various publications are cited throughout the present application . the contents of these publications and contents of documents cited in these publications are incorporated herein by reference . histone deacetylase ( hdac ) proteins play a critical role in regulating gene expression in vivo by altering the accessibility of genomic dna to transcription factors . specifically , hdac proteins remove the acetyl group of acetyl - lysine residues on histones , which can result in nucleosomal remodelling ( grunstein , m ., 1997 , nature , 389 : 349 - 352 ). due to their governing role in gene expression , hdac proteins are associated with a variety of cellular events , including cell cycle regulation , cell proliferation , differentiation , reprogramming of gene expression , and cancer development ( ruijter , a - j - m ., 2003 , biochem . j ., 370 : 737 - 749 ; grignani , f ., 1998 , nature , 391 : 815 - 818 ; lin , r - j ., 1998 , 391 : 811 - 814 ; marks , p - a ., 2001 , nature reviews cancer , 1 : 194 ). in fact , hdac inhibitors have been demonstrated to reduce tumor growth in various human tissues and in animal studies , including lung , stomach , breast , and prostrate ( dokmanovic , m ., 2005 , j . cell biochenm ., 96 : 293 - 304 ). mammalian hdacs can be divided into three classes according to sequence homology . class i consists of the yeast rpd3 - like proteins ( hdac 1 , 2 , 3 , 8 and 11 ). class ii consists of the yeast hda1 - like proteins ( hdac 4 , 5 , 6 , 7 , 9 and 10 ). class iii consists of the yeast sir2 - like proteins ( sirt 1 , 2 , 3 , 4 , 5 , 6 and 7 ). the activity of hdac1 has been linked to cell proliferation , a hallmark of cancer . particularly , mammalian cells with knock down of hdac1 expression using sirna were antiproliferative ( glaser , k - b ., 2003 , biochem . biophys . res . comm ., 310 : 529 - 536 ). while the knock out mouse of hdac1 was embryonic lethal , the resulting stem cells displayed altered cell growth ( lagger , g ., 2002 , embo j ., 21 : 2672 - 2681 ). mouse cells overexpressing hdac1 demonstrated a lengthening of g 2 and m phases and reduced growth rate ( bartl . s ., 1997 , mol . cell . biol ., 17 : 5033 - 5043 ). therefore , the reported data implicate hdac1 in cell cycle regulation and cell proliferation . hdac2 regulates expression of many fetal cardiac isoforms . hdac2 deficiency or chemical inhibition of histone deacetylase prevented the re - expression of fetal genes and attenuated cardiac hypertrophy in hearts exposed to hypertrophic stimuli . resistance to hypertrophy was associated with increased expression of the gene encoding inositol polyphosphate - 5 - phosphatase f ( inpp5f ) resulting in constitutive activation of glycogen synthase kinase 3β ( gsk3β ) via inactivation of thymoma viral proto - oncogene ( akt ) and 3 - phosphoinositide - dependent protein kinase - 1 ( pdk1 ). in contrast , hdac2 transgenic mice had augmented hypertrophy associated with inactivated gsk3β . chemical inhibition of activated gsk3β allowed hdac2 - deficient adults to become sensitive to hypertrophic stimulation . these results suggest that hdac2 is an important molecular target of hdac inhibitors in the heart and that hdac2 and gsk3β are components of a regulatory pathway providing an attractive therapeutic target for the treatment of cardiac hypertrophy and heart failure ( trivedi , c - m ., 2007 , nat . med . 13 : 324 - 331 ). hdac3 are maximally expressed in proliferating crypt cells in normal intestine . silencing of hdac3 expression in colon cancer cell lines resulted in growth inhibition , a decrease in cell survival , and increased apoptosis . similar effects were observed for hdac2 and , to a lesser extent , for hdac1 . hdac3 gene silencing also selectively induced expression of alkaline phosphatase , a marker of colon cell maturation . concurrent with its effect on cell growth , overexpression of hdac3 inhibited basal and butyrate - induced p21 transcription in a sp1 / sp3 - dependent manner , whereas silencing of hdac3 stimulated p21 promoter activity and expression . these findings identify hdac3 as a gene deregulated in human colon cancer and as a novel regulator of colon cell maturation and p21 expression ( wilson , a - j ., 2006 , j . biol . chem ., 281 : 13548 - 13558 ). hdac6 is a subtype of the hdac family that deacetylates alpha - tubulin and increases cell motility . using quantitative real - time reverse transcription polymerase chain reaction and western blots on nine oral squamous cell carcinoma ( oscc )- derived cell lines and normal oral keratinocytes ( noks ), hdac6 mrna and protein expression were commonly up - regulated in all cell lines compared with the noks . immunofluorescence analysis detected hdac6 protein in the cytoplasm of oscc cell lines . similar to oscc cell lines , high frequencies of hdac6 up - regulation were evident in both mrna ( 74 %) and protein ( 51 %) levels of primary human oscc tumors . among the clinical variables analyzed , the clinical tumor stage was found to be associated with the hdac6 expression states . the analysis indicated a significant difference in the hdac6 expression level between the early stage ( stage i and ii ) and advanced - stage ( stage iii and iv ) tumors ( p = 0 . 014 ). these results suggest that hdac6 expression may be correlated with tumor aggressiveness and offer clues to the planning of new treatments ( sakuma , t ., 2006 , int . j . oncol ., 29 : 117 - 124 ). epigenetic silencing of functional chromosomes by hdac is one of major mechanisms occurred in many pathological processes , in which functionally critical genes are repressed or reprogrammed by hdac activities leading to the loss of phenotypes in terminal differentiation , maturation and growth control , and the loss of functionality of tissues . for example , tumor suppressor genes are often silenced during development of cancer and chemical inhibitor of hdac can derepressed the expression of these tumor suppressor genes , leading to growth arrest and differentiation ( glaros s et al ., 2007 , oncogene june 4 epub ahead of print ; mai , a , et al ., 2007 , int j . biochem cell bio ., april 4 , epub ahead of print ; vincent a . et al ., 2007 , oncogene , april 30 , epub ahead of print ; our unpublished results ); and repression of structural genes such as fxn in friedreich &# 39 ; s ataxia and smn in spinal muscular atrophy can be reversed by hdac inhibitors that lead to re - expression of fxn and smn genes and resume the functions in the tissues ( herman d et al ., 2006 , nature chemical biology , 2 ( 10 ): 551 - 8 ; avila a m et al ., 2007 , j clinic investigation , 117 ( 3 ) 659 - 71 ; de bore j , 2006 , tissue eng . 