Abstract:
The present invention relates to styryl quinazoline derivatives of the general formula (I) and pharmaceutically acceptable solvates, hydrates, salts, regioisomeric and polymorphic forms thereof as well as pharmaceutical compositions containing at least one of the described compounds as pharmaceutically active agent. The compounds have been identified as new drug candidates for the prevention and/or treatment of diseases related to disfunction(s) of hematopoiesis and cancer or any other form of neo- or hyperplasias related to Fms-like tyrosine kinase 3 (FLT3) containing Internal Tandem Duplications (ITD), especially in the case of myeloid leukemia. The compounds have been also identified as new drug candidates as antibacterial agents (having bactericidal or bacteriostatic activity) which can be used for the prevention and/or treatment of bacterial infectious diseases.

Description:
FIELD OF THE INVENTION 
       [0001]    In accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention includes styryl quinazoline derivatives of the general formula (I) and pharmaceutically acceptable solvates, hydrates, salts, regioisomeric and polymorphic forms thereof as well as pharmaceutical compositions containing at least one of the described compounds as pharmaceutically active agent, together with pharmaceutically acceptable carrier, excipient and/or diluents and the use of them for therapeutic or preventive purposes, especially regarding cancer or any other form of neo- or hyperplasias. 
         [0002]    Moreover, the present invention provides processes for the preparation of the described compounds. The styryl quinazoline derivatives disclosed in this invention have been identified as new drug candidates for the prevention and/or treatment of diseases related to disfunction(s) of hematopoiesis and cancer or any other form of neo- or hyperplasias related to (depending on) Fms-like tyrosine kinase 3 (FLT3) containing Internal Tandem Duplications (ITD), especially in the case of myeloid leukemia. Accordingly, the styryl quinazoline derivatives of the general formula (I) and pharmaceutically acceptable solvates, hydrates, salts, regioisomeric and polymorphic forms thereof have inhibitory effect on Fms-like tyrosine kinase 3 (FLT3) containing Internal Tandem Duplications (ITD). 
         [0003]    The discussed styryl quinazoline compounds have been also identified as new drug candidates as antibacterial agents (having bactericidal or bacteriostatic activity) which can be used for the prevention and/or treatment of bacterial infectious diseases e.g. meningitis of bacterial origin, gastroenteritis of bacterial origin,  E - coli  and  Staphylococcus saprophyticus  caused Urinary Tract Infections (UTI),  E. coli, Shigella  and  Campylobacter  associated Hemolytic-Uremic Syndrome (HUS), infected peritonitis, infectious mastitis, bacteraernia (bacteria caused sepsis),  E. coli, Klebsiella, Pseudomonas, B. fragilis  and  Enterococcus  caused cholecystitis, and common types of pneumonia. 
       BACKGROUND OF THE INVENTION 
       [0004]    Fms-like tyrosine kinase 3 (FLT3), also known as Cluster of Differentiation antigen 135 (CD135), Fetal liver kinase-2 (Flk2) and Stem cell Tyrosine Kinase 1 (STK1) is a human protein (Uniprot ID: P36888) encoded by the human gene FLT3 (HGNC ID: 3765). This protein is specifically appearing on the surface of hematopoietic progenitor cells after they cease to be hematopoietic stem cells related to FLT3 expression. FLT3 regulates the maturation processes in order to develop them into functional blood cells, especially to develop properly functioning lymphocytes, alias T-cells and B-cells. The hematopoietic progenitor cells are multipotent cells, and the dysregulation of their differentiation processes often results pathologic conditions. FLT3 is one the most important regulators of this cellular maturation process, therefore mutations or overexpression of this protein are associated with several types of blood cell malignancies, including acute myeloid leukemia. As more and more information has been gathered about FLT3&#39;s role as an oncogene, FLT3&#39;s Internal Tandem Duplications (ITD) type of mutation is by now considered as a disease-specific ‘driver’ mutation. FLT(ITD) is a mutation that is a crucial turning point-like factor that moves differentiation and proliferation processes toward the initiation and progression of acute myeloid leukemia in a disease-specific way. The unique expression pattern of the mutated protein makes it a highly promising target in terms of developing really targeted and protein-specific signal transduction therapies. 
         [0005]    FLT3 is a member of receptor tyrosine kinases class III. This class&#39;s domain structure significantly differs from the other classes&#39; and the class contains only a few members. The kinase domain of FLT3 is relatively different compared to the mainstream targeted Tyrosine Kinases This fact indicates that the potent inhibitors of FLT3(ITD) are having a rather selective profile among Receptor Tyrosine Kinases. The effectiveness and the selectivity has been proven by in vitro biochemical assays, cellular viability assays and using a wide kinase selectivity panel. 
         [0006]    As it was mentioned above, the styryl quinazoline compounds according to the present invention also can be applied as antibacterial agents (having bactericidal or bacteriostatic activity) for the prevention and/or treatment of bacterial infectious diseases such as meningitis of bacterial origin, gastroenteritis of bacterial origin,  E. coli  and  Staphylococcus saprophyticus  caused Urinary Tract Infections (UTI),  E. coli, Shigella  and  Campylobacter  associated Hemolytic-Uremic Syndrome (HUS), infected peritonitis, infectious mastitis, bacteraernia (bacteria caused sepsis),  E. coli, Klebsiella, Pseudomonas, B. fragilis  and  Enterococcus  caused cholecystitis, and common types of pneumonia. 
         [0007]    Pathogenic bacteria are a major cause of human death and disease and cause infectious diseases—besides inflammation based pathogenic states mentioned above—such as tetanus, typhoid fever, diphtheria, syphilis, cholera, foodborne illness, leprosy and tuberculosis. Bacterial infections may be treated with antibiotics (antibacterial agents), which are classified as bactericidal if they kill bacteria, or bacteriostatic if they just prevent bacterial growth. 
         [0008]      Escherichia coli  ( E. coli , named after Theodor Escherich) is a Gram-negative, facultatively anaerobic, rod-shaped bacterium of the genus  Escherichia  that is commonly found in the lower intestine of endothermic organisms. 
         [0009]    Most  E. coli  strains are harmless, but certain serotypes are pathogenic to humans or domestic animals. Virulent strains of  E. coli  are the dominant causes of various diseases; such as meningitis, gastroenteritis and UTI and less often can cause HUS, peritonitis, mastitis, bacteraernia and gram-negative pneumonia. Certain strains of  E. coli  produce also potentially lethal toxins, e.g. Enterotoxigenic  E. coli  (ETEC), Enteropathogenic  E. coli  (EPEC), Enteroinvasive  E. coli  (EIEC), Enterohemorrhagic  E. coli  (EHEC), Enteroaggregative  E. coli  (EAEC) which are causative agents of diarrhea and other gastrointestinal symptoms, and Uropathogenic  E. coli  (UPEC) which causes urinary tract inflammation and infection. There are also some  E. coli  strains that contain a polyketide synthase (PKS) genomic island whose function is to encode multiple PKSs, a multi-enzymatic machinery that produces a genotoxic substance, named colibactin. This substance can promote tumorigenesis by DNA damage. 
       SUMMARY OF THE INVENTION 
       [0010]    1. The present invention relates to compounds of general formula (I) and pharmaceutically acceptable salts, solvates, hydrates, regioisomeric and polymorphic forms thereof, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0011]    wherein 
         [0012]    R1 is N(R5)(R6), wherein 
         [0013]    R5 and R6 are independently selected from the group of hydrogen, alkyl or ALK-N(R7)(R8), wherein
       ALK is an alkanediyl group and   R7 and R8 are independently selected from the group of hydrogen, alkyl, alkylcarbonyl and alkoxycarbonyl; or   R7 and R8 taken together with the adjacent N form a saturated heterocyclyl which is optionally substituted with alkyl;       
 
         [0017]    or R5 and R6 taken together with the adjacent N may form a heterocyclyl optionally substituted heterocyclyl-alkyl or a cycloketal group is joined to it; 
         [0018]    R2 is hydrogen or halogen; 
         [0019]    R3 and R4 are independently selected from the group of hydrogen, halogen, alkoxy or nitro group; 
         [0020]    or R3 and R4 together with the carbon atoms they attached to may form an aryl fused to the quinazoline ring; 
         [0021]    Q is aryl optionally mono or polysubstituted with halogen, alkyl, dialkylamine, alkoxy, alkylsulfanyl, alkylsulfinyl, or alkylsulfonyl; or heteroaryl group; 
         [0022]    2. Compound according to point 1, wherein 
         [0023]    R7 and R8 are independently selected form hydrogen, methyl, ethyl, methylcarbonyl and methoxycarbonyl, or R7 and R8 taken together with N form morpholin-4-yl or 4-methylpiperazin-1-yl ring. 
         [0024]    3. Compound according to point 1 or 2, wherein R5 and R6 are independently selected form hydrogen, propyl, ethyl-N(R7)(R8), 1-prop-3-yl-N(R7)(R8), pent-1,4-diyl-N(R7)(R8) or 
         [0025]    R5 and R6 taken together with N form 1,4-dioxa-8-azaspiro[4.5]dec-8-yl or (pyrrolidin-1-ylmethyl)pyrrolidin-1-yl. 
         [0026]    4. Compound according to any of points 1 to 3, wherein R2 is hydrogen or bromine. 
         [0027]    5. Compound according to any of points 1 to 4, wherein R3 is hydrogen, chlorine, nitro or methoxy. 
         [0028]    6. Compound according to any of points 1 to 5, wherein R4 is hydrogen, fluorine, chlorine, bromine or methoxy; or 
         [0029]    R3 and R4 together with the carbon atoms they attached to may form an aryl fused to the quinazoline ring. 
         [0030]    7. Compound according to any of points 1 to 6, wherein Q is phenyl mono or polysubstituted with fluorine, chlorine, methoxy, dimethylamino, i-propyl, methylthio, methylsulfonyl group; or thienyl. 
         [0031]    8. Compound according to any of points 1 to 7, wherein 
         [0032]    R1 is 1-dimethylamino-propane-3-ylamino, 1-diethylamino-propane-3-ylamino, 3-(morpholin-4-yl)propyl-amino, 3-(4-methylpiperazin-1-yl)propylamino, 1-dimethylamino-2-ethylamino, 1-dimthylamino-2-ethylamino, 1-diethylamino-pentane-4-yl-amino, 1-(tertbutylcarbamate)-propane-3-yl-amino, 1-amino-propane-3-yl-amino, 1-acetylmino-propane-3-yl-amino, 1-(piperidin-4-one-ethylenketal), 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, propane-3-yl-amino; 
         [0033]    R2, R3 and R4 being as defined in point 4 to 6; 
         [0034]    Q is 4-methoxy-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-(dimethylamino)phenyl, 3,4,5-trimethoxyphenyl, 3,4-difluorophenyl, 4-(methylthio)phenyl, 2-thienyl, 4-isopropylphenyl or 4-(methylsulfonyl)phenyl. 
         [0035]    9. Pharmaceutical composition containing as active ingredient one or more compound(s) of general formula (I) according to any of points 1 to 8 together with one or more usual pharmaceutical auxiliary material(s). 
         [0036]    10. Compounds according to any of points 1 to 8 for use in the prevention and/or treatment of a disease related to disfunction of hematopoiesis and/or a cancerous, neoplastic or hyperplastic disease. 
         [0037]    11. Compounds for use according to point 10, wherein the disfunction of hematopoiesis and the cancer or any other form of neo- or hyperplasias are related to the Fms-like tyrosine kinase 3 (FLT3) containing Internal Tandem Duplications (ITD). 
         [0038]    12. Compounds according to any of points 1 to 8 for use in the prevention and/or the treatment of bacterial infectious diseases. 
         [0039]    13. Compounds for use according to point 12, wherein the bacterial infectious diseases is selected from meningitis of bacterial origin, gastroenteritis of bacterial origin,  E. coli  and  Staphylococcus saprophyticus  caused Urinary Tract Infections (UTI),  E. coli, Shigella  and  Campylobacter  associated Hemolytic-Uremic Syndrome (HUS), infected peritonitis, infectious mastitis, bacteraernia (bacteria caused sepsis),  E. coli, Klebsiella, Pseudomonas, B. fragilis  and  Enterococcus  caused cholecystitis, and common types of pneumonia. 
         [0040]    14. The compounds invented can be applied in a method for the prevention and/or the treatment of a disease related to disfunction of hematopoiesis and/or a cancerous, neoplastic or hyperplastic disease, where a compound of general formula (I) according to any of points 1 to 8 is administered to an individual in need thereof. Specifically, the disfunction of hematopoiesis and cancer or any other form of neo- or hyperplasias are related to the Fms-like tyrosine kinase 3 (FLT3) containing Internal Tandem Duplications (ITD). 
         [0041]    15. The compounds invented can be applied in a method for the prevention and/or the treatment of bacterial infectious diseases, where a compound of general formula (I) according to any of points 1 to 8 is administered to an individual in need thereof. Specifically, the bacterial infectious diseases is selected from meningitis of bacterial origin, gastroenteritis of bacterial origin,  E. coli  and  Staphylococcus saprophyticus  caused Urinary Tract Infections (UTI),  E. coli, Shigella  and  Campylobacter  associated Hemolytic-Uremic Syndrome (HUS), infected peritonitis, infectious mastitis, bacteraernia (bacteria caused sepsis),  E. coli, Klebsiella, Pseudomonas, B. fragilis  and  Enterococcus  caused cholecystitis, and common types of pneumonia. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0042]    In the context of this description the phrase “cancer” embraces adenocarcinomas (breast, colon, colorectal and colorectal adenocarcinoma, epidermoid, lung bronchioalveolar and lung adenocarcinoma), the cancerous disease of the genital system (including uterine cervix, uterine corpus, ovary, vulva, vagina and other genital female, prostate, testis, penis and other genital male), digestive system (including esophagus, stomach, small intestine, colon, rectum, anus anal canal and anorectum, liver and intrahepatic bile duct, gallbladder and other biliary, pancreas, other digestive organs), respiratory system (including larynx, lung and bronchus, other respiratory organs), breast, urinary system (including urinary bladder, kidney and renal pelvis, ureter and other urinary organs), skin (excluding basal and squamous; including skin melanoma, other nonepithelial skin), endocrine system (including thyroid, other endocrine), oral cavity and pharynx (including tongue, mouth, pharynx, other oral cavity), brain and other nervous system, myeloma, soft tissue (including heart), bones and joints, eye and orbit, and the following diseases: lymphoma (including Hodgkin lymphoma, Non-Hodgkin lymphoma), leukemia (including acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, other leukemia), especially acute T-cell leukemia, breast, colon, colorectal and colorectal adenocarcinoma, epidermoid, lung bronchioalveolar and lung adenocarcinoma, prostate. 
         [0043]    Hyperplasia (or “hypergenesis”) is a general term referring to the proliferation of cells within an organ or tissue beyond that which is ordinarily seen. Hyperplasia may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/benign tumor. 
         [0044]    Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of the cells exceeds, and is uncoordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the stimuli. It usually causes a lump or tumor. Neoplasms may be benign, pre-malignant or malignant. 
         [0045]    FLT3 is naturally expressed by immature hematopoietic (blood cell forming) cells and is important for the normal development of stem cells and the immune system. The ligand for FLT3 synergizes with other growth factors to stimulate proliferation of stem cells, progenitor cells, dendritic cells, and natural killer cells. Mutations of FLT3 (mainly the FLT3[ITD] mutation which is investigated in our case) have been detected in about 30% of patients with acute myelogenous leukemia and a small number of patients with acute lymphocytic leukemia or myelodysplastic syndrome. FLT3 is also expressed in a wild type form at high levels in 70% to 100% of cases of acute myelogenous leukemia and in a high percentage of acute lymphocytic leukemia cases [D. Gary Gilliland and James D. Griffin: The roles of FLT3 in hematopoiesis and leukemia, Sep. 1, 2002; Blood: 100 (5)]. 
         [0046]    As used herein in the meaning of R1 (i.e. in the meaning of R5, R6, R7 and R8), the term “heterocyclyl” alone or in combination, means a group derived from a saturated, partially unsaturated or aromatic ring system with 4 to 9 carbon atoms and 1 to 4 heteroatom(s) selected from the group of N, O and S [i.e. group of N (nitrogen), O (oxygen) or S (sulfur) atoms]. In a preferred embodiment the term “heterocyclyl” alone or in combination, means a saturated ring system with 4 to 7 carbon atoms and 1 to 3 heteroatom(s) selected from the group of N, O and S. In a more preferred embodiment the term “heterocyclyl” means a saturated ring system with 4 to 6 carbon atoms and 1 to 2 heteroatom(s) selected from the group of N and O. Examples for heterocyclyl (includes but not limited to) are morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, indolyl, indazolyl, 1,3-benzodioxolyl, dihydro-1,4-benzodioxinyl, furanyl, pyrrolyl, pyridinyl, quinolinyl, isoquinolinyl, pyranyl, oxazinyl, imidazolyl, benzoimidazolyl, pyrazolyl, purinyl, where morpholinyl, pyrrolidinyl, piperazinyl and piperidinyl are preferred. 
         [0047]    Those substituted heterocyclyl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of heterocyclyl groups. So, the substituted heterocyclyl groups carry one or more, preferably 1 to 4 substituent(s), e.g. 1 to 3 or 1 to 2 substituent(s), independently selected from the group of halogen, alkyl, hydroxyl, hydroxyalkyl [preferably the substituent is alkyl, more preferably methyl]. 
         [0048]    As used herein the term “aryl”, alone or in combinations means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. Non-limiting examples of suitable aryl groups include phenyl, and naphthyl, where phenyl is a preferred embodiment. 
         [0049]    Those substituted aryl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of aryl groups. So, the substituted aryl groups carry one or more, preferably 1 to 4, e.g. 1 to 3 or 1 to 2 substituent(s), independently selected from the group of halogen, alkyl, alkoxy, amino, optionally mono- or disubstituted with alkyl, amide, acylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano. 
         [0050]    In specific embodiments the substituent of the aryl can be optionally substituted alkyl (more preferably propyl, e.g. isopropyl), halogen (e.g. fluoro or chloro), alkoxy (more preferably methoxy), dialkylamino (e.g. dimethylamino), alkylthio (e.g. methylthio), alkylsulfonyl (e.g. methylsulfonyl). 
         [0051]    As used herein, the term “alkanediyl” means a bivalent group formed by the removal of 2 hydrogen atoms from different carbon atoms of an C1-6 alkane group, i.e. it can be a straight or branced group, e.g. ethane-1,2-diyl, propane-1,3-diyl and pentane-1,4-diyl group. 
         [0052]    As used herein, the term “halogen” means fluorine, chlorine, bromine or iodine. 
         [0053]    As used herein, the term “alkyl” alone or in combinations means a straight or branched-chain alkyl group containing from 1 to 6, preferably 1 to 5 carbon atom(s) (i.e. “C 1-6 ” or “C 1-5 ” alkyl groups), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl and pentyl. In special cases this phrase can relate to alkyl groups containing from 1 to 4, or 1 to 3 or 1 to 2 carbon atom(s) (i.e. “C 1-4 ” or “C 1-3 ” or “C 1-2 ” alkyl groups). Those substituted alkyl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of alkyl groups. So, the substituted alkyl groups carry one or more, preferably one or two substituent(s), independently selected from the group of halogen, aryl, hydroxyl, carboxyl, benzyloxy, alkoxy, nitro, sulphate, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano. 
         [0054]    As used herein, the term “alkylcarbonyl” means an alkyl-CO— group. 
         [0055]    As used herein, the term “alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen. If the alkoxy group is substituted with halogen then it is named as haloalkoxy group. 
         [0056]    As used herein, the term “alkoxycarbonyl” means an alkoxy-CO— group [i.e. alkyl-O(CO) group]. 
         [0057]    As used herein, the term “cycloketal” means a bivalent group of —O—(CH 2 ) n —O— which is joined to the same carbon atom (e.g. of a ring system), where n is 1 to 4, preferably 2 or 3, more preferably 2. 
         [0058]    As used herein in the meaning of Q the term “heteroaryl” means a group derived from an aromatic ring system with 4 to 9 carbon atoms and 1 to 4 heteroatom(s) selected from the group of N, O and S [i.e. group of N (nitrogen), O (oxygen) or S (sulfur) atoms]. In a preferred embodiment the term “heteroaryl”, means an aromatic ring system with 4 to 7 carbon atoms and 1 to 3 heteroatom(s) selected from the group of N, O and S. In a more preferred embodiment the term “heteroaryl” means an aromatic ring system with 4 to 5 carbon atoms and 1 to 2 heteroatom(s) selected from the group of N, O and S. In a specific embodiment the heteroatom(s) is (are) sulphur. Examples for heteroaryl are indolyl, imidazolyl, azaindolyl, pyrrolyl, quinolinyl, isoquinolinyl, oxazolyl, thiazolyl, thienyl and pyrimidinyl where thienyl is preferred. 
         [0059]    The term “salt” means any ionic compound formed between one of the embodiments of the present invention and an acidic or basic molecule that can donate or accept ionic particle to/from its partner. The quaternary amine salts are also included. 
         [0060]    Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. 
         [0061]    Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates, and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are known. 
         [0062]    The term “solvate” means a compound formed by the combination of solvent molecules with molecules or ions of the solute (solvation). Solute can be any of the embodiments of the present invention and the solvent can be water (forming hydrates) or any organic solvent. 
         [0063]    The phrases of regioisomeric and polymorphic forms have the general meaning usually applied in organic chemistry (see e.g. in March&#39;s Advanced Organic Chemistry, John Wiley &amp; Sohns, inc. USA. ISBN 0-471-58589-0). 
         [0064]    Materials and Methods: 
         [0065]    Synthetic Methods: 
       Step A: Preparation of mono- or di substituted 2-methylquinazolin-4(3H)-ones 
       [0066]    
       
                 
         
             
             
         
       
