Substituted quinazoline derivatives and their use as inhibitors

Abstract

The use of a compound of formula (I) or a salt, ester or amide thereof; where X is O, or S, S(O) or S(O) 2 , or NR 6 where R 6 is hydrogen or C 1-6 alkyl; R 5 is an optionally substituted 5-membered heteroaromatic ring, R 1 , R 2 , R 3 , R 4 are independently selected from various specified moieties, in the preparation of a medicament for use in the inhibition of aurora 2 kinase. Certain compounds are novel and these, together with pharmaceutical compositions containing them are also described and claimed.

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       or a salt, ester or amide thereof; 
 where X is O, or S, S(O) or S(O) 2 , or NR 6  where R 6  is hydrogen or C 1-6 alkyl;  
 R 5  is pyrrole, pyrazole, pyrazolone, imidazole, oxazole, furan, tetrazole or triazole, any of which may be optionally substituted,  
 R 1 , R 2 , R 3 , R 4  are independently selected from, halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, —NR 7 R 8  (wherein R 7  and R 8 , which may be the same or different, each represents hydrogen or C 1-3 alkyl), or —X 1 R 9  (wherein X 1  represents a direct bond, —O—, —CH 2 —, —OCO—, carbonyl, —S—, —SO—, —SO 2 —, —NR 10 CO—, —CONR 11 —, —SO 2 NR 12 —, —NR 13 SO 2 — or —NR 14 — (wherein R 10 , R 11 , R 12 , R 13  and R 14  each independently represents hydrogen, C 1-3 alkyl or C 2-3 alkoxyC 2-3 alkyl), and R 9  is selected from one of the following groups:  
 1) hydrogen or C 1-5 alkyl which may be unsubstituted or which may be substituted with one or more groups selected from hydroxy, fluoro or amino,  
 2) C 1-5 alkylX 2 COR 15  (wherein X 2  represents —O— or —NR 16 — (in which R 15  represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 16  represents C 1-3 alkyl, —NR 17 R 18  or —OR 19  (wherein R 17 , R 18  and R 19  which may be the same or different each represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 3) C 1-5 alkylX 3 R 20  (wherein X 3  represents —O—, —S—, —SO—, —SO 2 —, —OCO—, —NR 21 CO—, —CONR 22 —, —SO 2 NR 23 —, —NR 24 SO 2 — or —NR 25 — (wherein R 21 , R 22 , R 23 , R 24  and R 25  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 20  represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl or a 5-6-membered saturated heterocyclic group with 1-2 heteroatoms, selected independently from O, S and N, which C 1-3 alkyl group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy and which cyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy);  
 4) C 1-5 alkylX 4 C 1-5 alkylX 5 R 26  (wherein X 4  and X 5  which may be the same or different are each —O—, —S—, —SO—, —SO 2 —, —NR 27 CO—, —CONR 28 —, —SO 2 NR 29 —, —NR 30 SO 2 — or —NR 31 — (wherein R 27 , R 28 , R 29 , R 30  and R 31  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 26  represents hydrogen or C 1-3 alkyl);  
 5) R 32  (wherein R 32  is a 5-6-membered saturated heterocyclic group (linked via carbon or nitrogen) with 1-2 heteroatoms, selected independently from O, S and N, which heterocyclic group may bear 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulphonylC 1-4 alkyl);  
 6) C 1-5 alkylR 32  (wherein R 32  is as defined hereinbefore);  
 7) C 2-5 alkenylR 32  (wherein R 32  is as defined hereinbefore);  
 8) C 2-5 alkynylR 32  (wherein R 32  is as defined hereinbefore);  
 9) R 33  (wherein R 33  represents a pyridone group, a phenyl group or a 5-6-membered aromatic heterocyclic group (linked via carbon or nitrogen) with 1-3 heteroatoms selected from O, N and S, which pyridone, phenyl or aromatic heterocyclic group may carry up to 5 substituents on an available carbon atom selected from hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxyalkoxy, carboxy, trifluoromethyl, cyano, —CONR 34 R 35  and —NR 36 COR 37  (wherein R 34 , R 35 , R 36  and R 37 , which may be the same or different, each represents hydrogen, C 1-4 alkyl or C 1-3 alkoxyC 2-3 alkyl));  
 10) C 1-5 alkylR 33  (wherein R 33  is as defined hereinbefore);  
 11) C 2-5 alkenylR 33  (wherein R 33  is as defined hereinbefore);  
 12) C 2-5 alkynylR 33  (wherein R 33  is as defined hereinbefore);  
 1 3 ) C 1-5 alkylX 6 R 33  (wherein X 6  represents —O—, —S—, —SO—, —SO 2 —, —NR 38 CO—, —CONR 39 —, —SO 2 NR 40 —, —NR 41 SO 2 — or —NR 42 — (wherein R 38 , R 39 , R 40 , R 41  and R 42  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore);  
 14) C 2-5 alkenylX 7 R 33  (wherein X 7  represents —O—, —S—, —SO—, —SO 2 —, —NR 43 CO—, —CONR 44 —, —SO 2 NR 45 —, —NR 46 SO 2 — or —NR 47 — (wherein R 43 , R 44 , R 45 , R 46  and R 47  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore);  
 15) C 2-5 alkynylX 8 R 33  (wherein X 8  represents —O—, —S—, —SO—, —SO 2 —, —NR 48 CO—, —CONR 49 —, —SO 2 NR 50 —, —NR 51 SO 2 — or —NR 52 — (wherein R 48 , R 49 , R 50 , R 51  and R 52  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore);  
 16) C 1-3 alkylX 9 C 1-3 alkylR 33  (wherein X 9  represents —O—, —S—, —SO—, —SO 2 —, —NR 53 CO—CONR 54 —, —SO 2 NR 55 —, —NR 56 SO 2 — or —NR 57 — (wherein R 53  , R 54 , R 55 , R 56  and R 57  each independently represents hydrogen, C 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl) and R 33  is as defined hereinbefore); and  
 17) C 1-3 alkylX 9 C 1-3 alkylR 32  (wherein X 9  and R 28  are as defined hereinbefore).  
 
