Pteridinones as kinase inhibitors

Abstract

Disclosed are compounds of the formula wherein: W is NH, S, SO, or SO 2 ; R 2 is (un)substituted aryl, (un)substituted heteroaryl, or (un)substituted carbocycle or heterocycle; Q is hydrogen or lower alkyl; R 4 and R 6 are the same or different and represent hydrogen, halogen, lower alkyl, lower alkoxy, (un)substituted aryl, (un)substituted heteroaryl, (un)substituted arylalkyl or (un)substituted heteroarylalkyl; and R 8 is hydrogen, lower alkyl or an (un)substituted carbocyclic group containing from 3-7 members, up to two of which members are optionally hetero atoms selected from oxygen and nitrogen; or R 8 is (un)substituted aryl, (un)substituted heteroaryl, (un)substituted arylalkyl or (un)substituted heteroarylalkyl. These compounds are useful for treating cell proliferative disorders, such as cancer and restenosis. These compounds are potent inhibitors of cyclin-dependent kinases (cdks) and growth factor-mediated kinases. The present invention also provides a method of treating cell proliferative disorders. Also provided by the present invention is a pharmaceutically acceptable composition containing a compound of Formula I.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts thereof, wherein:  
       R 2  is:  
       C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, C 3 -C 10  cycloalkyl, (CH 2 ) n -aryl, COR 4 , (CH 2 ) n -heteroaryl, and (CH 2 ) n -heterocyclyl, wherein each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted with from 1 to 5 substituent groups selected from: 
 (a) halogen  
 (b) amino, alkylamino, and dialkylamino  
 (c) alkoxy, aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy  
 (d) phenyl, substituted phenyl, phenoxy, and substituted phenoxy  
 (e) hydroxy  
 (f) thio, alkylthio  
 (g) cyano  
 (h) nitro  
 (i) alkanoyl, aminoalkanoyl, alkylaminoalkanoyl, and dialkylaminoalkanoyl  
 (j) aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl  
 (k) amino-C 3 -C 7  cycloalkylcarbonyl, alkylamino-C 3 -C 7  cycloalkylcarbonyl, and dialkylamino-C 3 -C 7  cycloalkylcarbonyl  
 (l) COZ, CO 2 Z, SOZ, SO 2 Z, and PO 3 Z, where Z is hydrogen, hydroxy, alkoxy, lower alkyl, substituted alkyl, amino, alkylamino, dialkylamino, piperidinyl, substituted piperidinyl, morpholinyl, substituted morpholinyl, piperazinyl, and substituted piperazinyl  
 (m) a carbocyclic group containing from 3 to 7 ring members, one or two of which may be a heteroatom selected from O or N, and wherein the carbocyclic group may be substituted with one, two, or three substituent groups selected from: 
 (1) halogen  
 (2) hydroxy  
 (3) alkyl, aminoalkyl, alkyl and dialkylaminoalkyl  
 (4) trifluoromethyl  
 (5) alkoxy  
 (6) amino, alkylamino, dialkylamino, alkanoylamino  
 (7) COZ, CO 2 Z, SOZ, SO 2 Z, or PO 3 Z  
 (8) aryl  
 (9) heteroaryl  
 (10) (CH 2 ) n  morpholino  
 (11) (CH 2 ) n  piperazinyl  
 (12) (CH 2 ) n  piperadinyl  
 (13) (CH 2 ) n  tetrazolyl  
 
 (n) trifluoromethyl;  
 
       R 4  is:  
       (a) the same or different and are independently hydrogen, halogen, lower alkyl, or lower alkoxy, substituted alkyl, (CH 2 ) n -alkenyl, (CH 2 ) n -alkynyl, (CH 2 ) n -cyano, amino, aminoalkoxy, phenoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, mono- or dialkylaminoalkoxy, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamides, SO 2 Z, PO 3 Z, COZ, CO 2 Z, SOZ, aminoalkanoyl, aminocarbonyl, amino-C 3 -C 7 -cycloalkylcarbonyl, and N-mono- or N,N-dialkylaminocarbonyl;  
       (b) the same or different and are independently (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, lower alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, lower alkoxy, amino, mono- or dialkylamino, trifluoromethyl, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamide, COZ, CO 2 Z, SOZ, SO 2 Z, and PO 3 Z;  
       R 8  is:  
       (a) hydrogen, lower alkyl, substituted alkyl, (CH 2 ) n -alkenyl, substituted alkenyl, (CH 2 ) n -alkynyl, substituted alkynyl, or a (CH 2 ) n -carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, acetoxy, amino, COZ, CO 2 Z, SOZ, SO 2 Z, PO 3 Z, carboxylic acids, esters, amides, mono- or dialkylamino, aryl and heteroaryl;  
       (b) (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl or heteroaryl is unsubstituted or substituted with up to five groups selected from the group consisting of halogen, hydroxy, lower alkyl, substituted alkyl, lower alkoxy, amino, mono- or dialkylamino, trifluoromethyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamides, COZ, CO 2 Z, SOZ, SO 2 Z, and PO 3 Z; and  
       n is an integer from 0 to 6, and provided that R 8  is other than hydrogen or C 1 -C 3  alkyl when R 2  is methyl, ethyl, or acetyl.  
     