     
       6-chloro-2-methylquinazolin-4(3H)-one 
       [0067]    10 g (58 mmol) 2-amino-5-chlorobenzoic acid was solved in 35 ml acetic anhydride and was stirred at reflux temperature for 4 hours. The reaction mixture was cooled down to room temperature and the solvent was rotary evaporated. The crude product was washed with hexane/ether 2:1 and than filtered. The solid 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (58 mmol) was suspended in 80 ml concentrated ammonium hydroxide and stirred at room temperature overnight. 10% sodium hydoxide solution was given to the reaction mixture resulting a transparent solution. The pH was adjusted to 7 with acetic acid. The product, which was precipitated from the solution, was filtered, washed with water and dried under vacuum overnight. 
         [0068]    Preparation of other 2-methylquinazolin-4(3H)-one derivatives were carried out with the same method. 
         [0069]    Yield: 8.76 g (77%) 
         [0070]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 7.98 (s, 1H); 7.76 (6 Hz, d, 1H); 7.57 (9 Hz, d, 1H); 2.34 (s, 3H). LC-MS (ESI): m/z (M+H) +  195, Rt: 2.43 min. 
       6-fluoro-2-methylquinazolin-4(3H)-one 
       [0071]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.29 (bs, NH); 7.74-7.63 (m, 3H); 2.34 (s, 3H). LC-MS (ESI): m/z (M+H) +  179, Rt: 2.01 min. 
       6-bromo-2-methylquinazolin-4(3H)-one 
       [0072]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 8.13 (s, 1H); 7.88 (9 Hz, d, 1H); 7.50 (9 Hz, d, 1H); 2.33 (s, 1H). LC-MS (ESI): m/z (M+H) +  239, Rt: 2.52 min. 
       2-methyl-7-nitroquinazolin-4(3H)-one 
       [0073]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.40 (bs, 1H); 8.29 (d, 1H); 8.26 (s, 1H); 8.16 (d, 1H); 2.40 (s, 3H). LC-MS (ESI): m/z (M+H) +  206, Rt: 2.34 min. 
       6,7-dimethoxy-2-methylquinazolin-4(3H)-one 
       [0074]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.00 (bs, 1H); 7.39 (s, 1H); 7.05 (s, 1H); 3.88 (s, 3H); 3.85 (s, 1H); 2.31 (s, 3H). LC-MS (ESI): m/z (M+H) +  221, Rt: 0.45 min, 1.78 min. 
       2-methylbenzo[g]quinazolin-4(3H)-one 
       [0075]    The starting 3-amino-2-naphthoic acid was only 85% pure and contained the other regioisomer too. The product was 67% pure to the right isomer. We used this product for the next reaction without purification. LCMS m/z 211 (M+H) + , Rt: 2.40 min (desired compound), 2.61 min (other isomer) 
       7-chloro-2-methylquinazolin-4(3H)-one 
       [0076]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 8.06 (d, 1H); 7.60 (d, 1H); 7.46 (dd, 1H); 3.50 (bs, 1H); 2.35 (s, 3H). LC-MS (ESI): m/z (M+H) +  195, Rt: 2.48 min. 
       6,8-dibromo-2-methylquinazolin-4(3H)-one 
       [0077]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 8.14 (s, 1H); 8.09 (s, 1H); 3.80 (bs, 1H); 2.32 (s, 3H). LC-MS (ESI): m/z (M+H) +  319, Rt: 3.27 min. 
       Step B: Preparation of substituted 2-[(E)-2-phenylvinyl]quinazolin-4(3H)-ones 
       [0078]    
       
                 
         
             
             
         
       
     
       6-chloro-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0079]    3 g (15 mmol) 6-chloro-2-methylquinazolin-4(3H)-one was mixed with 3.06 g (22.5 mmol) 4-methoxybenzaldehyde and 1 drop concentrated sulphuric acid was given to this mixture. The reaction was carried out in microwave set at 190° C. Reaction time was 2 hour. The crude product was washed with 5% sodium hydrogen carbonate and filtered. The product was crystallized from dimethyl formamide and dried under vacuum. 
         [0080]    Yield: 4.58 g (95%) 
         [0081]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 8.02 (d, 1H); 7.92 (d, 1H); 7.81 (d, 1H); 7.66 (d, 1H); 7.66 (d, 1H); 7.61 (d, 2H); 7.03 (d, 2H); 6.85 (d, 1H); 3.81 (s, 3H). LC-MS (ESI): m/z (M+H) +  313, Rt: 4.07 min. 
         [0082]    Preparation of other 2-[(E)-2-phenylvinyl]quinazolin-4(3H)-one derivatives were carried out with the same method. 
       6-chloro-2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0083]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.47 (bs, 1H); 8.04 (d, 1H); 7.95 (d, 1H); 7.83 (dd, 1H); 7.72 (m, 3H); 7.30 (t, 2H); 6.95 (d, 1H). LC-MS (ESI): m/z (M+H) +  301, Rt: 4.13 min. 
       6-chloro-2-[(E)-2-(3,4-difluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0084]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.48 (bs, 1H); 8.03 (s, 1H); 7.90 (d, 1H); 7.79 (m, 2H); 7.68 (d, 1H); 7.53 (m, 2H); 6.99 (d, 1H). LC-MS (ESI): m/z (M+H) +  319, Rt: 4.21 min. 
       6-chloro-2-{(E)-2-[4-(methylthio)phenyl]vinyl}quinazolin-4(3H)-one 
       [0085]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.40 (bs, 1H); 8.02 (s, 1H); 7.91 (d, 1H); 7.80 (d, 1H); 7.67 (d, 1H); 7.59 (d, 2H); 7.33 (d, 2H); 6.95 (d, 1H); 2.52 (s, 3H). LC-MS (ESI): m/z (M+H) +  329, Rt: 4.38 min. 
       6-fluoro-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0086]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.35 (bs, 1H); 7.90 (d, 1H); 7.71 (m, 3H); 7.61 (d, 2H); 7.03 (d, 2H); 6.84 (d, 1H); 3.81 (s, 3H). LC-MS (ESI): m/z (M+H) +  297, Rt: 3.70 min. 
       6-fluoro-2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0087]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.42 (bs, 1H); 7.93 (d, 1H); 7.72 (m, 5H); 7.30 (t, 2H); 6.95 (d, 1H). LC-MS (ESI): m/z (M+H) +  285, Rt: 3.79 min. 
       6-fluoro-2-[(E)-2-(3,4-difluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0088]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.44 (bs, 1H); 7.88 (d, 1H); 7.65 (m, 4H); 7.51 (bs, 2H); 6.98 (d, 1H). LC-MS (ESI): (M+H) +  303, Rt: 3.90 min. 
       6-bromo-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0089]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.39 (bs, 1H); 8.16 (s, 1H); 7.95 (s, 1H); 7.94 (d, 1H); 7.61 (bs, 3H); 7.03 (d, 2H); 8.85 (d, 1H); 3.82 (s, 3H). LC-MS (ESI): m/z (M+H) +  357, Rt: 4.15 min. 
       6-bromo-2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0090]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.47 (bs, 1H); 8.18 (d, 1H); 7.95 (d, 1H); 7.92 (s, 1H); 7.73 (m, 2H); 7.62 (d, 1H); 7.30 (t, 2H); 6.95 (d, 1H). LC-MS (ESI): m/z (M+H) +  345, Rt: 4.22 min. 
       6-bromo-2-[(E)-2-(3,4-difluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0091]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.47 (bs, 1H); 8.18 (s, 1H); 7.91 (d, 1H); 7.93 (s, 1H); 7.78 (t, 1H); 7.61 (d, 1H); 7.52 (bs, 2H); 6.99 (d, 1H). LC-MS (ESI): m/z (M+H) +  363, Rt: 4.30 min. 
       2-[(E)-2-(4-methoxyphenyl)vinyl]-7-nitroquinazolin-4(3H)-one 
       [0092]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.56 (bs, 1H); 8.30 (s, 1H); 8.29 (d, 1H); 8.13 (d, 1H); 7.98 (d, 1H); 7.62 (d, 2H); 7.03 (d, 2H); 6.86 (d, 1H); 3.82 (s, 3H). LC-MS (ESI): m/z (M+H) +  324, Rt: 3.96 min. 
       2-[(E)-2-(4-fluorophenyl)vinyl]-7-nitroquinazolin-4(3H)-one 
       [0093]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.65 (bs, 1H); 8.33 (d, 1H); 8.30 (s, 1H); 8.17 (dd, 1H); 8.02 (d, 1H); 7.74 (m, 2H); 7.32 (t, 2H); 6.97 (d, 1H). LC-MS (ESI): m/z (M+H) +  312, Rt: 4.01 min. 
       6,7-dimethoxy-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0094]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 8.17 (t, 1H); 8.06 (dd, 1H); 7.87 (d, 1H); 7.74 (m, 3H); 7.64 (dt, 1H); 7.25 (t, 2H); 7.08 (d, 1H); 3.67 (q, 2H); 3.57 (t, 4H); 2.40 (m, 6H); 1.86 (m, 2H). LC-MS (ESI): m/z (M+H) +  339, Rt: 3.26 min. 
       6,7-dimethoxy-2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0095]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.45 (bs, 1H); 7.88 (d, 1H); 7.69 (m, 2H); 7.45 (s, 1H); 7.30 (t, 2H); 7.14 (s, 1H); 6.91 (d, 1H). LC-MS (ESI): m/z (M+H) +  327, Rt: 3.40 min. 
       6,7-dimethoxy-2-[(E)-2-(3,4-difluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0096]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm LC-MS (ESI): m/z (M+H) +  345, Rt: 3.52 min. 
       2-[(E)-2-(4-methoxyphenyl)vinyl]benzo[g]quinazolin-4(3H)-one 
       [0097]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.(bs, 1H); 8.80 (s, 1H); 8.19 (bs, 2H); 8.08 (d, 1H); 7.95 (d, 1H); 7.64 (d, 2H); 7.58 (t, 2H); 7.04 (d, 2H); 6.89 (d, 1H); 3.82 (s, 3H). LC-MS (ESI): m/z (M+H) +  329, Rt: 4.03 min. 
       2-[(E)-2-(4-fluorophenyl)vinyl]benzo[g]quinazolin-4(3H)-one 
       [0098]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 11.5 (bs, 1H); 8.82 (s, 1H); 8.31 (s, 1H); 8.13 (d, 1H); 8.10 (d, 1H); 7.92 (d, 1H); 7.75 (m, 2H); 7.67 (t, 1H); 7.60 (t, 1H); 7.32 (t, 2H); 7.01 (d, 1H). LC-MS (ESI): m/z (M+H) +  317, Rt: 4.18 min. 
       2-[(E)-2-(4-chlorophenyl)vinyl]benzo[g]quinazolin-4(3H)-one 
       [0099]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 11.5 (bs, 1H); 8.82 (s, 1H); 8.24 (s, 1H); 8.19 (d, 1H); 8.10 (d, 1H); 7.99 (d, 1H); 7.70 (m, 3H); 7.55 (m, 3H); 7.6 (d, 1H). LC-MS (ESI): m/z (M+H) +  333, Rt: 4.53 min. 
       2-[(E)-2-(3,4-difluorophenyl)vinyl]benzo[g]quinazolin-4(3H)-one 
       [0100]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 9.5 (bs, 1H); 8.84 (s, 1H); 8.32 (m, 2H); 8.10 (m, 1H); 7.94 (d, 1H); 7.82 (m, 1H); 7.62 (m, 4H); 7.06 (d, 1H). LC-MS (ESI): m/z (M+H) +  335, Rt: 4.28 min. 
       7-chloro-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0101]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.37 (bs, 1H); 8.09 (d, 1H); 7.92 (d, 1H); 7.68 (d, 1H); 7.62 (d, 2H); 7.48 (dd, 1H); 7.03 (d, 2H); 6.85 (d, 1H); 3.82 (s, 3H). LC-MS (ESI): m/z (M+H) +  313, Rt: 4.14 min. 
       7-chloro-2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0102]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.46 (bs, 1H); 8.9 (d, 1H); 7.96 (d, 1H); 7.73 (m, 3H); 7.51 (dd, 1H); 7.31 (t, 2H); 6.94 (d, 1H). LC-MS (ESI): m/z (M+H) +  301, Rt: 4.22 min. 
       7-chloro-2-{(E)-2-[4-(dimethylamino)phenyl]vinyl}quinazolin-4(3H)-one 
       [0103]      1 H NMR (300 MHz, DMSO-d 8 ) δ ppm 12.23 (s, 1H); 8.06 (d, 1H); 7.87 (d, 1H); 7.63 (s, 1H); 7.45 (m, 3H); 6.72 (m, 3H); 2.99 (s, 6H). LC-MS (ESI): m/z (M+H) +  301, Rt: 4.22 min. 
       6,8-dibromo-2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0104]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.5 (bs, 1H); 8.21 (bs, 1H); 8.13 (bs, 1H); 7.92 (d, 1H); 7.73 (bs, 2H); 7.28 (t, 2H); 6.93 (t, 2H). LC-MS (ESI): m/z (M+H) +  423, Rt: 4.93 min. 
       2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0105]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.25 (bs, NH); 8.09 (d, 1H); 7.90 (d, 1H); 7.79 (t, 1H); 7.66 (m, 3H); 7.45 (t, 1H); 7.02 (d, 2H); 6.87 (d, 1H); 3.78 (s, 3H). LC-MS (ESI): m/z (M+H) +  279, Rt: 3.42 min. 
       2-[(E)-2-(4-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0106]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.33 (bs, 1H); 8.11 (d, 1H); 7.95 (d, 1H); 7.72 (m, 4H); 7.48 (t, 1H); 7.30 (t, 2H); 6.99 (d, 1H). LC-MS (ESI): m/z (M+H) +  267, Rt: 3.57 min. 
       2-[(E)-2-(3,4-difluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0107]      1 H NMR (300 MHz, DMSO-d 8 ) δ ppm 12.3 (bs, 1H); 8.12 (d, 1H); 7.92 (d, 1H); 7.80 (m, 2H); 7.68 (d, 1H); 7.512 (m, 3H); 7.04 (d, 1H). LC-MS (ESI): m/z (M+H) +  285, Rt: 3.69 min. 
       2-[(E)-2-(3-fluorophenyl)vinyl]quinazolin-4(3H)-one 
       [0108]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12. (bs, 1H); 8.12 (d, 1H); 7.97 (d, 1H); 7.83 (t, 1H); 7.71 (d, 1H); 7.50 (m, 4H); 7.26 (t, 1H); 7.10 (d, 1H). LC-MS (ESI): m/z (M+H) +  267, Rt: 3.61 min. 
       2-{(E)-2-[(4-(methylthio)phenyl]vinyl}quinazolin-4(3H)-one 
       [0109]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.27 (bs, 1H); 8.13 (d, 1H); 7.90 (d, 1H); 7.79 (t, 1H); 7.63 (m, 3H); 7.38 (t, 1H); 7.13 (d, 2H); 6.92 (d, 1H); 2.51 (s, 3H). LC-MS (ESI): m/z (M+H) +  295, Rt: 3.82 min. 
       2-[(E)-2-(3,4,5-trimethoxyphenyl)vinyl]quinazolin-4(3H)-one 
       [0110]      1 H NMR (300 MHz, DMSO-d 8 ) δ ppm 12.24 (bs, 1H); 8.10 (d, 1H); 7.90 (d, 1H); 7.80 (t, 1H); 7.65 (d, 1H); 7.47 (t, 1H); 7.03 (d, 1H); 7.00 (bs, 2H) 3.85 (s, 6H); 3.71 (s, 3H). LC-MS (ESI): m/z (M+H) +  339, Rt: 3.30 min. 
       2-[(E)-2-(4-isopropylphenyl)vinyl]quinazolin-4(3H)-one 
       [0111]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.32 (bs, 1H); 8.10 (d, 1H); 7.93 (d, 1H); 7.80 (t, 1H); 7.67 (d, 1H); 7.59 (d, 2H); 7.47 (t, 1H); 7.34 (d, 2H); 7.00 (d, 1H); 2.90 (m, 1H); 1.23 (d, 6H). LC-MS (ESI): m/z (M+H) +  291, Rt: 4.31 min. 
       2-{(E)-2-[4-(methylsulfonyl)phenyl]vinyl}quinazolin-4(3H)-one 
       [0112]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.42 (bs, 1H); 8.15 (d, 1H); 8.14-7.13 (m, 5H); 7.83 (t, 1H); 7.71 (d, 1H); 7.52 (t, 1H); 7.19 (d, 1H); 3.26 (s, 3H). LC-MS (ESI): m/z (M+H) +  327, Rt: 2.96 min. 
       2-[(E)-2-(2-thienyl)vinyl]quinazolin-4(3H)-one 
       [0113]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.30 (bs, 1H); 8.12 (d, 1H); 8.10 (s, 1H); 7.79 (t, 1H); 7.66 (m, 2H); 7.46 (m, 2H); 7.16 (bs, 1H); 6.78 (d, 1H). LC-MS (ESI): m/z (M+H) +  255, Rt: 3.36 min. 
       6-chloro-2-[(E)-2-(2-thienyl)vinyl]quinazolin-4(3H)-one 
       [0114]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.40 (bs, 1H); 8.12 (d, 1H); 8.02 (s, 1H); 7.81 (d, 1H); 7.68 (m, 2H); 7.49 (bs, 1H); 7.16 (bs, 1H); 6.72 (d, 1H). LC-MS (ESI): m/z (M+H) +  289, Rt: 3.99 min. 
       6-bromo-2-[(E)-2-(2-thienyl)vinyl]quinazolin-4(3H)-one 
       [0115]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.41 (bs, 1H); 8.13 (d, 1H); 8.15 (s, 1H); 7.92 (d, 1H); 7.70 (d, 1H); 7.59 (d, 1H); 7.49 (d, 1H); 7.16 (dd, 1H); 6.72 (d, 1H). LC-MS (ESI): m/z (M+H) +  333, Rt: 4.08 min. 
       2-[(E)-2-(2-thienyl)vinyl]benzo[g]quinazolin-4(3H)-one 
       [0116]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 12.06 (bs, 1H); 8.80 (s, 1H); 8.14 (m, 4H); 7.67 (m, 2H); 7.56 (t, 1H); 7.50 (bs, 1H); 7.16 (t, 1H); 6.77 (d, 1H). LC-MS (ESI): m/z (M+H) +  305, Rt: 4.04 min. 
       Step C: Preparation of substituted 4-chloro-2-[(E)-2-phenylvinyl]quinazoline and 4-chloro-2-[(E)-2-(2-thienyl)vinyl]quinazoline 
       [0117]    
       
                 
         
             
             
         
       
     
         [0118]    The starting material was dissolved in phosphorous oxychloride and stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and the phosphorous oxychloride was evaporated. The crude product was dissolved in chloroform, washed with cold water and with 10% sodium hydrogen carbonate solution. The organic layer was stirred over magnesium sulfate 1 hour, was evaporated and dried under vacuum. Due to the instability of the intermediates the purity was checked only by TLC. 
       Step D: Preparation of substituted 2-[(E)-2-phenylvinyl]quinazolin-4-amines and 2-[(E)-2-(2-thienyl)vinyl]quinazolin-4-amine 
       [0119]    
       
                 
         
             
             
         
       
     
       N′-{6-chloro-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazolin-4-yl}-N,N-dimethylpropane-1,3-diamine 
       [0120]    0.87 g (2.62 mmol) 4,6-dichloro-2-[(E)-2-(4-methoxyphenyl)vinyl]quinazoline was solved in 10 ml abs. dioxane. 0.45 ml (2.62 mmol) diisopropyl-ethylamine and 0.36 ml (2.88 mmol) N,N-dimethylpropane-1,3-diamine were given to this solution. The reaction was stirred 12 hours under Argon atmosphere at 80° C. The solvent was evaporated under vacuum, and the product was purified by column chromatography or preparative TLC. The product was prepared as oxalate salt. 
         [0121]    Preparation of other 2-[(E)-2-phenylvinyl]quinazolin-4-amines and 2-[(E)-2-(2-thienyl)vinyl]quinazolin-4-amine derivatives were carried out with the same method. 
         [0122]    Yield: 0.35 g (27%) 
         [0123]      1 H NMR (300 MHz, DMSO-d 6 ) δ ppm. LC-MS (ESI): m/z (M+H) +  397, Rt: 0.46 min., 1.95 min., 2.13 min. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Identification of the prepared compounds. 
               
             
          
           
               
                 Ex- 
                   
                   
                   
                   
               
               
                 am- 
                   
                   
                   
                   
               
               
                 ple 
                 Structure 
                 Name 
                 Formula 
                 Salt 
               
               
                   
               
               
                  1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C22H25ClN4O 
                 Oxalate 
               
               
                   
               
               
                  2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]-N-(3- morpholin-4-ylpropyl)quinazolin-4- amine 
                 C24H27ClN4O2 
                   
               
               
                   
               
               
                  3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C24H29ClN4O 
                 HCl 
               
               
                   
               
               
                  4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-fluoro-2-[(E)-2-(4- methoxyphenyl)vinyl]-N-(3- morpholin-4-ylpropyl)quinazolin-4- amine 
                 C24H27FN4O2 
                   
               
               
                   
               
               
                  5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{6-fluoro-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C24H29FN4O 
                   
               
               
                   
               
               
                  6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C22H25FN4O 
                   
               
               
                   
               
               
                  7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C22H25BrN4O 
                 Oxalate 
               
               
                   
               
               
                  8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]-N-(3- morpholin-4-ylpropyl)quinazolin-4- amine 
                 C24H27BrN4O2 
                   
               
               
                   
               
               
                  9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- methoxyphenyl)vinyl]-7- nitroquinazolin-4-yl}-N,N- dimethylpropane-1,3-diamine 
                 C22H25N5O3 
                   
               
               
                   
               
               
                  10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- methoxyphenyl)vinyl]-7- nitroquinazolin-4-yl}propane-1,3- diamine 
                 C24H29N5O3 
                   
               
               
                   
               
               
                  11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C24H29BrN4O 
                   
               
               
                   
               
               
                  12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C22H26N4O 
                 Fum- arate 
               
               
                   
               
               
                  13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-methoxyphenyl)vinyl]-N- (3-morpholin-4-ylpropyl)quinazolin- 4-amine 
                 C24H28N4O2 
                 Oxalate 
               
               
                   
               
               
                  14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-methoxyphenyl)vinyl]-N- (3-morpholin-4-ylpropyl)-7- nitroquinazolin-4-amine 
                 C24H27N5O4 
                 Oxalate 
               
               
                   
               
               
                  15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H22BrFN4 
                   
               
               
                   
               
               
                  16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H23FN4 
                   
               
               
                   
               
               
                  17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C23H27FN4 
                   
               
               
                   
               
               
                  18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-diethylpropane-1,3-diamine 
                 C23H26BrFN4 
                   
               
               
                   
               
               
                  19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-fluorophenyl)vinyl]-N-(3- morpholin-4-ylpropyl)quinazolin-4- amine 
                 C23H25FN4O 
                 Oxalate 
               
               
                   
               
               
                  20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H22ClFN4 
                 Fum- arate 
               
               
                   
               
               
                  21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-diethylpropane-1,3-diamine 
                 C23H26ClFN4 
                   
               
               
                   
               
               
                  22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-fluoro-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H22F2N4 
                   
               
               
                   
               
               
                  23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{6-fluoro-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C23H26F2N4 
                 HCl 
               
               
                   
               
               
                  24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-bromo-2-[(E)-2-(4- fluorophenyl)vinyl]-N-(3-morpholin- 4-ylpropyl)quinazolin-4-amine 
                 C23H24BrFN4O 
                   
               
               
                   
               
               
                  25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-fluoro-2-[(E)-2-(4- fluorophenyl)vinyl]-N-(3-morpholin- 4-ylpropyl)quinazolin-4-amine 
                 C23H24F2N4O 
                   
               
               
                   
               
               
                  26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]-N-(3-morpholin- 4-ylpropyl)quinazolin-4-amine 
                 C23H24ClFN4O 
                   
               
               
                   
               
               
                  27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4-fluorophenyl)vinyl]-7- nitroquinazolin-4-yl}-N,N- dimethylpropane-1,3-diamine 
                 C21H22FN5O2 
                   
               
               
                   
               
               
                  28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-methoxyphenyl)vinyl]-N- [3-(4-methylpiperazin-1- yl)propyl]quinazolin-4-amine 
                 C25H31N5O 
                 Oxalate 
               
               
                   
               
               
                  29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- fluorophenyl)vinyl]-6,7- dimethoxyquinazolin-4-yl}propane- 1,3-diamine 
                 C25H31FN4O2 
                 Oxalate 
               
               
                   
               
               
                  30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4-fluorophenyl)vinyl]- 6,7-dimethoxyquinazolin-4-yl}-N,N- dimethylpropane-1,3-diamine 
                 C23H27FN4O2 
                 Oxalate 
               
               
                   
               
               
                  31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- fluorophenyl)vinyl]-7- nitroquinazolin-4-yl}propane-1,3- diamine 
                 C23H26FN5O2 
                 Oxalate 
               
               
                   
               
               
