Abstract:
The present invention describes heterocyclic compounds of general Formula 1 and their method of preparation thereof. The present invention describes general Formula 1 which inhibits phosphoinositide 3-kinase (PI3K) and can be used as the anticancer agents.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to novel 1,3,5-substituted triazine containing heterocyclic compounds of general formula 1, which inhibits phosphoinositide 3-kinase (PI3K). The invention also relates to their method of preparation and their use as an agents or drugs for cancer therapy. 
       BACKGROUND AND PRIOR ART OF THE INVENTION 
       [0002]    At cellular level, phosphoinositide-3-kinase (PI3K) signalling contributes to many important processes, such as cell cycle progression, cell growth, survival and migration and intracellular vesicular transport. The PI3K represents the family of lipid kinases that can be classified into three subfamilies according to structure and substrate specificity viz., class I, class II and class III (Liu et al., Nature review drug discovery, 2009, 8, 627; Courteny et al., J Clin Oncol, 2010, 28, 1075). The class I PI3Ks are the most extensively studied among lipid kinases, are heterodimeric proteins; each containing a smaller regulatory domain and a larger 110 kDa catalytic domain, which occur in four isoforms differentiated as p110α, p110β, p110γ, and p110δ (Walker et al., Mol. Cell 2000, 6, 909). Moreover, Isoform selective inhibitors capable of attenuating PI3K signalling should have significant therapeutic potential for the treatment of cancer, inflammatory (Barber et al., Nat. Med. 2005, 11, 933), cardiovascular diseases and autoimmune disorders. In cancer, evidence suggests that inhibition of the class 1A PI3 kinase p110α appear to be the most appropriate to target, as in number of cancer, p110α isoform is amplified and activated (Stephens et al., Curr. Opin. Pharmacol. 2005, 5, 357). 
         [0003]    In the last decade, many small molecules have been discovered as PI3K isoform inhibitors and presenting the new opportunities as therapeutic agents. Some of the small molecules are presently in either phase I or II clinical trial against different type of cancers. Examples includes NVP-BEZ235 developed by Novartis, (Garcia-Echeverria et al., WO2006/122806A2), NVP-BGT226 developed by Novartis, (Kwang et al., Clin cancer res. 2011, 17(22), 7114), XL-147, XL-765 developed by Exelixis, (P. Wu et al., Eur. J. Med. Chem. 2011, 46, 5540), GDC0941 developed by Genentech, (Adrian et al., J. Med. Chem. 2008, 51, 5522), PKI-587 developed by Pfizer, (Mallon et al., Clin cancer res. 2011, 17(10), 3194), GSK1059615 developed by GSK, (Steven D. Knight et al., ACS Med. Chem. Lett. 2010, 1, 39), ZSTK474 developed by Zenyaku kogyo, (Yaguchi et al., J. Natl. Cancer inst. 2006, 98, 545; Kong et al., Cancer sci. 2007, 98, 1439; Gordon et al., J. Med. Chem. 2011, 54, 7105-7126; Gordon et al., WO2010/110686A1; Vladimir et al., WO2011/135520A1; Gordon et al., WO2010/110685A2; Venkatesan et al., WO2009/143317A1) etc. In spite of having many PI3K inhibitors in pre-clinical and different clinical trials, still there is need for the discovery of new PI3K inhibitors for the treatment of cancer. 
       Objective of the Invention 
       [0004]    The main object of the present invention is to provide 1,3,5-substituted triazine containing heterocyclic compounds as anti-cancer agents. Still another object of the present invention is to provide a process for the preparation of novel 1,3,5-substituted based compounds. Yet another object of the present invention is to provide the therapy for the treatment of cancer 
       SUMMARY OF THE INVENTION 
       [0005]    The present invention relates to 1,3,5-substituted triazine containing heterocyclic compounds, their method of preparation and their use as drugs for treating cancer. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0006]    In a first aspect, the present invention pertains to a compound having a general formula 1: 
         [0007]    Wherein substituent ‘S 1 ’ is selected from one of the formula Ia or Ib 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and substituent ‘S 2 ’ selected from the group consisting of 1c 
         [0000]    
       
                 
         
             
             
         
       
     
         [0008]    ‘X’ is independently selected from any of NR 3 , O, CH 2 , 
         [0009]    ‘R 1 , R 2 ,’ are independently selected from any of un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly at any of the available position 
         [0010]    R 3  is independently selected from any of H, un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly at any of the available position 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    is independently selected from any of following un/substituted N-heterocyles such as indolyl, triazolyl, pyrrolyl, imidazoyl, benzotriazolyl, benzoimidazolyl, thiazoyl etc attached though N-atom or any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl 
         [0011]    ‘Ar’ is independently selected from any of un/substituted phenyl, un/substituted napthyl and attached through any of the available ring position and further substitution selected from any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl 
         [0012]    ‘Hetero-Ar’ is independently selected from any of un/substituted hetrocycles such as pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl, and benzothiazolyl, indolyl, benzotriazolyl, benzoimidazolyl etc and attached through any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl 
         [0013]    R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 14  and R 17 ′ are independently selected from any of following substitution such as H, linear alkyl chain C 1 -C 10 , branched alkyl chain C 3 -C 10 , un/substituted phenyl ring. 
         [0014]    In another aspect, a preferred subclass have following formulas 1A or 1B belong to general formula 1 
         [0000]    
       
                 
         
             
             
         
       
     
         [0015]    ‘X’ is independently selected from any of NR 3 , O, CH 2 , 
         [0016]    ‘R 1 , R 2 ,’ are independently selected from any of following atom or groups un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring, un/substituted heterocycles and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly substituted at any of the available position 
         [0017]    R 3  is independently selected from any of H, un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl either mono or di or poly at any of the available position 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    is independently selected from any of following un/substituted N-heterocyles such as indolyl, triazolyl, pyrrolyl, imidazoyl, benzotriazolyl, benzoimidazolyl, thiazoyl etc attached though N-atom or any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0018]    ‘Ar’ is independently selected from any of un/substituted phenyl, un/substituted napthyl etc and attached through any of the available ring position and further substitution selected from any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0019]    ‘Hetero-Ar’ is independently selected from any of un/substituted hetrocycles such as pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl, and benzothiazolyl, indolyl, benzotriazolyl, benzoimidazolyl etc and attached through any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0020]    R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 14  and R 17 ′ are independently selected from any of following substitution such as H, linear alkyl chain C 1 -C 10 , branched alkyl chain C 3 -C 10 , un/substituted phenyl ring. 
         [0021]    In yet another embodiment of the present invention, the compounds of general formula 1 are useful as PI3K anti-cancer agent. 
         [0022]    In still another embodiment of the present invention, the compounds of general formula 1 inhibit PI3Kα isoform. 
         [0023]    In yet another embodiment of the present invention, the compounds of general formula 1 exhibit an in vitro cancer cell line activity. 
         [0024]    In another embodiment of the present invention, a process for the preparation of the compounds of general formula 1 comprising of following steps:
   (i) reacting disubstituted triazine compound of formula 5 or 8 with aryloxy piperidines or piperidones in an organic solvent selected from a group consisting of DMF, THF, CH 3 CN (added) in the presence of alkali metal carbonate selected from a group consisting of K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3  (added) at a temperature ranging between 10° C. to 80° C. for a period ranging between 1 to 24 hrs, to obtain compound of formula 1A(1-20) or 1B(1-20) or trisubstituted triazine compound 10 or 15,   (ii) reacting trisubstituted triazine compound 10 or 15 with substituted aryl amine of formula 11, wherein FG4 is selected from a group consisting of 4F, 4-CF 3 , 4-OCH 3 , 4-Br, 3, 4 DiCl, 2-F, 2-OCH 3 , 2-CF 3 , 3-OCH 3 , 2-CH 3 , 4-CH 3  (added) in an organic solvent selected from a group consisting of DCM, DCE, THF, MeOH (added) in presence of acetic acid and a reducing agent selected from a group consisting of sodium triacetoxy borohydride, sodium borohydride (added) at a temperature ranging between 10° C. to 80° C. for a period renging between 1 to 24 hrs, to obtain compound 1B (21-40) or 1B (46-50) respectively,   (iii) reacting trisubstituted triazine compound 1B21 with substituted aryl boronic acid of formula 12, wherein FG5 is selected from a group consisting of halogen or CF 3 , in an organic solvent selected from a group consisting of DCM, DCE, MeOH, CH 3 CN (added) in presence of triethylamine and copper acetate at a temperature ranging between 10° C. to 80° C. for a period in the range of 1 to 24 hrs, to obtain compound of formula 1B(41-45).   
 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0028]      FIG. 1  shows the general structure of representative of compounds referred to in Table 1, 2, 3, 4, 5, 6 and 7 
           [0029]      FIG. 2  shows the synthetic approach (scheme1) for the synthesis of compounds 1A (1-20). 
           [0030]      FIG. 3  shows the synthetic approach (scheme2) for the synthesis of compounds 1B (1-20). 
           [0031]      FIG. 4  shows the synthetic approach (scheme3) for the synthesis of compounds 1B (20-40). 
           [0032]      FIG. 5  shows the synthetic approach (scheme4) for the synthesis of compounds 1B (41-45). 
           [0033]      FIG. 6  shows the synthetic approach (scheme6) for the synthesis of compounds 1B (45-50). 
       
    
    
       [0034]    Table 1 shows the structures of representative compounds IA (1-10) belong to formula IA and synthesized as per scheme 1 provided in ( FIG. 1 ). 
         [0035]    Table 2 shows the structures of representative compounds IA (10-20) belong to formula IA and synthesized as per scheme 1 provided in ( FIG. 1 ). 
         [0036]    Table 3 shows the structures of representative compounds IB (1-10) belong to formula IB and synthesized as per scheme 2 provided in ( FIG. 2 ). 
         [0037]    Table 4 shows the structures of representative compounds IB (10-20) belong to formula IB and synthesized as per scheme 2 provided in ( FIG. 2 ). 
         [0038]    Table 5 shows the structures of representative compounds IB (21-30) belong to formula IB and synthesized as per scheme 3 provided in ( FIG. 3 ). 
         [0039]    Table 6 shows the structures of representative compounds IB (31-40) belong to formula IB and synthesized as per scheme 3 provided in ( FIG. 3 ). 
         [0040]    Table 7 shows the structures of representative compounds IB (40-50) belong to formula IB and synthesized as per scheme 4 and scheme 5 provided in ( FIG. 4  &amp;  FIG. 5 ). 
         [0041]    Table 8 shows the inhibition results of compounds general formula 1 by enzyme based assay PI3Kα. 
         [0042]    *In vitro PI3K alpha kinase inhibition at 500 nm; + indicates greater than 50% to 70% of inhibition and ++ indicates greater than 70% of inhibition. 
         [0043]    Table 9 shows the inhibition results of compounds of general formula 1 by MTT assay on cancer cell line *In vitro cell line inhibition at 10 μM: + indicates 30% to 50% of inhibition and ++ indicates greater than 50% of inhibition. 
       DETAILED DESCRIPTION OF THE INVENTION 
       [0044]    The present invention relates to newer generation of triazine based compounds, their method of preparation and to their use as drugs for treating cancer. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0045]    In a first aspect, the present invention pertains to a compound having a general formula 1: 
         [0046]    Wherein substituent ‘S 1 ’ is selected from one of the formula Ia or Ib 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and substituent ‘S 2 ’ selected from the group consisting of 1c 
         [0000]    
       
