Benzimidazole derivatives and their use as protein kinase inhibitors

Abstract

The invention provides compounds of the formula (I): The compounds have activity against cyclin dependent kinases, glycogen synthase kinase and Aurora kinases and are therefore useful to treat cancer and viral diseases.

1 . A combination comprising:
 (i) a compound of the formula (VII):   
       
         
           
           
               
               
           
         
       
       or a salt or N-oxide thereof; 
       wherein A is —(CH 2 ) m —B—; where m is 0 or 1, and B is C═O or NH(C═O); and 
       R 1d  is a group R 1  where R 1  is hydrogen, an optionally substituted carbocyclic or heterocyclic group having from 3 to 12 ring members, or an optionally substituted C 1-8  hydrocarbyl group, 
       wherein the optional substituents for the C 1-8  hydrocarbyl group are selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C 1-4  hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 ring members; 
       and, wherein the carbocyclic and heterocyclic groups in each instance are unsubstituted or substituted by one or more substituent groups R 10  selected from: 
       halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R a -R b  wherein R a  is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c  or NR c SO 2 ; and R b  is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C 1-8  hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-8  hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1  or X 1 C(X 2 )X 1 ; or two adjacent groups R 10 , together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S; 
       R c  is selected from hydrogen and C 1-4  hydrocarbyl; and
 X 1  is O, S or NR c  and X 2  is ═O, ═S or ═NR c ; 
 
       and provided that where the substituent group R 10  comprises or includes a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or is itself substituted with one or more further substituent groups R 10′ , wherein (a) such further substituent groups R 10′  include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (b) the said further substituent groups R 10′  do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R 10 ; and
 (ii) one or more other therapeutic agents. 
 
     
     
         2 . A combination according to  claim 1 , wherein the compound or salt or N-oxide thereof, is of the formula (VIIa): 
       
         
           
           
               
               
           
         
       
     
     
         3 . A combination according to  claim 1 , wherein R 1  is unsubstituted. 
     
     
         4 . A combination according to  claim 1 , wherein R 1  is a substituted or unsubstituted non-aromatic carbocyclic group having from 3 to 6 ring members. 
     
     
         5 . A combination according to  claim 4 , wherein the substituted or unsubstituted non-aromatic carbocyclic group R 1  is a cycloalkyl group. 
     
     
         6 . A combination according to  claim 2 , wherein A is NH(C═O). 
     
     
         7 . A combination according to  claim 5 , wherein R 1  is an unsubstituted cycloalkyl group and A is NH(C═O). 
     
     
         8 . A combination according to  claim 1 , wherein at least one of the one or more other therapeutic agents is an anticancer agent selected from:
 topoisomerase inhibitors;   alkylating agents;   antimetabolites;   DNA binders;   microtubule inhibitors; and   radiotherapy.   
     
     
         9 . A combination according to  claim 8 , wherein at least one of the one or more other therapeutic agents is an anticancer agent selected from cisplatin, cyclophosphamide, doxorubicin, irinotecan, fludarabine, 5FU, taxanes, and mitomycin C. 
     
     
         10 . A combination according to  claim 1 , wherein the compound of the formula (VII) or salt or N-oxide thereof and one, two, three, four or more other therapeutic agents are formulated together in a dosage form containing two, three, four or more therapeutic agents. 
     
     
         11 . A pharmaceutical composition comprising a combination as defined in  claim 1 , together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, or lubricants. 
     
     
         12 . A pharmaceutical composition comprising a combination as defined in  claim 8 , together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, or lubricants. 
     
     
         13 . A process for the preparation of a compound as defined in  claim 1 , which process comprises:
 reacting a compound of the formula:   
       
         
           
           
               
               
           
         
         with a compound of the formula R 1d -A′ wherein A′ is an isocyanate group N═C═O, or a group CO 2 H or an activated derivative thereof and R 1d  is a group R 1  as defined in  claim 1 ; 
         and optionally thereafter converting one compound of the formula (VII) into another compound of the formula (VII). 
       
     
     
         14 . A process for the preparation of a compound as defined in  claim 1 , which process comprises:
 reacting a compound of the formula:   
       
         
           
           
               
               
           
         
         with a diamine compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein R 1d  is R 1  as defined in  claim 1 ; and optionally thereafter converting one compound of the formula (VII) into another compound of the formula (VII). 
       
     
     
         15 . A method for treating cancer, which method comprises administering to a mammal in need thereof a combination according to  claim 1 . 
     
     
         16 . A method according to  claim 15 , wherein the compound of formula (VII) or salt or N-oxide thereof and the one or more other therapeutic agents are administered either simultaneously or sequentially. 
     
