Chemical Compounds 251

Abstract

The invention relates to chemical compounds of formula I, and salts thereof. In some embodiments, the invention relates to inhibitors or modulators of PIM-1 and/or PIM-2, and/or PIM-3 protein kinase activity or enzyme function. In still further embodiments, the invention relates to pharmaceutical compositions comprising compounds disclosed herein, and their use in the prevention and treatment of PIM kinase related conditions and diseases, preferably cancer.

1 . A method of treating or preventing cancer comprising,
 a) providing a pharmaceutical composition comprising a compound of formula I,   
       
         
           
           
               
               
           
         
         
           or salts thereof, functioning to inhibit a PIM kinase, wherein
 R 1  is selected from a carbocyclyl, aryl, and heterocyclyl, wherein R 1  is optionally substituted with one or more, the same or different, R 2 ; 
 R 2  is selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, amino, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, and heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 3 ; 
 R 3  is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 3  is optionally substituted with one or more, the same or different, R 4 ; 
 R 4  is selected from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 4  is optionally substituted with one or more, the same or different, R 5 ; and 
 R 5  is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl; and 
 
         
         b) administering said pharmaceutical composition to a subject diagnosed with, exhibiting symptoms of, or at risk for cancer. 
       
     
     
         2 . A compound of formula IA, 
       
         
           
           
               
               
           
         
         or salts thereof, wherein,
 --- is individually at each occurrence selected from a single and double bond; 
 n is selected from 0, 1, or 2; 
 m is selected from 0, 1, or 2; 
 A is selected from N and CR 7 ; 
 X is selected from O, S, CHR 10  and NR 11 ; 
 Y is selected from N, CH, and C; 
 R 5 , R 6 , and R 7  are each individually and independently from hydrogen, C 1-6 alkyl, halogen, cyano, nitro, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carbocyclyl, aryl, and heterocyclyl, wherein R 5 , R 6 , and R 7  are each optionally substituted with one or more, the same or different, R 12 ; 
 R 8  and R 9  are each individually and independently selected from hydrogen, amino, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 alkylamino, carbocyclyl, aryl, and heterocyclyl wherein R 8  and R 9  are each optionally substituted with one or more, the same or different, R 15 ; 
 R 10  is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 12 ; 
 R 11  is selected from hydrogen, formyl, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, C 1-6 alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 11  is optionally substituted with one or more, the same or different, R 12 ; 
 R 12  is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 12  is optionally substituted with one or more, the same or different, R 16 ; 
 R 15  is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 15  is optionally substituted with one or more, the same or different, R 12 ; 
 R 16  is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, aminomethyl, aminoethyl, aminopropyl, aminobutyl, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl; and 
 provided that R 5 , R 6 , and R 7  are not all hydrogen and 
 provided the compound is not 5-((5-nitro-2-(1-piperidinyl)phenyl)methylene)-2,4-thiazolidinedione or 5-((2-(4-morpholinyl)-5-nitrophenyl)methylene)-2,4-thiazolidinedione. 
 
       
     
     
         3 . A compound of formula IB, 
       
         
           
           
               
               
           
         
         or salts thereof, wherein,
 n is selected from 0, 1, or 2; 
 X is selected from O, CHR 10  and NR 11 ; 
 R 5 , R 6 , and R 7  are each individually and independently from hydrogen, halogen, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl; 
 R 8  and R 9  are each individually and independently selected from hydrogen, amino, C 1-6 alkyl, C 1-6 alkylamino, wherein R 8  and R 9  are each optionally substituted with one or more, the same or different, R 15 ; 
 R 10  is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 12 ; 
 R 11  is selected from hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, C 1-6 alkoxycarbonyl, carbocyclyl, aryl, and heterocyclyl, wherein R 11  is optionally substituted with one or more, the same or different, R 12 ; 
 R 12  is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 12  is optionally substituted with one or more, the same or different, R 16 ; 
 R 15  is selected from C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 15  is optionally substituted with one or more, the same or different, R 12 ; 
 R 16  is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, and N-methyl-N-ethylsulfamoyl.; and 
 
         provided that said compound is not,
 5-[[2-(4-methyl-1-piperazinyl)phenyl]methylene]-2,4-thiazolidinedione or 
 5-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-2,4-thiazolidinedione. 
 
