferative agents, antimitotic alkylating agents, platinum coordination complexes, hormones, hormone analogs, aromatase inhibitors, anticoagulants, 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, chromatin disruptors, and toxins. 
     
     
         42 . The method of  claim 40 , wherein the compound of formula (III) is 
       
         
           
           
               
               
           
         
       
       and the chemotherapeutic agent is selected from the group consisting of: 5-fluorouracil, floxuridine, capecitabine, gemcitabine, mercaptopurine, thioguanine, pentostatin, 2-chlorodeoxyadenosine, vinblastine, vincristine, and vinorelbine, taxane, vincristin, vinblastin, nocodazole, epothilones, navelbine, etoposide, teniposide, actinomycin, amsacrine, anthracyclines, bleomycin, busulfan, camptothecin, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan, merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin, procarbazine, taxol, taxotere, temozolamide, teniposide, triethylenethiophosphoramide, etoposide, dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin, mitomycin, L-asparaginase, mechlorethamine, cyclophosphamide, melphalan, chlorambucil, hexamethylmelamine, thiotepa, carmustine, streptozocin, trazenes-dacarbazinine, methotrexate, cisplatin, carboplatin, procarbazine, hydroxyurea, mitotane, aminoglutethimide, estrogen, tamoxifen, goserelin, bicalutamide, nilutamide, letrozole, anastrozole, heparin, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab, breveldin, cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolate mofetil, TNP470, genistein, trastuzumab, rituximab, tretinoin, doxorubicin, amsacrine, camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, topotecan, irinotecan, cortisone, dexamethasone, hydrocortisone, methylpednisolone, prednisone, prednisolone, Cholera toxin, ricin,  Pseudomonas  exotoxin, Bordetellapertussis adenylate cyclase toxin, and diphtheria toxin. 
     
     
         43 . The method of  claim 38 , wherein the compound of formula (III) is administered concurrently with the anticancer agent. 
     
     
         44 . The method of  claim 38 , wherein the compound of formula (III) is administered at separately staggered times from the anticancer agent. 
     
     
         45 . The method of  claim 40 , wherein the immune checkpoint molecule is selected from the group consisting of PD-L1, PD-L2, CD80, CD86, B7-H3, B7-H4, HVEM, adenosine, GAL9, VISTA, CEACAM-1, CEACAM-3, CEACAM-5, PVRL2, PD-1, CTLA-4, BTLA, KIR, LAG3, TIM3, A2aR, CD244/2B4, CD160, TIGIT, LAIR-1, PVRIG/CD112R, arginase, indoleamine 2,3-dioxygenase, IL-10, IL-4, IL-1RA, and IL-35. 
     
     
         46 . The method of  claim 34 , wherein the fibrotic disease is selected from the group consisting of viral hepatitis, hepatic fibrosis, schistosomiasis, steatohepatitis, cirrhosis, idiopathic pulmonary fibrosis, systemic sclerosis, nephrogenic systemic fibrosis, diabetes, untreated hypertension, heart attack, hypertension, atherosclerosis, restenosis, macular degeneration, retinal and vitreal retinopathy, keloids, hypertrophic scars, Crohn's disease and Alzheimer's disease. 
     
     
         47 . The method of  claim 34 , wherein the inflammatory disease is selected from the group consisting of chronic inflammation, acute inflammation, chronic inflammatory arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter's syndrome, rheumatoid traumatic arthritis, rubella arthritis, acute synovitis, gouty arthritis; inflammatory skin diseases, sunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema, dermatitis, acute graft formation, chronic graft formation, atopic dermatitis, contact dermatitis, urticaria scleroderma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis, 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, 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, bursitis, gout, pseudo gout, vasculitides, granulomatous thyroiditis, lymphocytic thyroiditis, invasive fibrous thyroiditis, acute thyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud's phenomenon, Sjögren'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. 
     
     
         48 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A compound having the formula: