Small molecule myristate inhibitors of bcr-abl and abl and methods of use

Abstract

The present invention provides novel heteroaryl compounds of formula (I) having a pyrimidine-containing core that is linked to a 4-trifluoromethoxyphenyl group via an amine linker. Such compounds are useful for the treatment of cancers.

1 . A compound of formula I, or pharmaceutically acceptable salt, thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each of X 1 , X 2 , or X 3  is independently NR 1 , CR 1 , C(O), O, or S; 
 each R 1  is independently selected from H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12  aryl, an optionally substituted C 3-12 heteroaryl, an optionally substituted aralkyl, an optionally substituted C 3 - 6 heteroaralkyl, an optionally substituted C 1-6 haloalkyl, an optionally substituted (CH 2 ) n C 3-12 heterocycloalkyl, an optionally substituted (CH 2 ) n C 6-12 aryl, an optionally substituted (CH 2 ) n C 3-12 heteroaryl, an opticnally substituted (CH 2 ) n C 3-12 cycloalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, hal, (CH 2 ) n C(O)R x , (CH 2 ) n C(O)OR x , (CH 2 ) n C(O)NR x R x , —(CH 2 ) n C(O)NR x R x S(O) 2 R x ; —C(O)R x , —C(S)R x , —C(NR)R x , —SR x , —S(O)R x , —S(O) 2 R x , —OR x , —N x R x , nitro, cyano, or absent; 
 each R x , for each occurrence, is independently H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, C 1-6 haloalkyl; NHNHR 2 , or C(NH)NH 2 ; 
 R 2  is H or C 1-6  alkyl; 
 Y is H, OH, NH 2  or CH 3 ; 
 m is 1 or 2; and 
 each n is independently 0, 1 or 2. 
 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , of formula III, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, an optionally substituted aralkyl, an optionally substituted C 3 - 6 heteroaralkyl, an optionally substituted C 1-6 haloalkyl, an optionally substituted (CH 2 ) n C 3-12 heterocycloalkyl, an optionally substituted (CH) n C 6-12 aryl, an optionally substituted (CH 2 ) n C 3-12 heteroaryl, an optionally substituted (CH 2 ) n C 3-12 cycloalkyl, (CH 2 ) n C(O)R x , (CH 2 ) n C(O)OR x , (CH 2 ) n C(O)NR x R x , —C(O)R x , —C(S)R x , —C(NR)R x , halo, C 1-6 haloalkyl, —S(O)R x , or —S(O) 2 R x ; 
 R x , for each occurrence, is independently, H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, or C 1-6 haloalkyl; and 
 each n is independently 0, 1 or 2. 
 
     
     
         5 . The compound of  claim 4 , selected from the following:
 2-(4-(4-(trifluoromethoxy)phenylamino)-2H-pyrazolo[3,4-d]pyrimidin-2-yl)ethanol;   (2-Ethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   (2-Cyclohexyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   2-[4-(4-Trifluoromethoxy-phenylamino)-pyrazolo[3,4-d]pyrimidin-2-yl]-ethanol;   2-[4-(4-Trifluoromethoxy-phenylamino)-pyrazolo[3,4-d]pyrimidin-2-yl]-acetamide;   [2-(Tetrahydro-furan-3-ylmethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxyphenyl)-amine;   (2-Butyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   [2-(2,2,2-Trifluoro-ethyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   (2-Benzyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   (2-Phenethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   [2-(3-Fluoro-4-trifluoromethyl-benzyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [2-(3-Bromo-benzyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   3-[4-(4-Trifluoromethoxy-phenylamino)-pyrazolo[3,4-d]-pyrimidin2-ylmethyl]-phenol;   (2-Pyridin-3-ylmethyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-4-trifluoromethoxy-phenyl)-amine;   (4-Trifluoromethoxy-phenyl)-[2-(4-trifluoromethyl-pyridin-2-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;   [2-(2,3-Dimethyl-phenyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [2-(2-Fluoro-phenyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [2-(2,4-Dichloro-phenyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [2-(2-Ethyl-phenyl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   (2-Pyridin-2-yl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine; or a pharmaceutically acceptable salt thereof.   
     
