4-(3-aminopyrazole) pyrimidine derivatives for use as tyrosine kinase inhibitors in the treatment of cancer

Abstract

This invention relates to novel compounds having the formula (I): and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment for cancer.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from hydrogen, hydroxy, amino, mercapto, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, C 1-6 alkylsulphonylamino, 3-5-membered carbocyclyl or 3-5-membered heterocyclyl; wherein R 1  may be optionally substituted on carbon by one or more R 6 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 7 ; 
 R 2  and R 3  are independently selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, (C 1-6 alkyl) 2 N—S(O) 2 —NH—, (C 1-6 alkyl)NH—S(O) 2 —NH—, NH 2 —S(O) 2 —NH—, (C 1-6 alkyl) 2 N—S(O) 2 —N(C 1-6 alkyl)-, (C 1-6 alkyl)NH—S(O) 2 —N(C 1-6 alkyl)-, NH 2 —S(O) 2 —N(C 1-6 alkyl)-, N—(C 1-6 alkyl)-N—(C 1-6 alkylsulphonyl)amino, C 1-6 alkylsulphonylamino, carbocyclyl-R 19 — or heterocyclyl-R 21 —; wherein R 2  and R 3  independently of each other may be optionally substituted on carbon by one or more R 8 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 9 ; 
 R 4  is selected from cyano, carboxy, carbamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkanoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkoxycarbonyl, carbocyclyl or heterocyclyl; wherein R 4  may be optionally substituted on carbon by one or more R 10 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 11 ; 
 R 5  is selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 5  may be optionally substituted on carbon by one or more R 12 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 13 ; 
 n=0, 1, 2 or 3; wherein the values of R 5  may be the same or different; 
 R 6 , R 8 , R 10  and R 12  are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 6 , R 8 , R 10  and R 12  independently of each other may be optionally substituted on carbon by one or more R 14 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 15 ; 
 
         R 7 , R 9 , R 1I , R 13  and R 15  are independently selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; wherein R 7 , R 9 , R 11 , R 13  and R 15  independently of each other may be optionally substituted on carbon by on or more R 16 ;
 R 14  and R 16  are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkanoyl, C 1-6 alkanoyloxy, N—(C 1-6 alkyl)amino, N,N—(C 1-6 alkyl) 2 amino, C 1-6 alkanoylamino, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl) 2 carbamoyl, C 1-6 alkylS(O) a  wherein a is 0 to 2, C 1-6 alkoxycarbonyl, N—(C 1-6 alkyl)sulphamoyl, N,N—(C 1-6 alkyl) 2 sulphamoyl, C 1-6 alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R 14  and R 16  independently of each other may be optionally substituted on carbon by one or more R 17 ; and wherein if said heterocyclyl contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from R 18 ; 
 R 17  is selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; and 
 R 19  and R 21  are independently selected from a direct bond, —O—, —N(R 22 )—, —C(O)—, —N(R 23 )C(O)—, —C(O)N(R 24 )—, —S(O) s —, —SO 2 N(R 25 )— or —N(R 26 )SO 2 —; wherein R 22 , R 23 , R 24 , R 25  and R 26  are independently selected from hydrogen or C 1-6 alkyl and s is 0-2; and 
 R 18  is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulphonyl, C 1-6 alkoxycarbonyl, carbamoyl, N—(C 1-6 alkyl)carbamoyl, N,N—(C 1-6 alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl; 
 
         or a pharmaceutically acceptable salt thereof, 
       
     
     
         2 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 1  is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, 3-5-membered carbocyclyl, and N,N(C 1-6 alkyl) 2 amino, wherein R 1  may be optionally substituted on carbon by one or more R 6 ; and   R 6  is selected from halo.   
     
     
         3 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 2  is selected from the group consisting of hydrogen, halo, nitro, and C 1-6 alkyl, wherein R 2  may be optionally substituted on carbon by one or more R 8 ; and   R 8  is halo.   
     
     
         4 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein
 R 3  is selected from the group consisting of hydrogen, halo, cyano, N—(C 1-6 alkyl)-N—(C 1-6 alkylsulphonyl)amino, C 1-6 alkyl, (C 1-6 alkyl) 2 N—S(O) 2 —N(C 1-6 alkyl)-, and heterocyclyl-R 21 —, wherein R 3  may be optionally substituted on carbon by one or more R 8 ,   R 8  is halo; and   R 21  is a bond.   
     