                  32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- chlorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-diethylpropane-1,3- diamine 
                 C27H29ClN4 
                 Oxalate 
               
               
                   
               
               
                  33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- chlorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-dimethylpropane-1,3- diamine 
                 C25H25ClN4 
                 Oxalate 
               
               
                   
               
               
                  34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6,7-dimethoxy-2-[(E)-2-(4- methoxphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C24H30N4O3 
                 Citrate 
               
               
                   
               
               
                  35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6,7-dimethoxy-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C26H34N4O3 
                 Citrate 
               
               
                   
               
               
                  36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- methoxyphenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-dimethylpropane- 1,3-diamine 
                 C26H28N4O 
                 Citrate 
               
               
                   
               
               
                  37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- methoxyphenyl)vinyl]benzo[g]quinazolin- 4-yl}propane-1,3-diamine 
                 C28H32N4O 
                 Citrate 
               
               
                   
               
               
                  38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-methoxyphenyl)vinyl]-N- (3-morpholin-4- ylpropyl)benzo[g]quinazolin-4- amine 
                 C28H30N4O2 
                 Citrate 
               
               
                   
               
               
                  39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- fluorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-dimethylpropane-1,3- diamine 
                 C25H25FN4 
                 Fum- arate 
               
               
                   
               
               
                  40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- fluorophenyl)vinyl]benzo[g]quinazolin- 4-yl}propane-1,3-diamine 
                 C27H29FN4 
                 Citrate 
               
               
                   
               
               
                  41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-fluorophenyl)vinyl]-N-(3- morpholin-4- ylpropyl)benzo[g]quinazolin-4- amine 
                 C27H27FN4O 
                 Oxalate 
               
               
                   
               
               
                  42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-fluorophenyl)vinyl]-6,7- dimethoxy-N-(3-morpholin-4- ylpropyl)quinazolin-4-amine 
                 C25H29FN4O3 
                   
               
               
                   
               
               
                  43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(4-fluorophenyl)vinyl]-N-[3- (4-methylpiperazin-1-yl)propyl]-7- nitroquinazolin-4-amine 
                 C24H27FN6O2 
                   
               
               
                   
               
               
                  44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{7-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C22H25ClN4O 
                   
               
               
                   
               
               
                  45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{7-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3-diamine 
                 C24H29ClN4O 
                   
               
               
                   
               
               
                  46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]-N-(3- morpholin-4-ylpropyl)quinazolin-4- amine 
                 C24H27ClN4O2 
                   
               
               
                   
               
               
                  47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7-chloro-2-[(E)-2-(4- methoxyphenyl)vinyl]-N-[3-(4- methylpiperazin-1- yl)propyl]quinazolin-4-amine 
                 C25H30ClN5O 
                   
               
               
                   
               
               
                  48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{7-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H22ClFN4 
                   
               
               
                   
               
               
                  49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{7-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-diethylpropane-1,3-diamine 
                 C23H26ClFN4 
                   
               
               
                   
               
               
                  50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]-N-(3-morpholin- 4-ylpropyl)quinazolin-4-amine 
                 C23H24ClFN4O 
                   
               
               
                   
               
               
                  51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 7-chloro-2-[(E)-2-(4- fluorophenyl)vinyl]-N-[3-(4- methylpiperazin-1- yl)propyl]quinazolin-4-amine 
                 C24H27ClFN5 
                   
               
               
                   
               
               
                  52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(7-chloro-2-{(E)-2-[4- (dimethylamino)phenyl]vinyl}quinazolin- 4-yl)-N,N-diethylpropane-1,3- diamine 
                 C25H32ClN5 
                   
               
               
                   
               
               
                  53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-{2-[(E)-2-(3,4,5- trimethoxyphenyl)vinyl]quinazolin- 4-yl}propane-1,3-diamine 
                 C24H30N4O3 
                   
               
               
                   
               
               
                  54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-(3-morpholin-4-ylpropyl)-2-[(E)-2- (3,4,5- trimethoxyphenyl)vinyl]quinazolin- 4-amine 
                 C26H32N4O4 
                 Citrate 
               
               
                   
               
               
                  55 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C21H21BrF2N4 
                   
               
               
                   
               
               
                  56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C23H25BrF2N4 
                   
               
               
                   
               
               
                  57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-dimethylethane-1,2-diamine 
                 C20H19BrF2N4 
                   
               
               
                   
               
               
                  58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-diethylethane-1,2-diamine 
                 C22H23BrF2N4 
                   
               
               
                   
               
               
                  59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6- fluoroquinazolin-4-yl}-N,N- dimethylpropane-1,3-diamine 
                 C21H21F3N4 
                   
               
               
                   
               
               
                  60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6- fluoroquinazolin-4-yl}-N,N- diethylpropane-1,3-diamine 
                 C23H25F3N4 
                   
               
               
                   
               
               
                  61 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6- fluoroquinazolin-4-yl}-N,N- dimethylethane-1,2-diamine 
                 C20H19F3N4 
                   
               
               
                   
               
               
                  62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6- fluoroquinazolin-4-yl}-N,N- diethylethane-1,2-diamine 
                 C22H23F3N4 
                   
               
               
                   
               
               
                  63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N4-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6- fluoroquinazolin-4-yl}-N1,N1- diethylpentane-1,4-diamine 
                 C25H29F3N4 
                   
               
               
                   
               
               
                  64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6,8-dibromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H21Br2FN4 
                   
               
               
                   
               
               
                  65 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6,8-dibromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-diethylpropane-1,3-diamine 
                 C23H25Br2FN4 
                   
               
               
                   
               
               
                  66 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6,8-dibromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylethane-1,2-diamine 
                 C20H19Br2FN4 
                   
               
               
                   
               
               
                  67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6,8-dibromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-diethylethane-1,2-diamine 
                 C22H23Br2FN4 
                   
               
               
                   
               
               
                  68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylethane-1,2-diamine 
                 C20H21FN4 
                   
               
               
                   
               
               
                  69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4- yl}ethane-1,2-diamine 
                 C22H25FN4 
                   
               
               
                   
               
               
                  70 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N1,N1-diethyl-N4-{2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4- yl}pentane-1,4-diamine 
                 C25H31FN4 
                   
               
               
                   
               
               
                  71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3- fluorophenyl)vinyl]quinazolin-4-yl}- N,N-dimethylpropane-1,3-diamine 
                 C21H23FN4 
                   
               
               
                   
               
               
                  72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(3- fluorophenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C23H27FN4 
                 HCl 
               
               
                   
               
               
                  73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N4-{6,8-dibromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4-yl}- N1,N1-diethylpentane-1,4-diamine 
                 C25H29Br2FN4 
                 HCl 
               
               
                   
               
               
                  74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 tert-butyl [3-({6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}amino)propyl]carbamate 
                 C25H29BrN4O3 
                   
               
               
                   
               
               
                  75 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-{6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C20H21BrN4O 
                 TFA 
               
               
                   
               
               
                  76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-[3-({6-bromo-2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}amino)propyl]acetamide 
                 C22H23BrN4O2 
                   
               
               
                   
               
               
                  77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-(2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)ethane-1,2-diamine 
                 C23H28N4S 
                 TFA 
               
               
                   
               
               
                  78 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-(2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)propane-1,3-diamine 
                 C22H26N4S 
                 Oxalate 
               
               
                   
               
               
                  79 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C21H21ClF2N4 
                 Oxalate 
               
               
                   
               
               
                  80 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C23H25ClF2N4 
                   
               
               
                   
               
               
                  81 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-dimethylethane-1,2-diamine 
                 C20H19ClF2N4 
                 Oxalate 
               
               
                   
               
               
                  82 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-{2-[(E)-2-(2- thienyl)vinyl]benzo[g]quinazolin-4- yl}propane-1,3-diamine 
                 C23H24N4S 
                   
               
               
                   
               
               
                  83 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-{2-[(E)-2-(4- methoxyphenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C20H22N4O 
                 Oxalate 
               
               
                   
               
               
                  84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(2- thienyl)vinyl]benzo[g]quinazolin-4- yl}propane-1,3-diamine 
                 C25H28N4S 
                 Fum- arate 
               
               
                   
               
               
                  85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-{2-[(E)-2-(2- thienyl)vinyl]benzo[g]quinazolin-4- yl}ethane-1,2-diamine 
                 C22H22N4S 
                 Fum- arate 
               
               
                   
               
               
                  86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-diethylethane-1,2-diamine 
                 C22H23ClF2N4 
                 Oxalate 
               
               
                   
               
               
                  87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N-{6,8-dibromo-2-[(E)-2-(4- fluorophenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C19H17Br2FN4 
                 TFA 
               
               
                   
               
               
                  88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-(2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)ethane-1,2-diamine 
                 C21H24N4S 
                 Fum- arate 
               
               
                   
               
               
                  89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C21H22F2N4 
                   
               
               
                   
               
               
                  90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]-4-(1,4-dioxa-8- azaspiro[4.5]dec-8-yl)quinazoline 
                 C23H20ClF2N3O2 
                   
               
               
                   
               
               
                  91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C23H26F2N4 
                   
               
               
                   
               
               
                  92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-dimethylethane-1,2-diamine 
                 C20H20F2N4 
                   
               
               
                   
               
               
                  93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]quinazolin-4- yl}-N,N-diethylethane-1,2-diamine 
                 C22H24F2N4 
                   
               
               
                   
               
               
                  94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-dimethylpropane-1,3- diamine 
                 C25H24F2N4 
                   
               
               
                   
               
               
                  95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-diethylpropane-1,3- diamine 
                 C27H28F2N4 
                   
               
               
                   
               
               
                  96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-dimethylethane-1,2- diamine 
                 C24H22F2N4 
                   
               
               
                   
               
               
                  97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]benzo[g]quinazolin- 4-yl}-N,N-diethylethane-1,2- diamine 
                 C26H26F2N4 
                   
               
               
                   
               
               
                  98 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C24H30N4 
                 Fum- arate 
               
               
                   
               
               
                  99 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C26H34N4 
                 Fum- arate 
               
               
                   
               
               
                 100 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylethane-1,2-diamine 
                 C23H28N4 
                 Fum- arate 
               
               
                   
               
               
                 101 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(2- thienyl)quinazolin-4-yl]-N,N- dimethylpropane-1,3-diamine} 
                 C19H21ClN4S 
                   
               
               
                   
               
               
                 102 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(2- thienyl)vinyl]quinazolin-4-yl}-N,N- diethylpropane-1,3-diamine 
                 C21H25ClN4S 
                   
               
               
                   
               
               
                 103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(2- thienyl)vinyl]quinazolin-4-yl}-N,N- dimethylethane-1,2-diamine 
                 C18H19ClN4S 
                   
               
               
                   
               
               
                 104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(2- thienyl)vinyl]quinazolin-4-yl}-N,N- diethylethane-1,2-diamine 
                 C20H23ClN4S 
                   
               
               
                   
               
               
                 105 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-{2-[(E)-2-(2- thienyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C19H22N4S 
                 Fum- arate 
               
               
                   
               
               
                 106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{2-[(E)-2-(2- thienyl)vinyl]quinazolin-4- yl}propane-1,3-diamine 
                 C21H26N4S 
                 Fum- arate 
               
               
                   
               
               
                 107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-bromo-2-[(E)-2-(2- thienyl)vinyl]quinazolin-4-yl}-N,N- dimethylpropane-1,3-diamine 
                 C19H21BrN4S 
                   
               
               
                   
               
               
                 108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-{2-[(E)-2-(2- thienyl)vinyl]quinazolin-4-yl)ethane- 1,2-diamine} 
                 C18H20N4S 
                 Fum- arate 
               
               
                   
               
               
                 109 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)-N,N-dimethylpropane-1,3- diamine 
                 C22H25ClN4S 
                 Fum- arate 
               
               
                   
               
               
                 110 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)-N,N-diethylpropane-1,3- diamine 
                 C24H29ClN4S 
                 Fum- arate 
               
               
                   
               
               
                 111 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)-N,N-diethylethane-1,2-diamine 
                 C23H27ClN4S 
                 Fum- arate 
               
               
                   
               
               
                 112 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylthio)phenyl]vinyl}quinazolin- 4-yl)-N,N-dimethylethane-1,2- diamine 
                 C21H23ClN4S 
                 Fum- arate 
               
               
                   
               
               
                 113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]-4-[(2S)-2- (pyrrolidin-1-ylmethyl)pyrrolidin-1- yl]quinazoline 
                 C25H25ClF2N4 
                   
               
               
                   
               
               
                 114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6,7- dimethoxyquinazolin-4-yl}-N,N- dimethylpropane-1,3-diamine 
                 C23H26F2N4O2 
                 Fum- arate 
               
               
                   
               
               
                 115 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6,7- dimethoxyquinazolin-4-yl}-N,N- diethylpropane-1,3-diamine 
                 C25H30F2N4O2 
                   
               
               
                   
               
               
                 116 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6,7- dimethoxyquinazolin-4-yl}-N,N- dimethylethane-1,2-diamine 
                 C22H24F2N4O2 
                   
               
               
                   
               
               
                 117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{2-[(E)-2-(3,4- difluorophenyl)vinyl]-6,7- dimethoxyquinazolin-4-yl}-N,N- diethylamine-1,2-diamine 
                 C24H28F2N4O2 
                   
               
               
                   
               
               
                 118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-[(E)-2-(3,4-difluorophenyl)vinyl]- 6,7-dimethoxy-N-propylquinazolin- 4-amine 
                 C21H21F2N3O2 
                   
               
               
                   
               
               
                 119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-(2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}quinazolin- 4-yl)propane-1,3-diamine 
                 C22H26N4O2S 
                   
               
               
                   
               
               
                 120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 6-chloro-2-[(E)-2-(3,4- difluorophenyl)vinyl]-4-[(2R)-2- (pyrrolidin-1-ylmethyl)pyrrolidin-1- yl]quinazoline 
                 C25H25ClF2N4 
                   
               
               
                   
               
               
                 121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-dimethyl-N′-(2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}quinazolin- 4-yl)ethane-1,2-diamine 
                 C21H24N4O2S 
                   
               
               
                   
               
               
                 122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}-N- propylquinazolin-4-amine 
                 C20H21N3O2S 
                   
               
               
                   
               
               
                 123 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C24H29ClN4 
                 Fum- arate 
               
               
                   
               
               
                 124 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-diethylpropane-1,3-diamine 
                 C26H33ClN4 
                 Fum- arate 
               
               
                   
               
               
                 125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylethane-1,2-diamine 
                 C23H27ClN4 
                 Fum- arate 
               
               
                   
               
               
                 126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-chloro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-diethylethane-1,2-diamine 
                 C25H31ClN4 
                 Fum- arate 
               
               
                   
               
               
                 127 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-fluoro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylpropane-1,3- diamine 
                 C24H29FN4 
                 Fum- arate 
               
               
                   
               
               
                 128 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-{6-fluoro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}-N,N-dimethylethane-1,2-diamine 
                 C23H27FN4 
                 Fum- arate 
               
               
                   
               
               
                 129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N,N-diethyl-N′-{6-fluoro-2-[(E)-2-(4- isopropylphenyl)vinyl]quinazolin-4- yl}ethane-1,2-diamine 
                 C25H31FN4 
                 Fum- arate 
               
               
                   
               
               
                 130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}quinazolin- 4-yl)-N,N-dimethylpropane-1,3- diamine 
                 C22H25ClN4O2S 
                   
               
               
                   
               
               
                 131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}quinazolin- 4-yl)-N,N-diethylpropane-1,3- diamine 
                 C24H29ClN4O2S 
                 Fum- arate 
               
               
                   
               
               
                 132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}quinazolin- 4-yl)-N,N-dimethylethane-1,2- diamine 
                 C21H23ClN4O2S 
                   
               
               
                   
               
               
                 133 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 N′-(6-chloro-2-{(E)-2-[4- (methylsulfonyl)phenyl]vinyl}quinazolin- 4-yl)-N,N-diethylethane-1,2- diamine 
                 C23H27ClN4O2S 
                 Fum- arate 
               
               
                   
               
             
          
         
       
     
       Analytical Characterization 
       [0124]    All of the prepared compounds were characterized by two independent analytical method. 
       NMR 
       [0125]    The 300 MHz  1 H-NMR analysis was performed with an apparatus of type Bruker AVANCE-300 at 25° C., exact frequency was 300.14 MHz. Generally DMSO-d 6  was used as solvent, exceptions given. Chemical shifts are given in parts per million (6) referenced to TMS (6=0.00 ppm). 
       LCMS 
       [0126]    The LCMS analysis was performed with a liquid chromatography mass-spectrometer Waters chromatograph with the following parameters: 
       Waters HPLC/MS: 
       [0127]    MS detector. Waters SQD 
         [0128]    UV detector: Waters 996 DAD 
         [0129]    Separation module: Waters Alliance 2795 
       HPLC: 
       [0130]    Column: Waters XBridge C18, 50 mm×4.6 mm, 3.5 μm 
         [0131]    Solvent I: Water/0.1% HCOOH 
         [0132]    Solvent II: AcCN 
         [0133]    Acetonitrile: Riedel-deHaën; G Chromesolv (34998) 
         [0134]    Water: Mili-Q Academic 
         [0135]    Formic acid: Riedel-deHaën; extra pure (27001) 
         [0136]    Flow rate: 2 ml/min 
         [0137]    Injection: 5 μg 
       Gradient: 
       [0138]      
         [0000]                                    time   Solv. I.   Solv. II.                   0.00 min   95%   5%       0.50 min   95%   5%       5.50 min    5%   95%        6.00 min    5%   95%        6.50 min   95%   5%       7.00 min   95%   5%                    
MS: Ionization: ES + /ES − 
 
         [0139]    Source block temperature: 110° C. 
         [0140]    Desolvation temperature: 250° C. 
         [0141]    Desolvation gas: 500 L/h 
         [0142]    Cone gas: 80 L/h 
         [0143]    Capillary voltage: 3000 V 
         [0144]    Cone voltage: 30 V 
         [0145]    Extractor voltage: 6 V 
         [0146]    Rf lens voltage: 0.1 V 
         [0147]    Scan: 80 to 1000 m/z in 1 sec. 
         [0148]    Inter-scan delay: 0.1 s 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 The analytical data of the prepared compounds 
               
             
          
           
               
                   
                   
                   
                 MW 
                 MW 
                 MW 
                   
               
               
                   
                   
                   
                 calculated, 
                 measured 
                 measured 
               
               
                 Example 
                   1 H-NMR 
                 Rt [min] 
                 monoisotopic 
                 [−] 
                 [+] 
                 Purity % 
               
               
                   
               
             
          
           
               
                 1 
                 8.46(bs, NH); 8.35(s, 1H); 7.91(d, 1H); 7.77(d, 
                 0.46; 1.95; 2.13 
                 396 
                 395 
                 397 
                 99 
               
               
                   
                 1H); 7.70-7.66(m, 3H); 7.04-6.98(m, 3H); 3.81(s, 
               
               
                   
                 3H); 2.73-2.71(m, 2H); 3.21-3.18(m, 2H); 2.79(s, 
               
               
                   
                 6H); 2.1-2.07(m, 2H) 
               
               
                 2 
                 8.25(s, 1H); 7.85(d, 1H); 7.72(d, 1H); 7.66-7.62(m, 
                 0.45; 2.04; 2.30 
                 438 
                 437 
                 439 
                 98 
               
               
                   
                 3H); 7.00-6.95(m, 3H); 3.8(s, 3H); 3.70-3.63(m, 
               
               
                   
                 2H); 3.58(1, 4H); 2.45-2.39(m, 6H); 1.91-1.82(m, 
               
               
                   
                 2H) 
               
               
                 3 
                 8.48(bs, NH); 8.41(s, 1H); 7.91(d, 1H); 7.75- 
                 0.48; 2.18; 2.36 
                 424 
                 423 
                 425 
                 99 
               
               
                   
                 7.68(m, 4H); 7.02-6.97(m, 3H); 3.8(s, 3H); 3.74- 
               
               
                   
                 3.72(m, 2H); 3.18-3.1(m, 6H); 2.12-2.10(m, 2H); 
               
               
                   
                 1.2(t, 6H) 
               
               
                 4 
                 8.11(bs, NH); 8.05(d, 1H); 7.84(d, 1H); 7.74- 
                 0.45; 1.93; 2.25 
                 422 
                 421 
                 423 
                 98 
               
               
                   
                 7.69(m, 1H); 7.61-7.59(m, 3H); 7.00-6.95(m, 3H); 
               
               
                   
                 3.8(s, 3H); 3.70-3.64(m, 2H); 3.59-3.56(m, 4H); 
               
               
                   
                 2.45-2.39(m, 6H); 1.91-1.82(m, 2H) 
               
               
                 5 
                 8.28(bs, NH); 8.08(d, 1H); 7.87(d, 1H); 7.75- 
                 0.47; 2.05; 2.30 
                 408 
                 407 
                 409 
                 100 
               
               
                   
                 7.70(m, 1H); 7.66-7.57(m, 3H); 7.02-6.96(m, 3H); 
               
               
                   
                 3.80(s, 3H); 3.70-3.68(m, 2H); 3.42-3.35(m, 6H); 
               
               
                   
                 1.98-1.91(m, 2H); 1.11-1.07(m, 6H) 
               
               
                 6 
                 8.16(bs, NH); 8.03(d, 1H); 7.85(d, 1H); 7.74- 
                 0.48; 1.98; 2.21 
                 380 
                 379 
                 381 
                 99 
               
               
                   
                 7.69(m, 1H); 7.65-7.57(m, 3H); 7.10-6.95(m, 3H); 
               
               
                   
                 3.8(s, 3H); 3.68-3.61(m, 2H); 2.41-2.36(m, 2H); 
               
               
                   
                 2.2(s, 6H); 1.89-1.80(m, 2H) 
               
               
                 7 
                 8.48(s, 1H); 8.32(bs, 1H); 7.9-7.82(m, 2H); 7.65- 
                 0.46; 1.96; 2.36 
                 440 
                 439 
                 441 
                 100 
               
               
                   
                 7.57(m, 3H); 7.00-6.95(m, 3H); 3.8(s, 3H); 3.68- 
               
               
                   
                 3.64(m, 2H); 2.28(s, 6H); 1.92-1.85(m, 2H) 
               
               
                 8 
                 8.48(s, 1H); 8.27(t, 1H); 7.84(m, 2H); 7.60(m, 3H); 
                 0.45; 2.12; 2.37 
                 482 
                 481 
                 482 
                 98 
               
               
                   
                 6.97(m, 3H); 3.80(s, 3H); 3.65(m, 2H); 3.59(bs, 4H); 
               
               
                   
                 2.41(m, 6H); 1.87(m, 2H) 
               
               
                 9 
                 8.66(bs, 1H); 8.41(d, 1H); 8.34(d, 1H); 8.15(dd, 1H); 
                 0.45; 2.20; 2.38 
                 407 
                 406 
                 408 
                 99 
               
               
                   
                 7.93(d, 1H); 7.66(d.2H); 7.01(m, 3H); 3.81(s, 3H); 
               
               
                   
                 3.67(q, 2H); 2.41(t, 2H); 2.22(s, 6H); 1.86(m, 2H) 
               
               
                 10 
                 10.10(bs, 1H); 8.84(t, 1H); 8.53(d, 1H); 8.36(d, 1H); 
                 0.44; 2.29; 2.49 
                 435 
                 434 
                 436 
                 99 
               
               
                   
                 8.17(dd, 1H); 7.98(d, 1H); 7.70(d, 2H); 7.01(m, 3H); 
               