       
     
     
         4 . A compound of formula IC, 
       
         
           
           
               
               
           
         
         or salts thereof, wherein,
 n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; 
 X is selected from O, S, CHR 10  and NR 11 ; 
 Y is selected from O, S, and NR 13 ; 
 R 5 , R 6 , and R 7  are each individually and independently from C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, carbocyclyl, aryl, and heterocyclyl, wherein R 5 , R 6 , and R 7  are each optionally substituted with one or more, the same or different, R 12 ; 
 R 10  is selected from hydrogen, C 1-6 alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, C 1-6 alkylsulfamoyl, arylsulfamoyl, carbocyclyl, aryl, and heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 12 ; 
 R 11 , R 13 , and R 14  are each individually and independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkanoyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, arylsulfonyl, and C 1-6 alkoxycarbonyl wherein R 11  is optionally substituted with one or more, the same or different, R 12 ; 
 or R 11  and R 14 , taken together with the atoms to which they are attached form a five, six, or seven membered heterocyclic ring optionally substituted with one or more, the same or different, R 12 ; 
 R 12  is selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, 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, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 
 
       
     
     
         5 . A compound of formula IC as defined in  claim 4 , or salts thereof, wherein Y is NR 13 . 
     
     
         6 . A compound of formula IA, IB, or IC, as defined in  claims 2 - 4 , or salts thereof, wherein R 5  is a halogenated C 1-6 alkyl. 
     
     
         7 . A compound of formula IA, IB, or IC, as defined in  claims 2 - 4 , or salts thereof, wherein R 7  is a halogen. 
     
     
         8 . A compound of formula IX, 
       
         
           
           
               
               
           
         
         or salts thereof, wherein
 R 5  is selected from hydrogen, C 1-6 alkoxy, carbamoyl, and halogenated C 1-6 alkyl; 
 R 6  is selected from hydrogen, halogen, C 1-6 alkoxy, and 2-(1-piperidyl)ethoxy; 
 R 7  is selected from hydrogen, halogen, and C 1-6 alkoxy; 
 R 17  is a heterocarbocylcyl, wherein R 17  is optionally substituted with one or more, the same or different, R 18 ; 
 R 18  is selected from halogen, formyl, amino, C 1-6 alkyl, C 1-6 alkylamino, (C 1-6 alkyl) 2 amino, carbocyclyl, aryl, heterocyclyl, wherein R 18  is optionally substituted with one or more, the same or different, R 19 ; 
 R 19  is selected from amino, C 1-6 alkyl, hydroxy, carbocyclyl, and heterocyclyl wherein R 19  is optionally substituted with one or more, the same or different, R 20 ; and 
 R 20  is selected from amino, C 1-6 alkyl, and halogen. 
 
       
     
