Pyrimidine derivatives for the treatment of cancer

Abstract

The invention provides compounds which are pyrimidines of formula (I): wherein —XR 3 is bonded at ring position 2 and —YR 4 is bonded at ring position 5 or 6; R 1 and R 2 form, together with the N atom to which they are attached, a morphorine ring which is unsubstituted or substituted; X is a direct bond; R 3 is selected from (i) a group of the following formula (1): wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from —OR, CH2OR and —NRS(O) mR, wherein each R is independently selected from H, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the group being unsubstituted or substituted, and m is 2; and (ii) an indazole group which is unsubstituted or substituted; and Y is selected from —O—(CH 2 ) n —, —NH—(CH 2 ) n , —NHC(O)—(CH 2 ) n — and —C(O)NH—(CH 2 ) n — wherein n is 0 or an integer of 1 to 3, and R 4 is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic group which is unsubstituted or substituted and a group —NR 5 R 6 wherein R 5 and R 6 , which are the same or different, are each independently selected from H, C 1 -C 6 alkyl which is unsubstituted or substituted, C 3 -C 10 cycloalkyl which is unsubstituted or substituted, —C(O)R, —C(O)N(R) 2 and —S(O) m R wherein R and m are as defined above, or R 5 and R6 together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7-membered N-containing heterocyclic group which is unsubstituted or substituted; and the pharmaceutically acceptable salts thereof. These compounds are inhibitors of PI3K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

1 . A compound which is a pyrimidine of formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 —XR 3  is bonded at ring position 2 and —YR 4  is bonded at ring position 5 or 6; 
 R 1  and R 2  form, together with the N atom to which they are attached, a morpholine ring which is unsubstituted or substituted; 
 X is a direct bond; 
 R 3  is selected from: 
 (i) a group of the following formula: 
 
       
         
           
           
               
               
           
         
         wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from —OR, CH 2 OR and —NRS(O) m R, wherein each R is independently selected from HC 1 -C 6  alkyl, C 3 -C 10  cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the group being unsubstituted or substituted, and m is 2; and 
         (ii) an indazole group which is unsubstituted or substituted; and 
         Y is selected from —O—(CH 2 ) n —, —NH—(CH 2 ) n —, —NHC(O)—(CH 2 ) n — and —C(O)NH—(CH 2 ) n — wherein n is 0 or an integer of 1 to 3, and R 4  is selected from an unsaturated 5- to 12-membered carbocyclic or heterocyclic group which is unsubstituted or substituted, and a group —NR 5 R 6  wherein R 5  and R 6 , which are the same or different, are each independently selected from H, C 1 -C 6  alkyl which is unsubstituted or substituted, C 3 -C 10  cycloalkyl which is unsubstituted or substituted, —C(O)R, —C(O)N(R) 2  and —S(O) m R wherein R and m are as defined above, or R 5  and R 6  together form, with the nitrogen atom to which they are attached, a saturated 5-, 6- or 7-membered N-containing heterocyclic group which is unsubstituted or substituted; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein the pyrimidine is of formula (Ia): 
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3 , R 5 , Y and X are as defined in  claim 1 . 
     
     
         3 . A compound according to  claim 1  wherein the pyrimidine is of formula (Ib): 
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3 , R 4 , Y and X are as defined in  claim 1 . 
     
     
         4 . A compound according to  claim 1  wherein R 3  is an indazol-4-yl group. 
     
     
         5 . A compound according to  claim 1  which is selected from: 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-(pyridin-3-ylmethylamino) pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethylamino) pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-(pyridin-4-ylmethylamino) pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino] pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino] pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino] pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy) pyrimidine; 
       2-(3-hydroxyphenyl)-4-(morpholin-4-yl)-6-[2-(morphlin-4-yl)ethylamino] pyrimidine; 
       2-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-[(pyridin-4-yl)carbonylamino] pyrimidine; 
       2-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-[(pyridin-3-yl)carbonylamino] pyrimidine; 
       2-(3-methoxyphenyl)-4-(morpholin-4-yl)-5-[(pyridin-3-yl)carbonylamino] pyrimidine; 
       2-[3-(methanesulfonylamino)phenyl]-4-(morpholin-4-yl)-2-[(2-(pyridin-2-yl)ethylamino]pyrimidine; 
       2-[3-(methanesulfonylamino)phenyl]-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine; 
       2-[3-(methanesulfonylamino)phenyl]-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine; 
       2-[3-(methanesulfonylamino)phenyl]-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine; 
       3-(4-Benzylamino-6-morpholin-4-yl-pyrimidin-2-yl)-phenol; 
       3-(4-Morpholin-4-yl-6-phenylamino-pyrimidin-2-yl)-phenol; 
       3-(4-Morpholin-4-yl-6-p-tolylamino-pyrimidin-2-yl)-phenol; 
       3-(4-Morpholin-4-yl-6-m-tolylamino-pyrimidin-2-yl)-phenol; 
       3-[4-(3-Fluoro-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[4-(4-Fluoro-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-(4-Morpholin-4-yl-6-o-tolylamino-pyrimidin-2-yl)-phenol; 
       3-[4-(2-Fluoro-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[4-(2-Methoxy-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[4-(3-Methoxy-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[4-(4-Methoxy-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[2-(3-Hydroxy-phenyl)-6-morpholin-4-yl-pyrimidin-4-ylamino]-benzonitrile; 
       4-[2-(3-Hydroxy-phenyl)-6-morpholin-4-yl-pyrimidin-4-ylamino]-benzonitrile; 
       3-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[4-(2-Methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-[4-(3-Methanesulfonyl-phenylamino)-6-morpholin-4-yl-pyrimidin-2-yl]-phenol; 
       3-(4-Morpholin-4-yl-6-phenoxy-pyrimidin-2-yl)-phenol; 2-(indazol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-2-yl)ethylamino]pyrimidine; 
       2-(indazol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-3-yl)ethylamino]pyrimidine; 
       2-(indazol-4-yl)-4-(morpholin-4-yl)-6-[(2-(pyridin-4-yl)ethylamino]pyrimidine; and 
       2-(indazol-4-yl)-4-(morpholin-4-yl)-6-(pyridin-2-ylmethyloxy)pyrimidine; 
       and the pharmaceutically acceptable salts thereof. 
     
     
         6 . A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as defined in  claim 1 . 
     
     
         7 - 10 . (canceled) 
     
     
         11 . A method of treating a disease or disorder arising from abnormal cell growth, function or behaviour associated with PI3 kinase, which method comprises administering to a patient in need thereof a compound as defined in  claim 1 . 
     
     
         12 . A method according to  claim 11  wherein the disease or disorder is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.