Patent Application: US-201414772334-A

Abstract:
the present invention relates to compounds as inhibitor of wnt signal transduction pathway , as well as a composition comprising the same . further , the present invention relates to the use of the compounds in the treatment of fibrosis . fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process . fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections , autoimmune reactions , allergic responses , chemical insults , radiation , and tissue injury .

Description:
several aspects of the invention are described below with reference to example applications for illustration . it should be understood that numerous specific details , relationships , and methods are set forth to provide a full understanding of the invention . one having ordinary skill in the relevant art , however , will readily recognize that the invention can be practiced without one or more of the specific details or with other methods . the present invention is not limited by the illustrated ordering of acts or events , as some acts may occur in different orders and / or concurrently with other acts or events . furthermore , not all illustrated acts or events are required to implement a methodology in accordance with the present invention . the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention . as used herein , the singular forms “ a ”, “ an ” and “ the ” are intended to include the plural forms as well , unless the context clearly indicates otherwise . furthermore , to the extent that the terms “ including ”, “ includes ”, “ having ”, “ has ”, “ with ”, or variants thereof are used in either the detailed description and / or the claims , such terms are intended to be inclusive in a manner similar to the term “ comprising ”. the term “ about ” or “ approximately ” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art , which will depend in part on how the value is measured or determined , i . e ., the limitations of the measurement system . for example , “ about ” can mean within 1 or more than 1 standard deviation , per the practice in the art . alternatively , “ about ” can mean a range of up to 20 %, preferably up to 10 %, more preferably up to 5 %, and more preferably still up to 1 % of a given value . alternatively , particularly with respect to biological systems or processes , the term can mean within an order of magnitude , preferably within 5 - fold , and more preferably within 2 - fold , of a value . where particular values are described in the application and claims , unless otherwise stated the term “ about ” meaning within an acceptable error range for the particular value should be assumed . unless defined otherwise , all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs . generally , the nomenclature used herein and the laboratory procedures in cell culture , molecular genetics , organic chemistry and nucleic acid chemistry and hybridization are those well known and commonly employed in the art . standard techniques are used for nucleic acid and peptide synthesis . the techniques and procedures are generally performed according to conventional methods in the art and various general references , which are provided throughout this document . the nomenclature used herein and the laboratory procedures in analytical chemistry , and organic synthetic described below are those well - known and commonly employed in the art . standard techniques , or modifications thereof , are used for chemical syntheses and chemical analyses . as used herein , “ wnt signaling pathway ” or “ wnt pathway ” refers to the pathway by which binding of the wnt protein to cellular receptors results in changes of cell behavior . the wnt pathway involves a variety of proteins including frizzled , disheveled , axin , apc , gsk3β , β - catenin , lef / tcf transcription factors , and molecules involved in the synthesis and secretion of wnt proteins . examples of proteins implicated in the secretion of functional wnts include , but are not limited to wntless / evenness interrupted ( wls / evi ), porcupine ( porcn ), and vps35p . wls / evi is a 7 pass transmembrane protein which resides in the golgi apparatus and is required for secretion of wg ( drosophila ) mom - 2 ( c . elegans ) and wnt3a . it contains a conserved structural motif whose structure and function are both unknown . porcupine ( porcn ) is a member of the membrane - bound o - acyltransferase ( mboat ) family of palmitoyl transferases . fatty acid modification of wnts is critical for their function . wnts are palmitoylated on one or two highly conserved sites inhibitors of porcn may therefore block all functional wnt signaling . vps35p is a subunit of a multiprotein complex called the retromer complex which is involved in intracellular protein trafficking . vps35p functions in binding target proteins like wnts for recruitment into vesicles . “ wnt pathway inhibitor ” or “ wnt signaling inhibitor ” is a small organic molecule that inhibits wnt signaling activity and typically has a molecular weight of about 800 g / mol or less . the term “ a method of inhibiting wnt pathway ” refers to methods of inhibiting known biochemical events associated with production of functional wnt proteins or with cellular responses to wnt proteins . as discussed herein , small organic molecules may inhibit wnt response in accordance with this definition . “ wnt protein ” is a protein binds to frizzled and lrp5 / 6 co - receptors so as to activate canonical or non - canonical wnt signaling . specific examples of wnt proteins include : wnt - 1 ( nm005430 ), wnt - 2 ( nm003391 ), wnt - 2b / wnt - 13 ( nm004185 ), wnt - 3 ( nm030753 ), wnt3a ( nm033131 ), wnt - 4 ( nm030761 ), wnt - 5a ( nm003392 ), wnt - 5b ( nm032642 ), wnt - 6 ( nm006522 ), wnt - 7a ( nm004625 ), wnt - 7b ( nm058238 ), wnt - 8a ( nm058244 ), wnt - 8b ( nm003393 ), wnt - 9a / wnt - 14 ) ( nm003395 ), wnt - 9b / wnt - 15 ( nm003396 ), wnt - 10a ( nm025216 ), wnt - 10b ( nm003394 ), wnt - 11 ( nm004626 ), wnt - 16 ( nm016087 ). “ wnt pathway disorder ” is a condition or disease state with aberrant wnt signaling . in one aspect , the aberrant wnt signaling is a level of wnt signaling in a cell or tissue suspected of being diseased that exceeds the level of wnt signaling in a normal cell or tissue . in one specific aspect , a wnt - mediated disorder includes cancer or fibrosis . the term “ cancer ” refers to the pathological condition in humans that is characterized by unregulated cell proliferation . examples include but are not limited to : carcinoma , lymphoma , blastoma , and leukemia . more particular examples of cancers include but are not limited to : lung ( small cell and non - small cell ), breast , prostate , carcinoid , bladder , gastric , pancreatic , liver ( hepatocellular ), hepatoblastoma , colorectal , head and neck squamous cell carcinoma , esophageal , ovarian , cervical , endometrial , mesothelioma , melanoma , sarcoma , osteosarcoma , liposarcoma , thyroid , desmoids , chronic myelocytic leukemia ( aml ), and chronic myelocytic leukemia ( cml ). the term “ fibrosis ” refers to the pathological condition in humans that is typically characterized by uncontrolled proliferation of fibroblast cells and tissue hardening . specific examples include but not limited to : lung fibrosis ( idiopathic pulmonary fibrosis and radiation - induced fibrosis ), renal fibrosis , cardiac fibrosis and liver fibrosis including liver cirrhosis . “ inhibiting ” or “ treating ” or “ treatment ” refers to reduction , therapeutic treatment and prophylactic or preventative treatment , wherein the objective is to reduce or prevent the aimed pathologic disorder or condition . in one example , following administering of a wnt signaling inhibitor , a cancer patient may experience a reduction in tumor size . “ treatment ” or “ treating ” includes ( 1 ) inhibiting a disease in a subject experiencing or displaying the pathology or symptoms of the disease , ( 2 ) ameliorating a disease in a subject that is experiencing or displaying the pathology or symptoms of the disease , and / or ( 3 ) affecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptoms of the disease . to the extent the wnt pathway inhibitor may prevent growth and / or kill cancer cells , it may be cytostatic and / or cytotoxic . the term “ therapeutically effective amount ” refers to an amount of a wnt pathway inhibitor effective to “ treat ” a wnt pathway disorder in a subject or mammal . in the case of cancer , the therapeutically effective amount of the drug may either reduce the number of cancer cells , reduce the tumor size , inhibit cancer cell infiltration into peripheral organs , inhibit tumor metastasis , inhibit tumor growth to certain extent , and / or relieve one or more of the symptoms associated with the cancer to some extent . administration “ in combination with ” one or more further therapeutic agents includes simultaneous ( concurrent ) and consecutive administration in any order . as used herein , the term “ pharmaceutical combination ” refers to a product obtained from mixing or combining active ingredients , and includes both fixed and non - fixed combinations of the active ingredients . the term “ fixed combination ” means that the active ingredients , e . g . a compound of formula ( 1 ) and a co - agent , are both administered to a patient simultaneously in the form of a single entity or dosage . the term “ non - fixed combination ” means that the active ingredients , e . g . a compound of formula ( 1 ) and a co - agent , are both administered to a patient as separate entities either simultaneously , concurrently or sequentially with no specific time limits , wherein such administration provides therapeutically effective levels of the active ingredients in the body of the patient . the latter also applies to cocktail therapy , e . g . the administration of three or more active ingredients . a “ chemotherapeutic agent ” is a chemical compound useful in the treatment of cancer . examples are but not limited to : gemcitabine , irinotecan , doxorubicin , 5 - fluorouracil , cytosine arabinoside (“ ara - c ”), cyclophosphamide , thiotepa , busulfan , cytoxin , taxol , methotrexate , cisplatin , melphalan , vinblastine and carboplatin . the term “ alkyl ,” by itself or as part of another substituent , means , unless otherwise stated , a straight or branched chain , or cyclic hydrocarbon radical , or combination thereof , which may be fully saturated , mono - or polyunsaturated and can include di - and multivalent radicals , having the number of carbon atoms designated ( i . e . c 1 - c 10 means one to ten carbons ). examples of saturated hydrocarbon radicals include , but are not limited to , groups such as methyl , ethyl , n - propyl , isopropyl , n - butyl , t - butyl , isobutyl , sec - butyl , cyclohexyl , ( cyclohexyl ) methyl , cyclopropylmethyl , homologs and isomers of , for example , n - pentyl , n - hexyl , n - heptyl , n - octyl , and the like . an unsaturated alkyl group is one having one or more double bonds or triple bonds . examples of unsaturated alkyl groups include , but are not limited to , vinyl , 2 - propenyl , crotyl , 2 - isopentenyl , 2 -( butadienyl ), 2 , 4 - pentadienyl , 3 -( 1 , 4 - pentadienyl ), ethynyl , 1 - and 3 - propynyl , 3 - butynyl , and the higher homologs and isomers . the term “ alkyl ,” unless otherwise noted , is also meant to include those derivatives of alkyl defined in more detail below , such as “ heteroalkyl .” alkyl groups , which are limited to hydrocarbon groups , are termed “ homoalkyl ”. the term “ alkylene ” by itself or as part of another substituent means a divalent radical derived from an alkane , as exemplified , but not limited , by — ch 2 ch 2 ch 2 ch 2 —, and further includes those groups described below as “ heteroalkylene .” typically , an alkyl ( or alkylene ) group will have from 1 to 24 carbon atoms , with those groups having 10 or fewer carbon atoms being preferred in the present invention . a “ lower alkyl ” or “ lower alkylene ” is a shorter chain alkyl or alkylene group , generally having eight or fewer carbon atoms . the terms “ alkoxy ,” “ alkylamino ” and “ alkylthio ” ( or thioalkoxy ) are used in their conventional sense , and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom , an amino group , or a sulfur atom , respectively . the term “ heteroalkyl ,” by itself or in combination with another term , means , unless otherwise stated , a stable straight or branched chain , or cyclic hydrocarbon radical , or combinations thereof , consisting of the stated number of carbon atoms and at least one heteroatom selected from the group consisting of o , n , si and s , and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized . the heteroatom ( s ) o , n and s and si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule . examples include , but are not limited to , — ch 2 — ch 2 — o — ch 3 , — ch 2 — ch 2 — nh — ch 3 , — ch 2 — ch 2 — n ( ch 3 )— ch 3 , — ch 2 — s — ch 2 — ch 3 , — ch 2 — ch 2 , — s ( o )— ch 3 , — ch 2 — ch 2 — s ( o ) 2 — ch 3 , — ch ═ ch — o — ch 3 , — si ( ch 3 ) 3 , — ch 2 — ch ═ n — och 3 , and — ch ═ ch — n ( ch 3 )— ch 3 . up to two heteroatoms may be consecutive , such as , for example , — ch 2 — nh — och 3 and — ch 2 — o — si ( ch 3 ) 3 . similarly , the term “ heteroalkylene ” by itself or as part of another substituent means a divalent radical derived from heteroalkyl , as exemplified , but not limited by , — ch 2 — ch 2 — s — ch 2 — ch 2 — and — ch 2 — s — ch 2 — ch 2 — nh — ch 2 —. for heteroalkylene groups , heteroatoms can also occupy either or both of the chain termini ( e . g ., alkyleneoxy , alkylenedioxy , alkyleneamino , alkylenediamino , and the like ). still further , for alkylene and heteroalkylene linking groups , no orientation of the linking group is implied by the direction in which the formula of the linking group is written . for example , the formula — c ( o ) 2 r ′— represents both — c ( o ) 2 r ′— and — r ′ c ( o ) 2 —. in general , an “ acyl substituent ” is also selected from the group set forth above . as used herein , the term “ acyl substituent ” refers to groups attached to , and fulfilling the valence of a carbonyl carbon that is either directly or indirectly attached to the polycyclic nucleus of the compounds of the present invention . the terms “ cycloalkyl ” and “ heterocycloalkyl ”, by themselves or in combination with other terms , represent , unless otherwise stated , cyclic versions of “ alkyl ” and “ heteroalkyl ”, respectively . additionally , for heterocycloalkyl , a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule . examples of cycloalkyl include , but are not limited to , cyclopentyl , cyclohexyl , 1 - cyclohexenyl , 3 - cyclohexenyl , cycloheptyl , and the like . examples of heterocycloalkyl include , but are not limited to , 1 -( 1 , 2 , 5 , 6 - tetrahydropyridyl ), 1 - piperidinyl , 2 - piperidinyl , 3 - piperidinyl , 4 - morpholinyl , 3 - morpholinyl , tetrahydrofuran - 2 - yl , tetrahydrofuran - 3 - yl , tetrahydrothien - 2 - yl , tetrahydrothien - 3 - yl , 1 - piperazinyl , 2 - piperazinyl , and the like . the terms “ halo ” or “ halogen ,” by themselves or as part of another substituent , mean , unless otherwise stated , a fluorine , chlorine , bromine , or iodine atom . additionally , terms such as “ haloalkyl ,” are meant to include monohaloalkyl and polyhaloalkyl . for example , the term “ halo ( c 1 - c 4 ) alkyl ” is mean to include , but not be limited to , trifluoromethyl , 2 , 2 , 2 - trifluoroethyl , 4 - chlorobutyl , 3 - bromopropyl , and the like . the term “ aryl ” means , unless otherwise stated , a polyunsaturated , aromatic , hydrocarbon substituent , which can be a single ring or multiple rings ( preferably from 1 to 3 rings ), which are fused together or linked covalently . the term “ heteroaryl ” refers to aryl groups ( or rings ) that contain from one to four heteroatoms selected from n , o , and s , wherein the nitrogen and sulfur atoms are optionally oxidized , and the nitrogen atom ( s ) are optionally quaternized . a heteroaryl group can be attached to the remainder of the molecule through a heteroatom . non - limiting examples of aryl and heteroaryl groups include phenyl , 1 - naphthyl , 2 - naphthyl , 4 - biphenyl , 1 - pyrrolyl , 2 - pyrrolyl , 3 - pyrrolyl , 3 - pyrazolyl , 2 - imidazolyl , 4 - imidazolyl , pyrazinyl , 2 - oxazolyl , 4 - oxazolyl , 2 - phenyl - 4 - oxazolyl , 5 - oxazolyl , 3 - isoxazolyl , 4 - isoxazolyl , 5 - isoxazolyl , 2 - thiazolyl , 4 - thiazolyl , 5 - thiazolyl , 2 - furyl , 3 - furyl , 2 - thienyl , 3 - thienyl , 2 - pyridyl , 3 - pyridyl , 4 - pyridyl , 2 - pyrimidyl , 4 - pyrimidyl , 5 - benzothiazolyl , purinyl , 2 - benzimidazolyl , 5 - indolyl , 1 - isoquinolyl , 5 - isoquinolyl , 2 - quinoxalinyl , 5 - quinoxalinyl , 3 - quinolyl , and 6 - quinolyl . substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below . for brevity , the term “ aryl ” when used in combination with other terms ( e . g ., aryloxy , arylthioxy , arylalkyl ) includes both aryl and heteroaryl rings as defined above . thus , the term “ arylalkyl ” is meant to include those radicals in which an aryl group is attached to an alkyl group ( e . g ., benzyl , phenethyl , pyridylmethyl and the like ) including those alkyl groups in which a carbon atom ( e . g ., a methylene group ) has been replaced by , for example , an oxygen atom ( e . g ., phenoxymethyl , 2 - pyridyloxymethyl , 3 -( 1 - naphthyloxy ) propyl , and the like ). each of the above terms ( e . g ., “ alkyl ,” “ heteroalkyl ,” “ aryl ” and “ heteroaryl ”) include both substituted and unsubstituted forms of the indicated radical . preferred substituents for each type of radical are provided below . substituents for the alkyl , and heteroalkyl radicals ( including those groups often referred to as alkylene , alkenyl , heteroalkylene , heteroalkenyl , alkynyl , cycloalkyl , heterocycloalkyl , cycloalkenyl , and heterocycloalkenyl ) are generally referred to as “ alkyl substituents ” and “ heteroakyl substituents ,” respectively , and they can be one or more of a variety of groups selected from , but not limited to : — or ′, ═ o , ═ nr ′, ═ n — or ′, — nr ′ r ″, — sr ′, - halogen , — sir ′ r ″ r ′″, — oc ( o ) r ′, — c ( o ) r ′, — co 2 r ′, — conr ′ r ″, — oc ( o ) nr ′ r ″, — nr ″ c ( o ) r ′, — nr ′— c ( o ) nr ″ r ′″, — nr ″ c ( o ) 2 r ′, — nr — c ( nr ′ r ″ r ′″)═ nr ″″, — nr — c ( nr ′ r ″)═ nr ′″, — s ( o ) r ′, — s ( o ) 2 r ′, — s ( o ) 2 nr ′ r ″, — nrso 2 r ′, — cn and — no 2 in a number ranging from zero to ( 2m ′+ 1 ), where m ′ is the total number of carbon atoms in such radical . r ′, r ″, r ′″ and r ″″ each preferably independently refer to hydrogen , substituted or unsubstituted heteroalkyl , substituted or unsubstituted aryl , e . g ., aryl substituted with 1 - 3 halogens , substituted or unsubstituted alkyl , alkoxy or thioalkoxy groups , or arylalkyl groups . when a compound of the invention includes more than one r group , for example , each of the r groups is independently selected as are each r ′, r ″, r ′″ and r ″″ groups when more than one of these groups is present . when r ′ and r ″ are attached to the same nitrogen atom , they can be combined with the nitrogen atom to form a 5 -, 6 -, or 7 - membered ring . for example , — nr ′ r ″ is meant to include , but not be limited to , 1 - pyrrolidinyl and 4 - morpholinyl . from the above discussion of substituents , one of skill in the art will understand that the term “ alkyl ” is meant to include groups including carbon atoms bound to groups other than hydrogen groups , such as haloalkyl ( e . g ., — cf 3 and — ch 2 cf 3 ) and acyl ( e . g ., — c ( o ) ch 3 , — c ( o ) cf 3 , — c ( o ) ch 2 och 3 , and the like ). similar to the substituents described for the alkyl radical , the aryl substituents and heteroaryl substituents are generally referred to as “ aryl substituents ” and “ heteroaryl substituents ,” respectively and are varied and selected from , for example : halogen , — or ′, ═ o , ═ nr ′, ═ n — or ′, — nr ′ r ″, — sr ′, - halogen , — sir ′ r ″ r ′″, — oc ( o ) r ′, — c ( o ) r ′, — co 2 r ′, — conr ′ r ″, — oc ( o ) nr ′ r ″, — nr ″ c ( o ) r ′, — nr ′— c ( o ) nr ″ r ′″, — nr ″ c ( o ) 2 r ′, — nr — c ( nr ′ r ″)═ nr ′″, — s ( o ) r ′, — s ( o ) 2 r ′, — s ( o ) 2 nr ′ r ″, — nrso 2 r ′, — cn and — no 2 , — r ′, — n 3 , — ch ( ph ) 2 , fluoro ( c 1 - c 4 ) alkoxy , and fluoro ( c 1 - c 4 ) alkyl , in a number ranging from zero to the total number of open valences on the aromatic ring system ; and where r ′, r ″, r ′″ and r ″″ are preferably independently selected from hydrogen , ( c 1 - c 8 ) alkyl and heteroalkyl , unsubstituted aryl and heteroaryl , ( unsubstituted aryl )-( c 1 - c 4 ) alkyl , and ( unsubstituted aryl ) oxy -( c 1 - c 4 ) alkyl . when a compound of the invention includes more than one r group , for example , each of the r groups is independently selected as are each r ′, r ″, r ′″ and r ″″ groups when more than one of these groups is present . two of the aryl substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - t - c ( o )—( crr ′) q — u —, wherein t and u are independently — nr —, — o —, — crr ′— or a single bond , and q is an integer of from 0 to 3 . alternatively , two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula - a -( ch 2 ) r — b —, wherein a and b are independently — crr ′—, — o —, — nr —, — s —, — s ( o ) 2 —, — s ( o ) 2 nr ′— or a single bond , and r is an integer of from 1 to 4 . one of the single bonds of the new ring so formed may optionally be replaced with a double bond . alternatively , two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula —( crr ′) s — x —( cr ″ r ′″) d —, where s and d are independently integers of from 0 to 3 , and x is — o —, — nr ′—, — s —, — s ( o )—, — s ( o ) 2 —, or — s ( o ) 2 nr ′—. the substituents r , r ′, r ″ and r ′″ are preferably independently selected from hydrogen or substituted or unsubstituted ( c 1 - c 6 ) akyl . as used herein , the term “ heteroatom ” includes oxygen ( o ), nitrogen ( n ), sulfur ( s ), phosphorus ( p ) and silicon ( si ). in one aspect , the present invention provides a compound as wnt signaling inhibitor , which has the structure of formula i : x1 , x2 , x3 , x4 , x5 , x6 , x7 , x8 are independently cr4 or n y 2 , y 3 are independently hydrogen , halo or cr 3 ; aryl , c 1 - 6 heterocycle , 5 or 6 membered heteroaryl containing 1 - 2 heteroatoms selected from n , o and s ; aryl , c 1 - 6 heterocycle , 5 or 6 membered heteroaryl containing 1 - 2 heteroatoms selected from n , o and s ; wherein 5 or 6 membered heteroaryl includes the following selected groups but is not limited to : r 1 and r 2 could be independently and optionally substituted with 1 - 2 r 4 groups ; r 3 is hydrogen , halo , cyano , c 1 - 6 alkyl , c 1 - 6 alkoxy optionally substituted with halo , amino , hydroxyl , alkoxy or cyano ; r 4 is hydrogen , halo , c 1 - 6 alkoxy , — s ( o ) 2 r 5 , — c ( o ) or 5 , — c ( o ) r 5 , — c ( o ) nr 6 r 7 , c 1 - 6 alkyl , c 2 - 6 alkenyl or c 2 - 6 alkynyl , each of which can be optionally substituted with halo , amino , hydroxyl , alkoxy or cyano ; r 5 , r 6 and r 7 are independently hydrogen , c 1 - 6 alkyl , c 2 - 6 alkenyl or c 2 - 6 alkynyl , each of which may be optionally substituted with halo , amino , hydroxyl , alkoxy or cyano ; as used herein , an h atom in any substituent groups ( e . g ., ch 2 ) encompasses all suitable isotopic variations , e . g ., h , 2 h and 3 h . as used herein , other atoms in any substituent groups encompasses all suitable isotopic variations , including but not limited to 11 c , 13 c , 14 c , 15 n , 17 o , 18 o , 35 s , 18 f , 36 i and / or 123 i . in some embodiments , example of the compound of the invention includes but is not limited to : n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 5 -( 2 - methylpyridin - 4 - yl ) pyridin - 2 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -( 4 - morpholinobenzyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 6 - morpholinopyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 6 -( 2 - methylmorpholino ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 6 -( 4 - methylpiperazin - 1 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; 4 -( 5 -((( 7 - phenylquinazolin - 4 - yl ) amino ) methyl ) pyridin - 2 - yl ) thiomorpholine 1 , 1 - dioxide ; n -(( 6 -( 6 - methylpyridin - 3 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 6 -( 5 - methylpyridin - 3 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; 7 - phenyl - n -(( 6 -( pyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 - phenyl - n -(( 6 -( pyridin - 3 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 - phenyl - n -(( 6 -( pyridin - 2 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 - phenyl - n -(( 6 -( pyridazin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 - phenyl - n -(( 6 -( pyrazin - 2 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 - phenyl - n -(( 6 -( pyrimidin - 5 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - fluoropyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 6 -( 4 - methyl - 1h - imidazol - 1 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 6 -( 1 - methyl - 1h - pyrazol - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -(( 5 -( 6 - methylpyridin - 3 - yl ) pyridin - 2 - yl ) methyl )- 7 - phenylquinazolin - 4 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 7 - phenylquinazolin - 4 - amine ; n -( 4 -( 2 - fluoropyridin - 4 - yl ) benzyl )- 7 - phenylquinazolin - 4 - amine ; n - benzyl - 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 - methylbenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 - methoxybenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 - fluorobenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 - chlorobenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 - bromobenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 -( trifluoromethyl ) benzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; 4 -(( 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - ylamino ) methyl ) benzonitrile ; n -( 4 - morpholinobenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 - phenylbenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 3 - fluoro - 4 - phenylbenzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 -( 3 - fluorophenyl ) benzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; 7 -( 3 - fluorophenyl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 3 - chlorophenyl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 - m - tolylquinazolin - 4 - amine ; 3 -( 4 -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methylamino ) quinazolin - 7 - yl ) benzonitrile ; 4 -( 4 -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methylamino ) quinazolin - 7 - yl ) benzonitrile ; 7 -( 2 - methylpyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 6 - methylpyridin - 3 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 5 - methylpyridin - 3 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( pyridin - 2 - yl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( pyridin - 3 - yl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( pyridin - 4 - yl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( pyridazin - 4 - yl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( pyrazin - 2 - yl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( pyrimidin - 5 - yl ) quinazolin - 4 - amine ; 7 -( 2 - fluoropyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 2 -( trifluoromethyl ) pyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 2 - methoxypyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 3 - methylpyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 - morpholinoquinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( piperidin - 1 - yl ) quinazolin - 4 - amine ; 7 -( 4 - methylpiperazin - 1 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 1 -( 4 -( 4 -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methylamino ) quinazolin - 7 - yl ) piperazin - 1 - yl ) ethanone ; 4 -( 4 -((( 2 ′- methyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl ) amino ) quinazolin - 7 - yl ) thiomorpholine 1 , 1 - dioxide ; 7 -( 1 , 2 , 3 , 6 - tetrahydropyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( 1 , 2 , 3 , 6 - tetrahydropyridin - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 1 -( 4 -( 4 -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methylamino ) quinazolin - 7 - yl ) piperidin - 1 - yl ) ethanone ; n -(( 2 ′- methyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 7 -( 4 -( methylsulfonyl ) piperazin - 1 - yl ) quinazolin - 4 - amine ; 7 -( 1 - methyl - 1h - pyrazol - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; 7 -( isoxazol - 4 - yl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) quinazolin - 4 - amine ; n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl )- 7 -( thiazol - 2 - yl ) quinazolin - 4 - amine ; n -( 3 - methyl - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 3 - fluoro - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 7 -( 2 - methylpyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 7 -( pyrazin - 2 - yl ) quinazolin - 4 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 7 -( 2 - fluoropyridin - 4 - yl ) quinazolin - 4 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 7 - morpholinoquinazolin - 4 - amine ; 2 -( 3 - fluorophenyl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; 2 -( 3 - fluorophenyl )- n -(( 2 ′- methyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; 2 -( 3 - fluorophenyl )- n -( 3 - methyl - 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; n -( 3 - fluoro - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 -( 3 - fluorophenyl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; 2 -( 2 - methylpyridin - 4 - yl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; n -(( 2 ′- methyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 2 -( 2 - methylpyridin - 4 - yl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; n -( 3 - methyl - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 -( 2 - methylpyridin - 4 - yl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; n -( 3 - fluoro - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 -( 2 - methylpyridin - 4 - yl ) pyrido [ 3 , 4 - b ] pyrazin - 5 - amine ; n -(( 2 ′, 3 - dimethyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 6 -( pyrazin - 2 - yl )- 2 , 7 - naphthyridin - 1 - amine ; 6 -( 2 - methylmorpholino )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; ( s )- 6 -( 2 - methylmorpholino )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; ( r )- 6 -( 2 - methylmorpholino )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; 1 -( 4 -( 8 -(( 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) amino )- 2 , 7 - naphthyridin - 3 - yl ) piperazin - 1 - yl ) ethanone ; 6 -( 1h - imidazol - 1 - yl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; 6 -( 4 - methyl - 1h - imidazol - 1 - yl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( 1h - tetrazol - 5 - yl )- 2 , 7 - naphthyridin - 1 - amine ; 6 -( 5 - methyl - 1 , 3 , 4 - oxadiazol - 2 - yl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; 6 -( 1 - methyl - 1h - pyrazol - 3 - yl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( thiazol - 5 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( oxazol - 5 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -(( 2 ′, 3 - dimethyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 6 -( 5 - methylpyridin - 3 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -(( 2 ′, 3 - dimethyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -(( 3 - fluoro - 2 ′- methyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -(( 2 ′, 3 - dimethyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 6 -( 5 - fluoropyridin - 3 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -( 3 - methyl - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( pyrazin - 2 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -( 3 - fluoro - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( pyrazin - 2 - yl )- 2 , 7 - naphthyridin - 1 - amine ; methyl 4 -( 8 -(( 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) amino )- 2 , 7 - naphthyridin - 3 - yl ) piperazine - 1 - carboxylate ; 4 -( 8 -(( 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) amino )- 2 , 7 - naphthyridin - 3 - yl ) piperazin - 2 - one ; 2 -( 4 -( 8 -(( 4 -( 2 - methylpyridin - 4 - yl ) benzyl ) amino )- 2 , 7 - naphthyridin - 3 - yl ) piperazin - 1 - yl ) acetonitrile ; 2 - methyl - 4 -( 4 -((( 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - yl ) amino ) methyl ) phenyl ) pyridine 1 - oxide ; 6 -( 2 - chloropyridin - 4 - yl )- n -(( 2 ′, 3 - dimethyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 2 , 7 - naphthyridin - 1 - amine ; 6 -( 2 - chloropyridin - 4 - yl )- n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 , 7 - naphthyridin - 1 - amine ; 2 ′- methyl - 4 -((( 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - yl ) amino ) methyl )- 2h -[ 1 , 4 ′- bipyridin ]- 2 - one ; 2 -( 2 - methylpyridin - 4 - yl )- 5 -((( 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - yl ) amino ) methyl ) benzonitrile ; n -( 3 - methoxy - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ; n -(( 3 - chloro - 2 ′- methyl -[ 2 , 4 ′- bipyridin ]- 5 - yl ) methyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ; 2 ′- methyl - 5 -((( 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - yl ) amino ) methyl )-[ 2 , 4 ′- bipyridine ]- 3 - carbonitrile ; n -( 4 -( 2 -( difluoromethyl ) pyridin - 4 - yl ) benzyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ; in some embodiments , examples of the compound of the invention include but are not limited to the compounds provided in examples 1 - 5 and table 1 . a person skilled in the art can clearly understand and know that the other compounds could be prepared by the same strategy as examples 1 - 5 . compounds of the invention are indicated as pharmaceuticals . according to a further aspect of the invention there is provided a compound of the invention , as hereinbefore ( but without any provisos , where applicable ), for use as a pharmaceutical . there is also provided a synthetic form of a compound of the invention ( but without any provisos , where applicable ), for use as a pharmaceutical . for the avoidance of doubt , although compounds of the invention may possess pharmacological activity as such , certain pharmaceutically - acceptable ( e . g . “ protected ”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity , but may be administered parenterally or orally and thereafter be metabolized in the body to form compounds of the invention . such compounds ( which may possess some pharmacological activity , provided that such activity is appreciably lower than that of the “ active ” compounds to which they are metabolized ) may therefore be described as “ prodrugs ” of compounds of the invention . by “ prodrug of a compound of the invention ”, we include compounds that form a compound of the invention , in an experimentally - detectable amount , within a predetermined time ( e . g . about 1 hour ), following oral or parenteral administration . all prodrugs of the compounds of the invention are included within the scope of the invention . furthermore , certain compounds of the invention may possess no or minimal pharmacological activity as such , but may be administered parenterally or orally , and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such . such compounds ( which also includes compounds that may possess some pharmacological activity , but that activity is appreciably lower than that of the “ active ” compounds of the invention to which they are metabolised ), may also be described as “ prodrugs ”. thus , the compounds of the invention are useful because they possess pharmacological activity , and / or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity . compounds of the invention ( as hereinbefore defined but without the proviso ( s )) may be useful in the treatment of a cancer . by “ cancer ”, we mean any disease that arises from an uncontrolled growth of cells ( e . g . uncontrolled division ), invasion ( e . g . direct growth into adjacent tissue ) or metastasis . by “ uncontrolled growth ”, we include an increase in the number and / or size of cancer cells ( also referred to herein as “ proliferation ”). by “ metastasis ” we mean the movement or migration ( e . g . invasiveness ) of cancer cells from a primary tumor site in the body of a subject to one or more other areas within the subject &# 39 ; s body ( where the cells can then form secondary tumors ). thus , in one embodiment the invention provides compounds and methods for inhibiting , in whole or in part , the formation of secondary tumors in a subject with cancer . advantageously , the compounds of the invention may be capable of inhibiting the proliferation and / or metastasis of cancer cells selectively . by “ selectively ” we mean that the compounds of the invention may inhibit the proliferation and / or metastasis of cancer cells to a greater extent than it modulates the function ( e . g . proliferation ) of non - cancer cells . preferably , the compounds of the invention inhibit the proliferation and / or metastasis of cancer cells only . in another aspect , the present invention provides a pharmaceutical composition comprising the compound of the present invention and at least one pharmaceutically acceptable carrier or diluent , wherein said compound is in free form or in a pharmaceutically acceptable salt form . such composition may be an oral composition , injectable composition or suppository . and the composition may be manufactured in a conventional manner by mixing , granulating or coating methods . in an embodiment