     
         9 . The compound of  claim 8 , or salts thereof, wherein, R 17  is selected from (3R)-3-aminopyrrolidin-1-yl, (3R)-3-dimethylaminopyrrolidin-1-yl, (3S)-3-(3-aminopropylamino)pyrrolidin-1-yl, (3S)-3-(5-aminopentanoylamino)pyrrolidin-1-yl, (3S)-3-amino-1-piperidyl, (3S)-3-aminopyrrolidin-1-yl, (3S)-3-dimethylaminopyrrolidin-1-yl, (3S,5R)-3,5-dimethylpiperazin-1-yl, 1,4-diazepan-1-yl, 2-(1-piperidyl)ethoxy, 2-diethylaminoethoxy, 2-dimethylaminoethyl-methyl-amino, 2-hydroxyethoxy, 2-morpholinoethoxy, 3-(2-aminoethylamino)pyrrolidin-1-yl, 3-(2-hydroxyethylamino)pyrrolidin-1-yl, 3-(2-methylaminoethylamino)pyrrolidin-1-yl, 3-(3-aminopropanoylamino)pyrrolidin-1-yl, 3-(3-aminopropylamino)pyrrolidin-1-yl, 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl, 3-(aminomethyl)-1-piperidyl, 3-(aminomethyl)pyrrolidin-1-yl, 3-acetamidopyrrolidin-1-yl, 3-aminopyrrolidin-1-yl, 3-dimethylaminopropoxy, 3-dimethylaminopropyl-methyl-amino, 3-dimethylaminopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-pyridyl, 4-(1-methyl-4-piperidyl)piperazin-1-yl, 4-(1-piperidyl)-1-piperidyl, 4-(2-aminoethyl)piperazin-1-yl, 4-(2-hydroxyethyl)-1,4-diazepan-1-yl, 4-(2-hydroxyethyl)-1-piperidyl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-(2-methylaminoethyl)piperazin-1-yl, 4-(2-morpholinoethyl)piperazin-1-yl, 4-(3-aminopropanoyl)-1,4-diazepan-1-yl, 4-(3-aminopropanoyl)piperazin-1-yl, 4-(3-aminopropyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidyl, 4-(4-aminobutanoyl)-1,4-diazepan-1-yl, 4-(4-aminobutanoyl)piperazin-1-yl, 4-(4-chloro-2-fluoro-phenyl)piperazin-1-yl, 4-(4-fluorophenyl)piperazin-1-yl, 4-(4-pyridylmethyl)piperazin-1-yl, 4-(5-aminopentanoyl)-1,4-diazepan-1-yl, 4-(5-aminopentanoyl)piperazin-1-yl, 4-(azetidine-3-carbonyl)piperazin-1-yl, 4-(benzo[1,3]dioxol-5-ylmethyl)piperazin-1-yl, 4-(cyclopropylmethyl)piperazin-1-yl, 4-(hydroxymethyl)-1-piperidyl, 4-(piperidine-3-carbonyl)-1,4-diazepan-1-yl, 4-(piperidine-3-carbonyl)piperazin-1-yl, 4-(piperidine-4-carbonyl)piperazin-1-yl, 4-[(2-chlorophenyl)methyl]piperazin-1-yl, 4-[3-(aminomethyl)benzoyl]piperazin-1-yl, 4-[4-(piperazin-1-ylmethyl)benzoyl]piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-amino-1-piperidyl, 4-butyl-1,4-diazepan-1-yl, 4-cyclopentylpiperazin-1-yl, 4-dimethylamino-1-piperidyl, 4-hydroxy-1-piperidyl, 4-isobutylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-morpholino-1-piperidyl, 4-pyridyl, 4-pyrrolidin-1-yl-1-piperidyl, 4-tert-butoxycarbonylpiperazin-1-yl, 4-tert-butylpiperazin-1-yl, morpholino, piperazin-1-yl, and pyrrolidin-1-yl. 
     
     
         10 . A compound selected from:
 5-({2-[(3S)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[2-(4-aminopiperidin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({2-[3-(aminomethyl)piperidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-(1,4-diazepan-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-(4-cyclopentylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(4-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[4-(1,3-benzodioxol-5-ylmethyl)piperazin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-(4-pyrrolidin-1-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(1-methylethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(2-methylpropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(2-hydroxyethyl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(4-chloro-2-fluorophenyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[3-(3-methyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(2-chlorobenzyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(2-morpholin-4-ylethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(cyclopropylmethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-(4-morpholin-4-ylpiperidin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(3-hydroxypropyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(dimethylamino)piperidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-{[3-(dimethylamino)propyl] (methyl)amino}-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[2-(4-butyl-1,4-diazepan-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({3-chloro-2-[4-(2-hydroxyethyl)piperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-morpholin-4-yl-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-{[2-(4-tert-butylpiperazin-1-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-{[2-(1,4′-bipiperidin-1′-yl)-3-chloro-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-{[3-chloro-2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   5-({3-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-chloro-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({3-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   2-{3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}acetamide;   (5Z)-5-{[3-(3-piperidin-1-ylpropoxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   (5Z)-5-({3-[(4-methylpiperazin-1-yl)methyl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   N-[2-(dimethylamino)ethyl]-2′-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-N-methylbiphenyl-4-sulfonamide;   5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-(trifluoromethyl)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({5-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylphenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-fluorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-5-methylphenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({5-bromo-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-3-fluorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   5-({2-chloro-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-methoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-bromophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-bromophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methylpropoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexylmethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclohexyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R,4R)-3-amino-4-hydroxypiperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-{[3-chloro-2-(1,4-diazepan-1-yl)phenyl]methylidene}-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(1-methylethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(1-methylethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-ethoxyphenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-{[4-(aminomethyl)benzyl]amino}piperidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({3-chloro-2-[(3R)-3-{[2-(methylamino)ethyl]amino}piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl]-3-chlorophenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({3-chloro-2-[4-methyl-3-(methylamino)piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-{[2-(3-amino-4-methylpiperidin-1-yl)-3-chlorophenyl]methylidene}-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2,2,2-trifluoroethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(2-methoxyethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3S)-3-aminopyrrolidin-1-yl]-3-(2-methoxyethoxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclopentyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]-3-(cyclobutyloxy)phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide;   4-[(3S)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzamide;   4-[(3R)-3-aminopiperidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid;   4-[(3S)-3-aminopyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzoic acid;   (5Z)-5-({2-[(3R)-3-aminopiperidin-1-yl]biphenyl-3-yl}methylidene)-1,3-thiazolidine-2,4-dione;   5-{[2-(3-aminopropoxy)-5-methoxyphenyl]methylidene}-1,3-thiazolidine-2,4-dione;   N-{4-[3-(dimethylamino)pyrrolidin-1-yl]-3-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}acetamide;   (5Z)-5-[(3-chloro-2-{(3R)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;   (5Z)-5-[(3-chloro-2-{(3R)-3-[(3-hydroxypropyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-imidazole-2-carboxamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-methoxyacetamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide;   N 2 -carbamoyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-pyridin-3-ylacetamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-pyridin-4-ylacetamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-1-methyl-1H-pyrazole-4-carboxamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-(1-oxidothiomorpholin-4-yl)acetamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-4-sulfamoylbutanamide;   N′-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-N,N-dimethylbutanediamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-N˜2˜,N˜2˜-dimethylglycinamide;   N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]-2-cyanoacetamide;   N 2 -acetyl-N-[(3S)-1-{2-chloro-6-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenyl}pyrrolidin-3-yl]glycinamide;   (5Z)-5-({3-chloro-2-[(3R)-3-(dipropylamino)piperidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione;   (5Z)-5-[(3-chloro-2-{(3R)-3-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;   5-[(5-methoxy-2-{3-[(1-methylethyl)amino]propoxy}phenyl)methylidene]-1,3-thiazolidine-2,4-dione;   (5Z)-5-({5-amino-2-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}methylidene)-1,3-thiazolidine-2,4-dione; and   5-[(2-amino-4,5-dimethoxyphenyl)methylidene]-1,3-thiazolidine-2,4-dione,   or salts thereof.   
     