                 
         
             
             
         
       
     
         [0047]    ‘X’ is independently selected from any of NR 3 , O, CH 2 , 
         [0048]    ‘R 1 , R 2 ’ are independently selected from any of un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly at any of the available position 
         [0049]    R 3  is independently selected from any of H, un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C1 to C14, COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly at any of the available position 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    is independently selected from any of following un/substituted N-heterocyles such as indolyl, triazolyl, pyrrolyl, imidazoyl, benzotriazolyl, benzoimidazolyl, thiazoyl etc attached though N-atom or any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0050]    ‘Ar’ is independently selected from any of un/substituted phenyl, un/substituted napthyl etc and attached through any of the available ring position and further substitution selected from any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0051]    ‘Hetero-Ar’ is independently selected from any of un/substituted hetrocycles such as pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl, and benzothiazolyl, indolyl, benzotriazolyl, benzoimidazolyl etc and attached through any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0052]    R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 14  and R 17 ′ are independently selected from any of following substitution such as H, linear alkyl chain C 1 -C 10 , branched alkyl chain C 3 -C 10 , un/substituted phenyl ring. 
         [0053]    In another aspect, a preferred subclass have following formulas 1A or 1B belong to general formula 1 
         [0000]    
       
                 
         
             
             
         
       
     
         [0054]    ‘X’ is independently selected from any of NR 3 , O, CH 2 , 
         [0055]    ‘R 1 , R 2 ’ are independently selected from any of following atom or groups un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring, un/substituted heterocycles and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly substituted at any of the available position 
         [0056]    R 3  is independently selected from any of following atom or groups H, un/substituted alkyl C 1 -C 14 , un/substituted acyl C 2  to C 14 , un/substituted phenyl ring, un/substituted heterocycles and further substitution contains any of the following atoms or groups such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR ii , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl etc either mono or di or poly substituted at any of the available position 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    is independently selected from any of following un/substituted N-heterocyles such as indolyl, triazolyl, pyrrolyl, imidazoyl, benzotriazolyl, benzoimidazolyl, thiazoyl etc attached though N-atom or any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0057]    ‘Ar’ is independently selected from any of un/substituted phenyl, un/substituted napthyl etc and attached through any of the available ring position and further substitution selected from any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0058]    ‘Hetero-Ar’ is independently selected from any of un/substituted hetrocycles such as pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazoyl, quinolinyl, isoquinolinyl, benzooxazolyl, and benzothiazolyl, indolyl, benzotriazolyl, benzoimidazolyl etc and attached through any of the available ring position and further substituted heterocycles contains any of the following atom or group such as F, Cl, Br, I, CN, NR 4 R 5 , CF 3 , CHCF 2 , CH 2 F, OCF 3 , OCH 2 CF 3 , OR 6 , NO 2 , NO, CHR 7 R 8 , alkyl chain from C 1  to C 14 , COOR 9 , CHO, COR 10 , COCF 3 , COCH 2 CF 3 , SR 11 , SOR 12 , SO 2 R 13 , SONR 14 R 15 , SO 2 NR 14 R 17 , cycloalkyl, 
         [0059]    R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 14  and R 17 ′ are independently selected from any of following substitution such as H, linear alkyl chain C 1 -C 10 , branched alkyl chain C 3 -C 10 , un/substituted phenyl ring. 
         [0060]    The compound of general formula 1 is useful as anti-cancer agent. 
         [0061]    The compounds of formula 1A and 1B of general formula 1 inhibit PI3K α isoform. 
         [0062]    The compounds of formula 1A and 1B of general formula 1 exhibit an in vitro cancer cell line activity. 
         [0063]    The compound of formula 1A of general formula 1, wherein said compounds prepared by reacting di-substituted triazine compounds of formula (5) with substituted aryloxy piperidines (6) in an organic solvent N,N-dimethylformamide, in the presence of base potassium carbonate at a room temperature for 24 hrs to obtain the compounds of 1A (1-20) of general formula 1. 
         [0064]    The compound of formula 1B of general formula 1, wherein said compounds prepared by reacting di-substituted triazine compounds of formula (8) with substituted aryloxy piperidines (6) in an organic solvent N,N-dimethylformamide in the presence of potassium carbonate at a room temperature for 24 hrs to obtain the compounds of 1B (1-20) of general formula 1. 
         [0065]    These compounds, as well as mixtures thereof, isomers, physiologically functionally salt derivatives and drugs thereof, are useful in prevention of or therapy for treating cancer. Suitable acids for the preparation of the pharmaceutically acceptable salts, but are not limited to hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salyilic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid and methanesulfonic acid, boric acid, galactaric acid, gentisic acid, glucoheptonoic acid, D-gluconic acid, D-glucuronic acid, glycolic acid, hyppuric acid. 
         [0066]    Suitable bases for the preparation of the pharmaceutically acceptable salts, but are not limited to sodium hydroxide, potassium hydroxide or ammonium hydroxide, ammonia, triethylamine, benethamine, benzathine, choline, deanol, isopropyl amine, L-lysine, L-arginine, morpholine, piperizine, pyrrolidine, pyridine quinoline, isoquinoline, triethanolamine. 
         [0067]    The combination of the standard drugs, which are being prescribed presently for anticancer therapy along with the analogs of novel 1,3,5 substituted triazine scaffold with general formula 1, in various proportions and dosage, with the suitable pharmaceutical composition and formulation. The combination of the molecules that are reported as anticancer agents that may be derived from the natural sources viz. marine or terrestrial and the synthetic molecules along with the analogs of novel 1,3,5 substituted triazine scaffold with general formula 1, in various proportions and dosage, with the suitable pharmaceutical composition and formulation. 
         [0068]    The compound of formula 1B of general formula 1, wherein said compounds prepared by reacting di substituted triazine compounds of formula (10) with substituted aryl amines (11) in an organic solvent DCM in the presence of acid acetic acid, and reducing agent like a sodium triacetoxy borohydride at a room temperature for 24 hrs to obtain the compounds of 1B (20-40) of general formula 1. 
         [0069]    The compound of formula 1B of general formula 1, wherein said compounds prepared by reacting tri-substituted triazine compounds of formula (1B21) with substituted aryl boronic acids compounds of formula (12) in an organic solvent DCM in the presence of triethyl amine and copper acetate at a room temperature for 24 hrs to obtain the compounds of 1B (41-45) of general formula 1. 
         [0070]    The compound of formula 1B of general formula 1, wherein said compounds prepared by reacting tri-substituted triazine compounds of formula (15) with substituted aryl amines of formula (11) in an organic solvent DCM in the presence of of acetic acid, and reducing agent sodium triacetoxy borohydride at a room temperature for 24 hrs to obtain the compounds of 1B (45-50) of general formula 1. 
         [0071]    The most highly preferred of the compounds of formula 1A and 1B, comprising of:
   4-(4-(4-fluorophenoxy)piperidin-1-yl)-N-methyl-6-morpholino-N-phenyl-1,3,5-triazin-2-amine (compound 1A1, Table 1)   4-(4-(2-fluorophenoxy)piperidin-1-yl)-N-methyl-6-morpholino-N-phenyl-1,3,5-triazin-2-amine (compound 1A2, Table 1)   4-(4-(4-fluorophenoxy)piperidin-1-yl)-N-(4-fluorophenyl)-N-methyl-6-morpholino-1,3,5-triazin-2-amine (compound 1A3, Table 1)   2,2,2-trifluoro-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A4, Table 1)   2,2,2-trifluoro-N-(4-fluorophenyl)-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)acetamide (compound 1A5, Table 1)   2,2,2-trifluoro-N-(4-(4-(4-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluoro phenyl)acetamide (compound 1A6, Table 1)   2,2,2-trifluoro-N-(4-morpholino-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A7, Table 1)   2,2,2-trifluoro-N-(4-morpholino-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A8, Table 1)   2,2,2-trifluoro-N-(4-morpholino-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A9, Table 1)   2,2,2-trifluoro-N-(4-morpholino-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A10, Table 1)   2,2,2-trifluoro-N-methyl-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)acetamide (compound 1A11, Table 2)   2,2,2-trifluoro-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-N-(2,2,2-trifluoro acetyl)acetamide (compound 1A12, Table 2)   2,2,2-trifluoro-N-(4-(4-(4-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2,2,2-trifluoroacetyl)acetamide (compound 1A13, Table 2)   2,2,2-trifluoro-N-(4-(4-(2-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2,2,2-trifluoroacetyl)acetamide (compound 1A14, Table 2)   2,2,2-trifluoro-N-(4-(4-(4-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-methyl acetamide (compound 1A15, Table 2)   N,N-dimethyl-4-morpholino-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-amine (compound 1A16, Table 2)   4-(4-(4-fluorophenoxy)piperidin-1-yl)-N,N-dimethyl-6-morpholino-1,3,5-triazin-2-amine (compound 1A12, Table 2) (compound 1A17, Table 2)   4-morpholino-6-(4-phenoxypiperidin-1-yl)-N,N-diphenyl-1,3,5-triazin-2-amine (compound 1A18, Table 2)   4-morpholino-N,N-diphenyl-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-amine (compound 1A19, Table 2)   4-morpholino-N,N-diphenyl-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-amine (compound 1A20, Table 2   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B1, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B2, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B3, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B4, Table 3)   4-(4-(4-(4-chlorophenoxy)piperidin-1-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B5, Table 3)   4-(4-(4-(3-chlorophenoxy)piperidin-1-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B6, Table 3)   4-(4-(4-(2-chlorophenoxy)piperidin-1-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B7, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(3-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B8, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(2-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B9, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B10, Table 3)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(m-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B11, Table 4)   4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(o-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B12, Table 4)   4-(4-(5-fluoro-1H-benzo[d]imidazol-1-yl)-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B13, Table 4)   4-(4-(5-fluoro-1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B14, Table 4)   4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B15, Table 4)   4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B16, Table 4)   4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(4-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B17, Table 4)   4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(2-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B18, Table 4)   4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(2-chlorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B19, Table 4)   4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B20, Table 4)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluoro phenyl)piperidin-4-amine (compound 1B21, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methyl)phenyl)piperidin-4-amine (compound 1B22, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methoxy)phenyl)piperidin-4-amine (compound 1B23, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-methoxy phenyl)piperidin-4-amine (compound 1B24, Table 5)   N-(4-bromophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound 1B25, Table 5)   N-(3,4-dichlorophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound 1B26, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-fluoro phenyl)piperidin-4-amine (compound 1B27, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-methoxy phenyl)piperidin-4-amine (compound 1B28, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-(trifluoro methyl)phenyl)piperidin-4-amine (compound 1B29, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(p-tolyl) piperidin-4-amine (compound 1B30, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(3-methoxy phenyl)piperidin-4-amine (compound 1B31, Table 5)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(o-tolyl) piperidin-4-amine (compound 1B32, Table 6)   1-(4-(2-(difluoromethyl)-5-fluoro-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(p-tolyl)piperidin-4-amine (compound 1B33, Table 6)   1-(4-(2-(difluoromethyl)-5-fluoro-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine (compound 1B34, Table 6)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methyl)phenyl)piperidin-4-amine (compound 1B35, Table 6)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methoxy)phenyl)piperidin-4-amine (compound 1B36, Table 6)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluoro phenyl)piperidin-4-amine (compound 1B37, Table 6)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-fluoro phenyl)piperidin-4-amine (compound 1B38, Table 6)   N-(2-chlorophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound 1B39, Table 6)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-(trifluoro methyl)phenyl)piperidin-4-amine (compound 1B40, Table 6)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N,N-bis(4-fluorophenyl)piperidin-4-amine (compound 1B41, Table 7)   N-(4-bromophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)piperidin-4-amine (compound 1B42, Table 7)   1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine (compound 1B43, Table 7)   N-(4-chlorophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)piperidin-4-amine (compound 1B44, Table 7)   N-(1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl) piperidin-4-yl)-N-(4-fluorophenyl)-3-(trifluoromethyl)pyridin-4-amine (compound 1B45, Table 7)   1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluoro phenyl)piperidin-4-amine (compound 1B46, Table 7)   1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-methoxy phenyl)piperidin-4-amine (compound 1B47, Table 7)   1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methoxy)phenyl)piperidin-4-amine (compound 1B48, Table 7)   1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methyl)phenyl)piperidin-4-amine (compound 1B49, Table 7)   N-(4-chlorophenyl)-1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound 1B50, Table 7)   
 