of the invention , the composition is an oral composition and it may be a tablet or gelatin capsule . preferably , the oral composition comprises the present compound together with a ) diluents , e . g ., lactose , dextrose , sucrose , mannitol , sorbitol , cellulose and / or glycine ; b ) lubricants , e . g ., silica , talcum , stearic acid , its magnesium or calcium salt and / or polyethyleneglycol ; for tablets , together with c ) binders , e . g ., magnesium aluminum silicate , starch paste , gelatin , tragamayth , methylcellulose , sodium carboxymethylcellulose and or polyvinylpyrrolidone ; and if desired , d ) disintegrants , e . g ., starches , agar , alginic acid or its sodium salt , or effervescent mixtures ; and / or e ) additives , e . g ., absorbents , colorants , flavors and sweeteners . in another embodiment of the invention , the composition is an injectable composition , and may be an aqueous isotonic solution or suspension . in yet another embodiment of the invention , the composition is a suppository and may be prepared from fatty emulsion or suspension . preferably , the composition is sterilized and / or contains adjuvant . such adjuvant can be preserving , stabilizing , wetting or emulsifying agent , solution promoter , salt for regulating the osmotic pressure , buffer and / or any combination thereof . alternatively or in addition , the composition may further contain other therapeutically valuable substances for different applications , like solubilizers , stabilizers , tonicity enhancing agents , buffers and / or preservatives . in an embodiment of the invention , the composition may be a formulation suitable for transdermal application . such formulation includes an effective amount of the compound of the present invention and a carrier . preferably , the carrier may include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host . a transdermal device contain the formulation may also be used . the transdermal device may be in the form of a bandage comprising a backing member , a reservoir containing the compound optionally with carriers , optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time , and means to secure the device to the skin . otherwise , a matrix transdermal formulation may also be used . in another embodiment of the invention , the composition may be a formulation suitable for topical application , such as to the skin and eyes , and may be aqueous solution , ointment , cream or gel well known in the art . in another aspect , the present invention provides a method of inhibiting wnt secretion from a cell . in one embodiment , the cell is contained within a mammal , and the administered amount is a therapeutically effective amount . in another embodiment , the inhibition of wnt signaling further results in the inhibition of the growth of the cell . in a further embodiment , the cell is a cancer cell . in yet another embodiment , the cell is a fibrogenic cell . cell proliferation is measured by using methods known to those skilled in the art . for example , a convenient assay for measuring cell proliferation is the celltiter - glo ™ assay commercially available from promega ( madison , wis .). the assay procedure involves adding the celltiter - glo ® reagent to cells cultured on multi - well dishes . the luminescent signal , measured by a luminometer or an imaging device , is proportional to the amount of atp present , which is directly proportional to the number of viable cells present in culture . in addition , cell proliferation may also be measured using colony formation assays known in the art . the present invention also provides a method for treating cancers or fibroses related to the wnt signaling pathway with an effective amount of the present compound . those skilled in the art would readily be able to determine whether a cancer is related to the wnt pathway by analyzing cancer cells using one of several techniques known in the art . for example , one could examine cancer cells for aberrations in the levels of proteins or mrnas involved in wnt signaling using immune and nucleic acid detection methods . cancers or fibroses related to the wnt pathway include those in which activity of one or more components of the wnt signaling pathways are upregulated from basal levels . in one embodiment , inhibiting the wnt pathway may involve inhibiting wnt secretion . as another example , inhibiting the wnt pathway may involve inhibiting components downstream of the cell surface receptors . in another embodiment , inhibition of wnt secretion may involve inhibiting the activity of any of the proteins implicated in the secretion of functional wnts . furthermore , the invention provides a method for treating a wnt pathway disorder in a subject suffering from the disorder by administering to the subject a therapeutically effective amount of a wnt inhibitor . in one embodiment , the disorder is a cell proliferative disorder associated with aberrant , e . g ., increased , activity of wnt signaling . in another embodiment , the disorder results from increased amount of a wnt protein . in yet another embodiment , the cell proliferative disorder is cancer , include but are not limited to : lung ( small cell and non - small cell ), breast , prostate , carcinoid , bladder , gastric , pancreatic , liver ( hepatocellular ), hepatoblastoma , colorectal , head cancer and neck squamous cell carcinoma , esophageal , ovarian , cervical , endometrial , mesothelioma , melanoma , sarcoma , osteosarcoma , liposarcoma , thyroid , desmoids , chronic myelocytic leukemia ( aml ), and chronic myelocytic leukemia ( cml ). in yet another embodiment , the cell proliferative disorder is fibrosis , include but are not limited to : lung fibrosis , such as idiopathic pulmonary fibrosis and radiation - induced fibrosis , renal fibrosis , cardiac fibrosis and liver fibrosis including liver cirrhosis . in yet another embodiment , the disorder is osteoarthritis , parkinson &# 39 ; s disease , retinopathy , macular degeneration . for therapeutically use , the compound of the present invention could be administered in a therapeutically effective amount via any acceptable way known in the art singly . as used herein , the therapeutically effective amount may vary widely depending on the severity of the disease , the age and relative health of the subject , the potency of the compound used and other factors . generally , the satisfactory result is indicated to be obtained systemically at a daily dosage of about 0 . 03 to 2 . 5 mg / kg per body weight of the subject . in one embodiment , the indicated daily dosage for larger mammal as human is in the range from about 0 . 5 mg to about 500 mg . preferably , the compound is administered in divided doses up to four times a day or in retard form . in another embodiment , suitable unit dosage forms for oral administration comprise from ca . 1 to 500 mg active ingredient . alternatively , the compound of the present invention may be administered in a therapeutically effective amount as the active ingredient in combination with one or more therapeutic agents , such as pharmaceutical combinations . there may be synergistic effects when the compound of the present invention is used with a chemotherapeutic agent known in the art . the dosage of the co - administered compounds could vary depending on the type of co - drug employed , the specific drug employed , the condition being treated and so forth . the compound of the present invention or the composition thereof may be administered by any conventional route . in one embodiment , it is administered enterally , such as orally , and in the form of tablets or capsules . in another embodiment , it is administered parenterally and in the form of injectable solutions or suspensions . in yet another embodiment , it is administered topically and in the form of lotions , gels , ointments or creams , or in a nasal or suppository form . in another aspect , the invention also provides a pharmaceutical combination , preferably , a kit , comprising a ) a first agent which is the compound of the present invention as disclosed herein , in free form or in pharmaceutically acceptable salt form , and b ) at least one co - agent . in addition , the kit may comprise instructions for its administration . the combination of the present invention may be used in vitro or in vivo . preferably , the desired therapeutic benefit of the administration may be achieved by contacting cell , tissue or organism with a single composition or pharmacological formulation that includes the compound of the present invention and one or more agents , or by contacting the cell with two or more distinct compositions or formulations , wherein one composition includes one agent and the other includes another . the agents of the combination may be administered at the same time or separately within a period of time . preferably , the separate administration can result in a desired therapeutic benefit . the present compound may precede , be co - current with and / or follow the other agents by intervals ranging from minutes to weeks . a person skilled in the art could generally ensure the interval of the time of each delivery , wherein the agents administered separately could still be able to exert an advantageously combined effect on the cell , tissue or organism . in one embodiment , it is contemplated that one may contact the cell , tissue or organism with two , three , four or more modalities substantially simultaneously as the candidate substance , i . e ., with less than about one minute . in another embodiment , one or more agents may be administered about between 1 minute to 14 days . in another aspect , the present provides a process for preparing the compound of the present invention or the salts or derivatives thereof . in one embodiment , the compound having formula ( i ) may be prepared following any one of the synthetic methodologies described in examples below . in the reactions described , reactive functional groups , for example hydroxy , amino , imino , thio or carboxy groups , where these are desired in the final product , may be protected to avoid their unwanted participation in the reactions . conventional protecting groups may be used in accordance with standard practice ( see e . g ., t . w . greene and p . g . m . wuts in “ protective groups in organic chemistry ”, john wiley and sons , 1991 ). suitable leaving groups for use in the synthetic methodologies described include halogen leaving groups and other conventional leaving groups known in the art . preferably , the leaving group is chloro or bromo . in another embodiment , the compound of the invention or the salts thereof may also be obtainable in the form of hydrates , or their crystals may include for example the solvent used for crystallization ( present as solvates ). salts can usually be converted to compounds in free form by treating with suitable basic agents , preferably with alkali metal carbonates , alkali metal hydrogen carbonates , or alkali metal hydroxides , more preferably with potassium carbonate or sodium hydroxide . a compound of the invention in a base addition salt form may be converted to the corresponding free acid by treating with a suitable acid , such as hydrochloric acid . in view of the close relationship between the novel compounds in free form and those in the form of their salts , including those salts that may be used as intermediates , for example in the purification or identification of the novel compounds , any reference to the free compounds is to be understood as referring also to the corresponding salts , as appropriate . salts of the present compound with a salt - forming group may be prepared in a manner known in the art . acid addition salts of compound of formula ( i ) may thus be obtained by treatment with an acid or with a suitable anion exchange reagent . pharmaceutically acceptable salts of the compound of the invention may be formed as acid addition salts from compound of formula ( i ) with a basic nitrogen atom with organic or inorganic acids . preferably , suitable inorganic acids include , but are not limited to , halogen acids , such as hydrochloric acid , sulfuric acid , or phosphoric acid . preferably , suitable organic acids include , but are not limited to , carboxylic , phosphoric , sulfonic or sulfamic acids , for example acetic acid , propionic acid , octanoic acid , decanoic acid , dodecanoic acid , glycolic acid , lactic acid , fumaric acid , succinic acid , adipic acid , pimelic acid , suberic acid , azelaic acid ,- malic acid , tartaric acid , citric acid , amino acids , such as glutamic acid or aspartic acid , maleic acid , hydroxymaleic acid , methylmaleic acid , cyclohexanecarboxylic acid , adamantanecarboxylic acid , benzoic acid , salicylic acid , 4 aminosalicylic acid , phthalic acid , phenylacetic acid , mandelic acid , cinnamic acid , methane - or ethane - sulfonic acid , 2 - hydroxyethanesulfonic acid , ethane - 1 , 2 - disulfonic acid , benzenesulfonic acid , 2 - naphthalenesulfonic acid , 1 , 5 - naphthalene - disuifonic acid , 2 -, 3 - or 4 methylbenzenesulfonic acid , methylsulfuric acid , ethylsulfuric acid , dodecylsulfuric acid , n cyclohexylsulfamic acid , n - methyl -, n - ethyl - or n - propyl - sulfamic acid , or other organic protonic acids , such as ascorbic acid . alternatively , it is also possible to use pharmaceutically unacceptable salts for isolation or purification , for example picrates or perchlorates . but for therapeutic use , only pharmaceutically acceptable salts or free compounds are employed , where applicable in the form of pharmaceutical preparations . in yet another embodiment , compound of the present invention in unoxidized form may be prepared from n - oxides of compound of the invention by treating with a reducing agent in a suitable inert organic solvent at 0 to 80 ° c . preferably , the reducing agent is sulfur , sulfur dioxide , triphenyl phosphine , lithium borohydride , sodium borohydride , phosphorus trichloride , tribromide , or the like . preferably , the invert organic solvent is acetonitrile , ethanol , aqueous dioxane , or the like . in yet another embodiment , prodrug derivatives of the compound of the present invention may be prepared by methods known in the art ( for further details see saulnier et al ., ( 1994 ), bioorganic and medicinal chemistry letters , vol . 