     
         11 . A pharmaceutical composition comprising a compound of formula I, IA, IB, IC, or IX, as defined in  claims 1 - 10 , or a pharmaceutically acceptable salt thereof. 
     
     
         12 . A method of inhibiting a PIM kinase comprising, providing a compound of formula I, IA, IB, IC, or IX, as defined in  claims 1 - 10  comprising mixing a PIM kinase and said compound under conditions such that PIM kinase phosphorylation is inhibited. 
     
     
         13 . The use of a compound of the formula I, IA, IB, IC, or IX, or a pharmaceutically acceptable salt thereof, as claimed in any one of  claims 1 - 10 , for the manufacture of a medicament for the production of an anti-cancer effect in a subject. 
     
     
         14 . A method of making a compound of formula IA as defined in  claim 2 , 
       
         
           
           
               
               
           
         
         or salt thereof, comprising 
         a) mixing a compound of formula XI, 
       
       
         
           
           
               
               
           
         
         or salt thereof, wherein E is a halogen, and R 5 , R 6 , and A are defined in  claim 2 , 
         with a compound of formula XII, 
       
       
         
           
           
               
               
           
         
         or salt thereof, wherein
 ---, R 8 , R 9 , n, m, Y and X are defined in  claim 2 , 
 if Y is N, then R 21  is hydrogen, 
 if Y is C, then R 21  is selected from boronic acid and a boronic ester, and 
 if Y is CH, then R 21  is selected from a metal halide, 
 
         under conditions such that composition comprising a compound of formula XIII, 
       
       
         
           
           
               
               
           
         
       
       or salt thereof, is formed; and 
       b) mixing the compound of formula XIII and thiazolidine-2,4-dione under conditions such that a compound of formula IA is formed. 
     
     
         15 . A method of making a compound of formula IC, or salt thereof comprising a) mixing a compound of formula V, 
       
         
           
           
               
               
           
         
         or salt thereof, wherein R 5 , R 6 , and R 7  are defined in  claim 4 , 
         with a compound of formula VI, 
       
       
         
           
           
               
               
           
         
         or salt thereof, wherein R 14 , n, X and Y are defined in  claim 4 , under conditions such that a composition comprising a compound of formula VIII, 
       
       
         
           
           
               
               
           
         
         or salt thereof, is formed; and 
         b) mixing the compound of formula VIII and thiazolidine-2,4-dione under conditions such that a compound of formula IC is formed.