Pyrazole derivatives as protein kinase modulators

Abstract

The invention provides compounds of the formula (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R 1 and NR 2 R 3 and a maximum chain length of 4 atoms extending between E and NR 2 R 3 , wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom α with respect to the NR 2 R 3 group and provided that the oxo group when present is located at a carbon atom α with respect to the NR 2 R 3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R 1 is an aryl or heteroaryl group; and R 2 , R 3 , R 4 and R 5 are as defined in the claims. Also provided are pharmaceutical compositions containing the compounds, methods for preparing the compounds and their use as anticancer agents.

1 - 75 . (canceled) 
     
     
         76 . 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 having the formula (IV): 
       
         
           
           
               
               
           
         
         or a salt, solvate, or tautomer thereof, 
         wherein z is 0, 1 or 2; 
         R 1  is unsubstituted phenyl or phenyl substituted with 1, 2, 3 or 4 substituents independently selected from hydroxy, C 1-4  acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, C 1-4  hydrocarbyloxy and C 1-4  hydrocarbyl optionally substituted by C 1-2  alkoxy or hydroxy; 
         R 2  and R 3  are independently selected from hydrogen and methyl; 
         R 4  is selected from hydrogen and methyl; 
         R 5  is selected from hydrogen and methyl; and 
         R 20  is selected from hydrogen, methyl, hydroxy and fluorine, provided that when z is 0, 
         R 20  is other than hydroxy. 
       
     
     
         77 . The method according to  claim 76 , wherein the group R 1  has one or two substituents selected from fluorine, chlorine, trifluoromethyl, methyl and methoxy. 
     
     
         78 . The method according to  claim 77 , wherein R 1  is a mono-chlorophenyl or dichlorophenyl group. 
     
     
         79 . The method according to  claim 76  wherein R 2  and R 3  are both hydrogen. 
     
     
         80 . The method according to  claim 76  comprising administering a compound which is:
 2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 
 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine; 
 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl amine; 
 {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 
 {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 
 {3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 
 3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 
 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 
 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine; 
 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 
 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (R); 
 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (S); 
 dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; 
 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R); 
 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S); 
 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 
 {2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 
 {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 
 {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 
 {2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 
 4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol; 
 3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 
 {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 
 1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 
 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 
 3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 
 2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 
 2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl amine; 
 2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl amine; 
 2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 
 {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 
 3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; or 
 C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine; 
 or a salt, solvate, or tautomer thereof. 
 
     
     
         81 . The method according to  claim 76 , wherein the compound is in the form of a salt. 
     
     
         82 . The method according to  claim 76 , wherein the compound is 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol or a salt or tautomer thereof. 
     
     
         83 . The method according to  claim 82 , wherein the compound is a salt of 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol. 
     
     
         84 . The method according to  claim 83 , wherein the compound is in the form of a methanesulphonic acid salt. 
     
     
         85 . The method according to  claim 76 , wherein the compound having the formula (IV) or the salt, solvate, or tautomer thereof is administered in combination with one or more other therapeutic agents. 
     
     
         86 . The method according to  claim 85 , wherein at least one of the one or more other therapeutic agents is selected from:
 Topoisomerase I inhibitors;   Antimetabolites;   Tubulin targeting agents;   DNA binder and topoisomerase II inhibitors;   Alkylating Agents;   Monoclonal Antibodies;   Anti-Hormones;   Signal Transduction Inhibitors;   Proteasome Inhibitors;   DNA methyl transferases; and   Cytokines and retinoids.   
     
     
         87 . The method according to  claim 85 , wherein the compound having the formula (IV), or the salt, solvate, or tautomer thereof, and the one or more other therapeutic agents are formulated together in a dosage form. 
     
     
         88 . The method according to  claim 85 , wherein the compound having the formula (IV), or the salt, solvate, or tautomer thereof, and the one or more other therapeutic agents are formulated separately and presented together in the form of a kit. 
     
     
         89 . A method of inhibiting protein kinase A (PKA) or protein kinase B (PKB), the method comprising contacting the PKA or PKB with a compound having the formula (IV) as described in  claim 76 , or a salt, solvate, or tautomer thereof, wherein the group R 1  has one or two substituents selected from fluorine, chlorine, trifluoromethyl, methyl and methoxy. 
     
     
         90 . A method according to  claim 89 , wherein R 1  is a mono-chlorophenyl or dichlorophenyl group. 
     
     
         91 . A method of inhibiting protein kinase A (PKA) or protein kinase B (PKB), the method comprising contacting the PKA or PKB with a compound having the formula (IV) as described in  claim 76 , or a salt, solvate, or tautomer thereof, wherein R 2  and R 3  are both hydrogen. 
     
     
         92 . A method of inhibiting protein kinase A (PKA) or protein kinase B (PKB), the method comprising contacting the PKA or PKB with a compound having the formula (IV) as described in  claim 76 , or a salt, solvate, or tautomer thereof, wherein the compound is:
 2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;   2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine;   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl amine;   {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;   {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;   {3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;   3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;   3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine;   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (R);   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (S);   dimethyl-{2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine;   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R);   2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S);   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;   {2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;   {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;   {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;   {2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;   4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol;   3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;   {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine;   1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;   2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol;   3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine;   2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;   2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl amine;   2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl amine;   2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine;   {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine;   3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; or   C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine;   
       or a salt, solvate, or tautomer thereof. 
     
     
         93 . A method of inhibiting protein kinase A (PKA) or protein kinase B (PKB), the method comprising contacting the PKA or PKB with a salt of a compound having the formula (IV) as described in  claim 76 . 
     
     
         94 . The method according to  claim 93 , wherein the compound is 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol. 
     
     
         95 . The method according to  claim 94 , wherein the compound is in the form of a methanesulphonic acid salt.