               
                   
                 3.81(s, 3H); 3.17(m, 2H); 3.10(bs, 4H); 2.12(bs, 2H); 
               
               
                   
                 1.20(t, 6H) 
               
               
                 11 
                 8.49(s, 1H); 8.41(t, 1H); 7.88(m, 2H); 7.62(m, 3H); 
                 0.45; 2.26; 2.45 
                 468 
                 467 
                 469 
                 99 
               
               
                   
                 6.99(m, 3H); 3.80(s, 3H); 3.68(q, 2H); 2.90(bs, 6H); 
               
               
                   
                 1.98(bs, 2H); 1.11(bs, 6H) 
               
               
                 12 
                 8.30(bs, 1H); 8.90(d, 1H); 7.87(d, 1H); 7.72(t, 1H); 
                 0.45; 2.19 
                 362 
                 361 
                 363 
                 100 
               
               
                   
                 7.65(m, 3H); 7.43(t, 1H); 7.00(m, 3H); 6.57(s, 3H); 
               
               
                   
                 3.80(s, 3H); 3.69(q, 2H); 2.84(t, 2H); 2.50(s, 6H); 
               
               
                   
                 1.99(m, 2H) 
               
               
                 13 
                 8.66(bs, 1H); 8.24(d, 1H); 7.96(d, 1H); 7.79(t, 1H); 
                 0.46; 2.03; 2.21 
                 404 
                 403 
                 405 
                 97 
               
               
                   
                 7.69(m, 3H); 7.51(t, 1H); 7.03(m, 3H); 3.81(s, 3H); 
               
               
                   
                 3.73(bs, 6H); 2.95(bs, 6H); 2.05(m, 2H) 
               
               
                 14 
                 8.69(bs, 1H); 8.48(bs, 1H); 8.36(bs, 1H); 
                 0.45; 2.17; 2.40 
                 449 
                 448 
                 450 
                 99 
               
               
                   
                 8.18(bs, 1H); 7.69(m, 2H); 7.00(m, 4H); 3.80(s, 3H); 
               
               
                   
                 3.75(bs, 6H); 3.05(bs, 6H); 2.07(bs, 2H) 
               
               
                 15 
                 8.50(d, 1H); 8.39(t, 1H); 7.87(m, 2H); 7.77(m, 2H); 
                 0.45; 2.17; 2.33 
                 428 
                 427 
                 429 
                 99 
               
               
                   
                 7.61(d, 1H); 7.25(t, 2H); 7.08(d, 1H); 3.87(q, 2H); 
               
               
                   
                 2.65(m, 2H); 2.39(s, 6H); 1.92(m, 2H) 
               
               
                 16 
                 8.29(t, 1H); 8.16(d, 1H); 7.89(d, 1H); 7.73(m, 4H); 
                 0.46; 2.19 
                 350 
                 349 
                 351 
                 99 
               
               
                   
                 7.45(t, 1H); 7.25(t, 2H); 7.09(d, 1H); 3.66(q, 2H); 
               
               
                   
                 2.43(t, 2H); 2.23(6H); 1.86(m, 2H) 
               
               
                 17 
                 8.36(s, 1H); 8.30(s, 1H); 7.89(d, 1H); 7.75(m, 3H); 
                 0.45; 1.97; 2.28 
                 378 
                 377 
                 379 
                 99 
               
               
                   
                 7.67(d, 1H); 7.25(m, 2H); 7.08(d, 1H); 3.66(m, 2H); 
               
               
                   
                 3.57(m, 4H); 2.38(bs, 6H); 1.86(m, 2H) 
               
               
                 18 
                 8.47(s, 1H); 8.41(t, 1H); 7.87(m, 2H); 7.76(m, 2H); 
                 0.44; 2.24; 2.44 
                 456 
                 455 
                 457 
                 98 
               
               
                   
                 7.60(d, 1H); 7.25(t, 2H); 7.08(d, 1H); 3.66(q, 2H); 
               
               
                   
                 2.64(bs, 6H); 1.87(t, 2H); 1.01(t.6H) 
               
               
                 19 
                 8.54(t, 1H); 8.23(d, 1H); 7.95(d, 1H); 7.79(m, 3H); 
                 0.46; 1.93; 2.21 
                 392 
                 391 
                 393 
                 97 
               
               
                   
                 7.71(d, 1H); 7.50(t, 1H); 7.27(t, 2H); 7.14(d, 1H); 
               
               
                   
                 3.75(bs, 6H); 3.01(bs, 6H); 2.06(m, 2H) 
               
               
                 20 
                 8.37(bs, 2H); 7.91(d, 1H); 7.75(m, 3H); 7.68(d, 1H); 
                 0.46; 1.96; 2.29 
                 384 
                 383 
                 385 
                 100 
               
               
                   
                 7.25(t, 2H); 7.09(d, 1H); 6.55(s, 2H); 3.67(q, 2H); 
               
               
                   
                 2.17(t, 2H); 2.42(s, 6H); 1.95(m, 2H) 
               
               
                 21 
                 8.37(bs, 1H); 8.33(s, 1H); 7.90(d, 1H); 7.75(m, 3H); 
                 0.46; 2.21; 2.39 
                 412 
                 411 
                 413 
                 98 
               
               
                   
                 7.68(d, 1H); 7.25(t, 2H); 7.08(d, 1H); 3.65(q, 2H); 
               
               
                   
                 2.58(bs, 6H); 1.85(bs, 2H); 0.99(t, 6H) 
               
               
                 22 
                 8.24(t, 1H); 8.07(dd, 1H); 7.89(d, 1H); 7.76(m, 3H); 
                 0.45; 1.85; 2.22 
                 368 
                 367 
                 369 
                 98 
               
               
                   
                 7.65(t, 1H); 7.24(t, 2H); 7.08(d, 1H); 3.66(q, 2H); 
               
               
                   
                 2.55(t, 2H); 2.32(s, 6H); 1.91(m, 2H) 
               
               
                 23 
                 10.15(bs, 1H); 8.42(bs, 1H); 8.15(dd, 1H); 
                 0.46; 2.01; 2.29 
                 396 
                 395 
                 397 
                 100 
               
               
                   
                 7.93(d, 1H); 7.75(m, 3H); 7.67(t, 1H); 7.25(t, 2H); 
               
               
                   
                 7.10(d, 1H); 3.73(q, 2H); 3.05(bs, 6H); 2.08(bs, 2H); 
               
               
                   
                 1.18(t, 6H) 
               
               
                 24 
                 8.50(s, 1H); 8.34(t, 1H); 7.88(d, 1H); 7.83(s, 1H); 
                 0.45; 2.05; 2.37 
                 470 
                 469 
                 471 
                 99 
               
               
                   
                 7.76(t, 2H); 7.60(d, 1H); 7.25(t, 2H); 7.07(d, 1H); 
               
               
                   
                 3.66(m, 1H); 3.59(bs, 4H); 2.43(bs, 6H); 1.87(m, 2H) 
               
               
                 25 
                 8.17(t, 1H); 8.06(dd, 1H); 7.87(d, 1H); 7.74(m, 3H); 
                 0.47; 2.22 
                 410 
                 409 
                 411 
                 96 
               
               
                   
                 7.64(dt, 1H); 7.25(t, 2H); 7.08(d, 1H); 3.67(q, 2H); 
               
               
                   
                 3.57(t, 4H); 2.40(m, 6H); 1.86(m, 2H) 
               
               
                 26 
                 8.36(s, 1H); 8.30(s, 1H); 7.89(d, 1H); 7.75(m, 3H); 
                 0.58; 2.08; 2.41 
                 426 
                 425 
                 427 
                 99 
               
               
                   
                 7.67(d, 1H); 7.25(m, 2H); 7.08(d, 1H); 3.66(m, 2H); 
               
               
                   
                 3.57(m, 4H); 2.38(bs, 6H); 1.86(m, 2H) 
               
               
                 27 
                 8.73(t, 1H); 8.43(d, 1H); 8.35(s, 1H); 8.18(d, 1H); 
                 0.44; 2.24; 2.45 
                 395 
                 394 
                 396 
                 95 
               
               
                   
                 7.96(d, 1H); 7.78(t, 2H); 7.26(t, 2H); 7.12(d, 1H); 
               
               
                   
                 3.67(q, 2H); 2.47(t, 2H); 2.56(s, 6H); 1.88(m, 2H) 
               
               
                 28 
                 8.55(bs, 1H); 8.29(d, 1H); 8.14(d, 1H); 7.93(t, 1H); 
                 0.46; 1.71; 2.13 
                 417 
                 416 
                 418 
                 100 
               
               
                   
                 7.72(m, 3H); 7.64(t, 1H); 7.04(m, 3H); 3.64(bs, 2H); 
               
               
                   
                 3.04(bs, 4H); 2.76(bs, 2H); 2.66(bs, 7H); 1.94(m, 2H) 
               
               
                 29 
                 8.34(bs, 1H); 7.91(d, 1H); 7.76(bs, 2H); 7.65(s, 1H); 
                 0.46; 2.10; 2.38 
                 438 
                 437 
                 439 
                 98 
               
               
                   
                 7.27(t, 2H(; 7.16(s, 1H); 7.09(d, 1H); 3.73(bs, 2H); 
               
               
                   
                 3.21(bs, 2H); 3.13(bs, 4H); 2.08(bs, 2H); 
               
               
                   
                 1.18(bs, 6H) 
               
               
                 30 
                 8.31(bs, 1H); 7.95(d, 1H); 7.77(bs, 2H); 7.64(s, 1H); 
                 0.45; 1.98; 2.30 
                 410 
                 409 
                 411 
                 95 
               
               
                   
                 7.27(t, 2H); 7.16(s, 1H); 7.09(d, 1H); 3.91(s, 6H); 
               
               
                   
                 3.73(bs, 2H); 3.20(bs, 2H); 2.79(s, 6H); 2.07(bs, 2H) 
               
               
                 31 
                 10.(bs, 1H); 8.86(bs, 1H); 8.52(d, 1H); 8.38(s, 1H); 
                 0.45; 2.45; 2.60 
                 423 
                 422 
                 424 
                 100 
               
               
                   
                 8.20(d, 1H); 8.02(d, 1H); 7.82(bs, 2H); 7.27(t, 2H); 
               
               
                   
                 7.14(d, 1H); 3.77(bs, 2H); 3.22(bs, 2H); 8.13(bs, 4H); 
               
               
                   
                 2.11(bs, 2H); 1.19(bs, 6H) 
               
               
                 32 
                 8.97(bs, 2H); 8.28(s, 1H); 8.04(m, 3H); 7.79(d, 2H); 
                 0.44; 2.54; 2.70 
                 444 
                 443 
                 445 
                 100 
               
               
                   
                 7.59(m, 2H); 7.50(d, 2H); 7.24(d, 1H); 3.84(bs, 2H); 
               
               
                   
                 3.26(bs, 2H); 3.14(bs, 4H); 2.15(bs, 2H); 
               
               
                   
                 1.92(bs, 6H) 
               
               
                 33 
                 8.93(s, 1H); 8.83(bs, 1H); 8.28(s, 1H); 8.07(m, 2H(; 
                 0.45; 2.45; 2.62 
                 416 
                 415 
                 417 
                 100 
               
               
                   
                 7.98(d, 1H); 7.79(m, 2H); 7.59(m, 2H); 7.50(m, 2H); 
               
               
                   
                 7.23(d, 1H); 3.95(bs, 2H); 3.23(bs, 2H); 2.79(6H); 
               
               
                   
                 2.15(bs, 2H) 
               
               
                 34 
                 10.8(bs, 2H); 8.08(bs, 1H); 7.84(d, 1H); 7.63(m, 3H); 
                 0.45; 2.08; 2.35 
                 422 
                 421 
                 423 
                 99 
               
               
                   
                 7.10(s, 1H); 6.98(m, 3H); 3.90(s, 6H); 3.80(s, 3H); 
               
               
                   
                 3.59(bs, 2H); 3.15(bs, 2H); 2.76(s, 6H); 2.59(m, 6H); 
               
               
                   
                 2.07(bs, 2H) 
               
               
                 35 
                 11.8(bs, 3H); 8.05(bs, 1H); 7.83(d, 1H); 7.62(m, 3H); 
                 0.46; 2.28; 2.43 
                 450 
                 449 
                 451 
                 100 
               
               
                   
                 7.10(s, 1H); 6.95(m, 3H); 3.90(s, 6H); 3.80(s, 3H); 
               
               
                   
                 3.45(bs, 2H); 3.25(bs, 4H); 2.59(m, 4H); 1.18(bs.6H) 
               
               
                 36 
                 11, (bs, 2H); 8.86(s, 1H); 8.69(bs, 1H); 8.24(s, 1H); 
                 0.46; 2.42; 2.57 
                 412 
                 411 
                 413 
                 97 
               
               
                   
                 7.97(m, 3H); 7.69(bs, 2H); 7.59(m, 2H); 7.05(m, 3H); 
               
               
                   
                 3.81(s, 3H); 3.52(bs, 2H); 3.17(bs, 2H); 2.76(s, 6H); 
               
               
                   
                 2.57(m, 6H); 2.12(bs, 2H) 
               
               
                 37 
                 11.(bs, 2H); 8.89(s, 1H), 8.72(bs, 1H); 8.24(s, 1H); 
                 0.45; 2.50; 2.65 
                 440 
                 439 
                 441 
                 97 
               
               
                   
                 7.99(m, 3H); 7.68(d, 2H); 7.58(m, 2H); 7.06(m, 3H); 
               
               
                   
                 3.81(s, 3H); 3.30(bs, 2H); 3.22(bs, 2H); 3.11(bs, 4H); 
               
               
                   
                 2.56(m, 4H); 2.12(bs, 2H); 1.18(bs, 6H) 
               
               
                 38 
                 8.90(s, 1H); 8.80(m, 1H); 822(s, 1H); 8.00(m, 3H); 
                 2.56 
                 454 
                 453 
                 455 
                 97 
               
               
                   
                 7.60(m, 4H); 7.01(bs, 3H); 3.81(bs, 3H); 
               
               
                   
                 3.64(bs, 4H); 2.64(m, 8H); 1.99(bs, 2H) 
               
               
                 39 
                 8.90(s, 1H); 8.73(bs, 1H); 8.25(s, 1H); 8.02(m, 3H); 
                 0.46; 2.18; 2.48 
                 400 
                 399 
                 401 
                 99 
               
               
                   
                 7.80(m, 2H); 7.57(m, 2H); 7.26(t, 2H); 7.17(d, 1H); 
               
               
                   
                 6.57(s, 3H); 3.77(q, 2H); 2.85(t, 2H); 2.50(s, 6H); 
               
               
                   
                 2.04(m, 2H) 
               
               
                 40 
                 11.(bs(2H); 8.89(s, 1H); 8.74(bs, 1H); 8.27(s, 1H); 
                 0.45; 2.45; 2.60 
                 428 
                 427 
                 429 
                 100 
               
               
                   
                 8.02(m, 3H); 7.81(bs, 2H); 7.57(m, 2H); 
               
               
                   
                 7.27(bs, 2H); 7.16(d, 1H); 3.82(bs, 2H): 3.24(bs, 2H); 
               
               
                   
                 3.12(bs, 4H); 2.59(m, 4H); 2.11(bs, 2H); 1.18(bs, 6H) 
               
               
                 41 
                 9.01(bs, 1H); 8.95(s, 1H); 8.28(s, 1H); 8.06(m, 3H); 
                 2.52 
                 442 
                 441 
                 443 
                 95 
               
               
                   
                 7.82(bs, 2H); 7.65(s, 1H); 7.58(s, 1H); 7.30(m, 2H); 
               
               
                   
                 7.19(d, 1H); 3.84(bs, 2H); 3.73(bs, 4H); 2.82(bs, 6H); 
               
               
                   
                 2.10(bs, 2H) 
               
               
                 42 
                 7.86-7.71(m, 4H); 7.58(bs, 1H); 7.24(m, 2H); 
                 0.45; 2.28 
                 452 
                 451 
                 453 
                 98 
               
               
                   
                 7.09(s, 1H); 7.02(d, 1H); 3.89(s, 6H); 3.64(bs, 2H); 
               
               
                   
                 3.58(bs, 4H); 2.40(bs, 6H); 1.87(m, 2H) 
               
               
                 43 
                 8.63(bs, 1H); 8.45(d, 1H); 8.36(s, 1H); 8.16(d, 1H); 
                 0.43; 2.08; 2.30 
                 450 
                 449 
                 451 
                 100 
               
               
                   
                 7.95(d, 1H); 7.79(bs, 2H); 7.26(bs, 2H); 7.10(d, 1H); 
               
               
                   
                 3.69(bs, 2H); 2.42(bs, 6H); 2.30(bs, 4H); 2.12(s, 3H); 
               
               
                   
                 1.86(bs, 2H) 
               
               
                 44 
                 8.39(bs, 1H); 8.19(d, 1H); 7.88(d, 1H); 7.64(m, 3H); 
                 0.44; 2.01; 2.29 
                 396 
                 395 
                 397 
                 100 
               
               
                   
                 7.47(d, 1H); 6.99(m, 3H); 3.80(s, 3H); 3.64(bs, 2H); 
               
               
                   
                 2.42(bs, 2H); 2.23(s, 6H); 1.85(m, 2H) 
               
               
                 45 
                 10.10(bs, 1H); 8.57(bs, 1H); 8.30(d, 1H); 
                 0.45; 2.05; 2.37 
                 424 
                 423 
                 425 
                 100 
               
               
                   
                 7.92(d, 1H); 7.67(bs, 3H); 7.49(d, 1H); 6.99(d, 3H); 
               
               
                   
                 3.80(s, 3H); 3.72(bs, 2H); 3.09(bs, 6H); 2.09(bs, 2H); 
               
               
                   
                 1.19(bs, 6H) 
               
               
                 46 
                 8.31(bs, 1H); 8.21(d, 1H); 7.86(d, 1H); 7.64(m, 3H); 
                 0.45; 1.95; 2.30 
                 438 
                 437 
                 439 
                 99 
               
               
                   
                 7.47(d, 1H); 6.96(m, 3H); 3.80(s, 3H); 3.66(bs, 2H); 
               
               
                   
                 3.57(bs, 4H); 2.40(m, 6H); 1.86(bs, 2H) 
               
               
                 47 
                 8.29(bs, 1H); 8.20(d, 1H); 7.87(d, 1H); 7.65(bs, 3H); 
                 0.45; 1.91; 2.25 
                 451 
                 450 
                 452 
                 100 
               
               
                   
                 7.46(d, 1H); 6.95(bs, 3H); 3.81(s, 3H); 3.66(bs, 2H); 
               
               
                   
                 2.41(bs, 6H); 2.32(bs, 4H); 1.85(bs, 2H) 
               
               
                 48 
                 8.43(bs, 1H); 8.21(d, 1H); 7.09(d, 1H); 7.76(bs, 2H); 
                 2.13; 2.29 
                 384 
                 383 
                 385 
                 99 
               
               
                   
                 7.68(s, 1H); 7.49(d, 1H); 7.25(t, 2H), 7.08(d, 1H); 
               
               
                   
                 3.64(bs, 2H); 2.42(bs, 2H); 2.22(s, 6H); 1.85(bs, 2H) 
               
               
                 49 
                 8.44(bs, 1H); 8.20(d, 1H); 7.90(d.1H); 7.75(bs, 2H); 
                 2.36 
                 412 
                 411 
                 413 
                 100 
               
               
                   
                 7.68(s, 1 H); 7.50(d, 1H); 7.25(bs, 2H); 7.07(d, 1H); 
               
               
                   
                 3.65(bs, 2H); 2.57(bs, 6H); 1.85(bs, 2H); 
               
               
                   
                 0.98(bs, 6H) 
               
               
                 50 
                 8.35(t, 1H); 8.23(d, 1H); 7.89(d, 1H); 7.76(m, 2H); 
                 2.31 
                 426 
                 425 
                 427 
                 100 
               
               
                   
                 7.568(s, 1H); 7.50(d, 1H); 7.25(m, 2H); 7.07(d, 1H); 
               
               
                   
                 3.66(bs, 2H); 3.56(bs, 4H); 2.39(bs, 6H); 1.86(m, 2H) 
               
               
                 51 
                 8.35(bs, 1H); 8.22(d, 1H); 7.89(d, 1H); 7.76(bs, 2H); 
                 2.23 
                 439 
                 438 
                 440 
                 99 
               
               
                   
                 7.68(s, 1H); 7.49(d, 1H); 7.25(m, 2H); 7.07(d, 1H); 
               
               
                   
                 3.68(bs, 2H); 2.41(bs, 6H); 2.31(bs, 4H); 
               
               
                   
                 1.84(bs, 2H) 
               
               
                 52 
                 14.6(bs, 1H); 10.25(bs, 1H); 10.10(bs, 1H); 
                 0.46; 2.36; 2.53 
                 437 
                 436 
                 438 
                 99 
               
               
                   
                 8.55(bs, 1H); 8.25(d, 1H); 7.86(s, 1H); 7.70(bs, 1H); 
               
               
                   
                 7.63(bs, 2H); 6.93(d.1H); 6.80(bs, 2H); 3.88(bs, 2H); 
               
               
                   
                 3.10(bs, 2H); 3.04(s, 6H); 2.14(bs, 2H); 1.21(s, 6H) 
               
               
                 53 
                 8.32(bs, 1H); 8.19(d, 1H); 7.85(d, 1H); 7.73(m, 1H); 
                 0.44; 2.12 
                 422 
                 421 
                 423 
                 100 
               
               
                   
                 7.65(d, 1H); 7.45(t, 1H); 7.14(d, 1H); 7.02(s, 2H); 
               
               
                   
                 3.86(s, 6H); 3.70(s, 5H); 2.68(bs, 2H); 2.41 (s, 6H); 
               
               
                   
                 1.94(m, 2H) 
               
               
                 54 
                 8.30(bs, 1H); 8.19(bs, 1H); 7.86(d, 1H); 7.74(m, 1H); 
                 0.45; 1.86; 2.13 
                 464 
                 483 
                 465 
                 99 
               
               
                   
                 7.67(m, 1H); 7.47(bs, 1H); 7.13(d, 1H); 7.02(s, 2H); 
               
               
                   
                 3.87(s, 6H); 3.70(bs, 12H); 2.68(m, 8H) 
               
               
                 55 
                 8.49(s, 1H); 8.36(bs, 1H); 7.85(m, 3H); 7.61(d, 1H); 
                 0.46; 2.13; 2.36 
                 446 
                 445 
                 447 
                 98 
               
               
                   
                 7.53(bs, 1H); 7.46(m, 1H); 7.15(d, 1H); 3.64(bs, 2H); 
               
               
                   
                 2.41(bs, 2H); 2.22(s, 6H); 1.85(bs, 2H) 
               
               
                 56 
                 8.48(s, 1H); 8.44(bs, 1H); 7.86(m, 3H); 7.61(d, 1H); 
                 0.46; 2.26; 2.47 
                 474 
                 473 
                 475 
                 97 
               
               
                   
                 7.53(bs, 1H); 7.47(d, 1H); 7.16(d, 1H); 3.65(bs, 2H); 
               
               
                   
                 2.63(bs, 6H); 1.87(bs, 2H); 1.01(bs, 6H) 
               
               
                 57 
                 8.52(s, 1H); 8.28(bs, 1H); 7.86(m, 3H); 7.61(d, 1H); 
                 0.46; 2.16; 2.38 
                 432 
                 431 
                 433 
                 99 
               