12 ( 10 ): 2927 - 37 ); induction of entire mhc ii family gene expression through reprogramming of hdac “ hot spot ” in chromosome 6p21 - 22 by hdac inhibitor further extend epigenetic modulation of immune recognition and immune response ( gialitakis m et al ., 2007 , nucleic acids res ., 34 ( 1 ); 765 - 72 ). several classes of hdac inhibitors have been identified , including ( 1 ) short - chain fatty acids , e . g . butyrate and phenylbutyrate ; ( 2 ) organic hydroxamic acids , e . g . suberoylanilide hydroxamic acid ( saha ) and trichostatin a ( tsa ); ( 3 ) cyclic tetrapeptides containing a 2 - amino - 8 - oxo 9 , 10 - expoxydecanoyl ( aoe ) moiety , e . g . trapoxin and hc - toxin ; ( 4 ) cyclic peptides without the aoe moiety , e . g . apicidin and fk228 ; and ( 5 ) benzamides , e . g . ms - 275 ( ep0847992a1 , us2002 / 0103192a1 , wo02 / 26696a1 , wo01 / 70675a2 , wo01 / 18171a2 ). although , hdac inherited very promising biological roles as a drug target especially on cancer biology side , such as preferential apoptosis - induction in malignant cells but not normal cells , differentiation of epithelia in cancer cells , anti - inflammatory and immunomodulation , and cell cycle arrest and can be consider as “ neo - chemotherapy ” with much improved toxicity over existing chemotherapy , the success of saha from merck is currently only limited to the treatment of cutaneous t cell lymphoma whereas no major solid tumors yet been reported to be highly effective by this treatment . therefore , there is still a need to discover new compounds with improved profiles , such as stronger hdac inhibitory activity and anti - cancer activity , more selective inhibition on different subtype of hdac , and lower toxicity . the favorite metaphor for cancer drug developers has long been the target therapy . one hoped to design a drug that could hit tumor cells in one specific target , knocking out tumor cells while leaving normal cells undamaged . cancer cells , however , can use multiple biological triggers and pathways to grow and spread throughout the body . hitting them in one target will also render them to regroup and redeploy along new growth paths . that realization has led to the development of combination target therapies , which are becoming the new paradigm for cancer treatment . several multi - target kinase inhibitors are now in development , two , sorafenib and suten , are already approved in the united states . for example , sorafenib , developed by bayer pharmaceuticals , is the first drug targeting both the raf / mek / erk pathway ( involved in cell proliferation ) and the vegfr2 / pdgfrβ signaling cascade ( involved in angiogenesis ). this drug was first approved in december 2005 for advanced kidney cancer , a disease that is believed to be highly dependent on angiogenesis . however , these target therapies , although are effective against some solid tumors , but far from satisfaction in terms of reaching a better efficacy as a single agent against other solid tumors while tolerable side - effects associated with treatment can be maintained . provided herein are new chemical compounds that combine anti - angiogenesis and anti - proliferation activities of rtk &# 39 ; s together with differentiation - inducing , immune modulation , cell cycle arrest and apoptosis - induction activities of more selective hdaci , to reach a better efficacy against solid tumors while overcoming side effects such as hypertension , qt prolongation , thyroid gland regression , skin rash and discoloration , and pains associated with currently marketed rtk inhibitors . particularly , the present invention provides a compound having the structure represented by formula ( i ), or its stereoisomer , enantiomer , diastereomer , hydrate , or pharmaceutically acceptable salts thereof : z is ch or n ; r 1 , r 2 and r 3 are independently hydrogen , halo , alkyl , alkoxy or trifluoromethyl ; r 4 is r 5 is one or more substituents selected from hydrogen , halo , alkyl , alkoxy or trifluoromethyl . in the preferred embodiment , the compounds of this invention are those of the formula ( i ), wherein z is ch ; r 1 , r 2 and r 3 are independently hydrogen , halo , alkyl , alkoxy or trifluoromethyl ; r 4 is r 5 is one or more substituents selected from hydrogen , halo , alkyl , alkoxy or trifluoromethyl . in another preferred embodiment , the compounds of this invention are those of the formula ( i ), wherein z is ch ; r 1 , r 2 and r 3 are independently hydrogen or alkoxy ; r 4 is r 5 is one or more substituents selected from hydrogen , halo , alkyl , alkoxy or trifluoromethyl . in another preferred embodiment , the compounds of this invention are those of the formula ( i ), wherein z is ch ; r 1 and r 2 are independently hydrogen or methoxy ; r 3 is h ; r 4 is r 5 is one or more substituents selected from hydrogen , halo , alkyl , alkoxy or trifluoromethyl . in another preferred embodiment , the compounds of this invention are those of the formula ( i ), wherein z is ch ; r 1 and r 2 are independently hydrogen or methoxy ; r 3 is h ; r 4 is in the above structural formula ( i ) and throughout the present specification , the following terms have the indicated meaning : the term “ halo ” as used herein means fluorine , chlorine , bromine or iodine . the term “ alkyl ” as used herein includes methyl , ethyl , n - propyl , iso - propyl , butyl , iso - butyl , sec - butyl , tert - butyl and the like . the term “ alkoxy ” as used herein includes methoxy , ethoxy , n - propoxy , isopropoxy , n - butoxy , isobutoxy and the like . the compound of formula ( ii ) is condensed with a compound of formula ( iii ) to give the title compound ( i ). the reaction is conducted by using a peptide condensing agent such as 1 - ethyl - 3 -( 3 - dimethylaminopropyl ) carbodiimide ( edc ), dicyclohexylcarbodiimide ( dcc ), n , n ′- carbonyldiimidazole ( cdi ), etc . the reaction may be conducted at 0 to 80 ° c . for 4 to 72 hours . solvents which may be used are normal solvents such as benzene , toluene , tetrahydrofuran , dioxane , dichloromethane , chloroform , n , n - dimethylformamide , etc . if necessary , a base such as sodium hydroxide , triethylamine and pyridine may be added to the reaction system . commercially available 6 - hydroxynaphthoic acid is heated in the presence of cesium carbonate and the appropriately substituted 4 - chloroquinoline ( iv ) in dmso to provide naphthoic acids ( ii ). the reaction may be conducted at 130 to 140 ° c . for 3 to 24 hours . the compounds of formula ( iii ) are commercially available or prepared as follows : commercially available compound ( v ) is condensed with a commercially available compound ( vi ) to provide compound ( vii ). the reaction is conducted by using a peptide condensing agent such as 1 - ethyl - 3 -( 3 - dimethylaminopropyl ) carbodiimide ( edc ), dicyclohexylcarbodiimide ( dcc ), n , n ′- carbonyldiimidazole ( cdi ), etc . the reaction may be conducted at 0 to 60 ° c . for 2 to 72 hours . solvents which may be used are normal solvents such as benzene , toluene , tetrahydrofuran , dioxane , dichloromethane , chloroform , n , n - dimethylformamide , etc . if necessary , a base such as sodium hydroxide , triethylamine and pyridine may be added to the reaction system . the compound ( vii ) is hydrogenated using 5 % palladium on charcoal catalyst in methanol to yield compound ( iiia ). the reaction may be conducted at room temperature . if necessary , an acid such as sulfuric acid may be added to the reaction system . the compounds represented by formula ( i ) may be purified or isolated by the conventional separation methods such as extraction , recrystallization , column chromatography and the like . the compounds represented by formula ( i ) are capable of inhibiting protein kinases and histone deacetylases and are therefore useful in treating diseases associated with abnormal protein kinase activities and abnormal histone deacetylase activities . in particular , they are highly effective against hematological malignancy and solid carcinomas . the compounds represented by formula ( i ) useful as a drug may be used in the form of a general pharmaceutical composition . the pharmaceutical composition may be in the forms normally employed , such as tablets , capsules , powders , syrups , solutions , suspensions , aerosols , and the like , may contain flavorants , sweeteners etc . in suitable solids or liquid carriers or diluents , or in suitable sterile media to form injectable solutions or suspensions . such composition typically contains from 0 . 5 to 70 %, preferably 1 to 20 % by weight of active compound , the remainder of the composition being pharmaceutically acceptable carriers , diluents or solvents or salt solutions . the compounds represented by formula ( i ) are clinically administered to mammals , including man and animals , via oral , nasal , transdermal , pulmonary , or parenteral routes . administration by the oral route is preferred , being more convenient and avoiding the possible pain and irritation of injection . by either route , the dosage is in the range of about 0 . 0001 to 200 mg / kg body weight per day administered singly or as a divided dose . however , the optimal dosage for the individual subject being treated will be determined by the person responsible for treatment , generally smaller dose being administered initially and thereafter increments made to determine the most suitable dosage . representative compounds of the present invention are shown in table 1 below . the compound numbers correspond to the “ example numbers ” in the examples section . that is , the synthesis of compound 16 as shown in the table 1 is described in “ example 16 ” and the synthesis of compound 44 as shown in the table 1 is described in “ example 44 ”. the compounds presented in the table 1 are exemplary only and are not to be construed as limiting the scope of this invention in any manner . further , all parts and percentages in the examples , as well as in the remainder of the specification , are by weight unless otherwise specified . any range of numbers recited in the specification or paragraphs hereinafter describing or claiming various aspects of the invention , such as that representing a particular set of properties , units of measure , conditions , physical states or percentages , is intended to literally incorporate expressly herein by reference or otherwise , any number falling within such range , including any subset of numbers or ranges subsumed within any range so recited . the term “ about ” when used as a modifier for , or in conjunction with , a variable , is intended to convey that the numbers and ranges disclosed herein are flexible and that practice of the present invention by those skilled in the art using temperatures , concentrations , amounts , contents , carbon numbers , and properties that are outside of the range or different from a single value , will achieve the desired result . 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 38 ml of dmso were stirred at room temperature while cesium carbonate ( 7 . 5 g , 22 . 9 mmol ) and 4 - chloro - 6 , 7 - dimethoxy - quinazoline ( 2 . 05 g , 9 . 14 mmol ) were added . the mixture was heated at 140 ° c . for 3 hours . the mixture was cooled to room temperature and diluted with 40 ml of h 2 o . the mixture was neutralized with 2 n hcl to 6 . 5 . the deposited solids were collected by vacuum filtration , washed with h 2 o , dried under vacuum and recrystallized from methanol to give the title compound ( 1 . 68 g , 59 % yield ) as a brown solid . lc - ms ( m / z ) 377 ( m + 1 ). the title compound ( 1 . 73 g , 66 % yield ) was prepared as a brown solid from 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 4 - chloro - 7 - methoxyquinoline ( 1 . 77 g , 9 . 14 mmol ) by an analogous procedure to that described in example 1 . lc - ms ( m / z ) 346 ( m + 1 ). the title compound ( 1 . 95 g , 68 % yield ) was prepared as a brown solid from 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 4 - chloro - 6 , 7 - dimethoxyquinoline ( 2 . 04 g , 9 . 14 mmol ) by an analogous procedure to that described in example 1 . lc - ms ( m / z ) 376 ( m + 1 ). the title compound ( 1 . 24 g , 52 % yield ) was prepared as a brown solid from 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 4 - chloroquinoline ( 1 . 49 g , 9 . 14 mmol ) by an analogous procedure to that described in example 1 . lc - ms ( m / z ) 316 ( m + 1 ). the title compound ( 1 . 25 g , 55 % yield ) was prepared as a brown solid from 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 4 - chloro - 8 - methylquinoline ( 1 . 62 g , 9 . 14 mmol ) by an analogous procedure to that described in example 1 . lc - ms ( m / z ) 330 ( m + 1 ). the title compound ( 1 . 57 g , 59 % yield ) was prepared as a brown solid from 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 4 , 7 - dichloroquinoline ( 1 . 81 g , 9 . 14 mmol ) by an analogous procedure to that described in example 1 . lc - ms ( m / z ) 350 ( m + 1 ). the title compound ( 1 . 43 g , 49 % yield ) was prepared as a brown solid from 6 - hydroxy - 1 - naphthoic acid ( 1 . 43 g , 7 . 6 mmol ) and 4 - chloro - 8 -( trifluoromethyl ) quinoline ( 2 . 12 g , 9 . 14 mmol ) by an analogous procedure to that described in example 1 . lc - ms ( m / z ) 384 ( m + 1 ). 4 - cyanobenzoic acid ( 294 mg , 2 mmol ) and 8 ml of dmf were stirred at room temperature while 1 - ethyl - 3 -( 3 - dimethyllaminopropyl ) carbodiimide hydrochloride ( 768 mg , 4 mmol ), hydroxybenzotriazole ( 324 mg , 2 . 4 mmol ), triethylamine ( 808 mg , 8 mmol ) and o - phenylenediamine ( 432 mg , 4 mmol ) were added . the mixture was stirred for 20 hours at room temperature . the mixture was diluted with 400 ml of brine . the solids were collected by vacuum filtration , washed with water and dried under vacuum to give n -( 2 - aminophenyl )- 4 - cyanobenzamide ( 364 mg , 77 %) as a grey solid . lc - ms ( m / z ) 238 ( m + 1 ). to a solution of n -( 2 - aminophenyl )- 4 - cyanobenzamide ( 237 mg , 1 mmol ) in methanol ( 40 ml ) was added sulfuric acid ( 196 mg , 1 mmol ) and 5 % palladium on charcoal ( 0 . 