         [0142]    The invention is further described by reference to following examples which are intended to illustrate, not to limit the scope of the invention. 
       Example 1 
     General Procedure for the Preparation of Compounds (IA1-20): 
       [0143]    Cynuric chloride (1) (10 g, 54.2 mmol, 1.0 eq) was substituted by morpholine (7) (4.72 ml, 5.42 mmol, 1.0 eq) in methylene chloride (60 ml), at −50° C. for 20 min to obtain intermediate (3). The intermediate (3) (5 g, 1.0 eq) on further treatment with di-substituted amine (4) (1.4 eq) in presence of K 2 CO 3  (1.44 eq) in DMF (20 ml), at −5° C. for 30 min and then at room temperature for 4 h led to intermediate (5). To the solution of intermediate (5) (100 mg, 1.0 eq) in DMF (3 ml) were added K 2 CO 3  (1.4 eq) and substituted aryloxy piperidines (6) (1.44 eq). This resulting reaction mixture was stirred at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate twice washed with 2N HCl solution and dried under vacuo. This crude product was purified by silica gel column chromatography using a ethyl acetate and hexane mixture as solvent to obtained the compound of formula 1A(1-20). 
       Example 2 
     General Procedure for the Preparation of Compounds (IB1-20): 
       [0144]    Cynuric chloride (1) (10 g, 54.2 mmol, 1.0 eq) was substituted by morpholine (7) (4.72 ml, 5.42 mmol, 1.0 eq) in methylene chloride (60 ml), at −50° C. for 20 min to obtain intermediate (3). The intermediate (3) (5 g, 1.0 eq) on further treatment with di-substituted benzimidazole (7) (1.4 eq) in presence of K 2 CO 3  (1.44 eq) in DMF (20 ml), at −5° C. for 30 min and then at room temperature for 4 h led to intermediate (8). To the solution of intermediate (8) (100 mg, 1.0 eq) in DMF (3 ml) are added K 2 CO 3  (1.4 eq) and substituted aryloxy piperidines (6) (1.44 eq). This resulting reaction mixture was stirred at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate twice washed with 2N HCl solution and dried under vacuo. This crude product was purified by silica gel column chromatography using an ethyl acetate and hexane mixture as solvent to obtained the compounds formula (1B1-20). 
       Example 3 
     General Procedure for the Preparation of Compounds (IB21-40): 
       [0145]    The intermediate (8) (5 g, 1.0 eq) on reaction with piperidone (9) (1.4 eq) in presence of K 2 CO 3  (1.44 eq) in DMF (20 ml), at room temperature for 24 h led to the formation of intermediate (10). To the solution of intermediate (10) (100 mg, 1.0 eq) in dichloromethane (3 ml) are added acetic acid (1 eq) and substituted primary aromatic amines (11) (1 eq). This resulting reaction mixture was stirred at room temperature for 6 h and then added Sodium triacetoxy borohydride (Na(OAC) 3 BH) (1 eq). This resulting reaction mixture again stirred at room temperature for 24 h. The thus-obtain mixture was poured into water (30 ml) and extracted with ethyl acetate and dried under vacuo. This crude product was purified by silica gel column chromatography using an ethyl acetate and hexane mixture as solvent to obtain the compounds of formula (1B21-40). 
       Example 4 
     General Procedure for the Preparation of Compounds (IB41-45): 
       [0146]    Take the (IB21) (100 mg, 1.0 eq) on reaction with substituted aryl boronic acid (12) (2 eq) and copper acetate (20 mole %) in dichloromethane solvent at room temperature. To this reaction mixture added the triethylamine (1 eq). This resulting mixture stirred at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate and dried under vacuo. This crude product was purified by silica gel column chromatography using an ethyl acetate and hexane mixture as solvent to obtained the compounds formula (1B41-45). 
       Example 5 
     General Procedure for the Preparation of Compounds (IB46-50): 
       [0147]    Cynuric chloride (1) (10 g, 54.2 mmol, 1.0 eq) was substituted by morpholine (7) (4.72 ml, 5.42 mmol, 1.0 eq) in methylene chloride (60 ml), at −50° C. for 20 min to obtain intermediate (3). The intermediate (3) (5 g, 1.0 eq) on further treatment with substituted indole (13) (1.4 eq) in presence of K 2 CO 3  (1.44 eq) in DMF (20 ml), at −5° C. for 30 min and further stirring at room temperature for 4 h led to intermediate (14). The intermediate (14) (5 g, 1.0 eq) on reaction with piperidone (9) (1.4 eq) in presence of K 2 CO 3  (1.44 eq) in DMF (20 ml), at room temperature for 24 h led to intermediate (15). To the solution of intermediate (15) (100 mg, 1.0 eq) in Dichloromethane (3 ml) are added acetic acid (1 eq) and substituted primary aromatic amines (11) (1 eq). This resulting reaction mixture was stirred at room temperature for 6 h and then added Sodium triacetoxy borohydride (Na(OAC) 3 BH) (1 eq). This resulting mixture was stirred again at room temperature for 24 h. The thus-obtained mixture was poured into water (30 ml) and extracted with ethyl acetate and dried under vacuo. This crude product was purified by silica gel column chromatography using an ethyl acetate and hexane mixture as solvent to obtain the compounds of formula (1B46-50). 
       4-(4-(4-fluorophenoxy)piperidin-1-yl)-N-methyl-6-morpholino-N-phenyl-1,3,5-triazin-2-amine (compound 1A1, Table 1, FIG.  1 ) 
       [0148]      1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (t, J=7.5 Hz, 2H), 7.08-6.91 (m, 7H), 4.53-4.43 (m, 1H), 3.77 (t, J=4.9 Hz, 4H), 3.52-3.42 (m, 4H), 3.40 (t, J=4.8 Hz, 2H), 3.32 (dt, J=12.3, 5.3 Hz, 2H), 2.15 (dqd, J=12.7, 5.4, 2.3 Hz, 2H), 1.88 (dqd, J=12.8, 5.4, 2.2 Hz, 2H) Mass: ESI [M+1]: 465. 
       4-(4-(2-fluorophenoxy)piperidin-1-yl)-N-methyl-6-morpholino-N-phenyl-1,3,5-triazin-2-amine (compound 1A2, Table 1, FIG.  1 ) 
       [0149]      1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (t, J=7.5 Hz, 2H), 7.09-6.84 (m, 7H), 4.31 (p, J=7.2 Hz, 1H), 3.53 (t, J=4.9 Hz, 2H), 3.39 (ddq, J=64.5, 12.3, 6.1 Hz, 6H), 2.34-2.20 (m, 2H), 1.92 (qd, J=12.4, 6.1 Hz, 2H) Mass: ESI [M+1]: 465. 
       4-(4-(4-fluorophenoxy)piperidin-1-yl)-N-(4-fluorophenyl)-N-methyl-6-morpholino-1,3,5-triazin-2-amine (compound 1A3, Table 1, FIG.  1 ) 
       [0150]      1 H NMR (400 MHz, CDCl 3 ) δ 7.09-6.87 (m, 8H), 4.54-4.40 (m, 1H), 3.77 (t, J=4.8 Hz, 4H), 3.52-3.24 (m, 8H), 3.01 (s, 3H), 2.20-2.07 (m, 2H), 1.99-1.80 (m, 2H) Mass: ESI [M+1]: 483. 
       2,2,2-trifluoro-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A4, Table 1, FIG.  1 ) 
       [0151]      1 H NMR (400 MHz, CDCl 3 ) δ 7.41-7.14 (m, 6H), 7.14-6.80 (m, 4H), 4.39 (tt, J=7.9, 3.8 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.54 (t, J=4.9 Hz, 2H), 3.47-3.20 (m, 6H), 2.30-2.12 (m, 2H), 1.90 (dqd, J=11.1, 5.4, 1.9 Hz, 2H) Mass: ESI [M+1]: 529. 
       2,2,2-trifluoro-N-(4-fluorophenyl)-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)acetamide (compound 1A5, Table 1, FIG.  1 ) 
       [0152]      1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.14 (m, 4H), 7.09 (t, J=7.8 Hz, 2H), 6.99-6.82 (m, 3H), 4.38 (tt, J=8.0, 4.0 Hz, 1H), 3.59-3.37 (m, 6H), 3.29 (dt, J=12.3, 5.3 Hz, 2H), 2.27-2.10 (m, 2H), 1.91 (tdd, J=11.4, 5.4, 1.8 Hz, 2H) Mass: ESI [M+1]: 547. 
       2,2,2-trifluoro-N-(4-(4-(4-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)acetamide (compound 1A6, Table 1, FIG.  1 ) 
       [0153]      1 H NMR (400 MHz, CDCl 3 ) δ 7.31-7.19 (m, 2H), 7.04 (dt, J=49.3, 7.8 Hz, 4H), 6.94-6.79 (m, 2H), 4.09 (p, J=7.4 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.57-3.37 (m, 6H), 3.21 (dt, J=12.2, 5.5 Hz, 2H), 2.14 (ddt, J=12.9, 7.5, 5.5 Hz, 2H), 1.92 (ddt, J=12.8, 7.5, 5.5 Hz, 2H) Mass: ESI [M+1]: 565. 
       2,2,2-trifluoro-N-(4-morpholino-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A7, Table 1, FIG.  1 ) 
       [0154]      1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J=7.5 Hz, 2H), 7.42-7.21 (m, 4H), 7.14-7.04 (m, 1H), 6.87 (d, J=7.5 Hz, 2H), 4.40 (tt, J=8.0, 4.0 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.54 (t, J=4.8 Hz, 2H), 3.45-3.18 (m, 6H), 2.32-2.10 (m, 2H), 1.99-1.80 (m, 2H) Mass: ESI [M+1]: 597. 
       2,2,2-trifluoro-N-(4-morpholino-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A8, Table 1, FIG.  1 ) 
       [0155]      1 H NMR (400 MHz, CDCl 3 ) δ 7.42-7.21 (m, 4H), 7.17-7.02 (m, 3H), 6.84 (d, J=7.5 Hz, 2H), 4.08 (p, J=7.4 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.59-3.39 (m, 6H), 3.19 (dt, J=12.4, 5.5 Hz, 2H), 2.32 (s, 3H), 2.19 (ddt, J=12.9, 7.5, 5.5 Hz, 2H), 1.95 (ddt, J=12.9, 7.5, 5.6 Hz, 2H) Mass: ESI [M+1]: 543. 
       2,2,2-trifluoro-N-(4-morpholino-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A9, Table 1, FIG.  1 ) 