               
                   
                 7.51(bs, 1H); 7.46(m, 1H); 7.15(d, 1H); 3.73(bs, 2H); 
               
               
                   
                 2.58(bs, 2H); 2.25(s, 6H) 
               
               
                 58 
                 8.47(s, 1H); 8.34(bs, 1H); 7.86(m, 3H); 7.61(d, 1H); 
                 0.46; 2.29; 2.51 
                 460 
                 459 
                 461 
                 97 
               
               
                   
                 7.48(bs, 2H); 7.16(d, 1H); 3.70(bs, 2H); 2.72(2H); 
               
               
                   
                 2.61(bs, 4H); 1.02(bs, 6H) 
               
               
                 59 
                 8.21(bs, 1H); 8.06(d, 1H); 7.86(bs, 1H); 7.82(s, 1H); 
                 0.45; 1.99; 2.22 
                 386 
                 385 
                 387 
                 99 
               
               
                   
                 7.73(m, 1H); 7.67(m, 1H); 7.52(m, 1H); 7.45(m, 1H); 
               
               
                   
                 7.15(d, 1H); 3.64(bs, 2H); 2.40(bs, 2H); 2.21(s, 6H); 
               
               
                   
                 1.85(bs, 2H) 
               
               
                 60 
                 8.26(bs, 1H); 8.06(d, 1H); 7.86(m, 2H); 7.74(s, 1H); 
                 0.45; 1.97; 2.32 
                 414 
                 413 
                 415 
                 98 
               
               
                   
                 7.66(d, 1H); 7.52(bs, 1H); 7.46(d, 1H); 7.16(d, 1H); 
               
               
                   
                 3.66(bs, 2H); 2.62(bs, 6H); 1.88(bs, 2H); 
               
               
                   
                 1.01(bs, 6H) 
               
               
                 61 
                 8.09(m, 2H); 7.87(bs, 1H); 7.82(s, 1H); 7.73(m, 1H); 
                 0.44; 1.76; 2.18 
                 372 
                 371 
                 373 
                 100 
               
               
                   
                 7.67(m, 1H); 7.51(bs, 1H); 7.47(m, 1H); 7.16(d, 1H); 
               
               
                   
                 3.74(bs, 2H); 2.59(bs, 2H); 2.26(s, 6H) 
               
               
                 62 
                 8.18(bs, 1H); 8.04(d, 1H); 7.85(m, 2H); 7.73(d, 1H); 
                 0.45; 2.02; 2.28 
                 400 
                 399 
                 401 
                 99 
               
               
                   
                 7.66(d, 1H); 7.48(bs, 2H); 7.16(d, 1H); 3.71(bs, 2H); 
               
               
                   
                 2.732(bs, 2H); 2.62(bs, 4H); 1.02(bs, 6H) 
               
               
                 63 
                 8.21(d, 1H); 7.85(m, 3H); 7.72(d, 1H); 7.66(d, 1H); 
                 0.45; 2.20; 2.50 
                 442 
                 441 
                 443 
                 99 
               
               
                   
                 7.53(bs, 1H); 7.46(d, 1H); 7.15(d, 1H); 4.63(bs, 1H); 
               
               
                   
                 3.31(bs, 2H); 2.50(bs, 4H); 1.61(bs, 4H); 
               
               
                   
                 1.28(bs, 3H); 0.91(bs, 6H) 
               
               
                 64 
                 8.50(bs, 2H); 8.25(s, 1H); 7.94(d, 1H); 7.79(bs, 2H); 
                 3.35 
                 506 
                 505 
                 507 
                 99 
               
               
                   
                 7.25(bs, 2H); 7.09(d, 1H); 3.65)bs, 2H); 2.39(bs, 2H); 
               
               
                   
                 2.21(s, 6H); 1.84(bs, 2H) 
               
               
                 65 
                 8.54(bs, 1H); 8.49(s, 1H); 8.26(s, 1H); 7.95(d, 1H); 
                 3.52 
                 534 
                 533 
                 535 
                 98 
               
               
                   
                 7.78(bs, 2H); 7.25(t, 2H); 7.09(d, 1H); 3.66(bs, 2H); 
               
               
                   
                 2.56(bs, 6H); 1.84(bs, 2H); 0.99(bs, 6H) 
               
               
                 66 
                 8.53(s, 1H); 8.42(bs, 1H); 8.26(s, 1H); 7.96(d, 1H); 
                 3.43 
                 492 
                 491 
                 493 
                 98 
               
               
                   
                 7.78(bs, 2H); 7.25(t, 2H); 7.09(d, 1H); 3.74(bs, 2H); 
               
               
                   
                 2.58(bs, 2H); 2.25(s, 6H) 
               
               
                 67 
                 8.48(bs, 2H); 8.26(s, 1H); 7.94(d, 1H); 7.76(bs, 2H); 
                 3.61 
                 520 
                 519 
                 521 
                 98 
               
               
                   
                 7.25(t, 2H); 7.09(d, 1H); 3.69(bs, 2H); 2.70(bs, 2H); 
               
               
                   
                 2.58(bs, 4H); 1.01(bs, 6H) 
               
               
                 68 
                 8.17(bs, 1H); 8.16(bs, 1H); 7.90(d, 1H); 7.73(bs, 2H); 
                 0.45; 2.03 
                 336 
                 335 
                 337 
                 100 
               
               
                   
                 7.68(s, 1H); 7.45(m, 1H); 7.27(bs, 2H); 7.10(d, 1H); 
               
               
                   
                 3.75(bs, 2H); 2.60(bs, 2H); 2.28(s, 6H) 
               
               
                 69 
                 8.21(bs, 1H); 8.15(d, 1H); 8.90(m, 4H); 7.45(s, 1H); 
                 0.44; 2.11 
                 364 
                 363 
                 365 
                 100 
               
               
                   
                 7.25(bs, 2H); 7.12(d, 1H); 3.72(bs, 2H); 2.73(bs, 2H); 
               
               
                   
                 2.63(bs, 4H); 1.04(bs, 6H) 
               
               
                 70 
                 8.30(d, 1H); 7.73(m, 6H); 7.44(t, 1H); 7.24(bs, 2H); 
                 0.45; 2.08; 2.40 
                 406 
                 405 
                 407 
                 100 
               
               
                   
                 7.08(d, 1H); 4.66(bs, 1H); 2.50(bs, 6H); 1.62(bs, 4H); 
               
               
                   
                 1.29(bs, 3H); 0.90(bs, 6H) 
               
               
                 71 
                 8.32(bs, 1H); 8.18(d, 1H); 7.89(d, 1H); 7.72(m, 2H); 
                 0.45; 2.13 
                 350 
                 349 
                 351 
                 100 
               
               
                   
                 7.53(m, 4H); 7.20(d, 1H); 7.18(s, 1H); 3.67(bs, 2H); 
               
               
                   
                 2.49(bs, 2H); 2.26(s, 6H); 1.88(bs, 2H) 
               
               
                 72 
                 14.55(bs, 1H); 10.49(bs, 1H); 10.41(bs, 1H); 
                 0.45; 1.90; 2.27 
                 378 
                 377 
                 379 
                 100 
               
               
                   
                 8.64(d, 1H); 7.98(m, 2H); 7.66(m, 4H); 7.40(m, 2H); 
               
               
                   
                 3.95(bs, 2H); 3.24(bs, 2H); 3.10(bs, 4H); 
               
               
                   
                 2.17(bs, 2H); 1.21(bs, 6H) 
               
               
                 73 
                 9.71(bs, 1H); 8.67(s, 1H); 8.27(s, 1H); 8.19(d, 1H); 
                 3.69 
                 562 
                 561 
                 563 
                 97 
               
               
                   
                 7.95(d, 1H); 7.83(bs, 2H); 7.25(bs, 2H); 7.10(d, 1H); 
               
               
                   
                 4.68(bs, 1H); 3.02(bs, 6H); 1.72(bs, 4H); 
               
               
                   
                 1.31(bs, 3H); 1.11(bs, 6H) 
               
               
                 74 
                 8.48(s, 1H); 8.20(bs, 1H); 7.85(m, 2H); 7.66(d, 2H); 
                 3.54 
                 512 
                 511 
                 513 
                 98 
               
               
                   
                 7.58(d, 1H); 6.98(d, 2H); 6.85(s, 1H); 3.80(s, 3H); 
               
               
                   
                 3.61(bs, 2H); 3.07(bs, 2H); 1.82(bs, 2H); 1.36(s, 9H) 
               
               
                 75 
                 9.62(bs, 1H); 8.65(s, 1H); 8.19(d, 1H); 8.09(d, 1H); 
                 0.45; 2.05; 2.28 
                 412 
                 411 
                 413 
                 100 
               
               
                   
                 7.84(bs, 2H); 7.73(m, 3H); 7.08(m, 3H); 3.84(s, 3H); 
               
               
                   
                 3.60(bs, 2H); 2.99(bs, 2H); 2.02(bs, 2H) 
               
               
                 76 
                 8.49(s, 1H); 8.27(bs, 1H); 7.90(s, 1H); 7.65(m, 3H); 
                 0.47; 2.67; 2.82 
                 454 
                 453 
                 455 
                 98 
               
               
                   
                 7.66(d, 2H); 7.58(d, 1H); 6.98(m, 2H); 3.80(s, 3H); 
               
               
                   
                 3.63(bs, 2H); 3.17(bs, 2H); 1.81(s, 5H) 
               
               
                 77 
                 9.99(bs, 1H); 9.73(bs, 1H); 8.36(d, 1H); 8.27(d, 1H); 
                 0.45; 2.05; 2.35 
                 392 
                 391 
                 393 
                 99 
               
               
                   
                 8.02(t, 1H); 7.83(d, 1H); 7.73(d, 3H); 7.40(d, 2H); 
               
               
                   
                 7.25(d, 1H); 4.21(bs, 2H); 3.47(bs, 2H); 3.32(bs, 4H); 
               
               
                   
                 2.55(s, 3H); 1.24(t.6H) 
               
               
                 78 
                 8.43(bs, 1H); 8.23(bs, 1H); 7.9(d, 1H); 7.68(m, 5H); 
                 0.45; 1.89; 2.15; 2.34 
                 378 
                 377 
                 379 
                 100 
               
               
                   
                 7.48-7.15(m, 5H); 7.13(d, 1H); 3.74(bs, 2H); 
               
               
                   
                 3.20(bs, 2H); 2.78(s, 6H); 2.11(bs, 2H) 
               
               
                 79 
                 8.44(bs, 1H); 8.36(s, 1H); 7.89(m, 2H); 7.74(m, 2H); 
                 0.46; 2.03; 2.36 
                 402 
                 401 
                 403 
                 100 
               
               
                   
                 7.59(bs, 1H); 7.47(m, 1H); 7.18(d, 1H); 3.72(bs, 2H); 
               
               
                   
                 3.18(bs, 2H); 2.77(s, 6H); 2.07(bs, 2H) 
               
               
                 80 
                 8.40(bs, 1H); 8.34(s, 1H); 7.87(m, 2H); 7.76(d, 1H); 
                 0.45; 2.20; 2.45 
                 430 
                 429 
                 431 
                 95 
               
               
                   
                 7.68(d, 1H); 7.53(bs, 1H); 7.47(m, 1H); 7.16(d, 1H); 
               
               
                   
                 3.66(bs, 2H); 2.60(bs, 6H); 1.72(bs, 2H); 
               
               
                   
                 1.00(bs, 6H) 
               
               
                 81 
                 8.56(bs, 1H); 8.32(s, 1H); 7.92(m, 2H); 7.77(m, 2H); 
                 0.45; 2.05; 2.37 
                 388 
                 387 
                 389 
                 100 
               
               
                   
                 7.59(bs, 1H); 7.47(d, 1H); 7.20(d, 1H); 4.00(bs, 2H); 
               
               
                   
                 3.41(bs, 2H); 2.89(s, 6H) 
               
               
                 82 
                 8.90(s, 1H); 8.78(bs, 1H); 8.23(s, 1H); 8.06(m, 3H); 
                 0.45; 2.13; 2.33 
                 388 
                 387 
                 389 
                 99 
               
               
                   
                 7.54(m, 3H); 7.43(s, 1H); 7.15(s, 1H); 6.88(d, 1H); 
               
               
                   
                 6.54(s, 1H); 3.75(bs, 2H); 2.64(bs, 2H); 2.37(m, 6H); 
               
               
                   
                 1.96 (bs, 2H) 
               
               
                 83 
                 8.36(bs, 1H); 8.20(d, 1H); 8.06(bs, 2H); 7.74(m, 5H); 
                 0.45; 1.88; 2.13 
                 334 
                 333 
                 335 
                 99 
               
               
                   
                 7.45(t, 1H); 7.00(m, 3H); 3.81(s, 3H); 3.72(bs, 2H); 
               
               
                   
                 2.95(m, 2H); 2.01(m, 2H) 
               
               
                 84 
                 8.90(s, 1H); 8.78(bs, 1H); 8.24(s, 1H); 8.08(m, 3H); 
                 0.44; 2.39 
                 416 
                 415 
                 417 
                 93 
               
               
                   
                 7.57(m, 3H); 7.43(s, 1H); 7.15(s, 1H); 6.89(d, 1H); 
               
               
                   
                 6.57(s, 2.5H); 3.77(bs, 2H); 2.96(bs, 2H); 
               
               
                   
                 2.88(m, 4H); 2.04(bs, 2H); 1.12(bs, 6H) 
               
               
                 85 
                 8.88(s, 1H); 8.68(bs, 1H); 8.24(s, 1H); 8.07(m, 3H); 
                 0.44; 1.89; 2.22 
                 374 
                 373 
                 375 
                 100 
               
               
                   
                 7.60(s, 1H); 7.54(m, 2H); 7.43(s, 1H): 7.14(s.1H); 
               
               
                   
                 6.89(d, 1H); 6.58(s, 2H); 3.92(bs, 2H); 2.94(bs, 2H); 
               
               
                   
                 2.56(s.6H) 
               
               
                 86 
                 8.60(bs, 1H); 8.31(s, 1H); 7.94-7.72(m, 4H); 
                 0.45; 2.25; 2.50; 2.83 
                 416 
                 415 
                 417 
                 100 
               
               
                   
                 7.57(bs, 1H); 7.49(m, 1H); 7.20(d, 1H); 6.(bs, 1H); 
               
               
                   
                 4.01(bs, 2H); 3.40(bs, 2H); 3.27(bs, 4H); 
               
               
                   
                 1.23(bs, 6H) 
               
               
                 87 
                 8.55(bs, 1H); 8.52(s, 1H); 8.29(s, 1H); 7.82(m, 4H); 
                 3.28 
                 478 
                 477 
                 479 
                 93 
               
               
                   
                 7.75(bs, 2H); 7.28(m, 2H); 7.12(d, 1H); 3.73(bs, 2H); 
               
               
                   
                 2.98(bs, 2H); 1.83(bs, 2H) 
               
               
                 88 
                 8.28(bs, 1H); 8.17(d, 1H); 7.88(d, 1H); 7.71(t, 1H); 
                 0.46; 2.25 
                 364 
                 363 
                 365 
                 100 
               
               
                   
                 7.65(m, 3H); 7.44(t, 1H); 7.29(m, 2H), 7.10(d, 1H); 
               
               
                   
                 7.10(d, 1H); 6.57)s, 2H); 3.85(bs, 2H); 3.90(bs, 2H); 
               
               
                   
                 2.48(s, 9H) 
               
               
                 89 
                 8.30(bs, 1H); 8.17(d, 1H); 7.87(d, 1H); 7.83(s, 1H); 
                 0.45; 1.95; 2.20 
                 368 
                 367 
                 369 
                 100 
               
               
                   
                 7.71(m, 2H); 7.47(m, 3H); 7.16(d, 1H); 3.66(q, 2H); 
               
               
                   
                 2.40(t, 2H); 2.21(s, 6H); 1.85(m, 2H) 
               
               
                 90 
                 7.90(m, 3H); 7.80(s, 2H); 7.58(m, 1H); 7.48(q, 1H); 
                 3.63 
                 443 
                 442 
                 444 
                 93 
               
               
                   
                 7.23(d, 1H); 3.98(s, 4H); 3.83(bs, 4H); 1.88(bs, 4H) 
               
               
                 91 
                 8.37(s, 1H); 8.19(d, 1H); 7.87(m, 2H); 7.70(m, 2H); 
                 0.48; 2.07; 2.31 
                 396 
                 395 
                 397 
                 100 
               
               
                   
                 7.47(m, 3H); 7.17(d, 1H); 3.70(bs, 2H); 2.76(bs, 6H); 
               
               
                   
                 1.94(bs, 2H); 1.06(bs.6H) 
               
               
                 92 
                 8.17(m, 2H); 7.86(m, 2H); 7.74(t, 1H); 7.67(d, 1H); 
                 0.46; 1.77; 2.14 
                 354 
                 353 
                 355 
                 100 
               
               
                   
                 7.47(m, 3H); 7.17(d, 1H); 3.76(m, 2H); 2.59(t, 2H); 
               
               
                   
                 2.26(s, 6H) 
               
               
                 93 
                 8.29(bs, 1H); 8.18(d, 1H); 7.87(m, 2H); 7.75(t, 1H); 
                 0.45; 1.87; 2.24 
                 382 
                 381 
                 383 
                 100 
               
               
                   
                 7.68(d, 1H); 7.48(m, 3H); 7.18(d, 1H); 3.80(bs, 2H), 
               
               
                   
                 2.76(bs, 6H); 1.09(bs, 6H) 
               
               
                 94 
                 8.87(s, 1H); 8.67(bs, 1H); 8.25(s, 1H); 8.04(m, 2H); 
                 0.45; 2.25; 2.50 
                 418 
                 417 
                 419 
                 99 
               
               
                   
                 7.88(m, 2H); 7.52(m, 4H); 7.10(d, 1H); 3.74(q, 2H); 
               
               
                   
                 2.46(t, 2H); 2.24(s, 3H); 1.92(m, 2H) 
               
               
                 95 
                 8.87(s, 1H); 8.75(bs, 1H); 8.26(s, 1H); 8.06(m, 2H); 
                 0.46; 2.38; 2.56 
                 446 
                 445 
                 447 
                 100 
               
               
                   
                 7.92(m, 2H); 7.54(m, 4H); 7.21(d, 1H); 3.765(q, 2H); 
               
               
                   
                 2.71(bs, 6H); 1.95(bs, 2H); 1.05(s, 6H) 
               
               
                 96 
                 8.90(s, 1H); 8.51(t, 1H); 8.26(s, 1H); 8.05(t, 2H); 
                 0.46; 2.17; 2.41 
                 404 
                 403 
                 405 
                 100 
               
               
                   
                 7.90(m, 2H); 7.54(m, 4H); 7.21 (d, 1H); 3.83(q.2H); 
               
               
                   
                 2.65(t, 2H); 2.29(s, 3H) 
               
               
                 97 
                 8.87(s, 1H); 8.60(t, 1H); 8.26(s, 1H); 8.07(d, 1H); 
                 0.46; 2.32; 2.49 
                 432 
                 431 
                 433 
                 100 
               
               
                   
                 8.02(d, 1H); 7.92(d, 1H); 7.84(d, 1H); 7.63- 
               
               
                   
                 7.43(m, 4H); 7.22(d, 1H); 3.81(q, 2H); 2.86(bs, 2H); 
               
               
                   
                 2.68(bs, 4H); 1.06(t, 6H) 
               
               
                 98 
                 8.52(bs, 1H); 8.20(d, 1H); 7.89(d, 1H); 7.73(t, 1H); 
                 0.44; 2.38; 2.53 
                 374 
                 373 
                 375 
                 92 
               
               
                   
                 7.68(d, 1H); 7.62(d, 2H); 7.45(t, 1H); 7.29(d, 2H); 
               
               
                   
                 7.09(d, 1H); 6.57(s, 4H); 3.69(q, 2H); 2.88(m, 3H); 
               
               
                   
                 2.54(s, 3H); 2.01 (m, 2H); 1.23(d, 6H) 
               
               
                 99 
                 8.40(bs, 1H); 8.24(s, 1H); 7.91(d, 1H); 7.74(t, 1H); 
                 0.46; 2.34; 2.59 
                 402 
                 401 
                 403 
                 100 
               
               
                   
                 7.69(s, 1H); 7.63(d, 2H); 7.46(t, 1H); 7.30(d, 2H); 
               
               
                   
                 7.09(d, 1H); 6.60(s, 3H); 3.73(m, 2H); 3.06(m, 2H); 
               
               
                   
                 2.95(m, 4H); 2.90(m, 1H); 2.08(bs, 2H); 1.20(d, 6H); 
               
               
                   
                 1.17(t, 6H) 
               
               
                 100 
                 8.33(bs, 1H); 8.17(d, 1H); 7.79(d, 1H); 7.72(m, 2H); 
                 0.45; 2.18; 2.45 
                 360 
                 359 
                 361 
                 100 
               
               
                   
                 7.61(d, 2H); 7.44(t, 1H); 7.29(d, 2H); 7.09(d, 1H); 
               
               
                   
                 6.58(s, 3.5H); 3.87(bs, 2H); 2.96(t, 2H); 2.91(m, 1H); 
               
               
                   
                 2.55(s, 6H); 1.22(d, 6H) 
               
               
                 101 
                 8.33(bs, 2H); 8.03(d, 1H); 7.73(dd, 1H); 7.66(s, 1H); 
                 0.46; 2.07 
                 372 
                 371 
                 373 
                 98 
               
               
                   
                 7.60(d, 1H); 7.42(d, 1H); 7.13(t, 1H); 6.82(d, 1H); 
               
               
                   
                 3.63(q, 2H); 2.39(t, 2H); 2.21(s, 6H); 1.83(m, 2H) 
               
               
                 102 
                 9.8(bs, 1H); 8.47(t, 1H); 8.38(s, 1H); 8.08(d, 1H); 
                 0.45; 2.17 
                 400 
                 399 
                 401 
                 98 
               
               
                   
                 7.76(dd, 1H); 7.67(d, 1H); 7.61(d, 1H); 7.44(d, 1H); 
               
               
                   
                 7.14(t, 1H); 6.86(d, 1H); 3.70(q, 2H); 3.08(bs, 6H); 
               
               
                   
                 2.06(bs, 2H); 1.18(t, 6H) 
               
               
                 103 
                 8.36(d, 1H); 8.23(t, 1H); 8.03(d, 1H); 7.74(dd, 1H); 
                 0.45; 2.00 
                 358 
                 357 
                 359 
                 100 
               
               
                   
                 7.62(s, 1H); 7.60(d, 1H); 7.41(d, 1H); 7.13(dd, 1H); 
               
               
                   
                 6.82(d, 1H); 3.72(q, 2H); 2.57(t, 2H); 2.25(s, 6H) 
               
               
                 104 
                 8.31(bs, 2H); 8.04(d, 1H); 7.74(dd, 1H(; 7.87(d, 1H); 
                 0.45; 2.12 
                 386 
                 385 
                 387 
                 100 
               
               
                   
                 7.60(d, 1H); 7.38(d, 1H); 7.13(dd, 1H); 6.83(d, 1H); 
               
               
                   
                 3.68(q, 2H); 2.74(bs, 2H); 2.62(bs, 4H); 1.03(t.6H) 
               
               
                 105 
                 8.33(bs, 1H); 8.20(d, 1H); 8.04(d, 1H); 7.73(t, 1H); 
                 0.45; 2.00 
                 338 
                 337 
                 339 
                 97 
               
               
                   