     
     
         2 . A method for inhibiting aurora 2 kinase in a warm blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof.  
     
     
         3 . A compound according to  claim 1  having a structure of formula (IA)  
       
         
           
           
               
               
           
         
       
       or a salt, ester or amide thereof; 
 where X is as defined in relation to formula (I);  
 R 1 , R 2 , R 3 , R 4  are equivalent to R 1 , R 2 , R 3 , R 4  as defined in relation to formula (I) and R 5a  is pyrrole, pyrazole, pyrazolone, imidazole, oxazole, furan, tetrazole or triazole, any of which may be optionally substituted , subject to the following provisos:  
 (i) that where R 5a  is a pyrazole group, it carries a substituent of formula (k),  
                     
   —B 1 —(CH 2 ) p -A 1   (IV)  
 (ii) that where X is NH and R 5a  is a substituted pyrazolone or tetrazolyl group, at least one of R 1′ , R 2′ , R 3′  and R 4′  is other than hydrogen; or  
 (iii) that where X is O and R 5a  is 1-methyl-4-nitro-1H-imidazol-5-yl, at least one of R 1′ , R 2′ , R 3′  and R 4′  is other than hydrogen;  
 or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof.  
 
     
     
         4 . A method for inhibiting aurora 2 kinase in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of  claim 3  or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof.  
     
     
         5 . A method according to  claim 2  or  4 , wherein the animal is a human.  
     
     
         6 . A pharmaceutical composition comprising a compound according to  claim 1  or  3 , in combination with a pharmaceutically acceptable carrier.  
     
     
         7 . The compound as recited in  claim 3 , wherein R 5a  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       wherein where R 60 , R 61  and R 62  are independently selected from hydrogen or a substituent group and * indicates the point of attachment to the group X in formula (IA).  
     
     
         8 . The composition as recited in  claim 7 , wherein R 60 , R 61  or R 62  is a group of sub-formula (k):  
       
         
           
           
               
               
           
         
       
       wherein p and q are independently 0 or 1 and R 1 ′ and R 1 ″ are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano, optionally substituted alkyl, or optionally substituted alkyenyl, wherein R 1 ′ can form with R 1 ″ a 3 to 6 membered ring; wherein T is C═O, SO n , C(═NOR)CO, C(O)C(O), C═NCN, or CV═NO or wherein n=0, 1 or 2 and V is independently R 63  or N(R 63 )R 64  wherein R 63  and R 64  are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R 63  and R 64  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring.  
     