     
         5 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R 4  is selected from the group consisting of C 1-6 alkyl. 
     
     
         6 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein R 5  is halo. 
     
     
         7 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 , wherein n is 1. 
     
     
         8 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 1  is selected from the group consisting of methyl, methoxy, trifluoroethoxy, isopropoxy, cyclopropyl, and N,N-dimethylamino; 
 R 2  is selected from the group consisting of hydrogen, chloro, fluoro, bromo, nitro, and trifluoromethyl; 
 R 3  is selected from the group consisting of hydrogen, chloro, cyano, trifluoromethyl, (CH 3 ) 2 N—S(O) 2 —N(CH 3 )—, N-methyl-N-mesylamino, and morpholino; 
 R 4  is methyl; 
 R 5  is fluoro; and 
 n is 1. 
 
       
     
     
         9 . A compound of formula (I), as claimed in  claim 1 , selected from the group consisting of:
 N-{5-fluoro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;   5-Fluoro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;   5-Chloro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;   N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methoxy-1H-pyrazol-3-yl)-6-(trifluoromethyl)pyrimidine-2,4-diamine;   N 2 -[(1S)-1-(5-Fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;   5-Chloro-N 4 -(5-cyclopropyl-1H-pyrazol-3-yl)-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine;   5-Fluoro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;   5-bromo-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;   N 4 -(5-Cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]pyrimidine-2,4-diamine;   N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-5-methyl-N 4 -(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine;   N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;   N-{5-chloro-2-{[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amino}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}-N-methylmethanesulfonamide;   N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;   5-chloro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;   5-fluoro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methyl-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine; and   5-fluoro-N 2 -[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N 4 -(5-methoxy-1H-pyrazol-3-yl)-6-morpholin-4-ylpyrimidine-2,4-diamine;   or a pharmaceutically acceptable salt thereof.   
     
     
         10 . A process for preparing a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein variable groups are, unless otherwise specified, as defined in  claim 1 , said process comprising:
 Process a) reaction of a pyrimidine of Formula (II):   
       
         
           
           
               
               
           
         
         wherein L is a displaceable group; with an pyrazole amine of Formula (III): 
       
       
         
           
           
               
               
           
         
         or 
         Process b) reacting a pyrimidine of Formula (IV): 
       
       
         
           
           
               
               
           
         
         wherein L is a displaceable group; with a compound of Formula (V): 
       
       
         
           
           
               
               
           
         
         Process c) reacting a compound of Formula (VI): 
       
       
         
           
           
               
               
           
         
         with a compound of Formula (VII): 
       
       
         
           
           
               
               
           
         
         wherein X is an oxygen atom and q is 1; or X is a nitrogen atom and q is 2; and wherein each R 20  independently represents a C 1-6 alkyl group; or 
         Process d) reacting a compound of Formula (VIII): 
       
       
         
           
           
               
               
           
         
       
       with hydrazine; or
 and thereafter if necessary: 
 i) converting a compound of the formula (I) into another compound of the formula (I); 
 ii) removing any protecting groups; 
 iii) forming a pharmaceutically acceptable salt. 
 
     
     
         11 . A pharmaceutical composition comprising:
 a. a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 ; and   b. at least one pharmaceutically acceptable carrier, diluent, or excipient.   
     
     
         12 - 19 . (canceled) 
     
     
         20 . A method for producing an anti-proliferative effect in a warm-blooded animal in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
     
     
         21 . A method for producing a pro-apoptotic effect in a warm-blooded animal in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically salt thereof, as claimed in  claim 1 . 
     
     
         22 . A method of treating myeloproliferative disorders, myelodysplastic syndrome, and cancer in a warm-blooded animal in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
     
     
         23 . A method of treating chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, myeloid metaplasia with myelofibrosis, idiopathic myelofibrosis, chronic myelomonocytic leukemia and hypereosinophilic syndrome, myelodysplastic syndromes and cancers selected from oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewings sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer—non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, renal cancer, lymphoma, and leukaemia in a warm-blooded animal in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), as claimed in  claim 1   
     
     
         24 . A method of treating cancer in a warm-blooded animal in need of such treatment, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in  claim 1 . 
     
     
         25 - 33 . (canceled)