20 g ). the mixture was stirred under an atmosphere of hydrogen at room temperature until hydrogen uptake ceased . the mixture was filtered through celite , and the filtrate was neutralized with 1 n naoh solution in methanol ( 2 ml ). the resulting mixture was filtered , and the filtrate was evaporated under vacuum to give the title compound ( 232 mg , 96 % yield ) as a grey solid . lc - ms ( m / z ) 242 ( m + 1 ). the title compound ( 186 mg , 72 % yield ) was prepared as a brown solid from 4 - cyano - benzoic acid ( 294 mg , 2 mmol ) and 4 - fluoro - o - phenylenediamine ( 302 mg , 2 . 4 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 260 ( m + 1 ). the title compound ( 173 mg , 68 % yield ) was prepared as a grey solid from 4 - cyano - benzoic acid ( 294 mg , 2 mmol ) and 4 - methyl - o - phenylenediamine ( 293 mg , 2 . 4 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 256 ( m + 1 ). the title compound ( 192 mg , 71 % yield ) was prepared as a grey solid from 4 - cyano - benzoic acid ( 294 mg , 2 mmol ) and 4 - methoxy - o - phenylenediamine ( 331 mg , 2 . 4 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 272 ( m + 1 ). the title compound ( 195 mg , 63 % yield ) was prepared as a grey solid from 4 - cyano - benzoic acid ( 294 mg , 2 mmol ) and 4 - trifluoromethyl - o - phenylenediamine ( 422 mg , 2 . 4 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 310 ( m + 1 ). the title compound ( 140 mg , 58 % yield ) was prepared as a grey solid from 3 - cyano - benzoic acid ( 294 mg , 2 mmol ) and o - phenylenediamine ( 432 mg , 4 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 242 ( m + 1 ). the title compound ( 157 mg , 65 % yield ) was prepared as a grey solid from 6 - cyano - nicotinic acid ( 296 mg , 2 mmol ) and o - phenylenediamine ( 864 mg , 8 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 243 ( m + 1 ). the title compound ( 135 mg , 52 % yield ) was prepared as a grey solid from 6 - cyano - nicotinic acid ( 296 mg , 2 mmol ) and 4 - fluoro - o - phenylenediamine ( 302 mg , 2 . 4 mmol ) by an analogous procedure to that described in example 8 . lc - ms ( m / z ) 261 ( m + 1 ). 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 ml of dmf were stirred at room temperature while 1 - ethyl - 3 -( 3 - dimethyllaminopropyl ) carbodiimide hydrochloride ( 38 . 4 mg , 0 . 2 mmol ), hydroxybenzotriazole ( 16 . 2 mg , 0 . 12 mmol ), triethylamine ( 40 . 4 mg , 0 . 4 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) were added . the mixture was stirred for 20 hours at room temperature . the mixture was diluted with 200 ml of brine . the solids were collected by vacuum filtration , washed with water and dried under vacuum to give the title compound ( 39 . 1 mg , 84 %) as a brown solid . 1 h nmr ( dmso - d 6 ) δ 4 . 01 ( s , 6h , 2 × och 3 ), 4 . 97 ( s , 2h , benzene - nh 2 ), 6 . 65 ( t , j = 7 . 2 hz , 1h , ar — h ), 6 . 82 ( d , j = 7 . 0 hz , 1h , ar — h ), 7 . 00 ( t , j = 7 . 1 hz , 1h , ar — h ), 7 . 38 ( d , j = 7 . 1 hz , 1h , ar — h ), 7 . 42 ( s , 1h , ar — h ), 7 . 60 ( dd , j = 2 . 4 and 9 . 2 hz , 1h , ar — h ), 7 . 64 - 7 . 68 ( m , 2h , ar — h ), 7 . 87 ( d , j = 6 . 7 hz , 1h , ar — h ), 7 . 97 ( d , j = 2 . 3 hz , 1h , ar — h ), 8 . 09 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 38 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 54 ( s , 1h , ar — h ), 9 . 85 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 467 ( m + 1 ). the title compound ( 43 . 1 mg , 89 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 - fluoro - o - phenylenediamine ( 15 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 01 ( s , 6h , 2 × och 3 ), 5 . 28 ( s , 2h , benzene - nh 2 ), 6 . 41 ( td , j = 2 . 6 and 8 . 5 hz , 1h , ar — h ), 6 . 59 ( dd , j = 2 . 6 and 11 . 2 hz , 1h , ar — h ), 7 . 35 ( td , j = 1 . 8 and 7 . 5 hz , 1h , ar — h ), 7 . 41 ( s , 1h , ar — h ), 7 . 59 ( dd , j = 2 . 2 and 8 . 4 hz , 1h , ar — h ), 7 . 63 - 7 . 67 ( m , 2h , ar — h ), 7 . 89 ( d , j = 6 . 9 hz , 1h , ar — h ), 7 . 96 ( d , j = 1 . 9 hz , 1h , ar — h ), 8 . 08 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 38 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 54 ( s , 1h , ar — h ), 9 . 77 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 485 ( m + 1 ). the title compound ( 39 . 4 mg , 82 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 - methyl - o - phenylenediamine ( 14 . 6 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) ( isomer ratio 0 . 77 / 0 . 23 ) δ 2 . 21 ( s , 1h , ar — ch 3 ), 4 . 01 ( s , 6h , 2 × och 3 ), 4 . 77 ( s , 0 . 23 × 2h , benzene - nh 2 ), 4 . 89 ( s , 0 . 77 × 2h , benzene - nh 2 ), 6 . 46 ( d , j = 7 . 6 hz , 0 . 77 × 1h , ar — h ), 6 . 64 ( s , 0 . 77 × 1h , ar — h ), 6 . 73 ( d , j = 7 . 9 hz , 0 . 23 × 1h , ar — h ), 6 . 81 ( s , 0 . 23 × 1h , ar — h ), 7 . 24 ( d , j = 8 . 1 hz , 1h , ar — h ), 7 . 41 ( s , 1h , ar — h ), 7 . 58 - 7 . 66 ( m , 3h , ar — h ), 7 . 85 ( d , j = 6 . 7 hz , 1h , ar — h ), 7 . 97 ( s , 1h , ar — h ), 8 . 08 ( d , j = 7 . 9 hz , 1h , ar — h ), 8 . 38 ( d , j = 9 . 0 hz , 1h , ar — h ), 8 . 54 ( s , 1h , ar — h ), 9 . 77 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 481 ( m + 1 ). the title compound ( 43 . 2 mg , 87 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 - methoxy - o - phenylenediamine ( 16 . 5 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 70 ( s , 3h , — och 3 ), 4 . 01 ( s , 6h , 2 × och 3 ), 5 . 00 ( s , 2h , benzene - nh 2 ), 6 . 23 ( dd , j = 2 . 6 and 8 . 6 hz , 1h , ar — h ), 6 . 40 ( d , j = 2 . 6 hz , 1h , ar — h ), 7 . 22 ( d , j = 8 . 6 hz , 1h , ar — h ), 7 . 41 ( s , 1h , ar — h ), 7 . 59 ( dd , j = 2 . 2 and 9 . 1 hz , 1h , ar — h ), 7 . 62 - 7 . 66 ( m , 2h , ar — h ), 7 . 86 ( d , j = 6 . 9 hz , 1h , ar — h ), 7 . 96 ( d , j = 2 . 0 hz , 1h , ar — h ), 8 . 07 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 38 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 54 ( s , 1h , ar — h ), 9 . 70 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 497 ( m + 1 ). the title compound ( 42 . 9 mg , 83 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 - chloro - o - phenylenediamine ( 17 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 01 ( s , 6h , 2 × och 3 ), 5 . 31 ( s , 2h , benzene - nh 2 ), 6 . 65 ( d , j = 8 . 3 hz , 1h , ar — h ), 6 . 86 ( d , j = 1 . 9 hz , 1h , ar — h ), 7 . 41 ( s , 1h , ar — h ), 7 . 58 - 7 . 67 ( m , 4h , ar — h ), 7 . 89 ( d , j = 6 . 8 hz , 1h , ar — h ), 8 . 01 ( s , 1h , ar — h ), 8 . 09 ( d , j = 8 . 1 hz , 1h , ar — h ), 8 . 37 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 55 ( s , 1h , ar — h ), 9 . 84 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 501 ( m + 1 ). the title compound ( 42 . 0 mg , 77 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 - bromo - o - phenylenediamine ( 22 . 4 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 01 ( s , 6h , 2 × och 3 ), 5 . 31 ( s , 2h , benzene - nh 2 ), 6 . 77 ( d , j = 8 . 