     
         6 . The compound of  claim 1 , of formula IV; or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each R 1  is independently selected from H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, an optionally substituted C 1-6 aralkyl, an optionally substituted C 3 - 6 heterocycloalkyl, an optionally substituted C 1 - 1 haloalkyl, an optionally substituted (CH 2 ) n C 3-12 heterocycloalkyl, an optionally substituted (CH 2 ) n C 6-12 aryl, an optionally substituted (CH 2 ) n C 3-12 heteroaryl, an optionally substituted (CH 2 ) n C 3-12 cycloalkyl, (CH 2 ) n C(O)R x , (CH 2 ) n C(O)OR x , (CH 2 ) n C(O)NR x R x , —C(O)R x , —C(S)R x , —C(NR)R x , halo, C 1-6 haloalkyl, —S(O)R x , —S(O) 2 R x , or absent; 
 R x , for each occurrence, is independently, H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 3-12 aryl, an optionally substituted C 3-12 heteroaryl, or C 1-6 haloalkyl; and 
 each n is independently 0, 1 or 2. 
 
     
     
         7 . The compound of  claim 6 , selected from the following:
 (9-Methyl-9H-purin-6-yl)-(4-trifluoromethoxy-phenyl)-amine;   (7-Methyl-7H-purin-6-yl)-(4-triflumomethoxy-phenyl)-amine;   2-Hydroxymethyl-5-[6-(4-trifluoromethoxy-phenylamino)-purin-9-yl]-tetrahydro-furan-3,4-diol; [9-(2-Morpholin-4-yl-ethyl)-9H-purin-6-yl]-(4-trifluoromethoxy-phenyl)-amine; or a pharmaceutically acceptable salt thereof.   
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , of formula VII; or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is selected from H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, an optionally substituted (CH 2 )NC 3-12 heterocycloalkyl, —C(O)R x , —OR x , —SR x , —NR x R x , nitro, cyano, C 1-6 haloalkyl, C 1-6 aminoalkyl, (CH 2 ) n C(O)R x , (CH 2 ) n C(O)OR x , (CH 2 ) n C(O)NR x R x , or (CH 2 ) n C(O)NR x R x S(O) 2 R x ; 
 R x , for each occurrence, is independently H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, NHNHR 2 , or C(NH)NH 2 ; 
 R 2  is H or C 1-4  alkyl; and 
 each n is independently 0, 1 or 2. 
 
     
     
         15 . The compound of  claim 14 , selected from the following:
 4-(4-(trifluoromethoxy)phenylamino)-N-(2-hydroxyethyl)quinazoline-7-carboxamide;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid methyl ester;   [4-(4-Trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanol;   (7-Diethylaminomethyl-quinazolin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid diethylamide;   [4-(Furan-3-carbonyl)-piperazin-1-yl]-[4-(4-trrfluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid (3-trifluoromethylphenyl)-amide;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid (3-methoxy-propyl)-amide;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid N′-ethyl-hydrazide;   (2-{[4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-amino}-thiazol-5-yl)-acetic acid ethyl ester;   (4-Methoxy-piperidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   (3-Hydroxy-pyrrolidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   (2-Hydroxymethyl-pyrrolidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   (3-Dimethylamino-pyrrolidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid (2-hydroxy-ethyl)-methyl-amide;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid methyl-(1-methylpiperidin-4-yl)-amide;   4-Methyl-N-[4-(4-trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-benzenesulfonamide;   2-Methyl-propane-2-sulfonic acid [4-(4-trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-amide;   (4-Methyl-[1,4]diazepan-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   (3,5-Dimethyl-piperazin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   (4-Hydroxy-piperidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid methyl-(2-methylaminoethyl)-amide;   4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carboxylic acid (2-hydroxy-ethyl)-amide;   1-Phenyl-8-[4-(4-trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-1,3,8-triaza-spiro[4,5]decan-4-one;   (4-Bromo-piperidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazolin-7-yl]-methanone;   1-[4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-piperidine-4-carboxylic acid amide;   1-[4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-piperidine-3-carboxylic acid amide;   1-[4-(4-Trifluoromethoxy-phenylamino)-quinazoline-7-carbonyl]-piperidine-3-carboxylic acid ethyl ester;   (3-Hydroxymethyl-piperidin-1-yl)-[4-(4-trifluoromethoxy-phenylamino)-quinazoline-7-yl]-methanone; or a pharmaceutically acceptable salt thereof.   
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . A compound of formula IX, or pharmaceutically acceptable salt thereof. 
       
         
           
           
               
               
           
         
       
       wherein
 R 3  is H or C 1-4  alkyl; 
 L is NR 3 , O, S, S(O), S(O) 2 , C(S), C(NR), C(NR)NR x , C(O)NR x , C(O)NR x NR x , C(O)NR x , C(O)NR x O, C(O)O, OC(O), OC(O)O, or a bond; 
 each R x , for each occurrence, is independently H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 1 - 2 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, C 1-6 haloalkyl, NHNHR 2 , or C(NH)NH 2 ; 
 A is an optionally substituted C 1-6 alkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, an optionally substituted C 3-12 cycloalkyl, or an optionally substituted C 3-12 heterocycloalkyl. 
 