       [0156]      1 H NMR (400 MHz, CDCl 3 ) δ 7.39-7.21 (m, 4H), 7.14-7.06 (m, 1H), 6.95 (dd, J=39.7, 7.5 Hz, 4H), 4.38 (tt, J=8.0, 4.1 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.57-3.36 (m, 6H), 3.29 (dt, J=12.3, 5.4 Hz, 2H), 2.30-2.10 (m, 2H), 1.99-1.80 (m, 2H) Mass: ESI [M+1]: 613. 
       2,2,2-trifluoro-N-(4-morpholino-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)-N-phenylacetamide (compound 1A10, Table 1, FIG.  1 ) 
       [0157]      1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (dd, J=7.4, 1.5 Hz, 1H), 7.31 (ddd, J=33.5, 7.5, 1.4 Hz, 5H), 7.17-6.89 (m, 3H), 4.68 (p, J=3.1 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.59-3.32 (m, 6H), 3.18 (dt, J=12.4, 5.6 Hz, 2H), 2.22 (dtd, J=12.2, 5.6, 2.9 Hz, 2H), 2.00 (dtd, J=12.4, 5.6, 2.9 Hz, 2H) Mass: ESI [M+1]: 597. 
       2,2,2-trifluoro-N-methyl-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)acetamide (compound 1A11, Table 2, FIG.  1 ) 
       [0158]      1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (t, J=7.5 Hz, 2H), 7.06-6.86 (m, 3H), 4.14 (p, J=7.5 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.57-3.39 (m, 6H), 3.32 (s, 3H), 3.20 (dt, J=12.4, 5.7 Hz, 2H), 2.22-2.05 (m, 2H), 2.00-1.87 (m, 2H) Mass: ESI [M+1]: 467. 
       2,2,2-trifluoro-N-(4-morpholino-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazin-2-yl)-N-(2,2,2-trifluoroacetyl)acetamide (compound 1A12, Table 2, FIG.  1 ) 
       [0159]      1 H NMR (400 MHz, CDCl 3 ) δ 7.23 (t, J=7.5 Hz, 2H), 6.99-6.79 (m, 3H), 4.38 (tt, J=7.6, 3.7 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.55-3.34 (m, 6H), 3.29 (dt, J=12.4, 5.3 Hz, 2H), 2.28-2.05 (m, 2H), 2.00-1.77 (m, 2H) Mass: ESI [M+1]: 549. 
       2,2,2-trifluoro-N-(4-(4-(4-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2,2,2-trifluoroacetyl)acetamide (compound 1A13, Table 2, FIG.  1 ) 
       [0160]      1 H NMR (400 MHz, CDCl 3 ) δ 7.11-6.84 (m, 4H), 4.12 (p, J=7.6 Hz, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.54-3.34 (m, 6H), 3.21 (dt, J=12.3, 5.6 Hz, 2H), 2.14 (ddt, J=13.0, 7.6, 5.5 Hz, 2H), 1.95 (ddt, J=13.0, 7.6, 5.6 Hz, 2H) Mass: ESI [M+1]: 567. 
       2,2,2-trifluoro-N-(4-(4-(2-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2,2,2-trifluoroacetyl)acetamide (compound 1A14, Table 2, FIG.  1 ) 
       [0161]      1 H NMR (400 MHz, CDCl 3 ) δ 7.14-6.82 (m, 4H), 4.26 (p, J=7.6 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.60-3.34 (m, 6H), 3.18 (dt, J=12.4, 5.5 Hz, 2H), 2.17 (ddt, J=12.9, 7.5, 5.5 Hz, 2H), 2.00 (ddt, J=12.8, 7.5, 5.5 Hz, 2H) Mass: ESI [M+1]: 567. 
       2,2,2-trifluoro-N-(4-(4-(4-fluorophenoxy)piperidin-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-methylacetamide (compound 1A15, Table 1, FIG.  1 ) 
       [0162]      1 H NMR (400 MHz, CDCl 3 ) δ 7.01 (t, J=7.7 Hz, 2H), 6.96-6.88 (m, 2H), 4.61-4.52 (m, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.56-3.41 (m, 6H), 3.39-3.31 (m, 5H), 2.22 (dqd, J=12.9, 5.4, 2.3 Hz, 2H), 1.94 (dqd, J=12.9, 5.4, 2.3 Hz, 2H) Mass: ESI [M+1]: 485. 
       N,N-dimethyl-4-morpholino-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-amine (compound 1A16, Table 1, FIG.  1 ) 
       [0163]      1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (d, J=7.5 Hz, 2H), 6.85 (d, J=7.5 Hz, 2H), 4.43-4.34 (m, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.52 (t, J=4.9 Hz, 2H), 3.48-3.39 (m, 4H), 3.30 (dt, J=12.4, 5.3 Hz, 2H), 2.99 (s, 6H), 2.33 (s, 3H), 2.24-2.13 (m, 2H), 1.89 (dqd, J=12.8, 5.4, 2.0 Hz, 2H) Mass: ESI [M+1]. 399. 
       4-(4-(4-fluorophenoxy)piperidin-1-yl)-N,N-dimethyl-6-morpholino-1,3,5-triazin-2-amine (compound 1A17, Table 2, FIG.  1 ) 
       [0164]      1 H NMR (400 MHz, CDCl 3 ) δ 7.12 (d, J=7.5 Hz, 2H), 6.85 (d, J=7.5 Hz, 2H), 4.43-4.34 (m, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.52 (t, J=4.9 Hz, 2H), 3.48-3.39 (m, 4H), 3.30 (dt, J=12.4, 5.3 Hz, 2H), 2.99 (s, 6H), 2.24-2.13 (m, 2H), 1.89 (dqd, J=12.8, 5.4, 2.0 Hz Mass: ESI [M+1]: 403. 
       4-morpholino-6-(4-phenoxypiperidin-1-yl)-N,N-diphenyl-1,3,5-triazin-2-amine (compound 1A18, Table 2, FIG.  1 ) 
       [0165]      1 H NMR (400 MHz, CDCl 3 ) δ 7.25 (td, J=7.7, 1.1 Hz, 6H), 7.04-6.86 (m, 9H), 4.50-4.41 (m, 1H), 3.44 (ddd, J=14.0, 10.1, 5.0 Hz, 4H), 3.32 (dt, J=12.3, 5.3 Hz, 2H), 3.98-2.00 (m, 14H), 3.51-2.00 (m, 8H), 2.17 (dqd, J=12.9, 5.4, 2.2 Hz, 2H), 1.91 (dqd, J=12.8, 5.4, 2.2 Hz, 2H) Mass: ESI [M+1]: 509. 
       4-morpholino-N,N-diphenyl-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-amine (compound 1A19, Table 2, FIG.  1 ) 
       [0166]      1 H NMR (400 MHz, CDCl 3 ) δ 7.51 (dd, J=7.4, 1.5 Hz, 1H), 7.33-7.21 (m, 5H), 7.05-6.86 (m, 8H), 4.10 (p, J=7.5 Hz, 1H), 3.78 (t, J=4.5 Hz, 4H), 3.58-3.49 (m, 4H), 3.40 (t, J=4.5 Hz, 2H), 3.20 (dt, J=12.3, 5.4 Hz, 2H), 2.19 (ddt, J=12.8, 7.4, 5.5 Hz, 2H), 1.94 (ddt, J=12.8, 7.4, 5.5 Hz, 2H) Mass: ESI [M+1]: 577. 
       4-morpholino-N,N-diphenyl-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-amine (compound 1A20, Table 2, FIG.  1 ) 
       [0167]      1 H NMR (400 MHz, CDCl 3 ) δ 7.26 (t, J=7.5 Hz, 4H), 7.05-6.94 (m, 6H), 6.89 (q, J=7.5 Hz, 4H), 4.48 (p, J=2.7 Hz, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.56-3.41 (m, 6H), 3.30 (dt, J=12.4, 5.4 Hz, 2H), 2.13 (dtd, J=12.4, 5.4, 2.8 Hz, 2H), 1.87 (dtd, J=12.4, 5.4, 2.8 Hz, 2H) Mass: ESI [M+1]: 593. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B1, Table 3, FIG.  2 ) 
       [0168]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (dd, J=7.2, 1.2 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.65 (d, J=53.7 Hz, 1H), 7.49-7.33 (m, 2H), 7.07-6.83 (m, 4H), 4.53 (tt, J=6.2, 3.1 Hz, 1H), 4.06 (d, J=4.8 Hz, 2H), 3.84 (dd, J=33.6, 4.7 Hz, 10H), 1.95 (d, J=40.2 Hz, 4H). Mass: ESI [M+1]: 526. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-methoxyphenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B2, Table 3, FIG.  2 ) 
       [0169]      1 H NMR (400 MHz, CDCl 3 ): δ8.36 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.73 (t, J=54, 1H), 7.45 (m, 2H), 6.92 (m, 4H), 4.50 (m, 1H), 4.08 (d, J=4 Hz, 2H), 3.89 (dd, J=6 Hz, J=39 Hz, 13H), 1.99 (dd, J=1 Hz, J=31 Hz, 4H). Mass: ESI [M+1]: 538. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethoxy)phenoxy) piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B3, Table 3, FIG.  2 ) 
       [0170]      1 H NMR (400 MHz, CDCl 3 ) δ8.36 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.73 (t, J=54, 1H), 7.45 (m, 2H), 6.92 (m, 4H), 4.50 (m, 1H), 4.08 (d, J=4 Hz, 2H), 3.89 (dd, J=6 Hz, J=39 Hz, 13H), 1.99 (dd, J=1 Hz, J=31 Hz, 4H). Mass: ESI [M+1]:592. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(2-(trifluoromethyl)phenoxy) piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B4, Table 3, FIG.  2 ) 
       [0171]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.1 Hz, 1H), 7.67 (d, J=41.7 Hz, 1H), 7.59 (d, J=3.9 Hz, 1H), 7.54-7.35 (m, 3H), 7.01 (dd, J=15.2, 8.7 Hz, 2H), 4.91-4.71 (m, 1H), 4.22 (d, J=10.4 Hz, 2H), 3.84 (d, J=35.7 Hz, 9H), 2.00 (dd, J=25.1, 14.4 Hz, 4H). Mass: ESI [M+1]:576. 
       4-(4-(4-(4-chlorophenoxy)piperidin-1-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B5, Table 3, FIG.  2 ) 
       [0172]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=7.2 Hz, 1H), 7.89 (d, J=7.0 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.50-7.33 (m, 2H), 7.29-7.23 (m, 2H), 6.88 (dd, J=6.6, 2.3 Hz, 2H), 4.62-4.52 (m, 1H), 4.05 (d, J=2.1 Hz, 2H), 3.84 (d, J=36.6 Hz, 9H), 1.96 (d, J=39.3 Hz, 4H). Mass: ESI [M+1]:542. 
       4-(4-(4-(3-chlorophenoxy)piperidin-1-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B6, Table 3, FIG.  2 ) 
       [0173]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.66 (d, J=53.6 Hz, 1H), 7.46-7.36 (m, 2H), 7.22 (t, J=8.4 Hz, 1H), 6.99-6.94 (m, 2H), 6.84 (d, J=9.2 Hz, 1H), 4.61 (dd, J=6.1, 3.0 Hz, 1H), 4.15-3.97 (m, 2H), 3.89 (ddd, J=37.4, 19.6, 4.2 Hz, 10H), 1.97 (d, J=34.7 Hz, 4H). Mass: ESI [M+1]: 542. 
       4-(4-(4-(2-chlorophenoxy)piperidin-1-yl)-6-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B7, Table 3, FIG.  2 ) 
       [0174]      1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J=7.4 Hz, 2H), 7.88 (d, J=6.9 Hz, 2H), 7.66 (d, J=53.6 Hz, 2H), 7.50-7.28 (m, 7H), 7.22 (t, J=12.5 Hz, 2H), 7.06-6.84 (m, 4H), 4.80-4.61 (m, 2H), 4.03 (d, J=24.4 Hz, 8H), 3.83 (d, J=34.1 Hz, 15H), 1.99 (s, 8H). Mass: ESI [M+1]:542. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(3-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B8, Table 3, FIG.  2 ) 
       [0175]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.4 Hz, 1H), 7.66 (d, J=53.6 Hz, 1H), 7.46-7.36 (m, 2H), 7.22 (t, J=8.4 Hz, 1H), 6.99-6.94 (m, 2H), 6.84 (d, J=9.2 Hz, 1H), 4.61 (dd, J=6.1, 3.0 Hz, 1H), 4.15-3.97 (m, 2H), 3.89 (ddd, J=37.4, 19.6, 4.2 Hz, 10H), 1.97 (d, J=34.7 Hz, 4H). Mass: ESI [M+1]: 526. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(2-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B9, Table 3, FIG.  2 ) 