4 , p . 1985 ). in a preferable embodiment , an appropriate prodrug may be prepared by reacting a non - derivatized compound of the invention with a suitable carbamylating agent such as 1 , 1 - acyloxyalkylcarbanochloridate , para - nitrophenyl carbonate , or the like . in yet another embodiment , protected derivatives of the compound of the present invention may be made by means known in the art . a detailed description of techniques applicable to the creation of protecting groups and their removal may be found in t . w . greene , “ protecting groups in organic chemistry ”, 3rd edition , john wiley and sons , inc ., 1999 . in yet another embodiment , compound of the present invention may be prepared as their individual stereoisomers . the process includes reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds , separating the diastereomers and recovering the optically pure enantiomers . resolution of enantiomers may be carried out using covalent diastereomeric derivatives of the compound of the present invention , or by using dissociable complexes such as crystalline diastereomeric salts . diastereomers have distinct physical properties presented by melting points , boiling points , solubilities , reactivity , etc ., and may be readily separated by taking advantage of these dissimilarities . the diastereomers may be separated by fractionated crystallization , chromatography , or by separation / resolution techniques based upon differences in solubility . the optically pure enantiomer is then recovered , along with the resolving agent , by any practical means that would not result in racemization . a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture may be found in jean jacques , andre collet , samuel h . wilen , “ enantiomers , racemates and resolutions ”, john wiley and sons , inc ., 1981 . in conclusion , the compound of the present invention could be made by the process described in the examples ; optionally a pharmaceutically acceptable salt may be converted from the compound of the present invention ; optionally a pharmaceutically acceptable n - oxide may be converted from an unoxidized form of the compound the present invention ; optionally an individual isomer of the compound of the present invention is resolved from a mixture of isomers ; and optionally a pharmaceutically acceptable prodrug derivative may be converted from a non - derivatized compound of the present invention . insofar as the production of the starting materials is not particularly described , the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the examples hereinafter . one of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention , and that other well - known methods can similarly be used . in another aspect , the present invention provides compositions and methods for prevention and / or treatment of fibrosis or fibrotic diseases ( or fibrosis diseases ) including fibrogenic and hypertrophic remodeling after myocardial infarction , scleroderma , systemic sclerosis , scleroderma - like disorders , sine scleroderma , liver cirrhosis , interstitial pulmonary fibrosis , dupuytren &# 39 ; s contracture , keloids , chronic kidney disease , chronic graft rejection , and other scarring / wound healing abnormalities , post operative adhesions , and reactive fibrosis comprising administering to a subject in need thereof , a composition that comprises a therapeutically effective amount of a compound of the formula ( i ) or its tautomers , its geometrical isomers , its optically active forms as enantiomers , diastereomers and its racemate forms , pharmaceutically acceptable salts thereof , polymorphs , or a combination thereof , to the subject . fibrosis is the abnormal accumulation of fibrous tissue that can occur as a part of the wound - healing process in damaged tissue . examples of fibrosis include liver fibrosis , lung fibrosis ( e . g ., silicosis , asbestosis , idiopathic pulmonary fibrosis ), myocardial fibrosis , oral fibrosis , endomyocardial fibrosis , fibrogenic and hypertrophic remodeling after myocardial infarction , retroperitoneal fibrosis , deltoid fibrosis , kidney fibrosis ( including diabetic nephropathy ), and glomerulosclerosis . liver fibrosis , for example , occurs as a part of the wound - healing response to chronic liver injury . fibrosis can occur as a complication of haemochromatosis , wilson &# 39 ; s disease , alcoholism , schistosomiasis , viral hepatitis , bile duct obstruction , exposure to toxins , and metabolic disorders . the formation of fibrotic tissue is believed to represent an attempt by the body to encapsulate injured tissue . liver fibrosis is characterized by the accumulation of extracellular matrix that can be distinguished qualitatively from that in normal liver . left unchecked , hepatic fibrosis progresses to cirrhosis ( defined by the presence of encapsulated nodules ), liver failure , and death . endomyocardial fibrosis is an idiopathic disorder that is characterized by the development of restrictive cardiomyopathy . in endomyocardial fibrosis , the underlying process produces patchy fibrosis of the endocardial surface of the heart , leading to reduced compliance and , ultimately , restrictive physiology as the endomyocardial surface becomes more generally involved . endocardial fibrosis principally involves the inflow tracts of the right and left ventricles and may affect the atrioventricular valves , leading to tricuspid and mitral regurgitation . oral submucous fibrosis is a chronic , debilitating disease of the oral cavity characterized by inflammation and progressive fibrosis of the submucosal tissues ( lamina propria and deeper connective tissues ). it results in marked rigidity and an eventual inability to open the mouth . the buccal mucosa is the most commonly involved site , but any part of the oral cavity can be involved , even the pharynx . retroperitoneal fibrosis is characterized by the development of extensive fibrosis throughout the retroperitoneum , typically centered over the anterior surface of the fourth and fifth lumbar vertebrae . this fibrosis leads to entrapment and obstruction of retroperitoneal structures , notably the ureters . in most cases , the etiology is unknown . scleroderma is a fibrotic disease that affects approximately 19 cases per 1 million persons . the cause of scleroderma is unknown . abnormalities involve autoimmunity and alteration of endothelial cell and fibroblast function are believed to be involved . indeed , systemic sclerosis is probably the most severe of the auto - immune diseases with 50 % mortality within 5 years of diagnosis . scleroderma is a disease of the connective tissue characterized by fibrosis of the skin and internal organs , leading to organ failure and death . scleroderma has a spectrum of manifestations and a variety of therapeutic implications . it comprises localized scleroderma , systemic sclerosis , scleroderma - like disorders , and sine scleroderma . while localized scleroderma is a rare dermatologic disease associated with fibrosis and manifestations limited to skin , systemic sclerosis is a multi - system disease with variable risk for internal organ involvement and variation in the extent of skin disease . systemic sclerosis can be diffuse or limited . limited systemic sclerosis is also called crest ( calcinosis , raynaud &# 39 ; s esophageal dysfunction , sclerodactyl ), telangiectasiae ). systemic sclerosis comprises : scleroderma lung disease , scleroderma renal crisis , cardiac manifestations , muscular weakness including fatigue or limited crest , gastrointestinal dysmotility and spasm , and abnormalities in the central , peripheral and autonomic nervous system . scleroderma - like disorders are believed to be related to industrial environment exposure . in sine disease , there is internal organ involvement without skin changes . the major symptoms or manifestations of scleroderma and in particular of systemic sclerosis are inappropriate excessive collagen synthesis and deposition , endothelial dysfunction , spasm , collapse and obliteration by fibrosis . in terms of diagnosis , an important clinical parameter is skin thickening proximal to the metacarpophalangeal joints . raynaud &# 39 ; s phenomenon is a frequent , almost universal component of scleroderma . it is diagnosed by color changes of the skin upon cold exposure . ischemia and skin thickening are symptoms of raynaud &# 39 ; s disease . several underlying biological processes are implicated in the initiation , severity and progression of the disease and include vascular dysfunction , endothelial cell activation and damage , leukocyte accumulation , auto - antibody production and crucially , an uncontrolled fibrotic response which may lead to death . fibroblasts have a pivotal role in the pathogenesis of this disease . primary fibroblasts obtained from patients with scleroderma exhibit many of the characteristic properties of the disease seen in vivo , notably increased extracellular matrix synthesis and deposition , notably of collagen and fibronectin , and altered growth factor and cytokine production such as of tgf - beta and ctgf (“ increased collagen synthesis by scleroderma skin fibroblasts in vitro ” j . clin . invest . 54 , p . 880 - 89 leroy ( 1974 )) [ 2 ]. recent investigations implicate wnt signaling in abnormal wound repair leading to fibrosis . in patients with fibrotic diseases , there is an elevated expression in components of the pathway . in animal models , activation of the wnt canonical signaling participates in injury repair that leads to fibrogenesis lam a p , gottardi c j . curr opin rheumatol . 2011 november ; 23 ( 6 ): 562 - 7 . several types of fibrosis have been linked to the wnt pathway . for example , idiopathic pulmonary fibrosis ( ipf ) patients have aberrant activation of the wnt / β - catenin signaling in the lungs königshoff et al , plos one . 2008 may 14 ; 3 ( 5 ): e2142 . also , it was found that significant increase in nuclear levels of β - catenin occur in fibroblasts in systemic sclerosis skin compared to fibroblasts in the skin of healthy individuals . it was further showed that the nuclear accumulation of β - catenin has direct implications for the development of fibrosis in mice with fibroblast - specific stabilization of β - catenin . in contrast , fibroblast - specific deletion of β - catenin significantly reduced bleomycin - induced dermal fibrosis . beyer c et al ., ann rheum dis . 2012 may ; 71 ( 5 ): 761 - 7 . a link between the canonical wnt pathway and the well - known fibrogenic pathway , transforming growth factor - β ( tgf - β ) pathway has been made recently . while activation of the canonical wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo , tgf - β stimulates canonical wnt signaling by decreasing the expression of the wnt antagonist dkk - 1 . transgenic over - expression of dkk - 1 ameliorates skin fibrosis induced by constitutively active tgf - β receptor signaling . this finding not only demonstrated that canonical wnt pathway is necessary for tgf - β - mediated fibrosis but also implicated the novel interaction between the two key pathways in fibrosis ( akhmetshina et al ., nat commun 2012 mar . 