Pim kinase inhibitor compositions, methods, and uses thereof

Abstract

This invention relates to compounds and compositions useful as inhibitors of PIM kinases. Also provided are methods of synthesis and methods of use of PIM inhibitors in treating individuals suffering from cancerous malignancies.

What is claimed is: 
     
         1 . A method of inhibiting or partially inhibiting activity of one or more PIM (proviral integration site for Moloney murine leukemia virus) kinase(s) comprising contacting a PIM kinase with a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt, solvate, hydrate, or N-oxide, prodrug, or isotopic variants thereof, as follows: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variants thereof, wherein: 
         Each A, B, C, and D is the same or different and independently selected from H, halogen, —N 3 , —CN, —NO 2 , —OH, —OCF 3 . —OCH 2 F, —OCF 2 H, —CF 3 , —SR 1 , —S(═O)R 2 , —S(═O) 2 R 2 , —OS(═O) 2 F, —OS(═O) 2 (OR 2 ), —S(═O) 2 (OR 2 ), —NR 3 S(═O) 2 R 2 , —S(═O) 2 N(R 3 ) 2 , —OC(═O)R 2 , —CO 2 R 3 , —OR 3 , —N(R 3 ) 2 , —NR 3 C(═O)R 2 , —NR 3 C(═O)OR 3 , —NR 3 C(═O)N(R 3 ) 2 , CH 2 NH 2 , —CH 2 N(R 3 ) 2 , —CH 2 SR 1 , —C(═O)NH 2 , —C(═O)N(R 3 ) 2 , —C(═O)R 3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or an optional substituent selected, for example, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group, a glycose, aminoglycose or alkylglycose residue; 
         Each A′, B′, C′, and D′ is the same or different and independently selected from H, halogen, —N 3 , —CN, —NO 2 , —OH, —OCF 3 . —OCH 2 F, —OCF 2 H, —CF 3 , —SR 1 , —S(═O)R 2 , —S(═O) 2 R 2 , —OS(═O) 2 F, —OS(═O) 2 (OR 2 ), —S(═O) 2 (OR 2 ), —NR 3 S(═O) 2 R 2 , —S(═O) 2 N(R 3 ) 2 , —OC(═O)R 2 , —CO 2 R 3 , —N(R 3 ) 2 , —OR 3 , —NR 3 C(═O)R 2 , —NR 3 C(═O)OR 3 , —NR 3 C(═O)N(R 3 ) 2 , CH 2 NH 2 , —CH 2 N(R 3 ) 2 , —CH 2 SR 1 , —C(═O)NH 2 , —C(═O)N(R 3 ) 2 , —C(═O)R 3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or an optional substituent selected, for example, haloalkyl, alkenyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, acyloxyalkyl, cyanoalkyl, amidinoalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, aryl, alkylaryl, aminoalkyl, heteroaryl, carbonylalkyl, amidinothioalkyl, nitroguanidinoalkyl, a protecting group, a glycose, aminoglycose or alkylglycose residue; 
         Each E, F, G, and M is independently C or N; 
         Each E′, F′, G′, and M′ is independently C or N; 
         Each Y and Z is independently H, —OH, —OR 3 , N(R 3 ) 2 , halogen, —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or Y and Z can be combined together to represent O, N(NR 3 ), N(OH), or S corresponding to C═O, C═NNR 3 , C═NOH, or C═S groups, respectively; 
         R 1  is H or linear or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
         R 2  is linear or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; 
         Each R 3  is independently H, linear or branched substituted or unsubstituted alkyl. substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocycloalkyl substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted acyl (—C(═O)R 1 ), or two R 3  together with the atoms to which they are attached form a substituted or unsubstituted heterocycle; 
       
