Fused Pentacyclic Imidazole Derivatives as Modulators of TNF Activity

Abstract

A compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 X represents N or C-F; 
 R 1  represents hydrogen or methyl; 
 R 2  represents hydrogen, methyl or trifluoromethyl; and 
 R 3  represents hydrogen, cyano, hydroxy or hydroxymethyl. 
 
     
     
         2 . A compound as claimed in  claim 1  represented by formula (IIA), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein X, R 1 , R 2  and R 3  are as defined in  claim 1 . 
     
     
         3 . A compound as claimed in  claim 1  represented by formula (IIB), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein X, R 1 , R 2  and R 3  are as defined in  claim 1 . 
     
     
         4 . A compound as claimed in  claim 1  selected from the following:
 cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-1-methyl-cyclobutanecarbonitrile; 
 cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]pyrimidin-2-yl}-1-methyl-cyclobutanecarbonitrile; 
 cis-3-amino-3-{5-[(7R,14R)-1-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzim idazo[1,2-b][2,5]benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-1-methylcyclobutanecarbonitrile; 
 cis-3-amino-3-{5-[(7R,14R)-1 -(difluoromethoxy)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-1-methyl-cyclobutanecarbonitrile; 
 (7R,14R)-11-{6-[(1S,2R)-1-amino-2-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; 
 (7R,14R)-11-{6-[(1R,2S)-1-amino-2-methylcyclobutyl]-5-fluoropyridin-3-yl}-1 -(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; 
 (7R,14R)-11-[6-(cis-1-amino-3-hydroxy-3-methylcyclobutyl)-5-fluoropyridin-3-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11-[6-(cis-1-amino-3-hydroxy-3-methylcyclobutyl)-5-fluoropyridin-3-yl]-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; 
 (7R,14R)-11-{2-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11-{6-[cis-1-am ino-3-(hydroxymethyl)-3-methylcyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11 -{6-[cis-1-am ino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11-{2-[cis-1-amino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11 -{6-[cis-1-am ino-3-hydroxy-3-(trifluoromethyl)cyclobutyl]-5-fluoropyridin-3-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11-(2-{cis-1-amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]-benzodiazocin-5(14H)-one; 
 (7R,14R)-11-{2-[cis-1-amino-3-(hydroxymethyl)-3-methylcyclobutyl]pyrimidin-5-yl}-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one; and 
 (7R,14R)-11-(6-{cis-1-amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-5-fluoropyridin-3-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b]-[2,5]benzodiazocin-5(14H)-one. 
 
     
     
         5 . A compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in therapy. 
     
     
         6 . A compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFα function is indicated. 
     
     
         7 . A compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder. 
     
     
         8 . A pharmaceutical composition comprising a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. 
     
     
         9 . A pharmaceutical composition as claimed in  claim 8  further comprising an additional pharmaceutically active ingredient. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . A method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFα function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         13 . A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method according to  claim 13  wherein the inflammatory or autoimmune disorder is selected from the group consisting of psoriasis, ankylosing spondylitis, psoriatic arthropathy, rheumatoid arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, hidradenitis suppurativa, inflammatory bowel disease, Behçet’s disease, scleroderma, systemic sclerosis, multiple sclerosis, systemic lupus erythematosus, lupus nephritis, fibrosing disorders, and diabetic nephropathy; the neurological or neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, and spinal cord injury; the cardiovascular disorder is selected from the group consisting of cardiac hypertrophy and myocardial infarction; the metabolic disorder is selected from the group consisting of diabetes and metabolic syndrome; the ocular disorder is retinopathy; and the oncological disorder is selected from the group consisting of haematological malignancy and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma). 
     
     
         15 . The method according to  claim 13  wherein the inflammatory bowel disease is selected from Crohn’s disease, ulcerative colitis, indeterminate colitis and pouchitis. 
     
     
         16 . The method according to  claim 13  wherein the inflammatory or autoimmune disorder is a fibrosing disorder selected from hepatic and pulmonary fibrosis. 
     
     
         17 . The method according to  claim 13  wherein the metabolic disorder is insulin-dependent diabetes mellitus or juvenile diabetes. 
     
     
         18 . The method according to  claim 13  wherein the ocular disorder is selected from diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity. 
     
     
         19 . The method according to  claim 13  wherein the oncological disorder is a haematological malignancy selected from leukaemia and lymphoma, or a non-haematological malignancy selected from solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma. 
     
     
         20 . A process for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 X represents N or C-F; 
 R 1  represents hydrogen or methyl; 
 R 2  represents hydrogen, methyl or trifluoromethyl; and 
 R 3  represents hydrogen, cyano, hydroxy or hydroxymethyl, 
comprising reacting a compound of formula (III) with a compound of formula (IV): 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein X, R 1 , R 2  and R 3  are as defined above, L 1  represents a leaving group, M 1  represents a boronic acid moiety —B(OH) 2  or a cyclic ester thereof formed with an organic diol, and R p  represents an N-protecting group; in the presence of a transition metal catalyst; followed, as necessary, by removal of the N-protecting group R p . 
     
     
         21 . The process according to  claim 20 , wherein the leaving group L 1  is a halogen atom. 
     
     
         22 . The process according to  claim 20 , wherein the leaving group L 1  is bromo. 
     
     
         23 . The process according to  claim 20 , wherein the N-protecting group R p  represents tert-butoxycarbonyl or tert-butylsulfinyl. 
     
     
         24 . The process according to  claim 23 , wherein the N-protecting group R p  is removed by treatment with an acid. 
     
     
         25 . The process according to  claim 20 , wherein the transition metal catalyst is tris(dibenzylideneacetone)dipalladium(0), or [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), or chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II). 
     
     
         26 . The process according to  claim 25 , wherein the transition metal catalyst is utilised in conjunction with 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl or tricyclohexylphosphonium tetrafluoroborate. 
     
     
         27 . The process according to  claim 20 , wherein the reaction between the compound of formula (III) and the compound of formula (IV) is performed in the presence of potassium phosphate or potassium carbonate. 
     
     
         28 . The process according to  claim 20 , wherein M 1  represents a cyclic ester of moiety —B(OH) 2  formed with pinacol and the compound of formula (IV) is prepared by reacting bis-(pinacolato)diboron with a compound of formula (V): 
       
         
           
           
               
               
           
         
       
       wherein L 2  represents a suitable leaving group; in the presence of a transition metal catalyst. 
     
     
         29 . A compound which is: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       .