13 ; 3 : 735 ). in yet another aspect , the present invention provide a combination therapy for fibrosis using a wnt inhibitor provided herein and a medicine used in standard - of - care . in some embodiments , the present invention provides a combination for treatment of lung fibrosis using a combination of a wnt inhibitor provided herein and a standard - of - care medicine , such as a steroid ( prednisone ), or esbriet ( pirfenidone ). myocardial infarction is an important complication of coronary artery disease and usually results from a critical reduction in coronary blood flow secondary to coronary thrombosis . the two important pathological changes of the cardiac tissue after acute myocardial infarction are fibrosis and hypertrophic growth of the cardiac tissues . both changes (“ remodeling ”) significantly contribute to the pathogenesis of heart failure . intravenous thrombolytic agent therapy has been widely used to restore flow to the occluded coronary artery . a thrombolytic agent is a medicament capable of lysing the fibrin - platelet thrombus , and thereby permitting blood to again flow through the affected blood vessel . such agents include streptokinase , urokinase , prourokinase , reteplase , alteplase and tissue - type plasminogen activator ( t - pa ). the mortality of patients with acute myocardial infarction even if treated with thrombolytic agents remains high . by “ acute myocardial infarction ” herein is meant immediate or sudden ( not chronic ) infarction of the heart muscle , i . e . an insufficiency of arterial blood flow as a result of occlusion of a coronary artery due to at least partial blockage of the artery by an embolus or thrombus . as an important regulator of differentiation and morphogenesis that control stem cell fates , wnt pathway is one of the important signals that form the heart . indeed , the organogenesis of the heart is tightly controlled by wnt signaling ( tzahor , dev cell . 2007 july ; 13 ( 1 ): 10 - 3 ). this knowledge has been used in the induction of mesoderm and subsequent cardiac differentiation from human es cells in culture by using modulators of the wnt pathway . in the early phase , activation of the canonical wnt signaling enhances mesoderm induction , while the later cardiac differentiation requires inhibition of the canonical signal . this biphasic control of the wnt pathway permits efficient generation of cardiomyocytes from human es or ips cells , and modulators of the wnt signaling have been postulated as useful tools or drugs for basic studies or cardiac repair applications ( paige , j bone miner res . 2011 january ; 26 ( 1 ): 19 - 26 ; lian , proc natl acad sci usa . 2012 jul . 3 ; 109 ( 27 ): e1848 - 57 .) upon myocardiac infarction , the heart reactivates several signaling pathways involved in the developing heart in an attempt to regenerate itself . it has been shown that inhibition of the canonical wnt signaling significantly reduced post - infarct mortality and functional decline . in addition , wnt signaling is activated during left ventricular ( lv ) remodeling by soluble frizzled - related proteins ( sfrps ) which block wnt - dependent activation of the canonical wnt pathway . in animal studies , sfrps injected into the heart attenuated lv remodeling . notably , sfrps are secreted from bone marrow - derived mononuclear cells , which may serve as a mechanism for the therapeutic action of such cells in human heart failure patients ( bergmann , circ res . 2010 nov . 12 ; 107 ( 10 ): 1198 - 208 ). the cellular mechanism by which wnt signaling is involved in cardiac remodeling processes may related to its action on fibrosis . as mentioned above , the wnt pathway plays in key role in fibrosis of various organs . much is needed to learn for its role and to more effectively explore its potential in therapeutic development for heart failure ( dawson k , aflaki m , nattel s . role of the wnt - frizzled system in cardiac pathophysiology : a rapidly developing , poorly understood area with enormous potential . j physiol . 2012 dec . 3 . [ epub ahead of print ]). as used herein , “ thrombus ” or “ embolus ” refer to a blood clot within the blood vessel . “ at least partial ” blockage of the artery means that the artery contains an embolus or thrombus , which reduces the cross sectional area of the artery . in another aspect , the present invention provides a combination therapy that combines the compound of formula ( i ) provided herein and a thrombolytic agent to provide synergistic effect . by “ thrombolytic agent : herein is meant any agent effective in helping to dissolving or breaking up an occluding thrombus . a thrombolytic agent may be selected from those thrombolytic agents , which are known in the art . these include , but are not limited to , streptokinase , urokinase , prourokinase , alteplase , reteplase , anistreplase and tissue plasminogen activator ( t - pa ) and biologically active variants thereof . a combination of two or several thrombolytic agents may be also used . the active ingredients are preferably administered concurrently as soon as possible , preferably within six hours , after the onset of symptoms of an acute myocardial infarction . if it is desired to avoid other medication during the thrombolytic therapy , which may be given e . g . as an intravenous bolus or infusion , the compound of formula ( i ) may be administered sequentially after the administration of the thrombolytic agent . while it is preferred to administer the compound of formula ( i ) during or immediately after the thrombolytic therapy , the synergistic effect of the combination is still obtained , if compound of formula ( i ) administration is started not later than five days , preferably not later than three days , more preferably not later than 48 hours , from the thrombolytic therapy or , preferably , from the onset of symptoms of an acute myocardial infarction . the administration routes of the active ingredients include , but are not limited to , enteral , e . g . oral or rectal , or parenteral , e . g . intravenous , intramuscular , intraperitoneal or transdermal . in the treatment of myocardial infarction , the active ingredients are preferably administered parenterally , intravenous route being particularly preferred . single or multiple dosages may be given . preferably , the active agents are administered via continuous infusion . preferably , the method comprises administering to a patient an amount of the combination , which is synergistically effective in reducing mortality of patients with myocardial infarction . compound of formula ( i ) may be administered intravenously using an infusion rate which is from about 0 . 05 to 0 . 4 μg / kg / min . for an intravenous bolus a suitable dose is in the range from about 5 to 30 μg / kg . in the treatment of patients with acute myocardial infarction an intravenous bolus followed by continuous infusion may be needed . compound of formula ( i ) may be administered orally to man in daily dose ranging from about 0 . 1 to 8 mg given once a day or divided into several doses a day , depending on the age , body weight and condition of the patient . the effective amount of compound of formula ( i ) to be administered to a subject depends upon the condition to be treated , the route of administration , age , weight and the condition of the patient . preferred thrombolytic agents include streptokinase , urokinase , prourokinase , alteplase , reteplase , anistreplase and tissue plasminogen activator ( t - pa ) and biologically active variants thereof as well as any combinations thereof . the thrombolytic agent may be administered using the conventional dosage ranges for these agents , for example a daily dosage used when the agent is administered in thrombolytic therapy as a monotherapy . the range will , of course , vary depending on the thrombolytic agent employed . examples of normal dosage ranges are as follows : urokinase — 500 , 000 to 6 , 250 , 000 units / patient ; streptokinase — 140 , 000 to 2 , 500 , 000 units / patient ; prourokinase — 5 , 000 to 100 , 000 units / patient ; anistreplase — 10 to 100 units / patient ; t - pa — 0 . 5 to 2 . 0 mg / kg body weight . thrombolytic therapy is typically given as an intravenous bolus alone or followed by intravenous infusion or as an infusion alone . the infusion is normally administered over a time ranging from less than one hour to about 12 hours , typically from about 1 to 3 hours . for example , the thrombolytic therapy may comprise administration of up to 10 % of the total dose as bolus injection over 1 to 5 minutes and the remaining 90 % then as a constant infusion during the next hour . when the symptoms have been alleviated to the desired level , treatment can be stopped . the combination may be supplemented with one or more other active ingredients , e . g . anticoagulants , or surgical methods such as angioplasty . the active ingredients can be formulated into pharmaceutical dosage forms suitable for the treatment according to the present invention using the principles known in the art . they are given to a patient as such or preferably in combination with suitable pharmaceutical excipients in the form of tablets , granules , capsules , suppositories , emulsions , suspensions or solutions whereby the contents of the active compound in the formulation is from about 0 . 5 to 100 % per weight . choosing suitable ingredients for the composition is a routine for those of ordinary skill in the art . it is evident that suitable carriers , solvents , gel forming ingredients , dispersion forming ingredients , antioxidants , colours , sweeteners , wetting compounds , release controlling components and other ingredients normally used in this field of technology may be also used . the active ingredients may be formulated in the same pharmaceutical formulation . preferably , such pharmaceutical composition of thrombolytic agent and compound of formula ( i ) is adapted to intravenous administration . such compositions may be prepared for storage by mixing these compounds with optional pharmaceutically acceptable carriers , excipients or stabilizers , e . g . into the form of infusion concentrates or aqueous solutions , or powders adapted to be reconstituted with sterile water or aqueous infusion vehicles for infusion . alternatively , the active ingredients are formulated as separate pharmaceutical dosage forms . the combination of the two pharmaceutical dosage forms may be packaged as a single medical product or kit for use in the method of the invention , optionally together with a package insert instructing to the correct use of the medical product . formulations suitable for intravenous administration such as injection or infusion formulation , comprise sterile isotonic solutions of the active ingredient and vehicle , preferably aqueous solutions . typically an intravenous infusion solution of compound of formula ( i ) comprises from about 0 . 01 to 0 . 1 mg / ml of compound of formula ( i ). compound of formula ( i ) composition as stored before use is preferably an infusion concentrate product , which can be reconstituted with sterile water or aqueous infusion vehicle for infusion . for oral administration of compound of formula ( i ) in tablet form , suitable carriers and excipients include e . g . lactose , corn starch , magnesium stearate , calcium phosphate and talc . for oral administration in capsule form , useful carriers and excipients include e . g . lactose , corn starch , magnesium stearate and talc . for controlled release oral compositions release controlling components can be used . typical release controlling components include hydrophilic gel forming polymers such as hydroxypropylmethyl cellulose , hydroxypropyl cellulose , carboxymethyl celluloses , alginic acid or a mixture thereof ; vegetable fats and oils including vegetable solid oils such as hydrogenated soybean oil , hardened castor oil or castor seed oil ( sold under trade name cutina h r ), cotton seed oil ( sold under the trade names sterotex or lubritab ) or a mixture thereof ; fatty acid esters such as triglycerides of saturated fatty acids or their mixtures e . g . glyceryl tristearates , glyceryl tripalmitates , glyceryl trimyristates , glyceryl tribehenates ( sold under the trade name compritol ) and glyceryl palmitostearic acid ester . tablets can be prepared by mixing compound of formula ( i ) with the carriers and excipients and compressing the powdery mixture into tablets . capsules can be prepared by mixing compound of formula ( i ) with the carriers and excipients and placing the powdery mixture in capsules , e . g . hard gelatin capsules . typically a tablet or a capsule comprises from about 0 . 