3 hz , 1h , ar — h ), 7 . 01 ( s , 1h , ar — h ), 7 . 41 ( s , 1h , ar — h ), 7 . 58 - 7 . 65 ( m , 5h , ar — h ), 7 . 89 ( d , j = 7 . 0 hz , 1h , ar — h ), 8 . 00 ( s , 1h , ar — h ), 8 . 14 ( d , j = 10 . 2 hz , 1h , ar — h ), 8 . 37 ( d , j = 9 . 1 hz , 1h , ar — h ), 8 . 54 ( s , 1h , ar — h ), 9 . 84 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 545 ( m + 1 ). the title compound ( 42 . 3 mg , 79 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 - trifluoromethyl - o - phenylenediamine ( 21 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 01 ( s , 6h , 2 × och 3 ), 5 . 72 ( s , 2h , benzene - nh 2 ), 6 . 92 ( d , j = 8 . 5 hz , 1h , ar — h ), 7 . 42 ( s , 1h , ar — h ), 7 . 59 - 7 . 65 ( m , 3h , ar — h ), 7 . 90 - 7 . 96 ( m , 2h , ar — h ), 7 . 98 ( s , 1h , ar — h ), 8 . 10 ( d , j = 8 . 3 hz , 1h , ar — h ), 8 . 17 ( d , j = 7 . 3 hz , 1h , ar — h ), 8 . 39 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 54 ( s , 1h , ar — h ), 9 . 90 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 535 ( m + 1 ). the title compound ( 43 . 1 mg , 72 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - aminophenyl ) benzamide ( 28 . 9 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 600 ( m + 1 ). the title compound ( 46 . 3 mg , 75 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - amino - 4 - fluorophenyl ) benzamide ( 31 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 618 ( m + 1 ). the title compound ( 41 . 4 mg , 69 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 6 -( aminomethyl )- n -( 2 - aminophenyl ) nicotinamide ( 29 . 0 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 601 ( m + 1 ). the title compound ( 43 . 3 mg , 77 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 6 -( aminomethyl )- n -( 2 - amino - 4 - fluorophenyl ) nicotinamide ( 31 . 2 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 619 ( m + 1 ). the title compound ( 48 . 5 mg , 81 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 3 -( aminomethyl )- n -( 2 - aminophenyl ) benzamide ( 28 . 9 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 600 ( m + 1 ). the title compound ( 52 . 7 mg , 86 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - amino - 4 - methylphenyl ) benzamide ( 30 . 6 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 614 ( m + 1 ). the title compound ( 51 . 6 mg , 82 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - amino - 4 - methoxyphenyl ) benzamide ( 32 . 5 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 630 ( m + 1 ). the title compound ( 46 . 7 mg , 70 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinazolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 6 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - amino - 4 - trifluoromethylphenyl ) benzamide ( 37 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 668 ( m + 1 ). the title compound ( 39 . 6 mg , 91 % yield ) was prepared as a brown solid from 6 -( 7 - methoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 34 . 5 mg , 0 . 1 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) by an analogous procedure to that described in example 16 . lc - ms ( m / z ) 1 h nmr ( dmso - d 6 ) δ 3 . 95 ( s , 3h , — och 3 ), 4 . 97 ( s , 2h , benzene - nh 2 ), 6 . 60 ( d , j = 5 . 2 hz , 1h , ar — h ), 6 . 64 ( t , j = 7 . 6 hz , 1h , ar — h ), 6 . 82 ( d , j = 7 . 8 hz , 1h , ar — h ), 6 . 99 ( t , j = 7 . 4 hz , 1h , ar — h ), 7 . 31 ( dd , j = 2 . 5 and 9 . 1 hz , 1h , ar — h ), 7 . 38 ( d , j = 7 . 6 hz , 1h , ar — h ), 7 . 45 ( d , j = 2 . 4 hz , 1h , ar — h ), 7 . 57 ( dd , j = 2 . 4 and 9 . 2 hz , 1h , ar — h ), 7 . 65 ( t , j = 7 . 8 hz , 1h , ar — h ), 7 . 87 - 7 . 88 ( m , 2h , ar — h ), 8 . 07 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 25 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 43 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 65 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 84 ( s , 1h , benzene - nh ). 436 ( m + 1 ). the title compound ( 33 . 1 mg , 73 % yield ) was prepared as a brown solid from 6 -( 7 - methoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 34 . 5 mg , 0 . 1 mmol ) and 4 - fluoro - o - phenylenediamine ( 15 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 95 ( s , 3h , — och 3 ), 5 . 27 ( s , 2h , benzene - nh 2 ), 6 . 41 ( td , j = 2 . 5 and 8 . 4 hz , 1h , ar — h ), 6 . 57 - 6 . 61 ( m , 2h , ar — h ), 7 . 30 - 7 . 36 ( m , 2h , ar — h ), 7 . 45 ( d , j = 2 . 2 hz , 1h , ar — h ), 7 . 56 ( dd , j = 2 . 2 and 9 . 2 hz , 1h , ar — h ), 7 . 65 ( t , j = 7 . 6 hz , 1h , ar — h ), 7 . 87 - 7 . 91 ( m , 2h , ar — h ), 8 . 07 ( d , j = 8 . 3 hz , 1h , ar — h ), 8 . 24 ( d , j = 9 . 1 hz , 1h , ar — h ), 8 . 43 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 65 ( d , j = 5 . 1 hz , 1h , ar — h ), 9 . 75 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 454 ( m + 1 ). the title compound ( 48 . 3 mg , 85 % yield ) was prepared as a brown solid from 6 -( 7 - methoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 34 . 5 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - aminophenyl ) benzamide ( 28 . 9 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 95 ( s , 3h , — och 3 ), 4 . 64 ( d , j = 5 . 6 hz , 2h , — ch 2 ), 4 . 87 ( s , 2h , benzene - nh 2 ), 6 . 58 - 6 . 62 ( m , 2h , ar — h ), 6 . 78 ( dd , j = 1 . 2 and 7 . 8 hz , 1h , ar — h ), 6 . 97 ( td , j = 1 . 4 and 8 . 1 hz , 1h , ar — h ), 7 . 18 ( d , j = 7 . 0 hz , 1h , ar — h ), 7 . 31 ( dd , j = 2 . 5 and 9 . 2 hz , 1h , ar — h ), 7 . 44 ( d , j = 2 . 4 hz , 1h , ar — h ), 7 . 53 - 7 . 56 ( m , 3h , ar — h ), 7 . 62 ( t , j = 8 . 0 hz , 1h , ar — h ), 7 . 72 ( d , j = 6 . 1 hz , 1h , ar — h ), 7 . 86 ( d , j = 2 . 5 hz , 1h , ar — h ), 7 . 98 - 8 . 06 ( m , 3h , ar — h ), 8 . 24 ( d , j = 9 . 1 hz , 1h , ar — h ), 8 . 39 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 64 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 21 ( t , j = 6 . 0 hz , 1h , — conh ), 9 . 61 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 569 ( m + 1 ). the title compound ( 46 . 6 mg , 82 % yield ) was prepared as a brown solid from 6 -( 7 - methoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 34 . 5 mg , 0 . 1 mmol ) and 6 -( aminomethyl )- n -( 2 - aminophenyl ) nicotinamide ( 29 . 0 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 95 ( s , 3h , — och 3 ), 4 . 74 ( s , 2h , — ch 2 ), 4 . 95 ( s , 2h , benzene - nh 2 ), 6 . 60 ( m , 2h , ar — h ), 6 . 79 ( s , 1h , ar — h ), 6 . 98 ( s , 1h , ar — h ), 7 . 17 ( s , 1h , ar — h ), 7 . 31 ( d , j = 8 . 6 hz , 1h , ar — h ), 7 . 44 ( s , 1h , ar — h ), 7 . 58 - 7 . 63 ( m , 3h , ar — h ), 7 . 77 ( s , 1h , ar — h ), 7 . 87 ( s , 1h , ar — h ), 8 . 05 ( d , j = 5 . 6 hz , 1h , ar — h ), 8 . 24 ( d , j = 8 . 3 hz , 1h , ar — h ), 8 . 33 ( s , 1h , ar — h ), 8 . 47 ( d , j = 7 . 5 hz , 1h , ar — h ), 9 . 13 ( s , 1h , ar — h ), 9 . 25 ( s , 1h , — conh ), 9 . 77 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 570 ( m + 1 ). the title compound ( 40 . 