                 7.65(d, 1H); 7.59(d, 1H); 7.45(m, 2H); 7.13(t, 1H); 
               
               
                   
                 6.84(d, 1H); 6.57(s, 2.5H); 3.68(q, 2H); 2.86(t, 2H); 
               
               
                   
                 2.53(s, 6H); 1.99(m, 2H) 
               
               
                 106 
                 8.39(bs, 1H); 8.22(d, 1H); 8.05(d, 1H); 7.72(t, 1H); 
                 0.44; 2.09 
                 366 
                 365 
                 367 
                 95 
               
               
                   
                 7.66(d, 1H); 7.59(d, 1H); 7.45(t, 1H); 7.43(bs, 1H); 
               
               
                   
                 7.13(t, 1H); 6.85(d, 1H); 6.59(s, 4H); 3.70(bs, 2H); 
               
               
                   
                 3.07(m, 2H); 3.00(q, 4H); 2.04(m.2H); 1.15(t, 6H) 
               
               
                 107 
                 8.47(s, 1H); 8.35(t, 1H); 8.04(d, 1H); 7.84(dd, 1H); 
                 0.46; 1.83; 2.18 
                 416 
                 415 
                 417 
                 98 
               
               
                   
                 7.58(m, 2H); 7.42(d, 1H); 7.13(t, 1H); 6.82(d, 1H); 
               
               
                   
                 3.62(q, 2H); 2.38(t, 2H); 2.20(s, 6H); 1.83(m, 2H) 
               
               
                 108 
                 8.34(bs, 1H); 8.17(d, 1H); 8.06(d, 1H); 7.74(t, 1H); 
                 0.44; 1.91 
                 324 
                 323 
                 325 
                 99 
               
               
                   
                 7.66(d, 1H); 7.60(d, 1H); 7.46(d, 1H); 7.41(bs, 1H); 
               
               
                   
                 7.13(bs, 1H)6.84(d, 1H); 6.58(s, 4H); 3.85(bs, 2H); 
               
               
                   
                 2.97(bs, 2H); 2.53(s, 6H) 
               
               
                 109 
                 8.37(bs, 2H); 7.88(d, 1H): 7.74(dd, 1H); 7.66(s, 1H); 
                 0.46; 2.11; 2.46 
                 412 
                 411 
                 413 
                 100 
               
               
                   
                 7.65(d, 2H); 7.29(d, 2H); 7.09(d, 1H); 8.56(s, 2.6H); 
               
               
                   
                 3.66(q, 2H); 2.76(t, 2H); 2.51(s, 3H); 2.46(s, 3H); 
               
               
                   
                 1.96(m, 2H) 
               
               
                 110 
                 8.43(bs, 1H); 8.38(s, 1H); 7.89(d, 1H); 7.76- 
                 0.46; 2.23; 2.56 
                 440 
                 439 
                 441 
                 93 
               
               
                   
                 7.63(m, 4H); 7.29(d, 2H); 7.09(d, 1H); 6.56(s, 2.5H); 
               
               
                   
                 3.69(bs, 2H); 2.90(t, 2H); 2.87(m, 4H); 2.50(s, 3H); 
               
               
                   
                 1.99(bs, 2H); 1.09(t, 6H) 
               
               
                 111 
                 8.45(bs, 1H); 8.31(s, 1H); 7.89(d, 1H); 7.76- 
                 0.46; 2.22; 2.52 
                 426 
                 425 
                 427 
                 95 
               
               
                   
                 7.60(m, 4H); 7.30(d, 2H); 7.09(d, 1H); 6.57(s, 2H); 
               
               
                   
                 3.79(q, 2H); 2.93(t, 2H); 2.80(q, 4H); 1.08(t, 6H) 
               
               
                 112 
                 8.40(bs, 1H); 8.34(s.1H); 7.90(d, 1H); 7.69(m, 4H); 
                 0.46; 2.01; 2.41 
                 398 
                 397 
                 399 
                 100 
               
               
                   
                 7.29(d, 2H); 7.09(d, 1H); 6.57(s, 2.6H); 3.83(bs, 2H); 
               
               
                   
                 2.89(bs, 2H); 2.50(s, 9H) 
               
               
                 113 
                 8.21(s, 1H); 7.87(d, 1H); 7.74(m, 3H); 7.46(m, 2H); 
                 2.66 
                 454 
                 453 
                 455 
                 93 
               
               
                   
                 7.17(d, 1H); 4.88(bs, 1H); 4.08(bs, 1H); 3.93(bs, 1H); 
               
               
                   
                 2.82(d, 1H); 2.57(m, 5H); 2.00(m, 4H); 1.71(bs, 4H) 
               
               
                 114 
                 8.03(bs, 1H); 7.81(m, 2H); 7.59(s, 1H); 7.50(bs, 1H); 
                 2.44 
                 428 
                 427 
                 429 
                 98 
               
               
                   
                 7.44(t, 1H); 7.11(d.1H); 7.10(s, 1H); 3.90(s, 6H); 
               
               
                   
                 3.66(q, 2H); 2.71(bs, 2H); 2.44(s, 6H); 1.95(m, 2H) 
               
               
                 115 
                 9.90(bs, 1H); 8.17(bs, 1H); 7.86(m, 1H); 7.80(s, 1H); 
                 2.53 
                 456 
                 455 
                 457 
                 98 
               
               
                   
                 7.66(s, 1H); 7.54(bs, 1H); 7.46(q, 1H); 7.10(m, 2H); 
               
               
                   
                 3.90(s, 6H); 3.70(q, 2H); 32.09(bs, 6H); 2.07(bs, 2H); 
               
               
                   
                 1.03(bs, 6H) 
               
               
                 116 
                 8.07(bs, 1H); 7.83(m, 2H); 7.57(s, 1H); 7.50(bs, 1H); 
                 0.48; 2.36 
                 414 
                 413 
                 415 
                 98 
               
               
                   
                 7.47(t, 1H); 7.11(d, 1H); 7.10(s, 1H); 6.58(s, 3.5H); 
               
               
                   
                 3.89(s, 6H); 3.85(bs, 2H); 2.92(bs, 2H); 2.50(s, 6H) 
               
               
                 117 
                 10.32(bs, 1H); 8.37(bs, 1H); 7.87(m, 2H); 
                 0.45; 2.30; 2.45 
                 442 
                 441 
                 443 
                 100 
               
               
                   
                 7.70(s, 1H); 7.54(bs, 1H); 7.47(q, 1H); 7.13(t, 2H); 
               
               
                   
                 4.01(bs, 2H); 3.91(s, 6H); 3.40(bs, 6H); 1.25(bs, 6H) 
               
               
                 118 
                 7.85(m, 2H); 7.78(d, 1H); 7.61(s, 1H); 7.54- 
                 3.62 
                 385 
                 384 
                 386 
                 98 
               
               
                   
                 7.39(m, 2H); 7.09(t, 2H); 3.89(s, 6H); 3.58(q, 2H); 
               
               
                   
                 1.72(m, 2H); 1.02(t, 3H) 
               
               
                 119 
                 8.35(t, 1H); 8.19(d, 1H); 7.96(m, 5H); 7.73(m, 2H); 
                 0.45; 1.95 
                 410 
                 409 
                 411 
                 100 
               
               
                   
                 7.48(t, 1H); 7.33(d, 1H); 3.68(q, 2H); 3.26(s, 3H); 
               
               
                   
                 2.43(t, 2H); 2.23(s, 6H); 1.87(m, 2H) 
               
               
                 120 
                 8.21(d, 1H); 7.87(d, 1H); 7.75(m, 3H); 7.47(m, 2H); 
                 2.62 
                 454 
                 453 
                 455 
                 97 
               
               
                   
                 7.17(d, 1H); 4.88(bs, 1H); 4.10(m, 1H); 3.93(bs, 1H); 
               
               
                   
                 2.82(dd, 1H); 2.54(m, 5H); 2.00(m, 4H); 1.71(bs, 4H) 
               
               
                 121 
                 8.22(bs, 1H); 8.19(s, 1H); 7.97(m, 5H); 7.76(t, 1H); 
                 0.39; 1.78 
                 396 
                 395 
                 397 
                 100 
               
               
                   
                 7.70(d, 1H); 7.48(t, 1H); 7.33(d, 1H); 3.77(q, 2H); 
               
               
                   
                 3.25(s, 3H); 2.60(t, 2H); 2.27(s, 6H) 
               
               
                 122 
                 8.27(d, 1H); 8.26(s, 1H); 7.95(m, 5H); 7.70(m, 2H); 
                 2.76 
                 367 
                 366 
                 368 
                 95 
               
               
                   
                 7.50(t, 1H); 7.33(d, 1H); 3.63(q, 2H); 3.25(s, 3H); 
               
               
                   
                 1.74(m, 2H); 1.00(t.3H) 
               
               
                 123 
                 8.36(bs, 2H); 7.89(d, 1H); 7.74(d, 1H); 7.67(d, 1H); 
                 2.77 
                 408 
                 407 
                 409 
                 97 
               
               
                   
                 7.61(d, 2H); 7.29(d, 2H); 7.07(d, 1H); 6.56(s, 3H); 
               
               
                   
                 3.67(q, 2H); 2.91(m, 1H); 2.76(m, 2H), 2.46(s, 6H); 
               
               
                   
                 1.98(m, 2H); 1.21(d, 6H) 
               
               
                 124 
                 8.41(t, 1H); 8.37(s, 1H); 7.90(d, 1H); 7.74(dd, 1H); 
                 2.88 
                 436 
                 435 
                 437 
                 97 
               
               
                   
                 7.68(d, 1H); 7.61(d, 2H); 7.29(d, 2H); 7.07(d, 1H); 
               
               
                   
                 6.56(s, 2H); 3.69(q, 2H); 2.91(m, 3H); 2.84(m, 4H); 
               
               
                   
                 1.99(m, 2H); 1.22(d, 6H); 1.09(t, 6H) 
               
               
                 125 
                 8.37(t, 1H); 8.33(d, 1H); 7.90(d, 1H); 7.74(dd, 1H); 
                 2.73 
                 394 
                 393 
                 395 
                 97 
               
               
                   
                 7.68(d, 1H); 7.61(d, 2H); 7.29(d, 2H); 7.08(d, 1H); 
               
               
                   
                 6.57(s, 2.8H); 3.83(q, 2H), 2.92(m, 1H); 2.88(m, 2H); 
               
               
                   
                 2.47(s, 6H); 1.22(d, 6H) 
               
               
                 126 
                 8.49(bs, 1H); 8.31(d, 1H); 7.90(d, 1H); 7.75(dd, 1H); 
                 2.80 
                 422 
                 421 
                 423 
                 90 
               
               
                   
                 7.68(d, 1H); 7.59(d, 2H); 7.29(d, 2H); 7.07(d, 1H); 
               
               
                   
                 6.57(s, 2.4H); 3.82(q, 2H); 2.97(m, 3H); 2.84(m, 4H); 
               
               
                   
                 1.22(d, 6H); 1.10(t, 6H) 
               
               
                 127 
                 8.27(bs, 1H); 8.08(dd, 1H); 7.88(d, 1H); 7.74(m, 1H); 
                 2.63 
                 392 
                 391 
                 393 
                 96 
               
               
                   
                 7.67(m, 1H); 7.61(d, 2H); 7.29(d, 2H); 7.07(d, 1H); 
               
               
                   
                 6.56(s, 3H); 3.68(q, 2H); 2.91(m, 1H); 2.81(t, 2H); 
               
               
                   
                 2.49(s, 6H); 1.98(t, 2H); 1.22(d, 6H) 
               
               
                 128 
                 8.27(bs, 1H); 8.04(d, 1H); 7.89(d, 1H); 7.72(m, 1H); 
                 2.51; 2.59 
                 378 
                 377 
                 379 
                 95 
               
               
                   
                 7.67(m, 1H); 7.61(d, 2H); 7.29(d, 2H); 7.07(d, 1H); 
               
               
                   
                 6.57(s, 2.7H); 3.84(m, 2H); 2.89(m, 3H); 2.47(s, 6H); 
               
               
                   
                 1.22(d, 6H) 
               
               
                 129 
                 8.36(bs, 1H); 8.02(d, 1H); 7.89(d, 1H); 7.73(m, 1H); 
                 2.67 
                 406 
                 405 
                 407 
                 90 
               
               
                   
                 7.66(m, 1H); 7.60(d, 2H); 7.30(d, 2H); 7.08(d, 1H); 
               
               
                   
                 6.59(s, 3H); 3.83(m, 2H); 3.01(m, 3H); 2.88(m, 4H); 
               
               
                   
                 1.22(d, 6H); 1.12(t, 6H) 
               
               
                 130 
                 8.37(bs, 2H); 7.96(m, 5H); 7.77(d, 1H); 7.69(d, 1H); 
                 0.44; 1.89; 2.07 
                 444 
                 443 
                 445 
                 94 
               
               
                   
                 7.31(d, 1H); 3.66(q, 2H); 3.24(s, 3H); 2.43(m, 2H); 
               
               
                   
                 2.23(s, 6H); 1.86(m, 2H) 
               
               
                 131 
                 8.48(bs, 1H); 8.39(d, 1H); 7.98(m, 5H); 7.77(dd, 1H); 
                 0.45; 2.04; 2.17 
                 472 
                 471 
                 473 
                 96 
               
               
                   
                 7.71(d, 1H); 7.31(d, 1H); 6.54(s 0.6H); 3.70(q, 2H); 
               
               
                   
                 3.24(s, 3H); 2.81(m, 6H); 1.95(m, 2H); 1.07(t, 6H) 
               
               
                 132 
                 8.39(d, 1H); 8.29(t, 1H); 7.95(m, 5H); 7.77(dd, 1H); 
                 0.44; 1.91; 2.06 
                 430 
                 429 
                 431 
                 95 
               
               
                   
                 7.70(d, 1H); 7.31(d, 1H); 3.75(q, 2H); 3.24(s, 3H); 
               
               
                   
                 2.59(t, 2H); 2.26(s, 6H) 
               
               
                 133 
                 8.57(bs, 1H); 8.35(d, 1H); 7.95(m, 5H); 7.78(dd, 1H); 
                 2.18 
                 458 
                 457 
                 459 
                 99 
               
               
                   
                 7.71(d, 1H); 7.33(d, 1H); 6.58(s, 2.2H); 3.84(q, 2H); 
               
               
                   
                 3.24(s, 3H); 3.00(t, 2H); 2.86(q, 4H); 1.10(t, 6H) 
               
               
                   
               
             
          
         
       
     
         [0149]    Biological Methods 
         [0150]    Biochemical Activity Assays 
         [0151]    FLT3(ITD) biochemical assays were performed on two different assay system platforms, using Transcreener® ADP Assay FP method (BellBrook Labs, Madison, Wis., US) and IMAP® FP biochemical activity assays (Molecular Devices, Sunnyvale, Calif., US). 
         [0152]    In each case the assays were performed in low protein binding, black, round bottom 384-well plates type 3676 (Corning, One Riverfront Plaza, NY, US). Kinase inhibitor compounds were dissolved in 100% DMSO to 5 mM and then we prepared serial dilutions in order to determine IC 50  values. 
         [0153]    In the TranScreener® FLT3(ITD) assay we used the following materials in the following final concentrations for the reaction: 8 nM FLT3(ITD) (ProQinase, Freiburg, Germany), 0.05 mg/ml Poly Glu-Tyr peptide (Sigma-Aldrich, Budapest, Hungary) as a substrate, 20 mM HEPES pH 7.5 (Sigma-Aldrich), 1 mM DTT (Sigma-Aldrich), 3 mM MgCl 2  (Sigma-Aldrich), 3 mM MnCl 2  (Sigma-Aldrich), and 0.01 V % V Tween20 (Sigma-Aldrich) as a detergent. The kinase reaction had started by the addition of 2 μl 5× enzyme, and the reaction had been progressing in the volume of 10 μl for 1 hour at room temperature. The reaction has been stopped by adding 10 μl Transcreener® Stop and Detection Solution and had been incubated for additional 1 hour. The solution contained in every case 20 mM HEPES pH 7.5, 40 mM EDTA, 0.02 V/V % Brij35 and 3 nM ADP Alexa633 Tracer. The ADP antibody concentration was 2.08 μg/ml according to the K mapp  value which was 1 μM. Then fluorescence polarization and fluorescence intensity was measured using Analyst GT Multimode Reader (Molecular Devices). 
         [0154]    In the IMAP FP assay the reaction conditions were the following: 16-45 nM FLT3(ITD) (ProQinase), 400 nM 5TAMRA-GEEPLYWSFPAKKK-NH2 dyed peptide for substrate (Genecust, Dudelenge, Luxembourg), 20 mM HEPES pH 8, 1 mM DTT, 10 mM MgCl 2 , 2 mM MnCl 2 , and 0.01V % V Brij35 detergent (Sigma-Aldrich). The ATP concentration was 5.1 μM. The kinase reaction had started by the addition of 2 μl 5× enzyme, and the reaction had been progressing in the volume of 10 μl for 1 hour at room temperature and then was terminated by adding 10 μl IMAP Detection mixture. Fluorescence polarization and fluorescence intensity was measured using Analyst GT Multimode Reader (Molecular Devices) after 1.5 hour of incubation on room temperature. 
         [0155]    Cell Line and Cell Viability Assays 
         [0156]    The cell line used was MV4-11, obtained from ATCC (American Type Culture Collection, Manassas, Va., US). It is a biphenotypic B myelomonocytic leukemia macrophage cell line which expresses exclusively the mutated form of FLT3, the above described FLT3(ITD). Using MV4-11 cell line, we performed cell viability assays, where the kinase inhibitors were incubated with the cells for 72 hours on 37° C./98.6° F. in 5 V/V % CO2 atmosphere in serial dilutions in order to determine IC 50  values. For the detection of the percentage of the survived cells we used CellTiter Glo® Luminescent Cell Viability Assay (Promega, Madison, Wis., US). The assays were performed according to the manufacturer&#39;s instructions except for the volumes used: we added 33.3 μl CellTiter Glo® Reagent to 66.6 μl of media containing the treated cells. Luminescence was measured using Analyst GT Multimode Reader (Molecular Devices). 
         [0157]    In all cases of the biochemical and cellular assays we used Microsoft Excel (Microsoft Corp., Redmond, Wash., US) for data processing and for generating IC 50  curves we used XLfit curve fitting add-in software (Guildford, UK) for Microsoft Office Excel. 
         [0158]    Biological Results 
         [0159]    The enzyme assay was performed using TranScreener® (BellBrook Labs) IMAP FP® (Molecular Devices) biochemical enzyme activity assay systems. Compounds were original molecules produced by Vichem Chemie Research Ltd. and were described above in detail. Primary screening was performed in one concentration (10 μM) of the compounds. Hits were subsequently measured in a twelve-point serial dilution set in order to determine compound specific IC 50  values. The assay conditions were described above. In each case we used Sunitinib, marketed as Sutent® by Pfizer, which is a broad-spectrum kinase inhibitor and a known inhibitor of FLT3 as well. Kinase assays were considered as acceptable when the Z prime value was &gt;0.5. In each case the average of the parallel measurements is shown. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 IC 50  values of presented hit derivatives 
               
               
                 in biochemical activity assay. 
               
             
          
           
               
                   
                 Average IC 50  values 
                 standard 
               
               
                 Example 
                 on FLT3(ITD) in μM 
                 deviation 
               
               
                   
               
             
          
           
               
                 1 
                 1.913 
                 0.035 
               
               
                 2 
                 10.000 
                 0.000 
               
               
                 3 
                 7.674 
                 3.289 
               
               
                 5 
                 13.801 
                 9.959 
               
               
                 6 
                 1.417 
                 0.282 
               
               
                 7 
                 1.394 
                 0.289 
               
               
                 11 
                 1.957 
                 0.703 
               
               
                 12 
                 5.110 
                 1.607 
               
               
                 15 
                 1.545 
                 0.326 
               
               
                 16 
                 3.076 
                 0.596 
               
               
                 17 
                 8.611 
                 0.000 
               
               
                 18 
                 2.280 
                 0.979 
               
               
                 20 
                 2.394 
                 0.729 
               
               
                 21 
                 2.258 
                 1.199 
               
               
                 22 
                 4.199 
                 1.222 
               
               
                 23 
                 4.759 
                 0.767 
               
               
                 37 
                 8.531 
                 2.078 
               
               
                 39 
                 10.000 
                 0.000 
               
               
                 55 
                 9.676 
                 0.000 
               
               
                 57 
                 1.996 
                 0.249 
               
               
                 68 
                 0.811 
                 0.224 
               
               
                 69 
                 2.124 
                 1.311 
               
               
                 75 
                 0.074 
                 0.045 
               
               
                 76 
                 3.696 
                 0.588 
               
               
                 77 
                 1.764 
                 0.885 
               
               
                 78 
                 4.496 
                 3.504 
               
               
                 79 
                 6.317 
                 3.023 
               
               
                 81 
                 1.703 
                 0.640 
               
               
                 82 
                 1.641 
                 0.706 
               
               
                 83 
                 0.134 
                 0.040 
               
               
                 84 
                 2.333 
                 0.224 
               
               
                 85 
                 0.950 
                 0.358 
               
               
                 88 
                 0.461 
                 0.000 
               
               
                 92 
                 9.080 
                 1.302 
               
               
                 93 
                 3.251 
                 0.118 
               
               
                 98 
                 2.018 
                 0.000 
               
               
                 99 
                 1.507 
                 0.018 
               
               
                 100 
                 0.258 
                 0.097 
               
               
                 101 
                 6.690 
                 1.351 
               
               
                 102 
                 10.694 
                 0.982 
               
               
                 103 
                 2.931 
                 1.051 
               
               
                 104 
                 2.305 
                 0.309 
               
               
                 105 
                 7.783 
                 0.000 
               
               
                 107 
                 10.000 
                 0.000 
               
               
                 108 
                 6.294 
                 0.000 
               
               
                 109 
                 2.385 
                 0.000 
               
               
                 110 
                 5.620 
                 0.000 
               
               
                 111 
                 6.953 
                 0.000 
               
               
                 112 
                 1.264 
                 0.000 
               
               
                 119 
                 1.511 
                 0.043 
               
               
                 121 
                 0.326 
                 0.005 
               
               
                 122 
                 3.823 
                 0.000 
               
               
                 123 
                 1.271 
                 0.973 
               
               
                 124 
                 2.970 
                 2.578 
               
               
                 125 
                 0.412 
                 0.411 
               
               
                 126 
                 1.404 
                 1.701 
               
               
                 127 
                 1.262 
                 1.223 
               
               
                 128 
                 0.582 
                 0.702 
               
               
                 129 
                 0.874 
                 1.046 
               
               
                 130 
                 0.873 
                 0.882 
               
               
                 131 
                 1.982 
                 1.087 
               
               
                 132 
                 0.246 
                 0.212 
               
               
                 133 
                 0.440 
                 0.316 
               
               
                   
               
             
          
         
       
     
         [0160]    The cell viability assays were performed on the MV4-11 cell line using Promega&#39;s CellTiter-Glo® Luminescent Cell Viability Assay method following the instructions of the supplier except the conditions described above. Primary screening was performed in one concentration (10 μM) of the compounds. Hits were subsequently measured in a ten-point serial dilution set in order to determine compound specific IC 50  values. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 IC 50  values of presented hit derivatives in cell viability assay. 
               