     
         17 . A method for treating a cancer, which method comprises administering to a patient in need thereof in an amount sufficient to achieve the desired therapeutic effect a compound of the formula (VII): 
       
         
           
           
               
               
           
         
         or a salt or N-oxide thereof; 
         wherein A is —(CH 2 ) m —B—; where m is 0 or 1, and B is C═O or NH(C═O); and 
         R 1d  is a group R 1  where R 1  is hydrogen, an optionally substituted carbocyclic or heterocyclic group having from 3 to 12 ring members, or an optionally substituted C 1-8  hydrocarbyl group, 
         wherein the optional substituents for the C 1-8  hydrocarbyl group are selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C 1-4  hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 ring members; 
         and, wherein the carbocyclic and heterocyclic groups in each instance are unsubstituted or substituted by one or more substituent groups R 10  selected from: 
         halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R a -R b  wherein R a  is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c  or NR c SO 2 ; and R b  is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C 1-8  hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-8  hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1  or X 1 C(X 2 )X 1 ; or two adjacent groups R 10 , together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S; 
         R c  is selected from hydrogen and C 1-4  hydrocarbyl; and
 X 1  is O, S or NR c  and X 2  is ═O, ═S or ═NR c ; 
 
         and provided that where the substituent group R 10  comprises or includes a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or is itself substituted with one or more further substituent groups R 10′ , wherein (a) such further substituent groups R 10′  include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (b) the said further substituent groups R 10′  do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R 10 . 
       
     
     
         18 . A method according to  claim 17 , wherein the cancer is a hematopoietic tumour of lymphoid lineage selected from leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, and Burkett's lymphoma. 
     
     
         19 . A method according to  claim 17 , wherein the cancer is a hematopoietic tumour of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia. 
     
     
         20 . A method for treating a disease or condition, which method comprises administering to a mammal in a therapeutically effective amount a compound of the formula (VII): 
       
         
           
           
               
               
           
         
         or a salt or N-oxide thereof; 
         wherein A is —(CH 2 ) m —B—; where m is 0 or 1, and B is C═O or NH(C═O); and 
         R 1d  is a group R 1  where R 1  is hydrogen, an optionally substituted carbocyclic or heterocyclic group having from 3 to 12 ring members, or an optionally substituted C 1-8  hydrocarbyl group, 
         wherein the optional substituents for the C 1-8  hydrocarbyl group are selected from hydroxy, oxo, alkoxy, carboxy, halogen, cyano, nitro, amino, mono- or di-C 1-4  hydrocarbylamino, and monocyclic or bicyclic carbocyclic and heterocyclic groups having from 3 to 12 ring members; 
         and, wherein the carbocyclic and heterocyclic groups in each instance are unsubstituted or substituted by one or more substituent groups R 10  selected from: 
         halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R a -R b  wherein R a  is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR c , SO 2 NR c  or NR c SO 2 ; and R b  is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C 1-8  hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C 1-8  hydrocarbyl group may optionally be replaced by O, S, SO, SO 2 , NR c , X 1 C(X 2 ), C(X 2 )X 1  or X 1 C(X 2 )X 1 ; or two adjacent groups R 10 , together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered heteroaryl ring or a 5- or 6-membered non-aromatic carbocyclic or heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S; 
         R c  is selected from hydrogen and C 1-4  hydrocarbyl; and
 X 1  is O, S or NR c  and X 2  is ═O, ═S or ═NR c ; 
 
         and provided that where the substituent group R 10  comprises or includes a carbocyclic or heterocyclic group, the said carbocyclic or heterocyclic group is unsubstituted or is itself substituted with one or more further substituent groups R 10′ , wherein (a) such further substituent groups R 10′  include carbocyclic or heterocyclic groups, which are not themselves further substituted; or (b) the said further substituent groups R 10′  do not include carbocyclic or heterocyclic groups but are otherwise selected from the groups listed above in the definition of R 10 , 
         wherein the disease or condition is:
 viral infections, for example herpes virus, pox virus, Epstein-Barr virus, Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDS development in HIV-infected individuals; or 
 chronic inflammatory diseases, for example systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes mellitus; or 
 neurodegenerative disorders, for example Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellar degeneration; or 
 cardiovascular diseases for example cardiac hypertrophy, restenosis, and atherosclerosis, or such as arrhythmia; or 
 glomerulonephritis; or 
 myelodysplastic syndrome; or 
 ischemic injury associated myocardial infarctions, stroke and reperfusion injury; or 
 toxin-induced or alcohol related liver diseases; or 
 haematological diseases, for example, chronic anemia and aplastic anemia; or 
 degenerative diseases of the musculoskeletal system, for example, osteoporosis and arthritis, or 
 aspirin-sensitive rhinosinusitis; or 
 cystic fibrosis; or 
 multiple sclerosis, or 
 kidney diseases; or 
 cancer pain.