       [0176]      1 H NMR (400 MHz, CDCl 3 ): δ8.36 (d, J=8 Hz, 1H), 7.90 (d, J=8 Hz, 1H), 7.73 (t, J=54, 1H), 7.45 (m, 2H), 7.21 (d, J=3 Hz, 1H), 7.01 (d, J=3 Hz, 1H), 6.96 (m, 2H), 4.50 (m, 1H), 4.08 (d, J=4 Hz, 2H), 3.89 (dd, J=6 Hz, J=39 Hz, 10H), 1.99 (dd, J=1 Hz, J=31 Hz, 4H). Mass: ESI [M+1]:526. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B10, Table 3, FIG.  2 ) 
       [0177]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=7.5 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.66 (d, J=53.6 Hz, 1H), 7.43-7.35 (m, 2H), 7.11 (d, J=8.2 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.65-4.48 (m, 1H), 4.15-3.98 (m, 2H), 3.87 (t, J=25.4 Hz, 9H), 2.30 (s, 3H), 2.05-1.87 (m, 4H). Mass: ESI [M+1]:522. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(m-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B11, Table 4, FIG.  2 ) 
       [0178]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.4 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.46-7.34 (m, 2H), 7.18 (t, J=7.9 Hz, 1H), 6.77 (dd, J=13.9, 8.3 Hz, 3H), 4.60 (dd, J=6.0, 3.0 Hz, 1H), 4.13-3.98 (m, 2H), 3.88 (ddd, J=35.9, 18.7, 4.2 Hz, 10H), 2.34 (s, 3H), 1.96 (d, J=30.2 Hz, 4H). Mass: ESI [M+1]:522. 
       4-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-(4-(o-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B12, Table 4, FIG.  2 ) 
       [0179]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=7.4 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.49-7.33 (m, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 4.57 (dq, J=9.3, 3.2 Hz, 1H), 4.15-3.97 (m, 2H), 3.86 (ddd, J=37.4, 7.5, 4.1 Hz, 10H), 2.29 (d, J=14.1 Hz, 3H), 1.96 (dd, J=29.1, 3.9 Hz, 4H). Mass: ESI [M+1]:522. 
       4-(4-(5-fluoro-1H-benzo[d]imidazol-1-yl)-6-(4-(p-tolyloxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B13, Table 4, FIG.  2 ) 
       [0180]      1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.79 (dd, J=7.5, 5.0 Hz, 1H), 7.43 (dd, J=8.0, 1.5 Hz, 1H), 7.13-7.04 (m, 3H), 6.82 (d, J=7.5 Hz, 2H), 4.42 (tt, J=7.8, 3.8 Hz, 1H), 3.79 (t, J=4.9 Hz, 4H), 3.55-3.41 (m, 6H), 3.32 (dt, J=12.4, 5.3 Hz, 2H), 2.31 (s, 3H), 2.30-2.19 (m, 2H), 2.01-1.90 (m, 2H) Mass: ESI [M+1]: 490. 
       4-(4-(5-fluoro-1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B14, Table 4, FIG.  2 ) 
       [0181]      1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, 1H), 7.83 (dd, J=7.5, 5.0 Hz, 1H), 7.49 (dd, J=7.9, 1.5 Hz, 3H), 7.07 (td, J=7.8, 1.5 Hz, 1H), 6.88 (d, J=7.4 Hz, 2H), 4.41 (p, J=7.0 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.58-3.41 (m, 6H), 3.39-3.28 (m, 2H), 2.29 (td, J=12.8, 6.0 Hz, 2H), 1.95 (td, J=12.8, 6.0 Hz, 2H) Mass: ESI [M+1]: 544. 
       4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B15, Table 4, FIG.  2 ) 
       [0182]      1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.14-7.76 (m, 1H), 7.74-7.61 (m, 1H), 7.49 (d, J=7.4 Hz, 2H), 7.37-7.23 (m, 2H), 6.88 (d, J=7.4 Hz, 2H), 4.41 (p, J=7.1 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.58-3.41 (m, 6H), 3.33 (dt, J=12.1, 5.9 Hz, 2H), 2.29 (td, J=12.7, 5.9 Hz, 2H), 1.95 (td, J=12.6, 5.9 Hz, 2H) Mass: ESI [M+1]: 526. 
       4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B16, Table 4, FIG.  2 ) 
       [0183]      1 H NMR (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 8.15-7.76 (m, 1H), 7.74-7.38 (m, 1H), 7.36-7.23 (m, 2H), 6.95-6.83 (m, 4H), 4.41 (p, J=7.0 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.58-3.41 (m, 6H), 3.33 (dt, J=12.2, 5.9 Hz, 2H), 2.29 (td, J=12.7, 5.9 Hz, 2H), 1.95 (td, J=12.7, 5.9 Hz, 2H) Mass: ESI [M+1]: 542. 
       4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(4-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl) morpholine (compound 1B17, Table 4, FIG.  2 ) 
       [0184]      1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 8.13-7.73 (m, 1H), 7.69-7.52 (m, 1H), 7.29 (dtd, J=20.1, 7.4, 1.6 Hz, 2H), 6.97 (t, J=7.8 Hz, 2H), 6.91-6.80 (m, 2H), 4.45 (tt, J=7.8, 4.0 Hz, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.57-3.40 (m, 6H), 3.33 (dt, J=12.4, 5.3 Hz, 2H), 2.28 (dqd, J=11.1, 5.4, 1.9 Hz, 2H), 1.97 (dqd, J=11.2, 5.5, 1.9 Hz, 2H) Mass: ESI [M+1]: 476. 
       4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(2-fluorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl) morpholine (compound 1B18, Table 4, FIG.  2 ) 
       [0185]      1 H NMR (400 MHz, CDCl 3 ) δ 8.55-7.71 (m, 2H), 7.68-7.52 (m, 1H), 7.29 (dtd, J=19.3, 7.4, 1.6 Hz, 2H), 7.03-6.81 (m, 4H), 4.83 (tt, J=7.8, 3.9 Hz, 1H), 3.79 (t, J=4.9 Hz, 4H), 3.56-3.40 (m, 6H), 3.32 (dt, J=12.4, 5.3 Hz, 2H), 2.28 (dqd, J=11.1, 5.4, 1.8 Hz, 2H), 1.94 (dqd, J=11.1, 5.4, 1.8 Hz, 2H) Mass: ESI [M+1]: 476. 
       4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(2-chlorophenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl) morpholine (compound 1B19, Table 4, FIG.  2 ) 
       [0186]      1 H NMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.90-7.73 (m, 1H), 7.69-7.52 (m, 1H), 7.37-7.22 (m, 3H), 7.14 (td, J=7.5, 1.5 Hz, 1H), 7.09-6.31 (m, 2H), 4.71 (p, J=7.2 Hz, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.57-3.40 (m, 6H), 3.33 (dt, J=12.2, 6.0 Hz, 2H), 2.28 (ddd, J=18.6, 10.1, 6.0 Hz, 2H), 1.96 (ddd, J=12.3, 10.1, 6.0 Hz, 2H) Mass: ESI [M+1]: 492. 
       4-(4-(1H-benzo[d]imidazol-1-yl)-6-(4-(2-(trifluoromethyl)phenoxy)piperidin-1-yl)-1,3,5-triazin-2-yl)morpholine (compound 1B20, Table 4, FIG.  2 ) 
       [0187]      1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (s, 1H), 8.14-7.76 (m, 1H), 7.74-7.62 (m, 1H), 7.54 (dd, J=7.5, 1.4 Hz, 1H), 7.37-7.23 (m, 3H), 7.05-6.93 (m, 2H), 4.25 (p, J=7.5 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.58-3.42 (m, 6H), 3.20 (dt, J=12.3, 5.4 Hz, 2H), 2.36 (ddt, J=12.8, 7.4, 5.4 Hz, 2H), 2.00 (ddt, J=12.9, 7.5, 5.5 Hz, 2H) Mass: ESI [M+1]: 526. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluoro phenyl)piperidin-4-amine (compound 1B21, Table 5, FIG.  3 ) 
       [0188]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=8.2 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.65 (d, J=53.7 Hz, 1H), 7.41 (dt, J=13.7, 5.8 Hz, 2H), 6.92 (t, J=8.6 Hz, 2H), 6.75-6.50 (m, 2H), 4.69 (d, J=10.4 Hz, 2H), 3.84 (m, 8H), 3.64-3.44 (m, 1H), 3.33-3.03 (m, 1H), 2.20 (dd, J=12.2, 9.5 Hz, 2H), 1.45 (dd, J=21.1, 9.9 Hz, 2H). Mass: ESI [M+1]:525. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(tri fluoromethyl)phenyl)piperidin-4-amine (compound 1B22, Table 5, FIG.  3 ) 
       [0189]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.65 (d, J=53.7 Hz, 1H), 7.53-7.28 (m, 4H), 6.64 (d, J=8.6 Hz, 2H), 4.78-4.58 (m, 2H), 3.84 (dd, J=34.4, 4.2 Hz, 8H), 3.71-3.58 (m, 1H), 3.36-3.12 (m, 2H), 2.22 (td, J=10.7, 5.4 Hz, 2H), 1.51-1.35 (m, 2H). Mass: ESI [M+1]: 575. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(tri fluoromethoxy)phenyl)piperidin-4-amine (compound compound 1B23, Table 5, FIG.  3 ) 
       [0190]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.65 (d, J=53.7 Hz, 1H), 7.48-7.35 (m, 2H), 7.05 (d, J=8.5 Hz, 2H), 6.60 (d, J=8.9 Hz, 2H), 4.69 (d, J=9.2 Hz, 2H), 3.84 (dd, J=34.0, 3.7 Hz, 8H), 3.64-3.52 (m, 1H), 3.23 (dt, J=17.6, 7.5 Hz, 2H), 2.21 (t, J=11.4 Hz, 2H), 1.45 (dd, J=22.7, 11.7 Hz, 2H). Mass: ESI [M+1]:591. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-meth oxyphenyl)piperidin-4-amine (compound compound 1B24, Table 5, FIG.  3 ) 
       [0191]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=7.6 Hz, 1H), 7.89 (d, J=7.3 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.48-7.33 (m, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.65 (d, J=8.7 Hz, 2H), 4.79-4.53 (m, 2H), 3.88 (d, J=4.4 Hz, 4H), 3.80 (d, J=4.1 Hz, 4H), 3.76 (s, 3H), 3.55-3.48 (m, 1H), 3.21 (dt, J=23.5, 11.7 Hz, 2H), 2.18 (dd, J=14.8, 9.0 Hz, 2H), 1.46-1.37 (m, 2H). Mass: ESI [M+1]:537. 
       N-(4-bromophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound compound 1B25, Table 5, FIG.  3 ) 
       [0192]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.49-7.34 (m, 2H), 7.27 (d, J=7.5 Hz, 2H), 6.52 (d, J=8.8 Hz, 2H), 4.68 (d, J=10.5 Hz, 2H), 3.84 (dd, J=33.5, 3.9 Hz, 8H), 3.64-3.50 (m, 1H), 3.34-3.07 (m, 2H), 2.28-2.08 (m, 2H), 1.44 (dd, J=21.4, 10.4 Hz, 2H). Mass: ESI [M+1]:585. 
       N-(3,4-dichlorophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound compound 1B26, Table 5, FIG.  3 ) 
       [0193]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.48-7.35 (m, 2H), 7.20 (d, J=8.7 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 6.46 (dd, J=8.7, 2.7 Hz, 1H), 4.69 (d, J=17.3 Hz, 2H), 3.84 (d, J=36.2 Hz, 8H), 3.55 (ddd, J=14.0, 9.9, 4.2 Hz, 1H), 3.21 (dd, J=14.7, 9.4 Hz, 2H), 2.26-2.11 (m, 2H), 1.47-1.38 (m, 2H). Mass: ESI [M+1]:575. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-fluorophenyl)piperidin-4-amine (compound compound 1B27, Table 5, FIG.  3 ) 