0 mg , 86 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 5 mg , 0 . 1 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 93 ( s , 3h , — och 3 ), 3 . 95 ( s , 3h , — och 3 ), 4 . 99 ( s , 2h , benzene - nh 2 ), 6 . 56 ( d , j = 5 . 2 hz , 1h , ar — h ), 6 . 63 ( t , j = 7 . 6 hz , 1h , ar — h ), 6 . 81 ( d , j = 7 . 6 hz , 1h , ar — h ), 6 . 98 ( t , j = 7 . 2 hz , 1h , ar — h ), 7 . 36 ( d , j = 7 . 6 hz , 1h , ar — h ), 7 . 43 ( s , 1h , ar — h ), 7 . 56 - 7 . 58 ( m , 2h , ar — h ), 7 . 65 ( t , j = 7 . 6 hz , 1h , ar — h ), 7 . 87 - 7 . 90 ( m , 2h , ar — h ), 8 . 08 ( d , j = 8 . 0 hz , 1h , ar — h ), 8 . 43 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 49 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 87 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 466 ( m + 1 ). the title compound ( 39 . 1 mg , 81 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 5 mg , 0 . 1 mmol ) and 4 - fluoro - o - phenylenediamine ( 15 . 1 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 93 ( s , 3h , — och 3 ), 3 . 95 ( s , 3h , — och 3 ), 5 . 31 ( s , 2h , benzene - nh 2 ), 6 . 40 ( s , 1h , ar — h ), 6 . 55 - 6 . 59 ( m , 2h , ar — h ), 7 . 30 ( d , j = 7 . 6 hz , 1h , ar — h ), 7 . 42 ( s , 1h , ar — h ), 7 . 54 - 7 . 57 ( m , 2h , ar — h ), 7 . 64 ( t , j = 8 . 0 hz , 1h , ar — h ), 7 . 89 - 7 . 91 ( m , 2h , ar — h ), 8 . 07 ( d , j = 8 . 0 hz , 1h , ar — h ), 8 . 42 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 49 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 79 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 484 ( m + 1 ). the title compound ( 49 . 0 mg , 82 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 5 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - aminophenyl ) benzamide ( 28 . 9 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 93 ( s , 3h , — och 3 ), 3 . 95 ( s , 3h , — och 3 ), 4 . 63 ( d , j = 5 . 6 hz , 2h , — ch 2 ), 4 . 90 ( s , 2h , benzene - nh 2 ), 6 . 56 - 6 . 59 ( m , 2h , ar — h ), 6 . 78 ( d , j = 7 . 6 hz , 1h , ar — h ), 6 . 96 ( t , j = 8 . 1 hz , 1h , ar — h ), 7 . 17 ( d , j = 7 . 6 hz , 1h , ar — h ), 7 . 42 ( s , 1h , ar — h ), 7 . 53 - 7 . 55 ( m , 4h , ar — h ), 7 . 62 ( t , j = 8 . 0 hz , 1h , ar — h ), 7 . 71 ( d , j = 6 . 8 hz , 1h , ar — h ), 7 . 87 ( s , 1h , ar — h ), 7 . 98 - 8 . 06 ( m , 3h , ar — h ), 8 . 39 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 49 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 26 ( t , j = 6 . 0 hz , 1h , — conh ), 9 . 66 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 599 ( m + 1 ). the title compound ( 47 . 9 mg , 80 % yield ) was prepared as a brown solid from 6 -( 6 , 7 - dimethoxyquinolin - 4 - yloxy )- 1 - naphthoic acid ( 37 . 5 mg , 0 . 1 mmol ) and 6 -( aminomethyl )- n -( 2 - aminophenyl ) nicotinamide ( 29 . 0 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 3 . 93 ( s , 3h , — och 3 ), 3 . 95 ( s , 3h , — och 3 ), 4 . 73 ( d , j = 5 . 6 hz , 2h , — ch 2 ), 4 . 97 ( s , 2h , benzene - nh 2 ), 6 . 57 ( m , 2h , ar — h ), 6 . 77 ( d , j = 6 . 4 hz , 1h , ar — h ), 6 . 98 ( t , j = 8 . 1 hz , 1h , ar — h ), 7 . 16 ( d , j = 5 . 6 hz , 1h , ar — h ), 7 . 42 ( s , 1h , ar — h ), 7 . 55 - 7 . 63 ( m , 4h , ar — h ), 7 . 62 ( t , j = 8 . 0 hz , 1h , ar — h ), 7 . 76 ( d , j = 6 . 8 hz , 1h , ar — h ), 7 . 88 ( s , 1h , ar — h ), 8 . 06 ( s , 1h , ar — h ), 8 . 33 ( s , 1h , ar — h ), 8 . 45 - 8 . 48 ( m , 2h , ar — h ), 9 . 12 ( s , 1h , ar — h ), 9 . 30 ( t , j = 6 . 0 hz , 1h , — conh ), 9 . 80 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 600 ( m + 1 ). the title compound ( 35 . 6 mg , 88 % yield ) was prepared as a brown solid from 6 -( quinolin - 4 - yloxy )- 1 - naphthoic acid ( 31 . 5 mg , 0 . 1 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 97 ( s , 2h , benzene - nh 2 ), 6 . 65 ( t , j = 7 . 3 hz , 1h , ar — h ), 6 . 75 ( d , j = 5 . 1 hz , 1h , ar — h ), 6 . 82 ( d , j = 7 . 8 hz , 1h , ar — h ), 7 . 00 ( t , j = 7 . 1 hz , 1h , ar — h ), 7 . 38 ( d , j = 7 . 5 hz , 1h , ar — h ), 7 . 59 ( dd , j = 2 . 3 and 9 . 2 hz , 1h , ar — h ), 7 . 64 - 7 . 71 ( m , 2h , ar — h ), 7 . 83 - 7 . 92 ( m , 3h , ar — h ), 8 . 08 ( d , j = 8 . 4 hz , 2h , ar — h ), 8 . 37 ( d , j = 7 . 9 hz , 1h , ar — h ), 8 . 45 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 73 ( d , j = 5 . 1 hz , 1h , ar — h ), 9 . 85 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 406 ( m + 1 ). the title compound ( 37 . 7 mg , 90 % yield ) was prepared as a brown solid from 6 -( 8 - methylquinolin - 4 - yloxy )- 1 - naphthoic acid ( 32 . 9 mg , 0 . 1 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 2 . 76 ( s , 3h , ar — ch 3 ), 4 . 97 ( s , 2h , benzene - nh 2 ), 6 . 64 ( t , j = 7 . 1 hz , 1h , ar — h ), 6 . 78 ( d , j = 5 . 0 hz , 1h , ar — h ), 6 . 82 ( d , j = 7 . 8 hz , 1h , ar — h ), 6 . 99 ( t , j = 7 . 3 hz , 1h , ar — h ), 7 . 38 ( d , j = 7 . 5 hz , 1h , ar — h ), 7 . 55 - 7 . 58 ( m , 2h , ar — h ), 7 . 65 ( t , j = 7 . 6 hz , 1h , ar — h ), 7 . 71 ( d , j = 7 . 0 hz , 1h , ar — h ), 7 . 87 - 7 . 89 ( m , 2h , ar — h ), 8 . 07 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 20 ( d , j = 7 . 9 hz , 1h , ar — h ), 8 . 44 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 76 ( d , j = 5 . 0 hz , 1h , ar — h ), 9 . 84 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 420 ( m + 1 ). the title compound ( 33 . 2 mg , 83 % yield ) was prepared as a brown solid from 6 -( 7 - chloroquinolin - 4 - yloxy )- 1 - naphthoic acid ( 35 . 0 mg , 0 . 1 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 97 ( s , 2h , benzene - nh 2 ), 6 . 65 ( t , j = 7 . 4 hz , ar — h ), 6 . 77 ( d , j = 5 . 5 hz , 1h , ar — h ), 6 . 82 ( d , j = 7 . 2 hz , 1h , ar — h ), 7 . 00 ( t , j = 7 . 0 hz , 1h , ar — h ), 7 . 38 ( d , j = 7 . 2 hz , 1h , ar — h ), 7 . 60 ( dd , j = 2 . 6 and 9 . 2 hz , 1h , ar — h ), 7 . 67 - 7 . 74 ( m , 2h , ar — h ), 7 . 89 ( d , j = 7 . 4 hz , 1h , ar — h ), 7 . 94 ( d , j = 2 . 4 hz , 1h , ar — h ), 8 . 09 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 13 ( d , j = 2 . 1 hz , 1h , ar — h ), 8 . 41 ( d , j = 9 . 0 hz , 1h , ar — h ), 8 . 46 ( d , j = 9 . 6 hz , 1h , ar — h ), 8 . 76 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 85 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 440 ( m + 1 ). the title compound ( 38 . 3 mg , 81 % yield ) was prepared as a brown solid from 6 -( 8 - trifluoromethylquinolin - 4 - yloxy )- 1 - naphthoic acid ( 39 . 8 mg , 0 . 1 mmol ) and o - phenylenediamine ( 43 . 2 mg , 0 . 4 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 98 ( s , 2h , benzene - nh 2 ), 6 . 65 ( t , j = 7 . 3 hz , 1h , ar — h ), 6 . 83 ( d , j = 7 . 6 hz , 1h , ar — h ), 6 . 89 ( d , j = 5 . 2 hz , 1h , ar — h ), 7 . 00 ( t , j = 7 . 2 hz , 1h , ar — h ), 7 . 38 ( d , j = 7 . 5 hz , 1h , ar — h ), 7 . 62 ( dd , j = 2 . 4 and 9 . 2 hz , 1h , ar — h ), 7 . 68 ( t , j = 7 . 7 hz , 1h , ar — h ), 7 . 