1 to 8 mg , more typically 0 . 2 to 5 mg , of compound of formula ( i ). thrombolytic agent compositions as used in clinical practice comprises generally water as a carrier and pharmaceutical adjuvants known in the art , i . e . isotonizing agents ; acid , base or buffer substances to adjust the ph of the solution ; and stabilizing agents for the thrombolytic agent . said thrombolytic agent composition as stored before use is preferably a sterile lyophilized product , which can be reconstituted with sterile water for injection . the concentration of the thrombolytic agent in the composition depends on the nature of the thrombolytic agent . for example , tissue plasminogen activator may be present in an amount from 20 mg to 100 mg per dosage form . the concentration of tissue plasminogen activator in a lyophilized product is typically in the range of from 1 . 5 to 2 % ( w / w ). as ph adjusting agents , phosphoric acid and optionally sodium hydroxide may be used , so that upon reconstitution with sterile water for injection , a ph of about 7 . 3 is reached . as stabilizing agent for the thrombolytic agent , an amino acid may be used , for example l - arginine in the case of tissue plasminogen activator . the stabilizing agent makes up the bulk of the lyophilized thrombolytic agent , typically from about 70 % to about 80 % ( w / w ). in another aspect , the present invention provide a combination therapy of the compounds provided herein ( e . g ., a compound of formula ( i )) and a hemodynamic agents such as ace inhibitor and beta blocker , and other medicines that are the standard - of - care . first - line therapy for all heart failure patients is angiotensin - converting enzyme ( ace ) inhibitors ( i . e ., enalapril , captopril , lisinopril , ramipril ). other drugs , such as oral loop diuretics , beta - blockers , angiotensin receptor blockers , vasodilators , and aldosterone receptor antagonists , are also frequently used and can be combined with wnt inhibitors provided herein . while preferred embodiments of the present invention have been shown and described herein , it will be obvious to those skilled in the art that such embodiments are provided by way of example only . numerous variations , changes , and substitutions will now occur to those skilled in the art without departing from the invention . it should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention . it is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby . akiri g , cherian m m , vijayakumar s , liu g , bafico a , aaronson s a . wnt pathway aberrations including autocrine wnt activation occur at high frequency in human non - small - cell lung carcinoma . oncogene . 2009 may 28 ; 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119 ( 4 ): 837 - 51 macdonald b t , tamai k , he x . wnt / beta - catenin signaling : components , mechanisms , and diseases . dev cell . 2009 july ; 17 ( 1 ): 9 - 26 . mikels a j , nusse r . wnts as ligands : processing , secretion and reception . oncogene . 2006 dec . 4 ; 25 ( 57 ): 7461 - 8 . morrisey e e . wnt signaling and pulmonary fibrosis . am j pathol . 2003 may ; 162 ( 5 ): 1393 - 7 . nusse r . wnt signaling and stem cell control ”. cell res . 18 ( 5 ): 523 - 7 , 2008 ouchi n , higuchi a , ohashi k , oshima y , gokce n , shibata r , akasaki y , shimono a , walsh k . sfrp5 is an anti - inflammatory adipokine that modulates metabolic dysfunction in obesity . science . 2010 jul . 23 ; 329 ( 5990 ): 454 - 7 . reya t , clevers h . wnt signalling in stem cells and cancer . nature . 2005 apr . 14 ; 434 ( 7035 ): 843 - 50 . rhee c s , sen m , lu d , wu c , leoni l , rubin j , corr m , carson d a . wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas . oncogene . 2002 sep . 26 ; 21 ( 43 ): 6598 - 605 . sullivan g j , et al . generation of functional human hepatic endoderm from human induced pluripotent stem cells . hepatology . 2010 january ; 51 ( 1 ): 329 - 35 . takahashi - yanaga f , kahn m . targeting wnt signaling : can we safely eradicate cancer stem cells ? clin cancer res . 2010 jun . 15 ; 16 ( 12 ): 3153 - 62 . ten berge , d . et al . wnt signaling mediates self - organization and axis formation in embryoid bodies . cell stem cell 3 , 508 - 518 , 2008 . yang l , soonpaa m h , adler e d , roepke t k , kattman s j , kennedy m , henckaerts e , bonham k , abbott g w , linden r m , field l j , keller g m . human cardiovascular progenitor cells develop from a kdr + embryonic - stem - cell - derived population . nature . 2008 may 22 ; 453 ( 7194 ): 524 - 8 . the present invention is further exemplified , but not limited , by the following and examples that illustrate the preparation of the compounds of the invention . 2 - cyanoacetamide ( 50 g , 601 . 8 mmol ) and ethyl acetoacetate ( 75 ml , 601 . 8 mmol ) were dissolved in meoh . koh ( 37 . 0 g , 1 . 1 eq ) was dissolved in meoh , and added dropwise into the mixture , some white solid came out . the mixture was heated up to reflex at oil bath for 8 h , and then cooled down to rt . the solid was filtered and then re - dissolved into hot water , and then filtered again . 6n hcl was added into the filtration to neutralize till ph & lt ; 7 . the white solid was out again and filtered . the solid was further washed with meoh , water and meoh , and then dried by vacuum to get the final product 3 - ethynyl - 4 - methylpyridine - 2 , 6 - diol ( yield ˜ 41 %). 3 - ethynyl - 4 - methylpyridine - 2 , 6 - diol ( 28 . 0 g , 195 . 2 mmol ) was dissolved in pocl 3 ( 60 . 0 ml ). the reaction mixture was sealed in a pressure tube and heated up to 180 ° c . for 6 h . after the reaction was cooled down to room temperature , the excessive pocl 3 was removed under the vacuum . slowly added crushed ice into the mixture , and the solid came out . filtered the solid out and dried under the vacuum to get the final product 2 , 6 - dichloro - 4 - methylpyridine - 3 - carbonitrile ( yield ˜ 92 %) without further purity . 2 , 6 - dichloro - 4 - methylpyridine - 3 - carbonitrile ( 20 . 0 g , 107 . 5 mmol ) in 200 ml of isopropyl alcohol was added n , n - dimethylformamide dimethlacetal ( 12 . 82 g , 107 . 5 mmol ) and the reaction was stirred at 65 ° c . for 18 h . after cooling down the reaction to rt , the precipitate was collected by filtration and washed with 50 ml of isopropyl alcohol , and air dried to give the product 2 , 6 - dichloro - 4 -(( e )- 2 -( dimethylamino ) vinyl ) pyridine - 3 - carbonitrile ( yield ˜ 26 %) without further purification . 2 , 6 - dichloro - 4 -(( e )- 2 -( dimethylamino ) vinyl ) pyridine - 3 - carbonitrile ( 4 . 0 g , 16 . 6 mmol ) was added with 20 ml concentrated hcl in a sealed tube . the reaction is stirred at 45 ° c . for 18 h . after cooling down the reaction to rt , ice water was added to the solution resulting heavy yellow slurry . the precipitate was collected by filtration , washed with cold water , ether and ethyl acetate , and dried under vacuum to get light yellow solid 6 , 8 - dichloro - 2 , 7 - naphthyridin - 1 ( 2h )- one ( yield ˜ 80 %). ms m / z 215 . 0 ( m + 1 ). 1 hnmr ( 300 mhz , dmso - d6 ): δ11 . 75 ( s , 1h ), 7 . 76 ( s , 1h ), 7 . 50 ( t , j = 6 . 6 hz , 1h ), 6 . 52 ( d , j = 6 . 6 hz , 1h ). 6 , 8 - dichloro - 2 , 7 - naphthyridin - 1 ( 2h )- one ( 3 . 0 g , 13 . 96 mmol ) was dissolved in iproh ( 120 ml ) to form a kind of suspension . the solution was cooled down to 0 ° c . in ice bath , and then hydrazine solution ( 5 . 6 g , 80 %, 10 eq ) was added dropwise . the mixture was stirred at rt for 15 minutes , and then heated in oil bath at 55 ° c . for overnight . after the reaction mixture was cooled down to rt , filtered to get the solid directly , and then the solid was washed with 70 ml meoh and dried by vacuum . the product 6 - chloro - 8 - hydrazinyl - 2 , 7 - naphthyridin - 1 ( 2h )- one ( yield ˜ 98 %) was used in the next step reaction directly without further purification . 6 - chloro - 8 - hydrazinyl - 2 , 7 - naphthyridin - 1 ( 2h )- one ( 1 . 50 g , 7 . 12 mmol ) was dissolved into mecn ( 90 ml ) to form a kind of suspension . 1n naoh ( 17 . 80 ml , 2 . 5 eq ) was added , and then equal amount of water ( 107 . 80 ml ) was added into the mixture . the reaction mixture was heated at 50 ° c ., stirred till becoming the clear solution . the solution was cooled down to 0 ° c . again , and naocl ( 11 . 05 g , 12 % solution , 2 . 5 eq ) was added dropwise , and then reaction was stirred at rt for overnight . after the reaction was done , the solution was cooled down to 0 ° c . and then added into 1n hcl to neutralize ( ph ˜ 6 ). precipitate was collected and the filtrate was extracted with 100 ml × 2 ea . the organic layer was combined and dried over na 2 so 4 and evaporated to give additional crude product . the combined solid material 6 - chloro - 2 , 7 - naphthyridin - 1 ( 2h )- one ( yield ˜ 93 %) was used in the next reaction without further purification . ms m / z 181 . 1 ( m + 1 ). 6 - chloro - 2 , 7 - naphthyridin - 1 ( 2h )- one ( 400 mg , 2 . 2 mmol ) was added in pocl 3 ( 20 . 0 ml ) in a pressure tube . the reaction mixture was heated up to 160 ° c . for 4 h to get a clear solution . the solution was cooled down to room temperature and poured in dcm , and added crushed ice slowly . saturated nahco 3 was added into the mixture to neutralize hcl generated in the reaction . vacuum to remove dcm and the left water solution was extracted by 100 ml × 2 ea . the combined organic layers were washed with brine once , and dried by na 2 so 4 , and then evaporated under the vacuum to get the solid 1 , 6 - dichloro - 2 , 7 - naphthyridine ( yield ˜ 73 %) to use in the next step reaction without further purifications . ms m / z 199 . 0 ( m + 1 ). ( 4 - bromophenyl ) methanamine ( 1 . 00 g , 5 . 37 mmol ) and 2 - methylpyridin - 4 - yl - 4 - boronic acid ( 883 . 30 mg , 6 . 45 mmol ) were dissolved in buoh ( 10 . 0 ml ) and water ( 2 . 0 ml ). k 3 po 4 ( 2 . 28 g , 10 . 75 mmol ), pd 2 ( dba ) 3 ( 120 . 20 mg , 0 . 27 mmol ) and s - phos ( 220 . 70 mg , 0 . 54 mmol ) were added in under n 2 . the reaction mixture was sealed in a pressure tube and heated up to 125 ° c . for 1 h . after cooling down the reaction to rt , the mixture was poured into the water and extracted by 100 ml × 3 ea . the combined organic layer was washed with brine , dried over na 2 so 4 , and concentrated under the vacuum to give the crude product . the solid was purified by silicone gel column with 10 % meoh ( containing ˜ 2n nh 3 ) in dcm to get the pure ( 4 -( 2 - methylpyridin - 4 - yl ) phenyl ) methanamine ( yield ˜ 89 %). ms m / z 199 . 1 ( m + 1 ). 1 , 6 - dichloro - 2 , 7 - naphthyridine ( 160 mg , 0 . 80 mmol ) and ( 4 -( 2 - methylpyridin - 4 - yl ) phenyl ) methanamine ( 239 . 10 mg , 1 . 21 mmol ) were dissolved in buoh ( 5 . 0 ml ) and heated up to 115 ° c . for overnight . after the reaction was cooled down to rt , the organic solvent was removed under the vacuum . the crude product was purified by silicone gel flash chromatography with ea / hexane ( 1 : 1 ) to get the solid n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 - chloro - 2 , 7 - naphthyridin - 1 - amine ( yield ˜ 90 %). ms m / z 361 . 1 ( m + 1 ). n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 - chloro - 2 , 7 - naphthyridin - 1 - amine ( 50 . 00 mg , 0 . 14 mmol ) and 2 - methylpyridin - 4 - yl - 4 - boronic acid ( 56 . 90 mg , 0 . 42 mmol ) were dissolved in buoh ( 3 . 0 ml ) and water ( 0 . 6 ml ). k 3 po 4 ( 88 . 20 mg , 0 . 028 mmol ), pd 2 ( dba ) 3 ( 6 . 20 mg , 0 . 014 mmol ) and s - phos ( 11 . 40 mg , 0 . 011 mmol ) were added into the mixture under n 2 . the reaction was sealed in a pressure tube and heated up to 105 ° c . for overnight . after cooling down the reaction to rt , the mixture was poured in water and extracted by ea for three times . the combined organic layer was washed with brine , dried by na 2 so 4 , and concentrated under the vacuum . the crude product was further purified by prep - tlc with 5 % meoh in dcm to get the final product n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ( yield ˜ 70 %). ms m / z 418 . 2 ( m + 1 ). 1 hnmr ( 300 mhz , cdcl 3 ): δ2 . 46 ( s , 3h ), 2 . 63 ( s , 3h ), 4 . 94 ( d , j = 5 . 10 hz , 2h ), 5 . 