             
          
           
               
                   
                 Average IC 50  values 
                 Standard 
               
               
                 Example 
                 on MV4-11 cells in μM 
                 deviation 
               
               
                   
               
             
          
           
               
                 3 
                 0.1844 
                 0.0000 
               
               
                 7 
                 0.8284 
                 0.0000 
               
               
                 10 
                 2.3221 
                 2.1380 
               
               
                 11 
                 2.3399 
                 1.3169 
               
               
                 12 
                 1.1613 
                 0.2574 
               
               
                 13 
                 2.7750 
                 0.4783 
               
               
                 14 
                 10.2472 
                 6.7842 
               
               
                 15 
                 0.3915 
                 0.0587 
               
               
                 18 
                 1.8553 
                 1.0508 
               
               
                 20 
                 0.4379 
                 0.1696 
               
               
                 21 
                 1.8513 
                 1.2464 
               
               
                 22 
                 1.0421 
                 0.0982 
               
               
                 23 
                 2.1214 
                 0.0899 
               
               
                 29 
                 4.8742 
                 1.6221 
               
               
                 32 
                 1.2649 
                 0.0353 
               
               
                 35 
                 2.8475 
                 2.0202 
               
               
                 36 
                 1.0507 
                 0.0000 
               
               
                 39 
                 1.0643 
                 0.3749 
               
               
                 42 
                 6.4081 
                 5.8036 
               
               
                 46 
                 9.5231 
                 1.3983 
               
               
                 52 
                 4.2082 
                 1.3561 
               
               
                 53 
                 4.5406 
                 0.5619 
               
               
                 54 
                 10.1229 
                 2.3004 
               
               
                 57 
                 0.9794 
                 1.2188 
               
               
                 61 
                 1.8149 
                 1.4286 
               
               
                 65 
                 6.6102 
                 3.9400 
               
               
                 68 
                 0.3178 
                 0.0107 
               
               
                 69 
                 0.9897 
                 0.8505 
               
               
                 71 
                 2.7308 
                 1.2503 
               
               
                 74 
                 4.9484 
                 0.0000 
               
               
                 75 
                 0.0231 
                 0.0327 
               
               
                 76 
                 3.4946 
                 2.7186 
               
               
                 77 
                 0.7257 
                 0.0181 
               
               
                 78 
                 0.7235 
                 0.1656 
               
               
                 79 
                 1.4264 
                 0.0000 
               
               
                 80 
                 1.5463 
                 1.4503 
               
               
                 81 
                 0.5095 
                 0.0160 
               
               
                 82 
                 0.4793 
                 0.0666 
               
               
                 83 
                 0.1215 
                 0.0153 
               
               
                 84 
                 0.9225 
                 0.0000 
               
               
                 85 
                 0.3291 
                 0.0623 
               
               
                 86 
                 1.1220 
                 0.0330 
               
               
                 87 
                 2.8622 
                 0.0000 
               
               
                 88 
                 0.2491 
                 0.0605 
               
               
                 89 
                 1.4336 
                 0.0000 
               
               
                 91 
                 2.7801 
                 0.2425 
               
               
                 92 
                 1.5429 
                 1.0002 
               
               
                 93 
                 1.0438 
                 0.0000 
               
               
                 95 
                 1.3899 
                 0.0274 
               
               
                 96 
                 2.3720 
                 1.2557 
               
               
                 97 
                 1.4636 
                 0.2658 
               
               
                 98 
                 0.5771 
                 0.0625 
               
               
                 99 
                 0.7892 
                 0.2361 
               
               
                 100 
                 0.1500 
                 0.1744 
               
               
                 101 
                 1.9627 
                 1.1799 
               
               
                 102 
                 2.8080 
                 0.9983 
               
               
                 103 
                 0.7504 
                 0.4937 
               
               
                 104 
                 0.6538 
                 0.0000 
               
               
                 105 
                 1.4767 
                 0.0000 
               
               
                 106 
                 2.1965 
                 0.0000 
               
               
                 107 
                 0.3674 
                 0.0000 
               
               
                 108 
                 0.5039 
                 0.0000 
               
               
                 109 
                 0.2845 
                 0.0000 
               
               
                 110 
                 0.8441 
                 0.0000 
               
               
                 111 
                 0.0955 
                 0.0000 
               
               
                 112 
                 0.0038 
                 0.0000 
               
               
                 113 
                 9.6182 
                 0.0000 
               
               
                 115 
                 1.9982 
                 0.0000 
               
               
                 119 
                 0.2951 
                 0.0000 
               
               
                 120 
                 13.7051 
                 0.0000 
               
               
                 121 
                 0.0562 
                 0.0000 
               
               
                 122 
                 0.3974 
                 0.0000 
               
               
                 123 
                 0.3994 
                 0.3055 
               
               
                 124 
                 0.7914 
                 0.4381 
               
               
                 125 
                 0.0255 
                 0.0015 
               
               
                 130 
                 0.1039 
                 0.0947 
               
               
                 132 
                 0.0080 
                 0.0077 
               
               
                   
               
             
          
         
       
     
         [0161]    In order to define the selectivity profile of styryl quinazoline derivatives enclosed in this invention we chose a both structurally and bioactive representative compound (Example 11). The measurements were performed by DiscoveRx Corp. (Fremont, Calif., US). The compound was tested in the scanMAX™ Kinase Assay Panel which covers more than 80% of the human protein kinome. It&#39;s an activation-state specific assay in which 456 kinases were tested using the compound at the concentration of 5 μM. The results are represented here as the percentage of activity loss caused by the compound. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Selectivity panel results of Example 11 
               
             
          
           
               
                   
                 Specifi- 
                 Kinase 
                 Inhibi- 
               
               
                 Kinase 
                 cation 
                 Family 
                 tion (%) 
               
               
                   
               
             
          
           
               
                 FLT3(D835H) 
                 TK 
                 PDGFR 
                 97.1 
               
               
                 FLT3(ITD) 
                 TK 
                 PDGFR 
                 95.8 
               
               
                 FLT3(N841I) 
                 TK 
                 PDGFR 
                 96 
               
               
                 FLT3(D835Y) 
                 TK 
                 PDGFR 
                 94.6 
               
               
                 FLT3 
                 TK 
                 PDGFR 
                 81 
               
               
                 FLT3(K663Q) 
                 TK 
                 PDGFR 
                 80 
               
               
                 CSNK1A1 
                 CK1 
                 CK1 
                 77 
               
               
                 RIOK3 
                 Atypical 
                 RIO 
                 74 
               
               
                 GAK 
                 Other 
                 NAK 
                 65 
               
               
                 MEK5 
                 STE 
                 STE7 
                 64 
               
               
                 RIOK1 
                 Atypical 
                 RIO 
                 63 
               
               
                 SRMS 
                 TK 
                 Src 
                 62 
               
               
                 TYK2(JH1domain-catalytic) 
                 TK 
                 JakA 
                 60 
               
               
                 KIT(A829P) 
                 TK 
                 PDGFR 
                 60 
               
               
                 BMPR1B 
                 TKL 
                 STKR 
                 59 
               
               
                 EGFR(T790M) 
                 TK 
                 EGFR 
                 56 
               
               
                 ULK1 
                 Other 
                 ULK 
                 56 
               
               
                 CSNK1E 
                 CK1 
                 CK1 
                 52 
               
               
                 FLT3(R834Q) 
                 TK 
                 PDGFR 
                 52 
               
               
                 PFCDPK1( P. falciparum ) 
                 Pathogen 
                 
                   P. Falciparum 
                 
                 50 
               
               
                 CSNK1D 
                 CK1 
                 CK1 
                 49 
               
               
                 CSNK2A2 
                 Other 
                 CK2 
                 49 
               
               
                 VRK2 
                 CK1 
                 VRK 
                 47 
               
               
                 KIT(V559D) 
                 TK 
                 PDGFR 
                 46 
               
               
                 PIM2 
                 CAMK 
                 PIM 
                 46 
               
               
                 PDGFRB 
                 TK 
                 PDGFR 
                 45 
               
               
                 CSNK1A1L 
                 CK1 
                 CK1 
                 45 
               
               
                 MEK4 
                 STE 
                 STE7 
                 44 
               
               
                 SGK 
                 AGC 
                 SGK 
                 44 
               
               
                 KIT(D816V) 
                 TK 
                 PDGFR 
                 43 
               
               
                 TAOK3 
                 STE 
                 STE20 
                 43 
               
               
                 IKK-epsilon 
                 Other 
                 IKK 
                 43 
               
               
                 RPS6KA4(Kin.Dom.2-C-terminal) 
                 AGC 
                 RSK 
                 42 
               
               
                 PIK3CA(M1043I) 
                 LIPID 
                 PI3K 
                 42 
               
               
                 TAOK1 
                 STE 
                 STE20 
                 41 
               
               
                 PIK3CA(H1047Y) 
                 LIPID 
                 PI3K 
                 41 
               
               
                 MKNK2 
                 CAMK 
                 MAPKAPK 
                 40 
               
               
                 ALK 
                 TK 
                 Alk 
                 40 
               
               
                 p38-gamma 
                 CMGC 
                 MAPK 
                 40 
               
               
                 ULK3 
                 Other 
                 ULK 
                 39 
               
               
                 DCAMKL1 
                 CAMK 
                 DCAMKL 
                 39 
               
               
                 PIK3CA(E545A) 
                 LIPID 
                 PI3K 
                 39 
               
               
                 INSR 
                 TK 
                 InsR 
                 38 
               
               
                 PDPK1 
                 AGC 
                 PKB 
                 38 
               
               
                 RSK2(Kin.Dom.1-N-terminal) 
                 AGC 
                 RSK 
                 37 
               
               
                 ABL1(F317L)-nonphosphorylated 
                 TK 
                 Abl 
                 36 
               
               
                 ABL1(F317I)-nonphosphorylated 
                 TK 
                 Abl 
                 36 
               
               
                 TRKC 
                 TK 
                 Trk 
                 36 
               
               
                 PIK3C2B 
                 LIPID 
                 PI3K 
                 36 
               
               
                 BIKE 
                 Other 
                 NAK 
                 35 
               
               
                 BLK 
                 TK 
                 Src 
                 35 
               
               
                 PIK3CD 
                 LIPID 
                 PI3K 
                 35 
               
               
                 FLT3-autoinhibited 
                 TK 
                 PDGFR 
                 34 
               
               
                 EGFR(L858R, T790M) 
                 TK 
                 EGFR 
                 34 
               
               
                 ABL1(F317I)-phosphorylated 
                 TK 
                 Abl 
                 33 
               
               
                 SRC 
                 TK 
                 Src 
                 32 
               
               
                 GRK1 
                 AGC 
                 GRK 
                 32 
               
               
                 ABL1(H39P)-nonphosphorylated 
                 TK 
                 Abl 
                 31 
               
               
                 KIT(L576P) 
                 TK 
                 PDGFR 
                 31 
               
               
                 TNIK 
                 TK 
                 Ack 
                 31 
               
               
                 EPHA3 
                 TK 
                 Eph 
                 31 
               
               
                 MARK2 
                 CAMK 
                 CAMKL 
                 31 
               
               
                 PIK3CA(C420R) 
                 LIPID 
                 PI3K 
                 31 
               
               
                 PKAC-alpha 
                 AGC 
                 PKA 
                 31 
               
               
                 PIPSK1A 
                 LIPID 
                 PIP 
                 29 
               
               
                 MAP3K2 
                 STE 
                 STE11 
                 29 
               
               
                 FYN 
                 TK 
                 Src 
                 29 
               
               
                 KIT 
                 TK 
                 PDGFR 
                 28 
               
               
                 FGFR2 
                 TK 
                 FGFR 
                 28 
               
               
                 BMX 
                 TK 
                 Tec 
                 28 
               
               
                 MKK7 
                 STE 
                 STE7 
                 28 
               
               
                 MAP4K2 
                 STE 
                 STE20 
                 26 
               
               
                 MYLK 
                 CAMK 
                 MLCK 
                 26 
               
               
                 TRKA 
                 TK 
                 Trk 
                 26 
               
               
                 PIK3CA(Q546K) 
                 LIPID 
                 PI3K 
                 26 
               
               
                 ABL1(F317L)-phosphorylated 
                 TK 
                 Abl 
                 24 
               
               
                 STK33 
                 CAMK 
                 CAMK-Unique 
                 24 
               
               
                 EGFR(G719C) 
                 TK 
                 EGFR 
                 23 
               
               
                 MERTK 
                 TK 
                 Axl 
                 22 
               
               
                 RIOK2 
                 Atypical 
                 RIO 
                 22 
               
               
                 CTK 
                 TK 
                 Csk 
                 22 
               
               
                 PLK3 
                 Other 
                 PLK 
                 22 
               
               
                 AKT1 
                 AGC 
                 AKT 
                 22 
               
               
                 ABL1-phosphorylated 
                 TK 
                 Abl 
                 21 
               
               
                 MELK 
                 CAMK 
                 CAMKL 
                 21 
               
               
                 RSK1(Kin.Dom.2-C-terminal) 
                 AGC 
                 RSK 
                 21 
               
               
                 PKNB( M. tuberculosis ) 
                 Pathogen 
                 MTB 
                 20 
               
               
                 PLK2 
                 Other 
                 PLK 
                 20 
               
               
                 RIPK4 
                 TKL 
                 RIPK 
                 20 
               
               
                 ROCK2 
                 AGC 
                 DMPK 
                 20 
               
               
                 MEK6 
                 STE 
                 STE7 
                 20 
               
               
                 PIK3C2G 
                 LIPID 
                 PI3K 
                 20 
               
               
                 ABL1(H396P)-phosphorylated 
                 TK 
                 Abl 
                 19 
               
               
                 JNK1 
                 CMGC 
                 MAPK 
                 19 
               
               
                 HASPIN 
                 Other 
                 Haspin 
                 19 
               
               
                 CSNK1G1 
                 CK1 
                 CK1 
                 19 
               
               
                 RSK3(Kin.Dom.1-N-terminal) 
                 AGC 
                 RSK 
                 19 
               
               
                 JAK2(JH1domain-catalytic) 
                 TK 
                 JakA 
                 18 
               
               
                 EGFR(S752-I759del) 
                 TK 
                 EGFR 
                 18 
               
               
                 OSR1 
                 STE 
                 STE20 
                 18 
               
               
                 TLK1 
                 Other 
                 TLK 
                 18 
               
               
                 PAK3 
                 STE 
                 STE20 
                 17 
               
               
                 HUNK 
                 CAMK 
                 CAMKL 
                 17 
               
               
                 AKT3 
                 AGC 
                 AKT 
                 17 
               
               
                 ABL1(E255K)-phosphorylated 
                 TK 
                 Abl 
                 16 
               
               
                 AXL 
                 TK 
                 Axl 
                 16 
               
               
                 EGFR(L747-S752del, P753S) 
                 TK 
                 EGFR 
                 16 
               
               
                 RIPK5 
                 TKL 
                 RIPK 
                 16 
               
               
                 PRKG1 
                 AGC 
                 PKC 
                 16 
               
               
                 ABL1(T315I)-nonphosphorylated 
                 TK 
                 Abl 
                 15 
               
               
                 ABL1(T315I)-phosphorylated 
                 TK 
                 Abl 
                 15 
               
               
                 KIT(D816H) 
                 TK 
                 PDGFR 
                 15 
               
               
                 LKB1 
                 CAMK 
                 CAMKL 
                 15 
               
               
                 RET(M918T) 
                 TK 
                 Ret 
                 15 
               
               
                 CSF1R-autoinhibited 
                 TK 
                 PDGFR 
                 15 
               
               
                 ADCK3 
                 Atypical 
                 ABC1 
                 15 
               
               
                 GRK7 
                 AGC 
                 GRK 
                 15 
               
               
                 CDC2L2 
                 CMGC 
                 CDK 
                 15 
               
               
                 CSNK1G3 
                 CK1 
                 CK1 
                 14 
               
               
                 NDR2 
                 AGC 
                 NDR 
                 14 
               
               
                 RSK4(Kin.Dom.2-C-terminal) 
                 AGC 
                 RSK 
                 14 
               
               
                 CAMK1D 
                 CAMK 
                 CAMK1 
                 13 
               
               
                 PLK4 
                 Other 
                 PLK 
                 13 
               
               
                 FGR 
                 TK 
                 Src 
                 13 
               
               
                 LIMK2 
                 TKL 
                 LISK 
                 13 
               
               
                 ASK1 
                 STE 
                 STE11 
                 13 
               
               
                 ABL1(M351T)-phosphorylated 
                 TK 
                 Abl 
                 12 
               
               
                 PDGFRA 
                 TK 
                 PDGFR 
                 12 
               
               
                 TBK1 
                 Other 
                 IKK 
                 12 
               
               
                 FGFR3 
                 TK 
                 FGFR 
                 12 
               
               
                 RET(V804L) 
                 TK 
                 Ret 
                 12 
               
               
                 RSK4(Kin.Dom.1-N-terminal) 
                 AGC 
                 RSK 
                 12 
               
               
                 MAPKAPK5 
                 CAMK 
                 MAPKAPK 
                 12 
               
               
                 ABL1-nonphosphorylated 
                 TK 
                 Abl 
                 11 
               
               
                 FLT1 
                 TK 
                 VEGFR 
                 11 
               
               
                 STK35 
                 Other 
                 NKF4 
                 11 
               
               
                 DAPK3 
                 CAMK 
                 DAPK 
                 11 
               
               
                 NEK5 
                 Other 
                 NEK 
                 11 
               
               
                 PAK7 
                 STE 
                 STE20 
                 11 
               
               
                 MEK1 
                 STE 
                 STE7 
                 11 
               
               
                 MST3 
                 STE 
                 STE20 
                 11 
               
               
                 PIK3CA 
                 LIPID 
                 PI3K 
                 11 
               
               
                 NEK1 
                 Other 
                 NEK 
                 10 
               
               
                 DMPK 
                 AGC 
                 DMPK 
                 10 
               
               
                 p38-delta 
                 CMGC 
                 MAPK 
                 10 
               
               
                 DYRK1A 
                 CMGC 
                 DYRK 
                 9 
               
               
                 JNK3 
                 CMGC 
                 MAPK 
                 9 
               
               
                 DAPK1 
                 CAMK 
                 DAPK 
                 9 
               
               
                 ERK8 
                 CMGC 
                 MAPK 
                 9 
               
               
                 PIK3CA(I800L) 
                 LIPID 
                 PI3K 
                 9 
               
               
                 RIPK1 
                 TKL 
                 RIPK 
                 9 
               
               
                 CHEK2 
                 CAMK 
                 RAD53 
                 9 
               
               
                 PRKD2 
                 AGC 
                 PKC 
                 9 
               
               
                 PKAC-beta 
                 AGC 
                 PKA 
                 9 
               
               
                 EPHA2 
                 TK 
                 Eph 
                 9 
               
               
                 DDR2 
                 TK 
                 DDR 
                 8 
               
               
                 LATS2 
                 AGC 
                 NDR 
                 8 
               
               
                 NEK2 
                 Other 
                 NEK 
                 8 
               
               
                 PIK3CG 
                 LIPID 
                 PI3K 
                 8 
               
               
                 PKN1 
                 AGC 
                 PKN 
                 8 
               
               
                 ITK 
                 TK 
                 Tec 
                 8 
               
               
                 SIK 
                 CAMK 
                 CAMKL 
                 8 
               
               
                 AURKC 
                 Other 
                 AUR 
                 7 
               
               
                 PRKR 
                 Other 
                 PEK 
                 7 
               
               
                 RIPK2 
                 TKL 
                 RIPK 
                 7 
               
               
                 FRK 
                 TK 
                 Src 
                 7 
               
               
                 MAP3K1 
                 STE 
                 STE11 
                 7 
               
               
                 PFTK1 
                 CMGC 
                 CDK 
                 7 
               
               
                 CLK4 
                 CMGC 
                 CLK 
                 6 
               
               
                 FLT4 
                 TK 
                 VEGFR 
                 6 
               
               
                 DRAK1 
                 CAMK 
                 DAPK 
                 6 
               
               
                 ROCK1 
                 AGC 
                 DMPK 
                 6 
               
               
                 CDK4-cyclinD3 
                 CMGC 
                 CDK 
                 6 
               
               
                 PRKCQ 
                 AGC 
                 PKC 
                 6 
               
               
                 AURKA 
                 Other 
                 AUR 
                 5 
               
               
                 ABL2 
                 TK 
                 Abl 
                 5 
               
               
                 NEK4 
                 Other 
                 NEK 
                 5 
               
               
                 PIM1 
                 CAMK 
                 PIM 
                 5 
               
               
                 EGFR(L747-E749del, A750P) 
                 TK 
                 EGFR 
                 4 
               
               
                 HPK1 
                 STE 
                 STE20 
                 4 
               
               
                 RET 
                 TK 
                 Ret 
                 4 
               
               
                 TTK 
                 Other 
                 TTK 
                 4 
               
               
                 ACVR2B 
                 TKL 
                 STKR 
                 4 
               
               
                 BRSK1 
                 CAMK 
                 CAMKL 
                 4 
               
               
                 HCK 
                 TK 
                 Src 
                 4 
               
               
                 DMPK2 
                 AGC 
                 DMPK 
                 4 
               
               
                 TAOK2 
                 STE 
                 STE20 
                 4 
               
               
                 ABL1(Y253F)-phosphorylated 
                 TK 
                 Abl 
                 3 
               
               
                 TAK1 
                 TKL 
                 MLK 
                 3 
               
               
                 NEK6 
                 Other 
                 NEK 
                 3 
               
               
                 TNNI3K 
                 Other 
                   
                 3 
               
               
                 ZAP70 
                 TK 
                 Syk 
                 3 
               
               
                 ABL1(Q252H)-nonphosphorylated 
                 TK 
                 Abl 
                 2 
               
               
                 CDKL5 
                 CMGC 
                 CDKL 
                 2 
               
               
                 RPS6KA5(Kin.Dom.2-C-terminal) 
                 AGC 
                 RSK 
                 2 
               
               
                 SYK 
                 TK 
                 Syk 
                 2 
               
               
                 FAK 
                 TK 
                 Fak 
                 2 
               
               
                 PIP5K2C 
                 LIPID 
                 PIP 
                 2 
               
               
                 BRK 
                 TK 
                 Src 
                 2 
               
               
                 CDK3 
                 CMGC 
                 CDK 
                 2 
               
               
                 ERK5 
                 CMGC 
                 MAPK 
                 2 
               
               
                 RET(V804M) 
                 TK 
                 Ret 
                 1 
               
               
                 PAK2 
                 STE 
                 STE20 
                 1 
               
               
                 CDC2L5 
                 CMGC 
                 CDK 
                 1 
               
               
                 CDM-cyclinD1 
                 CMGC 
                 CDK 
                 1 
               
               
                 PCTK2 
                 CMGC 
                 CDK 
                 1 
               
               
                 IRAK3 
                 TKL 
                 IRAK 
                 0 
               
               
                 KIT(V559D, V654A) 
                 TK 
                 PDGFR 
                 0 
               
               
                 AAK1 
                 Other 
                 NAK 
                 0 
               
               
                 ABL1(Q252H)-phosphorylated 
                 TK 
                 Abl 
                 0 
               
               
                 AURKB 
                 Other 
                 AUR 
                 0 
               
               
                 CIT 
                 AGC 
                 DMPK 
                 0 
               
               
                 CLK1 
                 CMGC 
                 CLK 
                 0 
               
               
                 CLK2 
                 CMGC 
                 CLK 
                 0 
               
               
                 EPHA1 
                 TK 
                 Eph 
                 0 
               
               
                 EPHB6 
                 TK 
                 Eph 
                 0 
               
               
                 HIPK1 
                 CMGC 
                 DYRK 
                 0 
               
               
                 HIPK4 
                 CMGC 
                 DYRK 
                 0 
               
               
                 IRAK1 
                 TKL 
                 IRAK 
                 0 
               
               
                 JAK3(JH1domain-catalytic) 
                 TK 
                 JakA 
                 0 
               