     
     
         19 . The compound of  claim 18 , wherein A is an optionally substituted C 1-6 alkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, or an optionally substituted C 3-12 heterocycloalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 19 , wherein A is an optionally substituted substituted phenyl ring, an optionally substituted naphthyl ring, an optionally substituted piperidine ring, an optionally substituted imidazole ring, an optionally substituted pyrazole ring, an optionally substituted 1H-pyrazole ring, an optionally substituted 1H-Pyrrolo[2,3-b]pyridine ring, an optionally substituted pyrimidine ring, an optionally substituted pyrazine ring, an optionally substituted pyridine ring, an optionally substituted indole ring, an optionally substituted 1H-indole ring, an optionally substituted furan ring, an optionally substituted benzo[b]thiophene ring, an optionally substituted dibenzofuran ring, an optionally substituted 1H-Pyridin-2-one ring, an optionally substituted thiazole ring, or an ethyl group; or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The compound of  claim 20 , wherein A is optionally substituted with C 1-6 alkyl, C 2-6 alkenyl, C 2-5 alkynyl, C 3-12 cycloalkyl, C 3-12 heterocycloalkyl, C 3-14 aralkyl, C 3-14 heteroaralkyl, C 6-12 aryl, (CH 2 ) p C 6-12 aryl, C 3-12 heteroaryl, (CH 2 ) p C 3-12 heteroaryl, halogen, haloalkyl, cyano, (CH 2 ) p CN, nitro, C 1-6 alkoxy, C 6-12 aryloxy, C 1 -C 4  haloalkoxy, C 1-6 haloalkyl, hydroxyl, C 1-6 hydroxylalkyl, C 1-6 carboxyl, CHO, amino, aminoalkyl, dialkylamino, OR 15 , SR 15 , NR 17 R 17 C(O)OR 15 , C(O)NR 15 R 16 , OC(O)NR 15 R 16 , NR 15 C(O)NR 15 R 16 , NR 17 S(O) 2 R 15 , NR 17 (CH 2 ) n R 17 , C(O)R 17 , C(O)NR 17 R 17 , NR 15 C(O)R 17 , S(O)R 17 , S(O) 2 R 17 , or S(O) 2 NR 17 R 17 ;
 each R 15  is independently hydrogen, aralkyl, C 1-6  alkyl, C 3-12 cycloalkyl, C 6-12 aryl, C 3-12 heterocycloalkyl, or C 3-12 heteroaryl; 
 each R 16  is independently hydrogen, aralkyl, or C 1-6  alkyl; 
 each R 17  is independently H, C 1-6  alkyl, C 1-6  hydroxyalkyl, C 1-6  alkoxy, C 3-12  cycloalkyl, C 6-12  aryl, C 3-12 heteroaryl, C 3-12 heterocycloalkyl, hydroxyl, or each R 17  may form a heterocycloalkyl ring with another R 17 ; 
 wherein each A, R 15 , R 16 , and R 17  may be further optionally substituted with C 1-6 alkyl, C 1-6  alkoxy, C 1-6  haloalkoxy, C 3-12 heterocycloalkyl, amino, halogen, C 1-6  haloalkyl, SO 2 alkyl, or NHC(O)aryl; and 
 each p is independently 0-6; or a pharmaceutically acceptable salt thereof. 
 
     
     