       [0194]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.41 (ddd, J=8.4, 7.1, 3.5 Hz, 2H), 7.06-6.94 (m, 2H), 6.77 (t, J=7.9 Hz, 1H), 6.71-6.59 (m, 1H), 4.67 (d, J=8.7 Hz, 2H), 3.84 (dd, J=33.4, 4.4 Hz, 8H), 3.70-3.55 (m, 1H), 3.36-3.15 (m, 2H), 2.21 (t, J=12.3 Hz, 2H), 1.50 (d, J=10.5 Hz, 2H). Mass: ESI [M+1]:525. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-methoxyphenyl)piperidin-4-amine (compound compound 1B28, Table 5, FIG.  3 ) 
       [0195]      1 H NMR (400 MHz, CDCl 3 ) δ 8.35 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.66 (d, J=53.6 Hz, 1H), 7.47-7.35 (m, 2H), 6.89 (td, J=7.8, 1.3 Hz, 1H), 6.79 (dd, J=8.2, 1.1 Hz, 1H), 6.69 (dd, J=10.1, 3.7 Hz, 2H), 4.63 (d, J=7.6 Hz, 2H), 3.88 (d, J=5.0 Hz, 4H), 3.84 (s, 3H), 3.80 (d, J=4.5 Hz, 4H), 3.68-3.55 (m, 1H), 3.29 (dt, J=23.5, 11.6 Hz, 2H), 2.30-2.09 (m, 2H), 1.58-1.44 (m, 2H). Mass: ESI [M+1]:537. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-(trifluoromethyl)phenyl)piperidin-4-amine (compound compound 1B29, Table 5, FIG.  3 ) 
       [0196]      1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J=7.5 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.65 (d, J=53.6 Hz, 1H), 7.41 (ddd, J=8.4, 7.1, 3.5 Hz, 2H), 7.06-6.94 (m, 2H), 6.92 (t, J=7.9 Hz, 1H), 6.71-6.59 (m, 1H), 4.67 (d, J=8.7 Hz, 2H), 3.84 (dd, J=33.4, 4.4 Hz, 8H), 3.70-3.55 (m, 1H), 3.36-3.15 (m, 2H), 2.21 (t, J=12.3 Hz, 2H), 1.50 (d, J=10.5 Hz, 2H). Mass: ESI [M+1]:575. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(p-tolyl)piperidin-4-amine (compound compound 1B30, Table 5, FIG.  3 ) 
       [0197]      1 H NMR (400 MHz, CDCl 3 ): δ 8.34 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.65 (t, J=53.7 Hz, 1H), 7.42 (m, 2H), 7.05 (d, J=8.5 Hz, 2H), 6.60 (d, J=8.9 Hz, 2H), 4.69 (d, J=17.1 Hz, 2H), 3.84 (dd, J=34.0, 3.7 Hz, 8H), 3.58 (m, 1H), 3.35-3.09 (m, 2H), 2.58 (s, 3H), 2.30-2.11 (m, 2H), 1.45 (dd, J=22.0, 9.8 Hz, 2H). Mass: ESI [M+1]: 522. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(3-methoxyphenyl)piperidin-4-amine (compound compound 1B31, Table 6, FIG.  3 ) 
       [0198]      1 H NMR (400 MHz, CDCl 3 ): δ 8.34 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.65 (t, J=53.7 Hz, 1H), 7.42 (m, 2H), 7.09 (s, 1H), 7.05 (d, J=6.5 Hz, 1H), 6.75 (d, J=8.9 Hz, 2H), 4.69 (d, J=17.1 Hz, 2H), 3.84 (dd, J=34.0, 3.7 Hz, 8H), 3.58 (m, 1H), 3.42 (s, 3H), 3.35-3.09 (m, 2H), 2.30-2.11 (m, 2H), 1.45 (dd, J=22.0, 9.8 Hz, 2H). Mass: ESI [M+1]: 537. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(o-tolyl)piperidin-4-amine (compound 1B32, Table 6, FIG.  3 ) 
       [0199]      1 H NMR (400 MHz, CDCl 3 ): δ 8.34 (d, J=7.4 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.65 (t, J=53.7 Hz, 1H), 7.42 (m, 2H), 7.15 (d, J=8.5 Hz, 1H), 7.05 (d, J=6.5 Hz, 1H), 6.60 (d, J=8.9 Hz, 2H), 4.69 (d, J=17.1 Hz, 2H), 3.84 (dd, J=34.0, 3.7 Hz, 8H), 3.58 (m, 1H), 3.35-3.09 (m, 2H), 2.43 (s, 3H), 2.30-2.11 (m, 2H), 1.45 (dd, J=22.0, 9.8 Hz, 2H). Mass: ESI [M+1]: 521. 
       1-(4-(5-fluoro-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(p-tolyl) piperidin-4-amine (compound 1B33, Table 6, FIG.  3 ) 
       [0200]      1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (s, 1H), 7.82 (dd, J=7.5, 5.0 Hz, 1H), 7.49 (dd, J=8.0, 1.5 Hz, 1H), 7.11-6.96 (m, 3H), 6.50 (d, J=7.4 Hz, 2H), 3.80 (dd, J=13.9, 9.2 Hz, 5H), 3.53 (dddd, J=20.4, 14.8, 7.8, 3.9 Hz, 7H), 3.29 (dt, J=12.3, 5.6 Hz, 2H), 2.30 (s, 3H), 1.92 (dtd, J=12.2, 5.6, 3.1 Hz, 2H), 1.79 (dtd, J=12.4, 5.6, 3.1 Hz, 2H) Mass: ESI [M+1]: 489. 
       1-(4-(2-(difluoromethyl)-5-fluoro-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine (compound 1B34, Table 6, FIG.  3 ) 
       [0201]      1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (s, 1H), 7.81 (dd, J=7.5, 5.0 Hz, 1H), 7.53-7.39 (m, 3H), 7.07 (td, J=7.8, 1.4 Hz, 1H), 6.63 (d, J=7.4 Hz, 2H), 3.79 (t, J=4.8 Hz, 4H), 3.63-3.41 (m, 7H), 3.13 (dt, J=12.3, 5.6 Hz, 2H), 1.90 (dtd, J=12.3, 5.6, 3.9 Hz, 2H), 1.78 (dtd, J=12.4, 5.6, 3.9 Hz, 2H), 0.36 (s, 1H) Mass: ESI [M+1]: 543. 
       1-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoromethyl) phenyl) piperidin-4-amine (compound 1B35, Table 6, FIG.  3 ) 
       [0202]      1 H NMR (400 MHz, CDCl 3 ) δ 8.45 (s, 1H), 8.18-7.75 (m, 1H), 7.74-7.48 (m, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.30 (pd, J=7.5, 1.7 Hz, 2H), 6.63 (d, J=7.4 Hz, 2H), 3.79 (t, J=4.8 Hz, 4H), 3.63-3.41 (m, 7H), 3.13 (dt, J=12.4, 5.6 Hz, 2H), 1.90 (dtd, J=12.3, 5.6, 3.9 Hz, 2H), 1.78 (dtd, J=12.3, 5.6, 3.8 Hz, 2H), 0.37 (s, 1H) Mass: ESI [M+1]: 525. 
       1-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoromethoxy) phenyl)piperidin-4-amine (compound 1B36, Table 6, FIG.  3 ) 
       [0203]      1 H NMR (400 MHz, CDCl 3 ) δ 8.18 (s, 1H), 8.15-7.72 (m, 1H), 7.68-7.52 (m, 1H), 7.29 (dtd, J=19.6, 7.4, 1.7 Hz, 2H), 6.77 (d, J=7.4 Hz, 2H), 6.50 (d, J=7.4 Hz, 2H), 3.95 (s, 1H), 3.79 (t, J=4.9 Hz, 4H), 3.61-3.42 (m, 7H), 3.29 (dt, J=12.5, 6.3 Hz, 2H), 1.97-1.74 (m, 4H) Mass: ESI [M+1]: 541. 
       1-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl) piperidin-4-amine (compound 1B37, Table 6, FIG.  3 ) 
       [0204]      1 H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 8.14-7.73 (m, 1H), 7.68-7.52 (m, 1H), 7.29 (dtd, J=19.5, 7.4, 1.6 Hz, 2H), 6.86 (t, J=7.7 Hz, 2H), 6.58-6.46 (m, 2H), 3.78 (t, J=4.9 Hz, 4H), 3.58-3.27 (m, 10H), 1.97 (ddt, J=12.2, 7.4, 6.0 Hz, 2H), 1.81 (ddt, J=12.3, 7.5, 6.1 Hz, 2H) Mass: ESI [M+1]: 475. 
       1-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-fluorophenyl) piperidin-4-amine (compound 1B38, Table 6, FIG.  3 ) 
       [0205]      1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1H), 8.15-7.71 (m, 1H), 7.68-7.52 (m, 1H), 7.29 (dtd, J=19.5, 7.4, 1.6 Hz, 2H), 6.93-6.80 (m, 2H), 6.69-6.51 (m, 2H), 4.00 (s, 1H), 3.79 (t, J=4.9 Hz, 4H), 3.57-3.38 (m, 7H), 3.36-3.25 (m, 2H), 2.06-1.93 (m, 2H), 1.91-1.79 (m, 2H) Mass: ESI [M+1]: 475. 
       1-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-chlorophenyl) piperidin-4-amine (compound 1B39, Table 6, FIG.  3 ) 
       [0206]      1 H NMR (400 MHz, CDCl 3 ) δ 8.60-7.71 (m, 2H), 7.68-7.52 (m, 1H), 7.29 (dtd, J=19.5, 7.4, 1.6 Hz, 2H), 7.14 (dd, J=7.5, 1.4 Hz, 1H), 7.02 (td, J=7.5, 1.4 Hz, 1H), 6.64-6.51 (m, 2H), 4.64 (s, 1H), 3.79 (t, J=4.9 Hz, 4H), 3.57-3.41 (m, 7H), 3.36-3.25 (m, 2H), 2.06-1.93 (m, 2H), 1.91-1.78 (m, 2H) Mass: ESI [M+1]: 491. 
       1-(4-(1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(2-(trifluoromethyl) phenyl) piperidin-4-amine (compound 1B40, Table 6, FIG.  3 ) 
       [0207]      1 H NMR (400 MHz, CDCl 3 ) δ 8.47 (s, 5H), 8.18-7.76 (m, 5H), 7.74-7.33 (m, 11H), 7.33 (d, J=1.9 Hz, 1H), 7.36-7.23 (m, 10H), 7.18 (td, J=7.5, 1.4 Hz, 5H), 6.65 (td, J=7.5, 1.5 Hz, 5H), 6.56 (dd, J=7.5, 1.5 Hz, 5H), 4.82 (s, 5H), 3.78 (t, J=4.5 Hz, 20H), 3.59-3.29 (m, 45H), 2.11-1.98 (m, 10H), 1.77-1.63 (m, 10H) Mass: ESI [M+1]: 525. 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N,N-bis(4-fluorophenyl)piperidin-4-amine (compound 1B41, Table 7, FIG.  4 ) 
       [0208]      1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (dt, J=14.5, 7.2 Hz, 1H), 7.59 (dd, J=7.3, 1.8 Hz, 1H), 7.33-7.20 (m, 2H), 7.07 (d, J=40.9 Hz, 1H), 7.05-6.87 (m, 8H), 4.02 (tt, J=8.0, 5.0 Hz, 1H), 3.78 (t, J=4.8 Hz, 4H), 3.54 (t, J=4.9 Hz, 2H), 3.49-3.37 (m, 4H), 3.31 (dt, J=12.4, 5.3 Hz, 2H), 2.26-2.15 (m, 2H), 1.88-1.75 (m, 2H). Mass: ESI [M+1]: 619 
       N-(4-bromophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)piperidin-4-amine (compound 1B42, Table 7, FIG.  4 ) 
       [0209]      1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (dd, J=6.9, 2.1 Hz, 1H), 7.65 (dd, J=6.9, 2.2 Hz, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.31-7.21 (m, 2H), 7.14-7.06 (m, 3H), 6.96 (t, J=7.7 Hz, 2H), 6.84 (d, J=7.4 Hz, 2H), 4.19 (p, J=3.7 Hz, 1H), 3.79 (t, J=4.8 Hz, 4H), 3.52 (ddt, J=22.1, 9.5, 5.2 Hz, 6H), 3.21-3.07 (m, 2H), 2.09 (dtdd, J=18.2, 12.3, 5.7, 3.7 Hz, 4H) Mass: ESI [M+1]: 679 
       1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)-N-(4-(trifluoromethyl)phenyl)piperidin-4-amine (compound 1B43, Table 7, FIG.  4 ) 
       [0210]      1 H NMR (400 MHz, CDCl 3 ) δ 7.85-7.74 (m, 1H), 7.70-7.58 (m, 1H), 7.48 (d, J=7.6 Hz, 2H), 7.33-7.21 (m, 2H), 7.12 (dd, J=7.7, 4.1 Hz, 5H), 7.02-6.89 (m, 2H), 4.14 (p, J=3.1 Hz, 1H), 3.78 (t, J=4.5 Hz, 4H), 3.64-3.47 (m, 4H), 3.41 (t, J=4.5 Hz, 2H), 3.25 (dt, J=12.4, 5.3 Hz, 2H), 1.98 (dtd, J=12.4, 5.3, 3.1 Hz, 2H), 1.83 (dtd, J=12.4, 5.3, 3.1 Hz, 2H). ESI [M+1]: 669 