               
                 JNK2 
                 CMGC 
                 MAPK 
                 0 
               
               
                 KIT(V559D, T670I) 
                 TK 
                 PDGFR 
                 0 
               
               
                 LCK 
                 TK 
                 Src 
                 0 
               
               
                 MAP4K4 
                 STE 
                 STE20 
                 0 
               
               
                 MINK 
                 STE 
                 STE20 
                 0 
               
               
                 SIK2 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 SLK 
                 STE 
                 STE20 
                 0 
               
               
                 SNARK 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 STK16 
                 Other 
                 NAK 
                 0 
               
               
                 VEGFR2 
                 TK 
                 VEGFR 
                 0 
               
               
                 YSK4 
                 STE 
                 STE20 
                 0 
               
               
                 ACVR1 
                 TKL 
                 STKR 
                 0 
               
               
                 BMPR2 
                 TKL 
                 STKR 
                 0 
               
               
                 BRAF(V600E) 
                 TKL 
                 RAF 
                 0 
               
               
                 BUB1 
                 Other 
                 BUB 
                 0 
               
               
                 CAMK1 
                 CAMK 
                 CAMK1 
                 0 
               
               
                 CDK7 
                 CMGC 
                 CDK 
                 0 
               
               
                 CDKL2 
                 CMGC 
                 CDKL 
                 0 
               
               
                 CLK3 
                 CMGC 
                 CLK 
                 0 
               
               
                 CSF1R 
                 TK 
                 PDGFR 
                 0 
               
               
                 CSNK2A1 
                 Other 
                 CK2 
                 0 
               
               
                 DAPK2 
                 CAMK 
                 DAPK 
                 0 
               
               
                 DRAK2 
                 CAMK 
                 DAPK 
                 0 
               
               
                 DYRK1B 
                 CMGC 
                 DYRK 
                 0 
               
               
                 DYRK2 
                 CMGC 
                 DYRK 
                 0 
               
               
                 ERK3 
                 CMGC 
                 MAPK 
                 0 
               
               
                 FGFR1 
                 TK 
                 FGFR 
                 0 
               
               
                 GCN2(Kin.Dom.2, S808G) 
                 Other 
                 PEK 
                 0 
               
               
                 GRK4 
                 AGC 
                 GRK 
                 0 
               
               
                 HIPK2 
                 CMGC 
                 DYRK 
                 0 
               
               
                 HIPK3 
                 CMGC 
                 DYRK 
                 0 
               
               
                 JAK1(JH2domain-pseudokinase) 
                 TK 
                 JakA 
                 0 
               
               
                 LOK 
                 STE 
                 STE20 
                 0 
               
               
                 LTK 
                 TK 
                 Alk 
                 0 
               
               
                 MAP4K3 
                 STE 
                 STE20 
                 0 
               
               
                 MAST1 
                 AGC 
                 MAST 
                 0 
               
               
                 MEK3 
                 STE 
                 STE7 
                 0 
               
               
                 MLCK 
                 CAMK 
                 MLCK 
                 0 
               
               
                 MYLK2 
                 CAMK 
                 MLCK 
                 0 
               
               
                 MYLK4 
                 CAMK 
                 MLCK 
                 0 
               
               
                 NEK3 
                 Other 
                 NEK 
                 0 
               
               
                 NEK9 
                 Other 
                 NEK 
                 0 
               
               
                 PAK4 
                 STE 
                 STE20 
                 0 
               
               
                 PHKG2 
                 CAMK 
                 PHK 
                 0 
               
               
                 PIP5K2B 
                 LIPID 
                 PIP 
                 0 
               
               
                 PRKD3 
                 AGC 
                 PKC 
                 0 
               
               
                 PRP4 
                 CMGC 
                 DYRK 
                 0 
               
               
                 SgK110 
                 Other 
                 NKF1 
                 0 
               
               
                 SGK3 
                 AGC 
                 SGK 
                 0 
               
               
                 SRPK1 
                 CMGC 
                 SRPK 
                 0 
               
               
                 SRPK2 
                 CMGC 
                 SRPK 
                 0 
               
               
                 SRPK3 
                 CMGC 
                 SRPK 
                 0 
               
               
                 TIE1 
                 TK 
                 Tie 
                 0 
               
               
                 TRKB 
                 TK 
                 Trk 
                 0 
               
               
                 TYK2(JH2domain-pseudokinase) 
                 TK 
                 JakA 
                 0 
               
               
                 ZAK 
                 TKL 
                 MLK 
                 0 
               
               
                 ADCK4 
                 Atypical 
                 ABC1 
                 0 
               
               
                 AMPK-alpha1 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 AMPK-alpha2 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 ANKK1 
                 TKL 
                 RIPK 
                 0 
               
               
                 ARK5 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 BRAF 
                 TKL 
                 RAF 
                 0 
               
               
                 BRSK2 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 CAMK2A 
                 CAMK 
                 CAMK2 
                 0 
               
               
                 CAMK2D 
                 CAMK 
                 CAMK2 
                 0 
               
               
                 CAMKK2 
                 Other 
                 CAMKK 
                 0 
               
               
                 CDKL1 
                 CMGC 
                 CDKL 
                 0 
               
               
                 CHEK1 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 CSNK1G2 
                 CK1 
                 CK1 
                 0 
               
               
                 DCAMKL3 
                 CAMK 
                 DCAMKL 
                 0 
               
               
                 EGFR 
                 TK 
                 EGFR 
                 0 
               
               
                 EGFR(E746-A750del) 
                 TK 
                 EGFR 
                 0 
               
               
                 EGFR(G719S) 
                 TK 
                 EGFR 
                 0 
               
               
                 EGFR(L747-T751del, Sins) 
                 TK 
                 EGFR 
                 0 
               
               
                 EGFR(L858R) 
                 TK 
                 EGFR 
                 0 
               
               
                 EGFR(L861Q) 
                 TK 
                 EGFR 
                 0 
               
               
                 EPHB4 
                 TK 
                 Eph 
                 0 
               
               
                 FGFR3(G697C) 
                 TK 
                 FGFR 
                 0 
               
               
                 GSK3A 
                 CMGC 
                 GSK 
                 0 
               
               
                 GSK3B 
                 CMGC 
                 GSK 
                 0 
               
               
                 IKK-alpha 
                 Other 
                 IKK 
                 0 
               
               
                 IKK-beta 
                 Other 
                 IKK 
                 0 
               
               
                 IRAK4 
                 TKL 
                 IRAK 
                 0 
               
               
                 KIT-autoinhibited 
                 TK 
                 PDGFR 
                 0 
               
               
                 LATS1 
                 AGC 
                 NDR 
                 0 
               
               
                 LRRK2 
                 TKL 
                 LRRK 
                 0 
               
               
                 LRRK2(G2019S) 
                 TKL 
                 LRRK 
                 0 
               
               
                 LYN 
                 TK 
                 Src 
                 0 
               
               
                 MAP3K15 
                 STE 
                 STE11 
                 0 
               
               
                 MAP3K3 
                 STE 
                 STE11 
                 0 
               
               
                 MARK3 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 MARK4 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 MEK2 
                 STE 
                 STE7 
                 0 
               
               
                 MET(M1250T) 
                 TK 
                 Met 
                 0 
               
               
                 MLK3 
                 TKL 
                 MLK 
                 0 
               
               
                 MST2 
                 STE 
                 STE20 
                 0 
               
               
                 MST4 
                 STE 
                 STE20 
                 0 
               
               
                 MUSK 
                 TK 
                 Musk 
                 0 
               
               
                 NDR1 
                 AGC 
                 NDR 
                 0 
               
               
                 NLK 
                 CMGC 
                 MAPK 
                 0 
               
               
                 PAK6 
                 STE 
                 STE20 
                 0 
               
               
                 PCTK1 
                 CMGC 
                 CDK 
                 0 
               
               
                 PHKG1 
                 CAMK 
                 PHK 
                 0 
               
               
                 PIK3CA(H1047L) 
                 LIPID 
                 PI3K 
                 0 
               
               
                 PIK4CB 
                 LIPID 
                 PI4K 
                 0 
               
               
                 PIP5K1C 
                 LIPID 
                 PIP 
                 0 
               
               
                 PKN2 
                 AGC 
                 PKN 
                 0 
               
               
                 PRKD1 
                 AGC 
                 PKC 
                 0 
               
               
                 ROS1 
                 TK 
                 Sev 
                 0 
               
               
                 S6K1 
                 AGC 
                 RSK 
                 0 
               
               
                 SBK1 
                 Other 
                 NKF1 
                 0 
               
               
                 STK39 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 TGFBR2 
                 TKL 
                 STKR 
                 0 
               
               
                 TNK1 
                 TK 
                 Ack 
                 0 
               
               
                 TSSK1B 
                 CAMK 
                 TSSK 
                 0 
               
               
                 TYRO3 
                 TK 
                 Axl 
                 0 
               
               
                 ULK2 
                 Other 
                 ULK 
                 0 
               
               
                 YSK1 
                 STE 
                 STE20 
                 0 
               
               
                 ACVR2A 
                 TKL 
                 STKR 
                 0 
               
               
                 ACVRL1 
                 TKL 
                 STKR 
                 0 
               
               
                 CAMK1G 
                 CAMK 
                 CAMK1 
                 0 
               
               
                 CAMK2B 
                 CAMK 
                 CAMK2 
                 0 
               
               
                 CAMK2G 
                 CAMK 
                 CAMK2 
                 0 
               
               
                 CAMK4 
                 CAMK 
                 CAMK1 
                 0 
               
               
                 CAMKK1 
                 Other 
                 CAMKK 
                 0 
               
               
                 CDKL3 
                 CMGC 
                 CDKL 
                 0 
               
               
                 DDR1 
                 TK 
                 DDR 
                 0 
               
               
                 DLK 
                 TKL 
                 MLK 
                 0 
               
               
                 EPHA6 
                 TK 
                 Eph 
                 0 
               
               
                 EPHB1 
                 TK 
                 Eph 
                 0 
               
               
                 ERBB2 
                 TK 
                 EGFR 
                 0 
               
               
                 ERBB3 
                 TK 
                 EGFR 
                 0 
               
               
                 ERK4 
                 CMGC 
                 MAPK 
                 0 
               
               
                 ERN1 
                 Other 
                 IRE 
                 0 
               
               
                 FGFR4 
                 TK 
                 FGFR 
                 0 
               
               
                 ICK 
                 CMGC 
                 RCK 
                 0 
               
               
                 INSRR 
                 TK 
                 InaR 
                 0 
               
               
                 JAK1(JH1domain-catalytic) 
                 TK 
                 JakA 
                 0 
               
               
                 LIMK1 
                 TKL 
                 LISK 
                 0 
               
               
                 LZK 
                 TKL 
                 MLK 
                 0 
               
               
                 MAP4K5 
                 STE 
                 STE20 
                 0 
               
               
                 MARK1 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 MKNK1 
                 CAMK 
                 MAPKAPK 
                 0 
               
               
                 MLK1 
                 TKL 
                 MLK 
                 0 
               
               
                 MLK2 
                 TKL 
                 MLK 
                 0 
               
               
                 MRCKA 
                 AGC 
                 DMPK 
                 0 
               
               
                 MRCKB 
                 AGC 
                 DMPK 
                 0 
               
               
                 MST1 
                 STE 
                 STE20 
                 0 
               
               
                 MST1R 
                 TK 
                 Met 
                 0 
               
               
                 NIM1 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 PAK1 
                 STE 
                 STE20 
                 0 
               
               
                 PIK3CA(E542K) 
                 LIPID 
                 PI3K 
                 0 
               
               
                 PIK3CA(E545K) 
                 LIPID 
                 PI3K 
                 0 
               
               
                 PIM3 
                 CAMK 
                 PIM 
                 0 
               
               
                 PRKCD 
                 AGC 
                 PKC 
                 0 
               
               
                 PRKCE 
                 AGC 
                 PKC 
                 0 
               
               
                 PRKG2 
                 AGC 
                 PKC 
                 0 
               
               
                 PYK2 
                 TK 
                 Fak 
                 0 
               
               
                 QSK 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 RPS6KA4(Kin.Dom.1-N-terminal) 
                 AGC 
                 RSK 
                 0 
               
               
                 RPS6KA5(Kin.Dom.1-N-terminal) 
                 AGC 
                 RSK 
                 0 
               
               
                 RSK1(Kin.Dom.1-N-terminal) 
                 AGC 
                 RSK 
                 0 
               
               
                 RSK3(Kin.Dom.2-C-terminal) 
                 AGC 
                 RSK 
                 0 
               
               
                 SNRK 
                 CAMK 
                 CAMKL 
                 0 
               
               
                 STK36 
                 Other 
                 ULK 
                 0 
               
               
                 TLK2 
                 Other 
                 TLK 
                 0 
               
               
                 WEE1 
                 Other 
                 WEE 
                 0 
               
               
                 WEE2 
                 Other 
                 WEE 
                 0 
               
               
                 WNK3 
                 Other 
                 Wnk 
                 0 
               
               
                 YANK1 
                 AGC 
                 YANK 
                 0 
               
               
                 YES 
                 TK 
                 Src 
                 0 
               
               
                 ACVR1B 
                 TKL 
                 STKR 
                 0 
               
               
                 AKT2 
                 AGC 
                 AKT 
                 0 
               
               
                 ASK2 
                 STE 
                 STE11 
                 0 
               
               
                 BMPR1A 
                 TKL 
                 STKR 
                 0 
               
               
                 BTK 
                 TK 
                 Tec 
                 0 
               
               
                 CASK 
                 CAMK 
                 CASK 
                 0 
               
               
                 CDC2L1 
                 CMGC 
                 CDK 
                 0 
               
               
                 CDK11 
                 CMGC 
                 CDK 
                 0 
               
               
                 CDK2 
                 CMGC 
                 CDK 
                 0 
               
               
                 CDK5 
                 CMGC 
                 CDK 
                 0 
               
               
                 CDK8 
                 CMGC 
                 CDK 
                 0 
               
               
                 CDK9 
                 CMGC 
                 CDK 
                 0 
               
               
                 CSK 
                 TK 
                 Csk 
                 0 
               
               
                 DCAMKL2 
                 CAMK 
                 DCAMKL 
                 0 
               
               
                 EIF2AK1 
                 Other 
                 PEK 
                 0 
               
               
                 EPHA4 
                 TK 
                 Eph 
                 0 
               
               
                 EPHA5 
                 TK 
                 Eph 
                 0 
               
               
                 EPHA7 
                 TK 
                 Eph 
                 0 
               
               
                 EPHA8 
                 TK 
                 Eph 
                 0 
               
               
                 EPHB2 
                 TK 
                 Eph 
                 0 
               
               
                 EPHB3 
                 TK 
                 Eph 
                 0 
               
               
                 ERBB4 
                 TK 
                 EGFR 
                 0 
               
               
                 ERK1 
                 CMGC 
                 MAPK 
                 0 
               
               
                 ERK2 
                 CMGC 
                 MAPK 
                 0 
               
               
                 FER 
                 TK 
                 Fer 
                 0 
               
               
                 FES 
                 TK 
                 Fer 
                 0 
               
               
                 IGF1R 
                 TK 
                 InsR 
                 0 
               
               
                 MAK 
                 CMGC 
                 RCK 
                 0 
               
               
                 MAP3K4 
                 STE 
                 STE11 
                 0 
               
               
                 MAPKAPK2 
                 CAMK 
                 MAPKAPK 
                 0 
               
               
                 MET 
                 TK 
                 Met 
                 0 
               
               
                 MET(Y1235D) 
                 TK 
                 Met 
                 0 
               
               
                 MTOR 
                 Atypical 
                 PIKK 
                 0 
               
               
                 MYO3A 
                 STE 
                 STE20 
                 0 
               
               
                 MYO3B 
                 STE 
                 STE20 
                 0 
               
               
                 NEK11 
                 Other 
                 NEK 
                 0 
               
               
                 NEK7 
                 Other 
                 NEK 
                 0 
               
               
                 p38-alpha 
                 CMGC 
                 MAPK 
                 0 
               
               
                 p38-beta 
                 CMGC 
                 MAPK 
                 0 
               
               
                 PCTK3 
                 CMGC 
                 CDK 
                 0 
               
               
                 PFPK5( P. falciparum ) 
                 Pathogen 
                 
                   P. Falciparum 
                 
                 0 
               
               
                 PFTAIRE2 
                 CMGC 
                 CDK 
                 0 
               
               
                 PIK3CB 
                 LIPID 
                 PI3K 
                 0 
               
               
                 PKMYT1 
                 Other 
                 WEE 
                 0 
               
               
                 PLK1 
                 Other 
                 PLK 
                 0 
               
               
                 PRKCH 
                 AGC 
                 PKC 
                 0 
               
               
                 PRKCI 
                 AGC 
                 PKC 
                 0 
               
               
                 PRKX 
                 AGC 
                 PKA 
                 0 
               
               
                 RAF1 
                 TKL 
                 RAF 
                 0 
               
               
                 RSK2(Kin.Dom.2-C-terminal) 
                 AGC 
                 RSK 
                 0 
               
               
                 TEC 
                 TK 
                 Tec 
                 0 
               
               
                 TESK1 
                 TKL 
                 LISK 
                 0 
               
               
                 TGFBR1 
                 TKL 
                 STKR 
                 0 
               
               
                 TIE2 
                 TK 
                 Tie 
                 0 
               
               
                 TNK2 
                 TK 
                 Ack 
                 0 
               
               
                 TRPM6 
                 Atypical 
                 Alpha 
                 0 
               
               
                 TXK 
                 TK 
                 Tec 
                 0 
               
               
                 WNK1 
                 Other 
                 Wnk 
                 0 
               
               
                 YANK2 
                 AGC 
                 YANK 
                 0 
               
               
                 YANK3 
                 AGC 
                 YANK 
                 0 
               
               
                   
               
             
          
         
       
     
         [0162]    Based on our measurements and the scientific literature we conclude that the presented styryl quinazoline derivatives are candidates for further development of signal transduction cancer therapy, especially for AML patients. The compounds are highly selective for FLT3 mutations, they have a considerably good IC 50  values in in vitro FLT3(ITD) biochemical assay and in MV11-4 cell viability assay. Together with the known effect of styryl quinazolines on P53 tumor suppressor protein the data presented shows that they are potent candidates to develop a selective and sophistically targeted therapy in case of FLT3(ITD) and other FLT3 mutations which is fairly common among leukemia patients. 
       Determination of Antibacterial Activity 
     Minimal Inhibitory Concentration (MIC) 
       [0163]    The European Committee for Antimicrobial Susceptibility Testing (EUCAST) defines the Minimal Inhibitory Concentration (MIC) as the lowest concentration of an antibiotic that inhibits the growth of a bacterial inoculum, under defined in vitro conditions. The MICs were determined for  Escherichia coli  strains LMC500 (F, araD139, D(argF-lac)U169deoC1, flbB5301, ptsF25, rbsR, relA1, rpsIL150, lysA1) and BW25113 (F, DE(araD-araB)567, lacZ4787(del):rmB-3, LAM, rph-1, DE(rhaD-rhaB)568, hsdR514 dAcrA dAcrB dtolC). The former stain is a wild type  E. coli  K12 strain and the latter strain modified in such a way that it cannot produce the ToIC multidrug efflux pump. Therefore, it is expected to be more susceptible to inhibitors that may be otherwise ignored. The defined medium used was tryptone yeast-extract (TY)-medium composed of 10 g/l Tryptone (Bacto), 5 g/l yeast extract (Bacto) and 5 g/l NaCl. 
         [0164]    The compounds were diluted to stock solutions of 1024 μg/ml in MilliQ ultrafiltrated distilled water (hereinafter MilliQ) and in DMSO and in a varying composition mixture of MilliQ and DMSO. Solubility was tested by visual inspection and poorly dissolving compounds were dissolved in higher concentrations of DMSO in the mixture but not higher than 50% to prevent adverse effects on bacterial growth by the suspension form it self. For the MIC test first the compounds were diluted to 256 μg/ml in MilliQ and two-fold serial dilutions in MilliQ were prepared from well A to D or E to H in a 96-well plate with an end volume of 75 μl. The inoculum was prepared by suspending a logarithmically growing bacterial culture in 2×TY medium to match an optical density at 600 nm wavelength (OD 600 ) of 0.001 (cuvettes 1 cm in diameter, VWR) using a spectrophotometer (Biochrom Libra S22). Seventy-five μl of this suspension was then added to the wells, resulting in antibiotic end concentrations ranging from 128 to 16 μg/ml in wells A to D and E to H. Groups without antibiotics but with comparable DMSO concentrations or groups without bacteria served as positive and negative controls, respectively. The 96-wells plates were incubated overnight at 37° C. and were shaken the platereader (SYNERGY BIOTEK) during which the OD 600  values were measured every 10 min. The next day the growth data were analysed and MIC values were determined. The inoculum was quantified by plating 10-fold serial dilutions in PBS (10 −2  to 10 −7 ) on TY agar plates, which were incubated overnight at 37° C. The next day the colonies were counted and the CFU/well values were calculated. All MIC experiments were performed in duplicates. For those compounds that showed a MIC of less than 16 μg/ml, the assay was repeated with antibiotic end concentrations of 128 to 0.125 μg/ml. 
       Minimal Bactericidal Concentration (MBC) 
       [0165]    The minimal bactericidal concentration (MBC) is defined as the lowest concentration of an antibiotic that, under defined in vitro conditions reduces the number of bacteria by 99.9%. All MIC experiments with compounds exhibiting growth reduction were chosen for MBC testing. MBC tests were performed by plating 10 μl of a finished liquid MIC test from the 96 well plate on TY agar. The plates were then incubated overnight at 37° C. The next day the MBC was determined as the lowest concentration at which less than 10 colonies grew (&gt;99.99% reduction of the inoculum). All MBC experiments were performed in duplicates. 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                   
                 
                   Bacillus 
                 
               
               
                   
                 ΔAcrAB TolC 
                 LMC500 
                   subtilis  168 
               
             
          
           
               
                   
                 MIC 
                 MBC 
                 MIC 
                 MBC 
                 MIC 
               
               
                 Example 
                 (μg/ml) 
                 (μg/ml) 
                 (μg/ml) 
                 (μg/ml) 
                 (μg/ml) 
               
               
                   
               
             
          
           
               
                 1 
                 8 
                 8 
                 32 
                 32 
                 8 
               
               
                 3 
                 32 
                 64 
                 &gt;128 
                 ND 
                 ND 
               
               
                 7 
                 8 
                 8 
                 32 
                 32 
                 8 
               
               
                 20 
                 8 
                 8 
                 &lt;16 
                 &lt;16 
                 4 
               
               
                 23 
                 32/64 
                 32 
                 &gt;128 
                 ND 
                 ND 
               
               
                 78 
                 32 
                 &lt;16 
                 64 
                 &gt;128 
                 ND 
               
               
                 99 
                 32 
                 &lt;16 
                 64 
                 64 
                 ND 
               
               
                 109 
                 &lt;16 
                 &lt;16 
                 64 
                 64 
                 ND 
               
               
                 112 
                 8 
                 8 
                 32 
                 &gt;128 
                 8