   
   
       2 . A compound of the formula  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts thereof, wherein:  
       R 5  and R 7  are the same or different and are selected from  
       (a) hydrogen halogen, amino, aminoalkoxy, lower alkoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, mono- or dialkylaminoalkoxy, alkanoylamino, carbamoyl, amino-C 3 -C 7 -cycloalkylcarbonyl, N-mono- or N,N-dialkylcarbamoyl, or  
       (b) CO 2 Z, COZ, SOZ, SO 2 Z, PO 3 Z, where Z is hydrogen, lower alkyl, hydroxy, alkoxy, amino, mono- or dialkylamino, piperidinyl, morpholinyl or piperazinyl, or (c) lower alkyl unsubstituted or substituted with one or two groups selected from lower alkoxy, halogen, amino, hydroxy, mono- or dialkylamino, aryl or a carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino, or  
       (d) a carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, morpholinoalkyl, piperazinylalkyl, piperadinylalkyl, tetrazolylalkyl, aminoalkyl and alkanoylamino;  
       R 4 , R 6 , R 6′ , and R 9  are:  
       (a) the same or different and are independently hydrogen, halogen, lower alkyl, or lower alkoxy, substituted alkyl, (CH 2 ) n -alkenyl, (CH 2 ) n -alkynyl, (CH 2 ) n -cyano, amino, aminoalkoxy, phenoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, mono- or dialkylaminoalkoxy, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamides, SO 2 Z, PO 3 Z, COZ, CO 2 Z, SOZ, aminoalkanoyl, aminocarbonyl, amino-C 3 -C 7 -cycloalkylcarbonyl, and N-mono- or N,N-dialkylaminocarbonyl;  
       (b) the same or different and are independently (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, lower alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, lower alkoxy, amino, mono- or dialkylamino, trifluoromethyl, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamide, COZ, CO 2 Z, SOZ, SO 2 Z, and PO 3 Z;  
       R 8  is:  
       (a) hydrogen, lower alkyl, substituted alkyl, (CH 2 ) n -alkenyl, substituted alkenyl, (CH 2 ) n -alkynyl, substituted alkynyl, or a (CH 2 ) n -carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, acetoxy, amino, carboxylic acids, esters, amides, mono- or dialkylamino, aryl and heteroaryl;  
       (b) (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl or heteroaryl is unsubstituted or substituted with up to five groups selected from the group consisting of halogen, hydroxy, lower alkyl, substituted alkyl, lower alkoxy, amino, mono- or dialkylamino, trifluoromethyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamides, COZ, CO 2 Z, SOZ, SO 2 Z, and PO 3 Z.  
     
   
   
       3 . A compound of the formula  
     
       
         
         
             
             
         
       
       and pharmaceutically acceptable salts thereof,  
       wherein:  
       R 5  and R 7  are the same or different and are selected from:  
       (a) hydrogen, halogen, amino, aminoalkoxy, lower alkoxy, hydroxy, phenoxy, thiol, thiolalkyl, nitro, nitril, phenyl, substituted phenyl, heteroaryl, trifluoromethyl, mono- or dialkylamino, mono- or dialkylaminoalkoxy, alkanoylamino, carbamoyl, amino-C 3 -C 7 -cycloalkylcarbonyl, N-mono- or N,N-dialkylcarbamoyl, or  
       (b) CO 2 Z, COZ, SOZ, SO 2 Z, PO 3 Z, where Z is hydrogen, lower alkyl, substituted alkyl, amino, mono- or dialkylamino, piperidinyl, morpholinyl or piperazinyl (with or without substitution), or  
       (c) lower alkyl unsubstituted or substituted with one or two groups selected from lower alkoxy, halogen, amino, hydroxy, mono- or dialkylamino, aryl or a carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, amino, or mono- or dialkylamino, or  
       (d) a carbocyclic group containing from 3-7 members, up to two of which members are hetero atoms selected from oxygen and nitrogen, wherein the carbocyclic group is unsubstituted or substituted with one, two or three groups independently selected from the group consisting of halogen, hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, amino, mono- or dialkylamino, aryl, heteroaryl, morpholinoalkyl, piperazinylalkyl, piperadinylalkyl, tetrazolylalkyl, aminoalkyl and alkanoylamino; and  
       R 4  and R 6  are the same or different and are selected from:  
       (a) the same or different and are independently hydrogen, halogen, lower alkyl, or lower alkoxy, substituted alkyl, (CH 2 ) n -alkenyl, (CH 2 ) n -alkynyl, (CH 2 ) n -cyano, amino, aminoalkoxy, phenoxy, hydroxy, trifluoromethyl, mono- or dialkylamino, mono- or dialkylaminoalkoxy, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamides, SO 2 Z, PO 3 Z, COZ, CO 2 Z, SOZ, aminoalkanoyl, aminocarbonyl, amino-C 3 -C 7 -cycloalkylcarbonyl, and N-mono- or N,N-dialkylaminocarbonyl;  
       (b) the same or different and are independently (CH 2 ) n -aryl, (CH 2 ) n -heteroaryl, arylalkyl, or heteroarylalkyl, wherein each aryl and heteroaryl is unsubstituted or substituted with up to five groups selected from halogen, hydroxy, lower alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, lower alkoxy, amino, mono- or dialkylamino, trifluoromethyl, thiol, thioalkyl, nitrile, nitro, carboxylic acid, carboxylic acid esters, carboxamide, COZ, CO 2 Z, SOZ, SO 2 Z, and PO 3 Z; and  
       Q is hydrogen, lower alkyl, or substituted alkyl.  
     