     
         9 . The composition as recited in  claim 7 , wherein R 60 , R 61  or R 62  is a group of sub-formula:  
       
         
           
           
               
               
           
         
       
       wherein p and q are independently 0 or 1, and r is 0, 1, 2, 3 or 4 and wherein R and R′ are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkyenyl, wherein R can form with R′ a 3 to 6 membered ring; wherein T is C═O, SO n , C(═NOR)CO, C(O)C(O), C═NCN, or CV═NO or wherein n=0, 1 or 2 and V is independently R 63  or N(R 63 )R 64  wherein R 63  and R 64  are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R 63  and R 64  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; wherein R 70  is hydrogen, hydroxy (other than where q is 0), C 1-6 alkyl, C 1-6 alkoxy, amino, N-C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino, hydroxyC 2-6 alkoxy, C 1-6 alkoxyC 2-6 alkoxy, aminoC 2-6 alkoxy, N—C 1-6 alkylaminoC 2-6 alkoxy, N,N—(C 1-6 -alkyl) 2 aminoC 2-6 alkoxy or C 3-7 cycloalkyl, or R 70  is of the Formula (III):  
         -K-J  (III)  
       wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy, imino, N—(C 1-6 alkyl)imino, oxyC 1-6 alkylene, iminoC 1-6 alkylene, N—(C 1-6 alkyl)iminoC 1-6 alkylene, —NHC(O)—, —SO 2 NH—, —NHSO 2 — or —NHC(O)—C 1-6 alkylene.  
     
     
         10 . The compound as recited in  claim 3 , wherein R 5a  is pyrrole, pyrazole, imidazole or triazole and wherein R 60  is halogen, CN, or CONR 63  R 64 , and wherein R 61  is sub-formula (k):  
       
         
           
           
               
               
           
         
       
       wherein p and q are independently 0 or 1 and R 1 ′ and R 1 ″ are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkyenyl, R 1 ′ can form with R 1 ″ a 3 to 6 membered ring; wherein T is C═O, SO n , C(═NOR)CO, C(O)C(O)), C═NCN, or V═NO or wherein n=0, 1 or 2 and V is independently R 63  or N(R 63 )R 64  wherein R 63  and R 64  are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R 63  and R 64  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring.  
     
     
         11 . The compound as recited in  claim 3 , wherein R  5a  is pyrrole, pyrazole, imidazole or triazole, and wherein R 60  is halogen, CN, or CONR 63  R 64 , and wherein R 61  is sub-formula (k):  
       
         
           
           
               
               
           
         
       
       wherein p and q are independently 0 or 1, r is 0, 1, 2, 3 or 4 and R and R′ are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkyenyl, R can form with the other R group a 3 to 6 membered ring; wherein T is C═O, SO n , C(═NOR)CO, C(O)C(O)), C═NCN, or V═NO or wherein n=0, 1 or 2 and V is independently R 63  or N(R 63 )R 64  wherein R 63  and R 64  are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R 63  and R 64  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; wherein R 70  is hydrogen, hydroxy (other than where q is 0), C 1-6 alkyl, C 1-6 alkoxy, amino, N—C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino, hydroxyC 2-6 alkoxy, C 1-6 alkoxyC 2-6 alkoxy, aminoC 2-6 alkoxy, N—C 1-6 alkylaminoC 2-6 alkoxy, N,N—(C 1-6 alkyl) 2 aminoC 2-6 alkoxy or C 3-7 cycloalkyl.  
     
     
         12 . The compound as recited in  claim 3 , wherein R 5a  is pyrrole, pyrazole, imidazole or triazole and wherein R 60  is halogen, CN, or CONR 63 R 64 , and wherein R 61  is sub-formula (k):  
       
         
           
           
               
               
           
