Pyrimidines as PLK inhibitors

Abstract

The present invention encompasses compounds of general formula (1), wherein A, W, X, Y, Z, Ra, Rb, Rc, R1 and R3 are defined as in claim 1 , which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and the use thereof for preparing a pharmaceutical composition having the above-mentioned properties.

1 . A method of treatment of a disease or condition responsive to an inhibitor of PLK, said disease or condition being selected from the group consisting of: cancer, infection, inflammation and an autoimmune disease, said method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the following formula (1): 
       
         
           
           
               
               
           
         
         wherein 
         W denotes N or C—R 2 , 
         X denotes —NR 1a , O or S, 
         Y denotes CH, 
         Z denotes —CF 3 ; 
         A is selected from one of the following formulas (i), (ii) and (iii): 
       
       
         
           
           
               
               
           
         
         Q 1  denotes that (i), (ii) and (iii) are mono- or bicyclic aryl; 
         B 1 , B 2 , B 3  and B 4  each independently of one another denote C—R g R h , N—R i , O or S; 
         R 1  and R 1a  each independently of one another denote hydrogen or methyl; 
         R 2  denotes one of hydrogen, halogen, —OR 4 , —C(═O)R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , pseudohalogen, and a mono- or polysubstituted group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; 
         R a , R h , R e , R d , R e , R f , R g  and R h  each independently of one another denote a group selected from the group consisting of hydrogen, halogen, ═O, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6 , pseudohalogen, and an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; wherein R g  and R h  are optionally located at the same or at adjacent C atoms and are attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms; 
         R i  denotes a group selected from the group consisting of hydrogen, —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6 , pseudohalogen and an unsubstituted or substituted mono- or polysubstituted group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; wherein the R i  groups located at adjacent N atoms are optionally joined together or R i  with R g  or R h  located at adjacent C atoms are optionally attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms; 
         R 3  is selected from the following formulas (iv)-(x): 
       
       
         
           
           
               
               
           
         
         R 4 , R 5  and R 6  each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-5 -alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; 
         L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; 
         Q 2  and Q 3  each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR B , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; 
         R 7  denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; and 
         R 8 , R 9  and R 10  each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C 1-8 -alkyl, C 2-8 alkenyl, C 2-8 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the substituted group are identical or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen; 
         or a pharmacologically acceptable acid addition salt thereof 
       
       in an excipient or carrier. 
     
     
         2 . A method of prevention of a disease or condition responsive to an inhibitor of PLK, said disease or condition being selected from the group consisting of: infection, and inflammation; said method comprising administering a therapeutically effective amount of a pharmaceutical composition-comprising the compound the following formula (1): 
       
         
           
           
               
               
           
         
         wherein 
         W denotes N or C—R 2 , 
         X denotes —NR 1a , O or S, 
         Y denotes CH, 
         Z denotes —CF 3 ; 
         A is selected from one of the following formulas (i), (ii) and (iii): 
       
       
         
           
           
               
               
           
         
         Q 1  denotes that (i), (ii) and (iii) are mono- or bicyclic aryl; 
         B 1 , B 2 , B 3  and B 4  each independently of one another denote C—R g R h , N—R i , O or S; 
         R 1  and R 1a  each independently of one another denote hydrogen or methyl; 
         R 2  denotes one of hydrogen, halogen, —OR 4 , —C(═O)R 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOW', —SO 2 R 4 , —SO 2 NR 4 R 5 , pseudohalogen, and a mono- or polysubstituted group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; 
         R a , R h , R e , R d , R e , R f , R g  and R h  each independently of one another denote a group selected from the group consisting of hydrogen, halogen, ═O, —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —C═NR i , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6 , pseudohalogen, and an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; wherein R g  and R h  are optionally located at the same or at adjacent C atoms and are attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms; 
         R i  denotes a group selected from the group consisting of hydrogen, —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6 , pseudohalogen and an unsubstituted or substituted mono- or polysubstituted group selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, R 8 , —NO 2 , —OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NR 4 R 5 , —NR 4 R 5 , —NR 4 C(═O)R 5 , —NR 4 C(═O)OR 5 , —NR 4 C(═O)NR 5 R 6 , —NR 4 SO 2 R 5 , —N═CR 4 R 5 , —SR 4 , —SOR 4 , —SO 2 R 4 , —SO 2 NR 4 R 5 , —NR 4 SO 2 NR 5 R 6 , —OSO 2 NR 5 R 6  and pseudohalogen; wherein the R i  groups located at adjacent N atoms are optionally joined together or R i  with R g  or R h  located at adjacent C atoms are optionally attached in any combination to a common saturated or partially unsaturated 3-5-membered alkyl bridge which contains one to two heteroatoms; 
         R 3  is selected from the following formulas (iv)-(x): 
       
       
         
           
           
               
               
           
         
         R 4 , R 5  and R 6  each independently of one another denote hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-5 -alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-10 cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of C 3-10 -cycloalkyl, aryl, heterocyclyl, heteroaryl, halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; 
         L denotes a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; 
         Q 2  and Q 3  each independently of one another denote a bond or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, —NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 C(═O)R 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR B , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; 
         R 7  denotes hydrogen or an unsubstituted or mono- or polysubstituted group selected from the group consisting of C 1-16 -alkyl, C 2-16 -alkenyl, C 2-16 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the mono- or polysubstituted group are identical or different and are selected from the group consisting of halogen, NO 2 , —OR 8 , —C(═O)R 8 , —C(═O)OR 8 , —C(═O)NR 8 R 9 , —NR 8 R 9 , —NR 8 COR 9 , —NR 8 C(═O)OR 9 , —NR 8 C(═O)NR 9 R 10 , —NR 8 C(═O)ONR 9 R 10 , —NR 8 SO 2 R 9 , —N═CR 8 R 9 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 NR 8 R 9 , —NR 8 SO 2 NR 9 R 10 , —OSO 2 NR 8 R 9  and pseudohalogen; and 
         R 8 , R 9  and R 10  each independently of one another denote hydrogen or a substituted or unsubstituted group selected from the group consisting of C 1-8 -alkyl, C 2-8 -alkenyl, C 2-8 -alkynyl, C 3-10 -cycloalkyl, aryl, heterocyclyl and heteroaryl, wherein the substituent(s) of the substituted group are identical or different and are selected from the group consisting of halogen, methyl, ethyl, amino, methylamino, dimethylamino, —OH and pseudohalogen; 
         or a pharmacologically acceptable acid addition salt thereof in an excipient or carrier.