         22 . The compound of  claim 18 , selected from the following:
 4-(6-(4-(trifluoromethoxy)phenylamino)-5-methylpyrimidin-4-yl)-N-(2-morpholinoethyl)benzamide;   6-(1H-pyrrolo[2,3-b]pyridin-1-yl)-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine;   N-(4-(trifluoromethoxy)phenyl)-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyrimidin-4-amine;   4-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzenesulfonamide;   4-[5-Methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzenesulfonamide;   N-Methyl-4-(5-methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl)-benzenesulfonamide;   N-Ethyl-4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzenesulfonamide;   N-(2-Hydroxy-ethyl)-4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzenesulfonamide;   [6-(4-Methanesulfonyl-phenyl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(4-Methanesulfonyl-phenyl)-5-methyl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   {6-[4-Propane-2-sulfonyl)-phenyl]-pyrimidin-4-yl}-(4-trifluoromethoxy-phenyl)-amine;   {5-Methyl-6-[4-(propane-2-sulfonyl)-phenyl]-pyrimidin-4-yl}-(4-trifluoromethoxy-phenyl)-amine;   N,N-Diethyl-4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzenesulfonamide;   N,N-Diethyl-4-[5-methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzenesulfonamide;   {6-[4-(Piperidine-1-sulfonyl)-phenyl]-pyrimidin-4-yl}-(4-trifluoromethoxy-phenyl)-amine;   4-Methyl-N-{4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-benzenesulfonamide;   4-Methyl-N-{4-[5-methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-benzenesulfonamide;   {6-[4-(Morpholine-4-sulfonyl)-phenyl]pyrimidin-4-yl}-(4-trifluoromethoxy-phenyl)-amine;   N-{4-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-methanesulfonamide;   Ethanesulfonic acid {4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide;   Butane-1-sulfonic acid {4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide;   Propane-2-sulfonic acid {4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide;   Pentane-2-sulfonic acid {4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-amide;   N-(2-Hydroxy-ethyl)-4-[5-methyl-6-(trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzamide;   4-[5-Methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide;   N-(3-Methoxy-propyl)-4-[5-methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzamide;   N-{3-[5-Methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-acetamide;   3-[5-Methyl-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzamide;   3-[5-Methyl-6-(4-trifluoromethoxy-phenylamino )-pyrimidin-4-yl]-benzoic acid;   (6-Biphenyl-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine:   (6-Biphenyl-4-yl-5-methyl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   [6-(5-Methoxy-naphthalen-2-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(5-Methoxy-naphthalen-2-yl)-5-methyl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   {3-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-acetonitrile;   [6-(3-Nitro-phenyl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine:   4-Methoxy-N{4-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-phenyl}-benzamide;   [6-(4-Aminomethyl-phenyl)-5-methyl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   5-Bromo-N-(2-Morpholin-4-yl-ethyl)-N′-(4-trifluoromethoxy-phenyl)-pyrimidine-4,6-diamine;   1-[5-Bromo-6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-piperidine-3-carboxylic acid amide;   {6-[2-(2-Morpholin-4-yl-ethylamino)-imidazol-1-yl]-pyrimidin-4-yl}-(4-trifluoromethoxyphenyl)-amine;   (4-Trifluoromethoxy-phenyl )-{6-[2-(4-trifluoromethoxy-phenylamino)-imidazol-1-yl]-pyrimidin-4-yl}-amine;   N-(5-Cyclopropyl-1H-pyrazol-3-yl)-N′-(4-trifluoromethoxy-phenyl)-pyrimidine-4,6-diamine;   [6-(3-Amino-5-cyclopropyl-pyrazol-1-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   N-(4-Trifluoromethoxy-phenyl)-N′-[1-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-pyrimidine-4,6-diamine;   (6-Pyrrolo[2,3-b]pyridin-1-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   [6-(1H-Pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1-Methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1-isobutyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1-Isobutyl-1H-pyrazol-4-yl)-5-methyl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   (4-Trifluoromethoxy-phenyl)-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-amine;   {6-[1-(4-Methanesulfonyl-benzyl)-1H-pyrazol-4-yl]-pyrimidin-4-yl}-(4-trifluoromethoxyphenyl)-amine;   [6-(1-Ethanesulfonyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1-Pyridin-4-ylmethyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   N6-(2-Morpholin-4-yl-ethyl)-N6′-(4-trifluoromethoxy-phenyl)-[4,4′]bipyrimidinyl-6,6′-diamine;   [5-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [5-Methyl-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluororoethoxyphenyl)-amine;   [6-(1H-Indol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1H-Indol-3-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1H-Indol-5-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   4-[6-(4-Trjfluoromethoxy-phenylamino)-pyrimidin-4-yl]-furan-2-carbaldehyde;   (6-Benzo[b]thiophen-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   [6-(1H-Indol-4-yl)-5-methyl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   (6-Dibenzofuran-4-yl-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine;   [6-(1-Benzyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1-Benzyl-1H-pyrazol-4-yl)-5-methyl-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   N6,N6′-Bis-(4-trifluoromethoxy-phenyl)-[4,4′]bipyrimidinyl-6,6′-diamine;   N6-(2-Morpholin-4-yl-ethyl)-N6′-(4-trifluoromethoxy-phenyl)-[4,4′]bipyrimidinyl-6,6′-diamine;   N-(4-Methyl-3-{1-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-benzamide;   N-(4-Methyl-3-{1-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-1H-imidazol-2-ylamino}-phenyl)-4-morpholin-4-ylmethyl-3-trifluoromethyl- benzamide.   [6-(1-Pyridin-3-ylmethyl-1H-pyrazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   [6-(1H-Pyrrolo[2,3-b]pyridin-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   4-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-1H-pyridin-2-one;   [6-(2-Methyl-thiazol-4-yl)-pyrimidin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;   2-Fluoro-5-[6-(4-trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzaldehyde;   {6-[2-(4-Methyl-piperazin-1-yl)-pyrimidin-yl]-pyrimidin-4-yl}-(4-trifluoromethoxy-phenyl-amine; or a pharmaceutically acceptable salt thereof.   
     