       N-(4-chlorophenyl)-1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluorophenyl)piperidin-4-amine (compound 1B44, Table 7, FIG.  4 ) 
       [0211]      1 H NMR (400 MHz, CDCl 3 ) δ 7.76 (dd, J=7.3, 1.6 Hz, 1H), 7.59 (dd, J=7.3, 1.8 Hz, 1H), 7.26 (dqd, J=14.5, 7.4, 1.6 Hz, 2H), 7.18 (d, J=7.4 Hz, 2H), 7.12 (t, J=12, 2H), 7.10-7.05 (m, 2H), 6.96 (t, J=7.7 Hz, 2H), 6.88 (d, J=7.6 Hz, 2H), 3.98 (tt, J=8.1, 5.1 Hz, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.51 (t, J=4.9 Hz, 2H), 3.47-3.39 (m, 4H), 3.30 (dt, J=12.4, 5.4 Hz, 2H), 2.22-2.11 (m, 2H), 1.84-1.73 (m, 2H). ESI [M+1]: 635 
       N-(1-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-yl)-N-(4-fluorophenyl)-3-(trifluoromethyl)pyridin-4-amine (compound 1B45, Table 7, FIG.  4 ) 
       [0212]      1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 4H), 8.80 (d, J=7.5 Hz, 4H), 7.89-7.77 (m, 4H), 7.65 (ddd, J=20.2, 14.0, 6.4 Hz, 8H), 7.36-7.21 (m, 9H), 7.12 (s, 2H), 6.96 (ddd, J=26.8, 11.5, 6.4 Hz, 17H), 4.41 (p, J=7.5 Hz, 4H), 3.78 (t, J=4.5 Hz, 14H), 3.62 (t, J=4.5 Hz, 8H), 3.40 (tdt, J=24.2, 12.2, 6.0 Hz, 24H), 2.22 (ddt, J=12.2, 7.4, 6.0 Hz, 8H), 2.10-1.92 (m, 8H). ESI [M+1]: 670 
       1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-fluoro phenyl)piperidin-4-amine (compound 1B46, Table 7, FIG.  5 ) 
       [0213]      1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.40 (m, 1H), 7.33-7.24 (m, 1H), 7.23-7.13 (m, 2H), 7.07 (dd, J=29.4, 28.0 Hz, 2H), 6.87 (t, J=7.8 Hz, 2H), 6.57-6.47 (m, 2H), 4.25 (s, 1H), 3.78 (t, J=4.5 Hz, 4H), 3.59-3.46 (m, 5H), 3.42 (t, J=4.5 Hz, 2H), 3.19 (dt, J=12.4, 5.4 Hz, 2H), 1.99 (dtd, J=12.4, 5.4, 3.2 Hz, 2H), 1.71 (dtd, J=12.4, 5.5, 3.2 Hz, 2H). ESI [M+1]:524 
       1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-methoxy phenyl)piperidin-4-amine (compound 1B47, Table 7, FIG.  5 ) 
       [0214]      1 H NMR (400 MHz, CDCl 3 ) δ 7.48-7.37 (m, 1H), 7.32-7.24 (m, 1H), 7.22-7.13 (m, 2H), 7.06 (dd, J=29.4, 28.0 Hz, 2H), 6.75 (d, J=7.4 Hz, 2H), 6.52 (d, J=7.4 Hz, 2H), 3.79 (dd, J=9.3, 4.8 Hz, 7H), 3.64 (s, 1H), 3.60-3.46 (m, 5H), 3.42 (t, J=4.5 Hz, 2H), 3.25 (dt, J=12.4, 5.5 Hz, 2H), 1.90 (dtd, J=12.3, 5.4, 3.2 Hz, 2H), 1.71 (dtd, J=12.4, 5.5, 3.2 Hz, 2H). ESI [M+1]: 536 
       1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methoxy)phenyl)piperidin-4-amine (compound 1B48, Table 7, FIG.  5 ) 
       [0215]      1 H NMR (400 MHz, CDCl 3 ) δ 7.44-7.36 (m, 1H), 7.28-7.22 (m, 1H), 7.18 (ddd, J=14.9, 7.2, 1.7 Hz, 2H), 7.13-6.96 (m, 2H), 6.76 (d, J=7.4 Hz, 2H), 6.51 (d, J=7.4 Hz, 2H), 3.79 (t, J=4.9 Hz, 4H), 3.58-3.40 (m, 7H), 3.31 (p, J=7.5 Hz, 1H), 3.20 (dt, J=12.3, 5.5 Hz, 2H), 2.00 (ddt, J=13.0, 7.6, 5.6 Hz, 2H), 1.81 (ddt, J=13.0, 7.5, 5.5 Hz, 2H). ESI [M+1]: 590 
       1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)-N-(4-(trifluoro methyl)phenyl)piperidin-4-amine (compound 1B49, Table 7, FIG.  5 ) 
       [0216]      1 H NMR (400 MHz, CDCl 3 ) δ 7.50-7.42 (m, 1H), 7.38 (d, J=7.4 Hz, 2H), 7.27-7.13 (m, 3H), 7.07 (dd, J=44.8, 14.7 Hz, 1H), 6.97 (d, J=1.4 Hz, 1H), 6.52 (d, J=7.4 Hz, 2H), 4.02 (s, 1H), 3.78 (t, J=4.9 Hz, 4H), 3.61 (t, J=4.9 Hz, 2H), 3.52-3.39 (m, 5H), 3.32 (dt, J=12.3, 5.3 Hz, 2H), 2.03-1.92 (m, 2H), 1.86-1.75 (m, 2H). ESI [M+1]: 574 
       N-(4-chlorophenyl)-1-(4-(2-(difluoromethyl)-1H-indol-1-yl)-6-morpholino-1,3,5-triazin-2-yl)piperidin-4-amine (compound 1B50, Table 7, FIG.  5 ) 
       [0217]      1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (dd, J=7.1, 1.8 Hz, 1H), 7.30-7.25 (m, 1H), 7.18 (ddt, J=7.8, 5.7, 1.6 Hz, 4H), 7.06 (dd, J=29.4, 28.0 Hz, 2H), 6.49 (d, J=7.4 Hz, 2H), 4.06 (s, 1H), 3.78 (t, J=4.5 Hz, 4H), 3.59-3.46 (m, 5H), 3.42 (t, J=4.5 Hz, 2H), 3.24 (dt, J=12.4, 5.4 Hz, 2H), 1.89 (dtd, J=12.4, 5.4, 3.2 Hz, 2H), 1.70 (dtd, J=12.4, 5.4, 3.2 Hz, 2H). ESI [M+1]: 540 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1. 
                 1A1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 2. 
                 1A2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 3. 
                 1A3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4. 
                 1A4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 5. 
                 1A5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 6. 
                 1A6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 7. 
                 1A7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 8. 
                 1A8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 9. 
                 1A9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 10. 
                 1A10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                 11 
                 1A11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 12 
                 1A12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 13 
                 1A13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 14 
                 1A14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15 
                 1A15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 16 
                 1A16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 17 
                 1A17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 18 
                 1A18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 19 
                 1A19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 20 
                 1A20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                 21 
                 1B1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22 
                 1B2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 23 
                 1B3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 24 
                 1B4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 25 
                 1B5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 26 
                 1B6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 27 
                 1B7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 28 
                 1B8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 29 
                 1B9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 30 
                 1B10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                 31 
                 1B11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 32 
                 1B12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 33 
                 1B13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 34 
                 1B14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 35 
                 1B15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 36 
                 1B16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 37 
                 1B17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 38 
                 1B18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 39 
                 1B19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 40 
                 1B20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                 41. 
                 1B21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 42. 
                 1B22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 43. 
                 1B23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 44. 
                 1B24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 45. 
                 1B25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 46. 
                 1B26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 47. 
                 1B27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 48. 
                 1B28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 49. 
                 1B29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 50. 
                 1B30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                 51 
                 1B31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 52 
                 1B32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 53 
                 1B33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 54 
                 1B34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 55 
                 1B35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 56 
                 1B36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 57 
                 1B37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 58 
                 1B38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 59 
                 1B39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 60 
                 1B40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Entry 
                 Code 
                 Structure 
               