       Each Q and R is independently H, —S(═O)R 2 , —S(═O) 2 R 2 , —NR 3 S(═O) 2 R 2 , —S(═O) 2 N(R 3 ) 2 , —C(═O)R 2 , —CO 2 R 3 , —N(R 3 ) 2 , —C(O)N(R 3 ) 2 , linear or branched substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, natural or non-natural substituted or unsubstituted glycose, natural or non-natural substituted or unsubstituted glycose aminoglycose groups, natural or non-natural substituted or unsubstituted glycose alkylglycose groups, natural or non-natural substituted or unsubstituted glycose, aminoglycose, or alkylglycose where Q and R are linked, substituted or unsubstituted alkyl where Q and R are linked, substituted or unsubstituted heteroalkyl where Q and R are linked, substituted or unsubstituted cycloalkyl where Q and R are linked, substituted or unsubstituted heterocycloalkyl where Q and R are linked, substituted or unsubstituted aryl where Q and R are linked, or substituted or unsubstituted heteroaryl where Q and R are linked to form a ring;
 Each U, V, U′ and V′ is independently H, OH, OR 3 , N(R 3 ) 2 , halogen, —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or U and V and/or U′ and V′ can be combined together to represent O, N(NR 3 ), N(OH), or S corresponding to C═O, C═NNR 3 , C═NOH, or C═S groups, respectively; 
 Each X is H, —OH, —OR 3 , N(R 3 ) 2 , halogen, —N 3 , —NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl 
 wherein said contacting inhibits or partially inhibits the activity of the one or more PIM kinase(s). 
 
     
     
         2 . The method of  claim 1 , wherein Y and Z are H. 
     
     
         3 . The method of  claim 1 , wherein Y and Z together form a carbon-oxygen double bond (C═O). 
     
     
         4 . The method of  claim 1 , wherein X is —CH 2 N(CH 3 ) 2  and U, V, U′, and V′ are H and wherein at least one of A, B, C, D, A′, B′, C′, D′ are not hydrogen or at least one E, F, G, M, E′, G′, F′, M are not carbon. 
     
     
         5 . The method of  claim 1 , wherein Q, R, or both Q and R is or are an alkyl or arylalkyl chain containing at least one heteroatom. 
     
     
         6 . The method of  claim 1 , wherein Q, R, or both Q and R is or are a branched or linear, substituted or unsubstituted carbon chain of 2-6 carbons, connected at the terminal carbon to a heterocycle containing one or more N, S, and/or O. 
     
     
         7 . The method of  claim 6 , wherein the terminal carbon is connected to the N of a heterocycle containing one or more N. 
     
     
         8 . The method of  claim 7 , wherein the terminal carbon is connected to the N of a group selected from the groups consisting of piperadinyl, pyrrolidinyl, piperizinyl, morpholinyl, imidazolyl, and pyrazolyl. 
     
     
         9 . The method of  claim 1 , wherein the compound inhibits catalytic activity of PIM1, PIM2, PIM3, or combinations thereof. 
     
     
         10 . The method of  claim 9 , wherein the compound selectively inhibits catalytic activity of PIM3 kinase. 
     
     
         11 . The method of  claim 1  wherein the compound selectively inhibits catalytic activity of PIM3 kinase over PIM1 and PIM2 kinases by a factor of 1.5, 10, 100, 1000, or more, wherein the method comprises contacting PIM1, PIM2, and PIM3 kinase, separately or together, in vitro or in vivo, with the compound. 
     
     
         12 . The method of  claim 1  wherein the one or more PIM kinase(s) are contacted with the compound in vitro. 
     
     
         13 . The method of  claim 1  wherein the one or more PIM kinase(s) are contacted with the compound in vivo. 
     
     
         14 . The method of  claim 1  wherein contacting modulates cancer cell growth and survival. 
     
     
         15 . A method of treating a patient or individual suffering from a malignant disease comprising administering to an individual in need thereof a therapeutically effective amount of a compound as in one of  claim 1  pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug, or isotopic variants thereof. 
     
     
         16 . The method of  claim 15  wherein the malignant disease is a cancer of the endodermal organs, including but not limited to the cecum, pancreas, liver, stomach, intestine, colon, prostate, thyroid, esophagus, lungs, and gallbladder. 
     
     
         17 . The method of  claim 16  wherein the cancer is pancreatic cancer, liver cancer, gastric cancer, colorectal cancer, prostate cancer, esophageal adenocarcinoma, squamous cell carcinoma, nasopharyngeal carcinoma, gastric adenocarcinoma, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, gallbladder adenocarcinoma, prostatic adenocarcinoma, colorectal adenocarcinoma, gastrointestinal stromal tumors (GIST), or gastrointestinal carcinoid tumors. 
     
     
         18 . The method of  claim 15  wherein the compound is present in a pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier or binder. 
     
     
         19 . The method of  claim 15  wherein the malignancy comprises a cell that overexpress PIM3 kinase, wherein said overexpression of PIM3 contributes to survival, growth, and proliferation of the cell leading to cancer pathology and disease progression.