83 ( t , j = 7 . 9 hz , 1h , ar — h ), 7 . 90 ( d , j = 7 . 0 hz , 1h , ar — h ), 7 . 97 ( d , j = 2 . 3 hz , 1h , ar — h ), 8 . 10 ( d , j = 8 . 3 hz , 1h , ar — h ), 8 . 29 ( d , j = 7 . 1 hz , 1h , ar — h ), 8 . 47 ( d , j = 9 . 2 hz , 1h , ar — h ), 8 . 70 ( d , j = 7 . 8 hz , 1h , ar — h ), 8 . 87 ( d , j = 5 . 2 hz , 1h , ar — h ), 9 . 86 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 474 ( m + 1 ). the title compound ( 42 . 4 mg , 74 % yield ) was prepared as a brown solid from 6 -( 7 - chloroquinolin - 4 - yloxy )- 1 - naphthoic acid ( 35 . 0 mg , 0 . 1 mmol ) and 4 -( aminomethyl )- n -( 2 - aminophenyl ) benzamide ( 28 . 9 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 64 ( d , j = 5 . 8 hz , 2h , — ch 2 ), 4 . 87 ( s , 2h , benzene - nh 2 ), 6 . 60 ( t , j = 7 . 0 hz , 1h , ar — h ), 6 . 75 - 6 . 79 ( m , 2h , ar — h ), 6 . 97 ( t , j = 7 . 5 hz , 1h , ar — h ), 7 . 18 ( d , j = 7 . 7 hz , 1h , ar — h ), 7 . 53 - 7 . 59 ( m , 3h , ar — h ), 7 . 66 ( t , j = 8 . 0 hz , 1h , ar — h ), 7 . 70 - 7 . 74 ( m , 2h , ar — h ), 7 . 92 ( d , j = 2 . 0 hz , 1h , ar — h ), 7 . 99 ( d , j = 7 . 9 hz , 2h , ar — h ), 8 . 06 ( d , j = 8 . 2 hz , 1h , ar — h ), 8 . 13 ( s , 1h , ar — h ), 8 . 39 - 8 . 42 ( m , 2h , ar — h ), 8 . 75 ( d , j = 5 . 1 hz , 1h , ar — h ), 9 . 22 ( t , j = 5 . 6 hz , 1h , — conh ), 9 . 62 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 573 ( m + 1 ). the title compound ( 47 . 3 mg , 78 % yield ) was prepared as a brown solid from 6 -( 8 - trifluoromethylquinolin - 4 - yloxy )- 1 - naphthoic acid ( 38 . 3 mg , 0 . 1 mmol ) and 6 -( aminomethyl )- n -( 2 - aminophenyl ) nicotinamide ( 29 . 0 mg , 0 . 12 mmol ) by an analogous procedure to that described in example 16 . 1 h nmr ( dmso - d 6 ) δ 4 . 64 ( d , j = 5 . 6 hz , 2h , — ch 2 ), 4 . 87 ( s , 2h , benzene - nh 2 ), 6 . 60 ( t , j = 7 . 2 hz , 1h , ar — h ), 6 . 78 ( d , j = 7 . 8 hz , 1h , ar — h ), 6 . 89 ( d , j = 5 . 1 hz , 1h , ar — h ), 6 . 97 ( t , j = 7 . 2 hz , 1h , ar — h ), 7 . 18 ( d , j = 7 . 9 hz , 1h , ar — h ), 7 . 53 - 7 . 66 ( m , 4h , ar — h ), 7 . 74 ( d , j = 6 . 9 hz , 1h , ar — h ), 7 . 83 ( t , j = 7 . 9 hz , 1h , ar — h ), 7 . 95 - 8 . 08 ( m , 4h , ar — h ), 8 . 29 ( d , j = 7 . 0 hz , 1h , ar — h ), 8 . 42 ( d , j = 9 . 1 hz , 1h , ar — h ), 8 . 69 ( d , j = 8 . 3 hz , 1h , ar — h ), 8 . 86 ( d , j = 5 . 0 hz , 1h , ar — h ), 9 . 22 ( t , j = 5 . 5 hz , 1h , — conh ), 9 . 61 ( s , 1h , benzene - nh ). lc - ms ( m / z ) 607 ( m + 1 ). compound 31 was sieved through a 100 - mesh sieve . microcrystalline cellulose , sodium carboxymethyl starch and talc powder were sieved through a 80 - mesh sieve respectively . microcrystalline cellulose and sodium carboxymethyl starch were weighed and blended with compound 31 uniformly . 4 % polyvidone ( k30 )/ ethanol solution was added to produce wet granules . the granules were dried and added talc powder . then the mixture was mixed and performed tablet compression to obtained tablets . compound 31 was sieved through a 100 - mesh sieve . microcrystalline cellulose , lactose , sodium carboxymethyl starch and magnesium stearate were sieved through a 80 - mesh sieve respectively . microcrystalline cellulose , lactose and sodium carboxymethyl starch were weighed and blended with compound 31 uniformly . then magnesium stearate was added and mixed . the mixture was performed capsule filling to obtained capsules . compound 31 was dissolved in dmso , and then ethanol was added to obtain injection . in vivo inhibition of receptor tyrosine kinase activity via ligand - dependent cell proliferation assay by compounds from formula ( i ) nih - 3t3 mouse fibroblasts cell line engineered to stably express human pdgfirβ was constructed and used to evaluate pdgf dependent cell proliferation . pdgfrβ nih - 3t3 cells were plated into 96 - well plates at 5 , 000 per well and incubated with serum - free medium for 24 hours . compounds and pdgf bb ( 50 ng / ml ) were added and incubated for 72 hours in serum - free medium . the effects on proliferation were determined by addition of mts reagent ( promega ) according to the instruction , incubation for 2 hours at 37 ° c . in co 2 incubator , and record the absorbance at 490 nm using an elisa plate reader . huvec cells were plated into 96 - well plates at 6 , 000 per well and incubated with serum - free medium for 2 hours . compounds and vegf 165 ( 50 ng / ml ) were added and incubated for 72 hours in serum - free medium . the effects on proliferation were determined by addition of mts reagent ( promega ) according to the instruction , incubation for 2 hours at 37 ° c . in co 2 incubator , and record the absorbance at 490 nm using an elisa plate reader . 1 . add assay buffer , diluted trichostatin a or test inhibitor to appropriate wells of the microtiter plate . following table lists examples of various assay types and the additions required for each test . 2 . add diluted hela extract or other hdac sample to all wells except those that are to be “ no enzyme controls ” ( blank ). 3 . allow diluted fluor de lys ™ substrate and the samples in the microtiter plate to equilibrate to assay temperature ( 25 ° c .). 4 . initiate hdac reactions by adding diluted substrate ( 25 μl ) to each well and mixing thoroughly . 5 . allow hdac reactions to proceed for desired length of time and then stop them by addition of fluor de lys ™ developer ( 50 μl ). incubate plate at room temperature ( 25 ° c .) for 10 - 15 min . 6 . read samples in a microtiter - plate reading fluorimeter capable of excitation at a wavelength in the range 350 - 380 nm and detection of emitted light in the range 440 - 460 nm . hdac subtype selectivity inhibition assay of tested compounds was carried out by several reporter gene assays experiments . briefly , hela cells were seeded in 96 - well plates the day before transfection to give a confluence of 50 - 80 %. cells were transfected with one of reporter gene plasmid containing a promoter sequence or response element upstream of a luciferase gene construct using fugene6 transfection reagent according to the manufacturer &# 39 ; s instruction ( roche ). the promoters or response elements including p21 - promoter was fused upstream to the luciferase gene reporter construct . for normalizing the transfection efficiency , a gfp expression plasmid was cotransfected . cells were allowed to express protein for 24 hours followed by addition of individual compounds or the vehicle ( dmso ). 24 hours later the cells were harvested , and the luciferase assay and gfp assay were performed using corresponding assay kits according to the manufacturer &# 39 ; s instructions ( promega ). tumor cells were trypsinized and plated into 96 - well plates at 3 , 000 per well and incubated in complete medium with 10 % fbs for 24 hours . compounds were added over a final concentration range of 100 μmol / l to 100 nmol / l in 0 . 