   
   
       4 . A compound which is selected from: 
 8-Cyclopentyl-2-[[4-(morpholin-4-yl]phenyl]amino]-5H,8H-pteridine-6,7-dione; and    8-Cyclopentyl-2-[[4-(4-methylpiperazin-1-yl)phenyl]amino]-5H,8H-pteridine-6,7-dione;    8-Cyclopentyl-5-methyl-2-(4-piperazin-1-yl-phenylamino)-5,8-dihydro-6H-pteridin-7-one;    2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-8-cyclopentyl-5-methyl-5,8-dihydro-6H-pteridin-7-one;    N-{1-[4-(8-Cyclopentyl-5-methyl-7-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-phenyl]-pyrrolidin-3-yl}-3,3-dimethyl-butyramide;    8-Cyclopentyl-5-methyl-2-(4-morpholin-4-yl-phenylamino)-5,8-dihydro-6H-pteridin-7-one;    8-cyclopentyl-2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-5-methyl-5,8-dihydro-6H-pteridin-7-one;    8-cyclopentyl-2-{4-[4-(2-hydroxy-ethyl)-3,5-dimethyl-piperazin-1-yl]-phenylamino}-5-methyl-5,8-dihydro-6H-pteridin-7-one;    1-[4-(8-Isopropyl-5-methyl-7-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-phenyl]-pyrrolidine-3-carboxylic acid butylamide; and    {4-[4-(8-Cyclopentyl-5-methyl-7-oxo-5,6,7,8-tetrahydro-pteridin-2-ylamino)-phenyl]-piperazin-1-yl}-acetic acid.    
   
   
       5 . A compound which is selected from: 
 1-tert-Butyl-3-[2-(4-fluoro-3-methyl-phenylamino)-pteridin-7-yl]-urea;    1-tert-Butyl-3-[2-(4-fluoro-3-methyl-phenylamino)-6-methyl-pteridin-7-yl]-urea;    1-tert-Butyl-3-(2-{4-[4-(3-morpholin-4-yl-propyl)-piperidin-1-yl]-phenylamino}-pteridin-7-yl)-urea;    1-tert-Butyl-3-(2-{4-[4-(3-piperazin-1-yl-propyl)-piperidin-1-yl]-phenylamino}-pteridin-7-yl)-urea; and    1-[2-(4-{4-[3-(3-Amino-pyrrolidin-1-yl)-propyl]-piperidin-1-yl}-phenylamino)-pteridin-7-yl]-3-tert-butyl-urea.    
   
   
       6 . A pharmaceutical formulation comprising a compound of  claim 1  in combination with a pharmaceutically acceptable carrier, diluent, or excipient.  
   
   
       7 . A pharmaceutical formulation comprising a compound of  claim 2  in combination with a pharmaceutically acceptable carrier, diluent, or excipient.  
   
   
       8 . A pharmaceutical formulation comprising a compound of  claim 3  in combination with a pharmaceutically acceptable carrier, diluent, or excipient.  
   
   
       9 . A pharmaceutical formulation comprising a compound of  claim 4  in combination with a pharmaceutically acceptable carrier, diluent, or excipient.  
   
   
       10 . A pharmaceutical formulation comprising a compound of  claim 5  in combination with a pharmaceutically acceptable carrier, diluent, or excipient.  
   
   
       11 . A method of inhibiting a cyclin-dependent kinase comprising contacting the cyclin-dependent kinase with a compound of  claim 1 .  
   
   
       12 . A method of inhibiting a cyclin-dependent kinase comprising contacting the cyclin-dependent kinase with a compound of  claim 2 .  
   
   
       13 . A method of inhibiting a cyclin-dependent kinase comprising contacting the cyclin-dependent kinase with a compound of  claim 3 .  
   
   
       14 . A method of inhibiting a cyclin-dependent kinase comprising contacting the cyclin-dependent kinase with a compound of  claim 4 .  
   
   
       15 . A method of inhibiting a cyclin-dependent kinase comprising contacting the cyclin-dependent kinase with a compound of  claim 5.