         
       
       wherein p and q are independently 0 or 1, r is 0, 1, 2, 3 or 4 and R and R′ are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted cycloalkyl, halogen, cyano, optionally substituted alkyl, optionally substituted alkyenyl, R can form with the other R group a 3 to 6 membered ring; wherein T is C═O, SO n , C(═NOR)CO, C(O)C(O)), C═NCN, or V═NO or wherein n=0, 1 or 2 and V is independently R 63  or N(R 63 )R 64  wherein R 63  and R 64  are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R 63  and R 64  together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; wherein R 70  is of the Formula (III):  
         -K-J  (III)  
       wherein J is aryl, heteroaryl or heterocyclyl and K is a bond, oxy, imino, N—(C 1-6 alkyl)imino, oxyC 1-6 alkylene, iminoC 1-6 alkylene, N—(C 1-6 -alkyl)iminoC 1-6 alkylene, —NHC(O)—, —SO 2 NH—, —NHSO 2 — or —NHC(O)—C 1-6 alkylene-, and any aryl, heteroaryl or heterocyclyl group in a R 70  group may be optionally substituted by one or more groups selected from hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —O—(C 1-3 alkyl)-O—, C 1-6 alkylS(O) n — (wherein n is 0-2), N—C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkoxycarbonyl, N—C 1-6 alkylcarbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 2-6 alkanoyl, C 1-6 alkanoyloxy, C 1-6 alkanoylamino, N—C 1-6 alkylsulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino and C 1-6 alkylsulphonyl-N—(C 1-6 alkyl)amino, or any aryl, heteroaryl or heterocyclyl group in a R 70  group may be optionally substituted with one or more groups of the Formula (IV):  
         —B 1 —(CH 2 ) p -A 1   (IV)  
       wherein A 1  is halo, hydroxy, C 1-6 alkoxy, cyano, amino, N—C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino, carboxy, C 1-6 alkoxycarbonyl, carbamoyl, N—C 1-6 alkylcarbamoyl or N,N—(C 1-6 alkyl) 2 carbamoyl, p is 1-6, and B 1  is a bond, oxy, imino, N—(C 1-6 alkyl)imino or —NHC(O)—, with the proviso that p is 2 or more unless B 1  is a bond or —NHC(O)—;  
       or any aryl, heteroaryl or heterocyclyl group in a R 70  group may be optionally substituted with one or more groups of the Formula (V):  
         -E 1 -D 1   (V)  
       wherein D 1  is aryl, heteroaryl or heterocyclyl and E 1  is a bond, C 1-6 alkylene, oxyC 1-6 alkylene, oxy, imino, N—(C 1-6 alkyl)imino, iminoC 1-6 alkylene, N—(C 1-6 alkyl)-iminoC 1-6 alkylene, C 1-6 alkylene-oxyC 1-6 alkylene, C 1-6 alkylene-iminoC 1-6 alkylene, C 1-6 alkylene-N—(C 1-6 alkyl)-iminoC 1-6 alkylene, —NHC(O)—, —NHSO 2 —, —SO 2 NH— or —NHC(O)—C 1-6 -alkylene-, and any aryl, heteroaryl or heterocyclyl group in a substituent on D 1  may be optionally substituted with one or more groups selected from hydroxy, halo, C 1-6 alkyl, C 1-6 alkoxy, carboxy, C 1-6 alkoxycarbonyl, carbamoyl, N—C 1-6 alkylcarbamoyl, N—(C 1-6 alkyl) 2 carbamoyl, C 2-6 alkanoyl, amino, N—C 1-6 alkylamino and N,N—(C 1-6 alkyl) 2 amino, and any C 3-7 cycloalkyl or heterocyclyl group in a R 70  group may be optionally substituted with one or two oxo or thioxo substituents, and any of the R 70  groups defined hereinbefore which comprises a CH 2  group which is attached to 2 carbon atoms or a CH 3  group which is attached to a carbon atom may optionally bear on each said CH 2  or CH 3  group a substituent selected from hydroxy, amino, C 1-6 alkoxy, N—C 1-6 alkylamino, N,N—(C 1-6 alkyl) 2 amino and heterocyclyl.  
     
     
         13 . A method for inhibiting aurora 2 kinase in a warm blooded animal in need of such treatment, which comprises administering to said animal an effective amount of a compound of any one of claims  7 - 12 , or a pharmaceutically acceptable salt, or an in vivo hydrolysable ester thereof.  
     
     
         14 . (canceled)  
     
     
         15 . A pharmaceutical composition comprising a compound according to any one of claims  7 - 12  in combination with a pharmaceutically acceptable carrier.  
     
     
         16 . (canceled)