1 % dmso and incubated for 72 hours in complete medium . the effects on proliferation were determined by addition of mts reagent ( promega ) according to the instruction , incubation for 2 hours at 37 ° c . in co 2 incubator , and record the absorbance at 490 nm using an elisa plate reader . the antitumor activity of compound 31 was measured in human a549 lung cancer xenograft model . the female nu / nu mice of 14 ˜ 16 g were fed by normal diet for 3 days . then the cultured a549 human lung cancer cells were implanted into the armpit of 50 mice . when tumors had reached approximately 6 mm in diameter , the mice were divided into 6 groups randomly . each group has 8 mice . one group was treated with vehicle . one group was treated with sutent , the positive control drug . the other four groups were treated with compound 31 at doses 5 , 10 , 20 and 40 mg / kg . each group was dosed orally once a day for 24 days . tumor volumes as established by caliper measurements were recorded twice per week , along with body weights . at the end of study , the mice were killed , and tumors were weighed . the tumor growth inhibition of each group was calculated using the formula {[( the average tumor weight of vehicle group )-( the average tumor weight of drug group )]/( the average tumor weight of vehicle group )}× 100 %. the experimental results are shown in table 5 and fig1 . the antitumor activity of compound 31 was measured in human hct - 8 colon cancer xenograft model . the female nu / nu mice of 18 ˜ 20 g were fed by normal diet for 3 days . then the cultured hct - 8 human colon cancer cells were implanted into the armpit of 50 mice . when tumors had reached approximately 100 mm 3 , the mice were divided into 6 groups randomly . each group has 8 mice . one group was treated with vehicle . one group was treated with sutent , the positive control drug . the other four groups were treated with compound 31 at doses 2 . 5 , 5 , 10 and 20 mg / kg . each group was dosed orally once a day for 20 days . tumor volumes as established by caliper measurements were recorded twice per week , along with body weights . at the end of study , the mice were killed , and tumors were weighed . the tumor growth inhibition of each group was calculated using the formula {[( the average tumor weight of vehicle group )−( the average tumor weight of drug group )]/( the average tumor weight of vehicle group )}× 100 %. the experimental results are shown in table 6 and fig2 . the antitumor activity of compound 31 was measured in human ssmc7721 liver cancer xenograft model . the female nu / nu mice of 18 ˜ 20 g were fed by normal diet for 3 days . then the cultured ssmc7721 human liver cancer cells were implanted into the armpit of 50 mice . when tumors had reached approximately 100 mm 3 , the mice were divided into 6 groups randomly . each group has 8 mice . one group was treated with vehicle . one group was treated with sutent , the positive control drug . the other four groups were treated with compound 31 at doses 2 . 5 , 5 , 10 and 20 mg / kg . each group was dosed orally once a day for 30 days . tumor volumes as established by caliper measurements were recorded twice per week , along with body weights . at the end of study , the mice were killed , and tumors were weighed . the tumor growth inhibition of each group was calculated using the formula {[( the average tumor weight of vehicle group )−( the average tumor weight of drug group )]/( the average tumor weight of vehicle group )}× 100 %. the experimental results are shown in table 7 and fig3 . the antitumor activity of compound 33 and compound 34 were measured in human hct - 8 colon cancer xenograft model . the female nu / nu mice of 18 ˜ 20 g were fed by normal diet for 3 days . then the cultured hct - 8 human colon cancer cells were implanted into the armpit of 50 mice . when tumors had reached approximately 100 mm 3 , the mice were divided into 6 groups randomly . each group has 8 mice . one group was treated with vehicle . one group was treated with sutent , the positive control drug . two groups were treated with compound 33 . the other two groups were treated with compound 34 . each group was dosed orally once a day for 20 days . tumor volumes as established by caliper measurements were recorded twice per week , along with body weights . at the end of study , the mice were killed , and tumors were weighed . the tumor growth inhibition of each group was calculated using the formula {[( the average tumor weight of vehicle group )−( the average tumor weight of drug group )]/( the average tumor weight of vehicle group )}× 100 %. the experimental results are shown in table 8 and fig4 . the antitumor activity of compound 33 and compound 37 were measured in human hct - 8 colon cancer xenograft model . the female nu / nu mice of 18 ˜ 20 g were fed by normal diet for 3 days . then the cultured hct - 8 human colon cancer cells were implanted into the armpit of 50 mice . when tumors had reached approximately 100 mm 3 , the mice were divided into 6 groups randomly . each group has 8 mice . one group was treated with vehicle . one group was treated with sutent , the positive control drug . two groups were treated with compound 33 . the other two groups were treated with compound 37 . compound 33 was administered twice a day with an interval of 6 hours . other drugs and vehicle were administered once a day . each group was dosed orally for 20 days . tumor volumes as established by caliper measurements were recorded twice per week , along with body weights . at the end of study , the mice were killed , and tumors were weighed . the tumor growth inhibition of each group was calculated using the formula {[( the average tumor weight of vehicle group )−( the average tumor weight of drug group )]/( the average tumor weight of vehicle group )}× 100 %. the experimental results are shown in table 9 and fig5 . the antitumor activity of compound 33 and compound 37 were measured in human ssmc7721 liver cancer xenograft model . the female nu / nu mice of 18 ˜ 20 g were fed by normal diet for 3 days . then the cultured ssmc7721 human liver cancer cells were implanted into the armpit of 50 mice . when tumors had reached approximately 100 mm 3 , the mice were divided into 6 groups randomly . each group has 8 mice . one group was treated with vehicle . one group was treated with sutent , the positive control drug . two groups were treated with compound 33 . the other two groups were treated with compound 37 . each group was dosed orally once a day for 30 days . tumor volumes as established by caliper measurements were recorded twice per week , along with body weights . at the end of study , the mice were killed , and tumors were weighed . the tumor growth inhibition of each group was calculated using the formula {[( the average tumor weight of vehicle group )−( the average tumor weight of drug group )]/( the average tumor weight of vehicle group )}× 100 %. the experimental results are shown in table 10 and fig6 .