     
         23 . A compcund of formula X, or pharmaceutically acceptable salt thereof; 
       
         
           
           
               
               
           
         
       
       wherein
 each of X 2  or X 3  is independently NR 1 , CR 1 , C(O), O, or S; 
 each R 1  is independently selected from H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, an optionally substituted aralkyl, an optionally substituted C 2-12 heteroaralkyl, an optionally substituted C 1-6 haloalkyl, an optionally substituted (CH 2 )mC 1-6   12 aryl, an optionally substituted (CH 2 ) n C 3-12 heteroaryl, an optionally substituted (CH 2 ) n C 3-12 cycloalkyl, an optionally substituted (CH 2 ) n C 3-12 heterocycloalkyl, C 1-6 haloalkyl, C 1-6 aminoalkyl, hal, (CH 2 ) n C(O)R x , (CH 2 ) n C(O)OR x , (CH 2 ) n C(O)NR x R x , (CH 2 ), C(O)NR x R x S(O) 2 R x , —C(O)R x , —C(S)R x , —C(NR)R x , —SR x , —S(O)R x , —S(O) 2 R x , —OR x , —NR x R x , nitro, cyano, or absent; 
 each R x , for each occurrence, is independently H, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-12 cycloalkyl, an optionally substituted C 3-12 heterocycloalkyl, an optionally substituted C 6-12 aryl, an optionally substituted C 3-12 heteroaryl, C 1-6 haloalkyl, NHNHR 2  , or C(NH)NH 2 ; 
 R 2  is H or C 1-6  alkyl; and 
 each n is independently 0, 1 or 2. 
 
     
     
         24 . The corroound of  claim 23 , of formula XI; or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is independently selected from H, an optionally substituted C 1-6 alkyl, an optionally substituted C 6-12 aryl, or an optionally substituted C 3-12 heteroaryl. 
 
     
     
         25 . The compound of  claim 24 , selected from the following:
   2 -( 3 -nitrophenyl)-N-( 4 -(trifluoromethoxy)phenyl)imidazo[ 1 , 2 -c]pyrimidin- 7 -amine; ard     2 -Hydroxy- 3 -[ 7 -( 4 -trifluoromethoxy-phenylamino)-imidazo[ 1 , 2 -c]pyrimidin- 2 -yl]-benzamide; or a pharmaceutically acceptable salt thereof.   
     
     
         26 . A method of treating a kinase activity related disorder in a subject, comprising administering to said subject in need thereof, an effective amount of a compound, or pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 26  wherein the subject is suffering from a cell proliferative disorder or disease 
     
     
         33 . The method of  claim 32  wherein the disorder is cancer, tumor, neoplasm, neovascularization, vascularization, cardiovascular disease, metastasis, infection, blood clot, atherosclerosis, melanoma, skin disorder, rheumatoid arthritis, diabetic retinopathy, macular edema, or macular degeneration, inflammatory and arthritic disease, or osteosarcoma. 
     
     
         34 . The method of  claim 33  wherein the subject is suffering from a solid tumor or disseminated cancer. 
     
     
         35 . The method of  claim 34 , wherein the cancer is leukemia, multiple myeloma or lymphoma. 
     
     
         36 . The method of clain  35 , wherein the leukemia is Chronic Myelogenous Leukemia. 
     
     
         37 . A method of treating cancer in a subject, the method comprising administering to said subject an effective amount of a compound, or pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . (canceled) 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . A method of inhibiting kinase activity in a subject, the method comprising the step of administering to the subject a compound, or pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
         47 . A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt thereof, of  claim 1 . 
     
     
         48 . The composition of  claim 47  further comprising an additional therapeutic agent. 
     
     
         49 . The composition of clain  48  wheretn the additional therapeutic agent is an ATP-site inhibitor 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . (canceled) 
     
     
         57 . (canceled)