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 method for treating a disease or condition comprising or arising from abnormal cell growth in a mammal, which method comprises administering to the mammal in an amount effective in inhibiting abnormal cell growth a compound of the formula (VII): 
       
         
           
           
               
               
           
         
         or a salt or N-oxide thereof; 
         wherein A is —(CH 2 ) m —(B) n —; where m is 0 or 1, n is 1 and B is C═O or 
         NR g (C═O); and 
         R g  is hydrogen; 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 may be unsubstituted or may itself be substituted with one or more further substituent groups selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, unsubstituted carbocyclic and unsubstituted 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 1  or NR 1 SO 2 ; and R b  is selected from hydrogen, unsubstituted carbocyclic and unsubstituted 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, unsubstituted carbocyclic and unsubstituted 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 of the further substituent group, together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered unsubstituted heteroaryl ring or a 5- or 6-membered non-aromatic unsubstituted carbocyclic or unsubstituted heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S. 
       
     
     
         2 . A method according to  claim 1 , wherein the compound or salt or N-oxide thereof, is of the formula (VIIa): 
       
         
           
           
               
               
           
         
       
     
     
         3 . A method according to  claim 1 , wherein R 1  is unsubstituted. 
     
     
         4 . A method 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 method according to  claim 4 , wherein the substituted or unsubstituted non-aromatic carbocyclic group R 1  is a cycloalkyl group. 
     
     
         6 . A method according to  claim 2 , wherein A is NH(C═O). 
     
     
         7 . A method according to  claim 1  wherein the disease state is a proliferative disorder. 
     
     
         8 . A method according to  claim 7  wherein the proliferative disorder is a cancer. 
     
     
         9 . A method according to  claim 2  wherein the disease or condition is a cancer. 
     
     
         10 . A method according to  claim 9  wherein the cancer is a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, oesophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, or skin; a hematopoietic tumour of lymphoid lineage; a hematopoietic tumour of myeloid lineage; thyroid follicular cancer; a tumour of mesenchymal origin; a tumour of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma. 
     
     
         11 . A method according to  claim 9  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. 
     
     
         12 . A method according to  claim 9  wherein the cancer is a hematopoietic tumour of myeloid lineage selected from acute and chronic myelogenous leukemias, myelodysplastic syndrome, and promyelocytic leukemia. 
     
     
         13 . A method according to  claim 9  wherein the cancer is selected from breast, bladder, colorectal, pancreatic, ovarian, non-Hodgkin's lymphoma, gliomas and nonendometrioid endometrial carcinomas. 
     
     
         14 . A method according to  claim 9  wherein the cancer is selected from breast cancer, ovarian cancer, colon cancer, prostate cancer, oesophageal cancer, squamous cancer, and non-small cell lung carcinomas. 
     
     
         15 . A method according to  claim 1  wherein the disease or condition is leukemia. 
     
     
         16 . A method according to  claim 6  wherein the disease or condition is leukemia. 
     
     
         17 . A method according to  claim 1  wherein the disease state or condition is mediated by an Aurora kinase. 
     
     
         18 . A method according to  claim 1  wherein the disease state or condition is characterised by up-regulation of an Aurora kinase. 
     
     
         19 . A method for the treatment of a disease state or condition characterised by up-regulation of an Aurora kinase; which method comprises (i) subjecting a patient to a diagnostic test to detect a marker characteristic of up-regulation of the Aurora kinase and (ii) where the diagnostic test is indicative of up-regulation of Aurora kinase, thereafter administering to the patient therapeutically effective amount of a compound of the formula (I) as defined in  claim 1 . 
     
     
         20 . A method for treating a disease or condition, which method comprises administering to the mammal in an amount effective a compound of the formula (VII): 
       
         
           
           
               
               
           
         
         or a salt or N-oxide thereof; 
         wherein A is —(CH 2 ) m —(B) n —; where m is 0 or 1, n is 1 and B is C═O or 
         NR g (C═O); and 
         R g  is hydrogen; 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 1-9  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 1  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 may be unsubstituted or may itself be substituted with one or more further substituent groups selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C 1-4  hydrocarbylamino, unsubstituted carbocyclic and unsubstituted 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, unsubstituted carbocyclic and unsubstituted 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, unsubstituted carbocyclic and unsubstituted 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 of the further substituent group, together with the carbon atoms or heteroatoms to which they are attached may form a 5-membered unsubstituted heteroaryl ring or a 5- or 6-membered non-aromatic unsubstituted carbocyclic or unsubstituted heterocyclic ring, wherein the said heteroaryl and heterocyclic groups contain up to 3 heteroatom ring members selected from N, O and S, 
         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 musculo skeletal system, for example, osteoporosis and arthritis, or 
 aspirin-sensitive rhinosinusitis; or 
 cystic fibrosis; or 
 multiple sclerosis, or 
 kidney diseases; or 
 cancer pain.