               
                   
               
             
             
               
                 61 
                 1B41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 62 
                 1B42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 63 
                 1B43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 64 
                 1B44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 65 
                 1B45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 66 
                 1B46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 67 
                 1B47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 68 
                 1B48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 69 
                 1B49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 70 
                 1B50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
         
       
     
         [0218]    Part B: Biological Evaluation 
       Bio-Chemical Assay (PI3K Inhibition Assays). 
       [0219]    Compounds were evaluated for their ability to inhibit class I PI3-kinase enzyme alpha as given below. 
       PI3K-α Assay: 
       [0220]    PI3K alpha (diluted in 12.5 mM Glycine-NaOH (pH 8.5), 50 mM KCl, 2.5 mM MgCl 2 , 1 mM DTT, 0.05% CHAPS) is assayed in total volume of 20 ul containing 12.5 mM glycine-NaOH (pH 8.5), 50 mM KCl, 2.5 mM MgCl 2 , 1 mM DTT, 0.05% CHAPS, 0.01 mM ATP and 0.05 mM diC8 PIP2. The enzyme is assayed for 80 min after which 20 ul of ADP-Glo reagent is added. After a further incubation of 40 min, 40 ul of Kinase Detection Buffer is added. The assays are incubated for 40 min and then read on PerkinElmer Envision for 1 sec/well. 
       Results: 
       [0221]    PI3K alpha % of inhibition values of a drug measures the effectiveness of a compound in inhibiting biological or biochemical function. The determination of enzyme based % of inhibition values helps in early analysis and estimation of the drug activities in order to narrow down drug candidates for further experimental purpose. The standard drug ZSTK474 shown greater than 70% inhibition at 500 nm against PI3K alpha and 30 compounds viz., 1A3, 1A5, 1A6, 1A8, 1A9, 1A10, 1A14, 1A15, 1A19, 1B1, 1B4, 1B8, 1B11, 1B12,  IBIS,  1B18, 1B19, 1B23, 1B24, 1B25, 1B26, 1B28, 1B31, 1B34, 1B37, 1B41, 1B42, 1B43, 1B47 and 1B49 shown greater than 70% inhibition at 500 nm against PI3K alpha. All the screening results given in Table 8. 
         [0222]    In Vitro Cell Line Activity: 
       Cell Culture, Growth Conditions and Treatments: 
       [0223]    Human breast cancer cell lines MDAMB231, MFC-7 and human prostate carcinoma cell line PC-3 were obtained from European Collection of Cell Cultures (ECACC). Cells were grown in RPMI-1440 medium supplemented with 10% fetal bovine serum (FBS), penicillin (100 units/ml), streptomycin (100 μg/ml), L-glutamine (0.3 mg/ml), sodium pyruvate (550 mg/ml), and NaHCO 3  (2 mg/ml). Cells were grown in CO 2  incubator (Thermocon Electron Corporation, USA) at 37° C. in an atmosphere of 95% air and 5% CO 2  with 98% humidity. Different molecules were dissolved in DMSO and were delivered to cell cultures in complete medium. 
       Cell Proliferation Assay: 
       [0224]    MTT assay was done to determine the viability of the cells and was done as described previously (Kumar et al, 2013). Briefly, 6×10 3  were seeded in 96 well plates and were treated with different concentrations of different molecules for 5 days. 20 μl of MTT dye (2.5 mg/ml) was added 3 h before the termination of the experiment. Formazen crystals were dissolved in 150 μl of DMSO and OD was measured at 570 nm. 
       Results: 
       [0225]    The several synthesized compounds were also checked for their antiproliferative activity against two breast cancer cell lines MDAMB231, MCF-7 and one prostate cancer cell line PC-3. Many molecules displayed potent anti proliferative activities in in vitro cancer cell lines assay and all the results given in Table 9. Standard drug ZSTK474 were taken as reference standard 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                   
                   
                 In vitro PI3K 
               
               
                 Entry 
                 Code 
                 α % of inhibition * 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1. 
                 1A1 
                 + 
               
               
                 2. 
                 1A2 
                 + 
               
               
                 3. 
                 1A3 
                 ++ 
               
               
                 4. 
                 1A4 
                 + 
               
               
                 5. 
                 1A5 
                 ++ 
               
               
                 6. 
                 1A6 
                 ++ 
               
               
                 7. 
                 1A7 
                 + 
               
               
                 8. 
                 1A8 
                 ++ 
               
               
                 9. 
                 1A9 
                 ++ 
               
               
                 10. 
                 1A10 
                 ++ 
               
               
                 11. 
                 1A11 
                 + 
               
               
                 12. 
                 1A12 
                 + 
               
               
                 13. 
                 1A13 
                 + 
               
               
                 14. 
                 1A14 
                 ++ 
               
               
                 15. 
                 1A15 
                 ++ 
               
               
                 16. 
                 1A16 
                 + 
               
               
                 17. 
                 1A17 
                 + 
               
               
                 18. 
                 1A18 
                 + 
               
               
                 19. 
                 1A19 
                 ++ 
               
               
                 20. 
                 1A20 
                 + 
               
               
                 21. 
                 1B1 
                 ++ 
               
               
                 22. 
                 1B2 
                 + 
               
               
                 23. 
                 1B3 
                 + 
               
               
                 24. 
                 1B4 
                 ++ 
               
               
                 25. 
                 1B5 
                 + 
               
               
                 26. 
                 1B6 
                 + 
               
               
                 27. 
                 1B7 
                 + 
               
               
                 28. 
                 1B8 
                 ++ 
               
               
                 29. 
                 1B9 
                 + 
               
               
                 30. 
                 1B10 
                 + 
               
               
                 31. 
                 1B11 
                 ++ 
               
               
                 32. 
                 1B12 
                 ++ 
               
               
                 33. 
                 1B13 
                 + 
               
               
                 34. 
                 1B14 
                 + 
               
               
                 35. 
                 1B15 
                 ++ 
               
               
                 36. 
                 1B16 
                 + 
               
               
                 37. 
                 1B17 
                 + 
               
               
                 38. 
                 1B18 
                 ++ 
               
               
                 39. 
                 1B19 
                 ++ 
               
               
                 40. 
                 1B20 
                 + 
               
               
                 41. 
                 1B21 
                 + 
               
               
                 42. 
                 1B22 
                 + 
               
               
                 43. 
                 1B23 
                 ++ 
               
               
                 44. 
                 1B24 
                 ++ 
               
               
                 45. 
                 1B25 
                 ++ 
               
               
                 46. 
                 1B26 
                 ++ 
               
               
                 47. 
                 1B27 
                 + 
               
               
                 48. 
                 1B28 
                 ++ 
               
               
                 49. 
                 1B29 
                 + 
               
               
                 50. 
                 1B30 
                 + 
               
               
                 51. 
                 1B31 
                 ++ 
               
               
                 52. 
                 1B32 
                 + 
               
               
                 53. 
                 1B33 
                 + 
               
               
                 54. 
                 1B34 
                 ++ 
               
               
                 55. 
                 1B35 
                 + 
               
               
                 56. 
                 1B36 
                 + 
               
               
                 57. 
                 1B37 
                 ++ 
               
               
                 58. 
                 1B38 
                 + 
               
               
                 59. 
                 1B39 
                 + 
               
               
                 60. 
                 1B40 
                 + 
               
               
                 61. 
                 1B41 
                 ++ 
               
               
                 62. 
                 1B42 
                 ++ 
               
               
                 63. 
                 1B43 
                 ++ 
               
               
                 64. 
                 1B44 
                 + 
               
               
                 65. 
                 1B45 
                 + 
               
               
                 66. 
                 1B46 
                 + 
               
               
                 67. 
                 1B47 
                 ++ 
               
               
                 68. 
                 1B48 
                 + 
               
               
                 69. 
                 1B49 
                 ++ 
               
               
                 70. 
                 1B50 
                 + 
               
               
                 71. 
                 ZSTK474 
                 ++ 
               
               
                   
               
               
                 * In vitro PI3K alpha kinase inhibition at 500 nm; + indicates greater than 50% to 70% of inhibition and ++ indicates greater than 70% of inhibition. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 9 
               
               
                   
               
               
                   
                   
                 MCF-7 Cell line 
                 PC-3 Cell line % inhibition 
                 MDA-MB231 Cell line 
               
               
                 Entry 
                 Code 
                 % inhibition at 10 μM* 
                 at 10 μM* 
                 % inhibition at 10 μM* 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1. 
                 1A5 
                 + 
                 ++ 
                 + 
               
               
                 2. 
                 1A9 
                 ++ 
                 + 
                 ++ 
               
               
                 3. 
                 1B1 
                 ++ 
                 ++ 
                 ++ 
               
               
                 4. 
                 1B2 
                 ++ 
                 + 
                 ++ 
               
               
                 5. 
                 1B4 
                 NC 
                 NC 
                 NC 
               
               
                 6. 
                 1B5 
                 ++ 
                 NC 
                 + 
               
               
                 7. 
                 1B6 
                 ++ 
                 + 
                 NC 
               
               
                 8. 
                 1B7 
                 ++ 
                 NC 
                 + 
               
               
                 9. 
                 1B10 
                 NC 
                 NC 
                 NC 
               
               
                 10. 
                 1B11 
                 NC 
                 ++ 
                 + 
               
               
                 11. 
                 1B12 
                 ++ 
                 + 
                 + 
               
               
                 12. 
                 1B22 
                 + 
                 + 
                 NC 
               
               
                 13. 
                 1B23 
                 + 
                 + 
                 NC 
               
               
                 14. 
                 1B24 
                 NC 
                 NC 
                 + 
               
               
                 15. 
                 1B25 
                 ++ 
                 + 
                 NC 
               
               
                 16. 
                 1B26 
                 ++ 
                 + 
                 ++ 
               
               
                 17. 
                 1B27 
                 ++ 
                 + 
                 + 
               
               
                 18. 
                 1B28 
                 ++ 
                 + 
                 NC 
               
               
                 19. 
                 1B30 
                 ++ 
                 + 
                 + 
               
               
                 20. 
                 1B32 
                 ++ 
                 + 
                 + 
               
               
                 21. 
                 ZSTK474 
                 ++ 
                 ++ 
                 ++ 
               
               
                   
               
               
                 *In vitro cell line inhibition at 10 μM: 
               
               
                 + indicates less than 30 to 50% of inhibition and 
               
               
                 ++ indicates greater than 50% of inhibition.