94 ( br , 1h ), 6 . 97 ( d , j = 5 . 70 hz , 1h ), 7 . 31 ( d , j = 4 . 20 hz , 1h ), 7 . 36 ( s , 1h ), 7 . 54 ( d , j = 8 . 10 hz , 2h ), 7 . 63 ( d , j = 8 . 40 hz , 2h ), 7 . 90 ( s , 1h ), 8 . 19 ( d , j = 6 . 00 hz , 1h ), 8 . 22 ( s , 1h ), 8 . 51 ( m , 2h ), 9 . 08 ( s , 1h ), 9 . 30 ( s , 1h ). 6 - chloro - 2 , 7 - naphthyridin - 1 ( 2h )- one ( 200 mg , 1 . 10 mmol ) and 2 - methylpyridin - 4 - yl - 4 - boronic acid ( 227 . 60 mg , 1 . 66 mmol ) were dissolved in buoh ( 5 . 0 ml ) and water ( 1 . 0 ml ). k 3 po 4 ( 705 . 20 g , 3 . 32 mmol ), pd 2 ( dba ) 3 ( 49 . 60 mg , 0 . 22 mmol ) and s - phos ( 91 . 00 mg , 0 . 11 mmol ) were added under n 2 . the reaction mixture in the pressure tube was heated up to 130 ° c . for 1 h . after cooling down the reaction to rt , poured the mixture into the water , extracted by ea for three times . the combined organic layer was washed with brine , dried over na 2 so 4 , concentrated under the vacuum to get the crude . the crude product was purified by column with 5 % meoh in dcm to get the final compound 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 ( 2h )- one ( yield ˜ 61 %). ms m / z 238 . 1 ( m + 1 ). 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 ( 2h )- one ( 150 mg , 0 . 63 mmol ) was dissolved in pocl 3 ( 15 . 0 ml ), the pressure tube was sealed and heated up to 160 ° c . for 4 h . after cooling down the reaction to rt , excessive pocl 3 was removed under vacuum . crushed ice was slowly added into the mixture , and then added into nahco 3 to neutralize until ph ˜ 7 . 5 . extracted the solution by ea three times , the combined organic layer was washed with brine , dried over na 2 so 4 , and concentrated under vacuum . the crude was purified by column with ea / hexane ( 1 : 1 ) to get the compound 1 - chloro - 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridine ( yield ˜ 55 %). ms m / z 256 . 1 ( m + 1 ). 1 - chloro - 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridine ( 10 . 00 mg , 0 . 039 mmol ) and ( 3 - methyl - 4 -( 2 - methylpyridin - 4 - yl ) phenyl ) methanamine ( 10 . 00 mg , 0 . 047 mmol ) were dissolved in toluene ( 1 . 0 ml ). ko t bu ( 8 . 80 mg , 0 . 078 mmol ), pd ( oac ) 2 ( 0 . 90 mg , 0 . 0039 mmol ) and binap ( 4 . 90 mg , 0 . 0078 mmol ) was added into the mixture under n 2 . the reaction was heated up to 100 ° c . for overnight . after cooling down the reaction to rt , poured the mixture into the water , extracted by ea for three times . the combined organic layer was washed with brine , dried over na 2 so 4 , then concentrated under vacuum . the crude product was purified by prep - tlc by ea / hexane ( 4 : 1 ) to get n -( 3 - methyl - 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 6 -( 2 - methylpyridin - 4 - yl )- 2 , 7 - naphthyridin - 1 - amine ( 8 . 8 mg , yield ˜ 52 %). 1h nmr ( 300 mhz , cdcl3 ): δ2 . 31 ( s , 3h ), 2 . 63 ( s , 3h ), 2 . 70 ( s , 3h ), 4 . 91 ( d , j = 5 . 10 hz , 2h ), 5 . 88 ( br , 1h ), 7 . 00 ( d , j = 5 . 40 hz , 1h ), 7 . 08 ( d , j = 5 . 10 hz , 1h ), 7 . 12 ( s , 1h ), 7 . 22 ( d , j = 7 . 50 hz , 1h ), 7 . 36 ( m , 2h ), 7 . 77 ( d , j = 4 . 50 hz , 1h ), 7 . 88 ( s , 1h ), 7 . 98 ( s , 1h ), 8 . 24 ( d , j = 6 . 00 hz , 1h ), 8 . 53 ( d , j = 4 . 80 hz , 1h ), 8 . 64 ( d , j = 5 . 40 hz , 1h ), 9 . 31 ( s , 1h ). ms m / z 432 . 2 ( m + 1 ). 6 - bromoisoquinoline ( 1 . 80 g , 8 . 66 mmol ) was dissolved in dcm ( 40 ml ), after cooling down the reaction to 0 ° c . m - cpba ( 2 . 30 g , 1 . 3 eq , 77 % max ) was added slowly in small portion . the reaction was warmed up to rt to become a kind of white suspension . in 4 hours , 100 ml dcm was added into the solution , and washed with saturated na 2 co 3 solution , water and brine . the separated organic layer was dried over na 2 so 4 and removed under the vacuum to get the yellow solid n - oxide 6 - bromoisoquinoline without further purification ( 1 . 82 g , yield ˜ 93 %). n - oxide 6 - bromoisoquinoline ( 1 . 82 g , 8 . 12 mmol ) was dissolved in dry dcm ( 80 ml ), pocl 3 ( 1 . 12 ml , 1 . 5 eq ) was added dropwise at rt . the reaction was heated to 45 ° c . for 2 hours . after cooling down the reaction to rt , dcm and excessive pocl 3 were removed under the vacuum . the crude was re - dissolved into 100 ml dcm and was washed by saturated na 2 co 3 , water and brine . the separated organic layer was dried over na 2 so 4 , and concentrated to give brown solid . the crude was purified by flash column using 2 % meoh in dcm to get the pale yellow solid 6 - bromo - 1 - chloroisoquinoline ( 1 . 27 g , yield ˜ 65 %). ms m / z 242 . 0 ( m + 1 ). ( 6 - chloropyridin - 3 - yl ) methanamine ( 300 mg , 2 . 1 mmol ) and 2 - methylpyridin - 4 - ylboronic acid ( 345 mg , 2 . 52 mmol ) were dissolved in a pressure tube with n - butanol ( 10 ml ) and water ( 2 ml ). k 3 po 4 ( 893 mg , 4 . 2 mmol ), pd 2 ( dba ) 3 ( 96 . 3 mg , 0 . 105 mmol ), and s - phos ( 86 . 4 mg , 0 . 21 mmol ) were added under the nitrogen protection . the reaction was heated to 125 ° c . for 30 minutes and then cooled down to room temperature . the solution was pull in water and extracted by ea for three times . the combined organic layer was washed by brine and dried over na 2 so 4 , and concentrated under the vacuum . the crude was further purified by flash chromatography with 10 % meoh ( containing ˜ 2n nh 3 ) in dcm to get the pure ( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methanamine ( 0 . 19 g , yield ˜ 45 %). ms m / z 200 . 1 ( m + 1 ). 6 - bromo - 1 - chloroisoquinoline ( 100 mg , 0 . 41 mmol ) and ( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methanamine ( 165 mg , 0 . 82 mmol ) were dissolved in 0 . 5 ml n - buoh in a sealed tube . the reaction was heat up to 160 ° c . for 6 h and cooled down to rt . the crude was purified by flash chromatography using 8 % meoh ( containing ˜ 2n nh3 ) in dcm to get the pure 6 - bromo - n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) isoquinolin - 1 - amine ( 116 mg , ˜ 70 %). ms m / z 405 . 2 ( m + 1 ). 6 - bromo - n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) isoquinolin - 1 - amine ( 20 mg , 0 . 05 mmol ), 3 - fluorophenylboronic acid ( 10 . 5 mg , 0 . 075 mmol ), na 2 co 3 ( 21 mg , 0 . 2 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 5 . 8 mg , 0 . 005 mmol ) were added in a pressure tube . dioxane / water ( 3 : 1 , 2 ml ) was added into the tube and heated to 125 ° c . for 10 minutes . after cooling down the reaction to rt , the solution was diluted by 50 ml water and extracted by ea for 3 times . the combined organic layer was dried over na 2 so 4 , and concentrated under the vacuum . the crude was further purified by flash chromatography with 10 % meoh ( containing ˜ 2n nh3 ) in dcm to get the pure 6 -( 3 - fluorophenyl )- n -(( 6 -( 2 - methylpyridin - 4 - yl ) pyridin - 3 - yl ) methyl ) isoquinolin - 1 - amine ( 15 . 8 mg , ˜ 75 %). 1h nmr ( 400 mhz , cdcl3 ): δ2 . 71 ( s , 3h ), 5 . 00 ( d , j = 5 . 6 hz , 2h ), 7 . 32 - 7 . 38 ( m , 2h ), 7 . 59 - 7 . 65 ( m , 1h ), 7 . 75 - 7 . 83 ( m , 3h ), 8 . 10 ( d , j = 8 . 4 hz , 1h ), 8 . 21 ( d , j = 8 . 8 hz , 1h ), 8 . 27 - 8 . 31 ( m , 2h ), 8 . 39 ( s , 2h ), 8 . 72 ( d , j = 8 . 8 hz , 1h ), 8 . 79 ( d , j = 6 . 0 hz , 1h ), 8 . 91 ( d , j = 1 . 6 hz , 1h ), 10 . 02 ( s , 1h ). ms m / z 421 . 2 ( m + 1 ). 1 , 6 - naphthyridin - 5 ( 6h )- one ( 2 . 9 g , 19 . 84 mmol ) was dissolved in pocl 3 ( 40 ml ) and heated up to 100 ° c . for 24 h . after cooling down the reaction to room temperature , the excessive pocl 3 was removed under the vacuum . small amount crushed ice in saturated na 2 co 3 solution was added slowly , and lots of bubbles and solid came out . the solid was filtered , and the solution was extracted by ea for 3 times . the combined organic layer was dried over na 2 so 4 , and concentrated under the vacuum . the combined solid was further dried under the vacuum to get 5 - chloro - 1 , 6 - naphthyridine without further purification ( 2 . 6 g , yield ˜ 80 %). ms m / z 165 . 1 ( m + 1 ). 5 - chloro - 1 , 6 - naphthyridine ( 1 . 5 g , 9 . 11 mmol ) was dissolved in dcm ( 45 ml ) and cooled down by ice bath , m - cpba ( 3 . 7 g , 2 eq , 77 % max ) was added in small portion and slowly . the reaction was warmed up to rt and continued for 3 hours . 100 ml more dcm was added into the solution , and washed with saturated na 2 co 3 solution , water and brine . the organic layer was dried over na 2 so 4 , and concentrated under the vacuum to get yellow solid n - oxide 5 - chloro - 1 , 6 - naphthyridine without further purification ( 1 . 25 g , yield ˜ 76 %). n - oxide 5 - chloro - 1 , 6 - naphthyridine ( 1 . 2 g , 6 . 64 mmol ) was dissolved in dry dcm ( 30 ml ), et3n ( 1 . 85 ml , 13 . 29 mmol ) was added and followed by dropwise adding pocl 3 ( 0 . 93 ml , 9 . 97 mmol ) in 5 ml dry dcm . the reaction was heated to 48 ° c . for 2 hours . 100 ml more dcm was added into the solution , and washed with saturated na 2 co 3 solution , water and brine . the organic layer was dried over na 2 so 4 , and concentrated under the vacuum to get the yellow solid . the crude was further purified by silicon column using ea / hexane ( 1 : 4 ) to get white solid 2 , 5 - dichloro - 1 , 6 - naphthyridine ( 0 . 6 g , yield ˜ 45 %). ms m / z 199 . 0 ( m + 1 ) 2 , 5 - dichloro - 1 , 6 - naphthyridine ( 200 mg , 1 . 0 mmol ), 2 - methylpyridin - 4 - yl - 4 - boronic acid ( 137 mg , 1 . 0 mmol ), na 2 co 3 ( 424 mg , 4 . 0 mmol ) and tetrakis ( triphenylphosphine ) palladium ( 116 mg , 0 . 1 mmol ) were added in a flask , dioxane 16 ml and water 4 ml were further added . the reaction was stirred very well and heated to 90 ° c . for 4 hours . after cooling down the reaction to rt , the solution was diluted by 100 ml water and extracted by ea for 3 times . the combined organic layer was dried over na2so4 , and concentrated under the vacuum . the crude was further purified by flash chromatography with ea / hexane ( 1 : 1 ) to get the solid 5 - chloro - 2 -( 2 - methylpyridin - 4 - yl )- 1 , 6 - naphthyridine ( 143 mg , yield ˜ 56 %). ms m / z 256 . 1 ( m + 1 ) 5 - chloro - 2 -( 2 - methylpyridin - 4 - yl )- 1 , 6 - naphthyridine ( 20 . 00 mg , 0 . 078 mmol ) and ( 4 -( 2 - methylpyridin - 4 - yl ) phenyl ) methanamine ( 25 mg , 0 . 118 mmol ) were dissolved in toluene ( 2 . 0 ml ). ko t bu ( 13 . 2 mg , 0 . 118 mmol ), pd ( oac ) 2 ( 2 . 7 mg , 0 . 012 mmol ) and binap ( 15 . 0 mg , 0 . 024 mmol ) were added into the mixture under n 2 . the reaction was heated up to 100 ° c . for overnight . after cooling down the reaction to rt , poured the mixture into the water , extracted by ea for three times . the combined organic layer was washed with brine , dried over na 2 so 4 , then concentrated under vacuum . the crude product was purified by prep - tlc by 8 % meoh in dcm to n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 -( 2 - methylpyridin - 4 - yl )- 1 , 6 - naphthyridin - 5 - amine ( 31 mg , yield ˜ 61 %). 1 h nmr ( 400 mhz , dmso - d6 ): δ9 . 12 ( d , j = 8 . 8 hz , 1h ), 8 . 77 - 8 . 83 ( m , 2h ), 8 . 49 ( d , j = 8 . 4 hz , 1h ), 8 . 40 ( s , 1h ), 8 . 31 ( d , j = 6 . 4 hz , 1h ), 8 . 21 ( s , 1h ), 8 . 11 ( d , j = 5 . 6 hz , 1h ), 8 . 06 ( d , j = 6 . 4 hz , 1h ), 7 . 99 ( d , j = 8 . 4 hz , 2h ), 7 . 65 ( d , j = 8 . 4 hz , 2h ), 7 . 23 ( d , j = 6 . 4 hz , 1h ), 5 . 76 ( s , 1h ), 4 . 93 ( d , j = 5 . 6 hz , 2h ), 2 . 72 ( s , 6h ). ms m / z 432 . 2 ( m + 1 ). to 20 ml of ethanol was added phenyl gloyoxal monohydrate ( 940 mg , 6 . 99 mmol ) and 2 - chloro - 3 , 4 - diaminopyridine ( 1000 mg , 6 . 99 mmol ). the mixture was refluxed for overnight . after cooling down the reaction , the crude precipitated product was filtered and washed with 15 ml ethanol and dried under vacuum to get 5 - chloro - 2 - phenylpyrido [ 3 , 4 - b ] pyrazine without further purification ( 1 . 28 g , yield ˜ 76 %), ms m / z 241 . 0 ( m + 1 ); 1h nmr ( 300 mhz , dmso - d6 ): δ 9 . 82 ( s , 1h ), 8 . 64 ( d , j = 6 . 0 hz , 1h ), 8 . 38 - 8 . 43 ( m , 2h ), 8 . 07 ( d , j = 6 . 0 hz , 1h ), 7 . 64 - 7 . 68 ( m , 3h ). n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 - phenylpyrido [ 3 , 4 - b ] pyrazin - 5 - amine ( 50 mg , 0 . 21 mmol ) and ( 4 -( 2 - methylpyridin - 4 - yl ) phenyl ) methanamine ( 42 mg , 0 . 21 mmol ) were dissolved in toluene ( 4 . 0 ml ). ko t bu ( 24 mg , 0 . 21 mmol ), pd ( oac ) 2 ( 4 . 5 mg , 0 . 021 mmol ) and binap ( 26 . 4 mg , 0 . 042 mmol ) was added into the mixture under n 2 . the reaction was heated up to 100 ° c . for overnight . after cooling down the reaction to rt , poured the mixture into the water , extracted by ea for three times . the combined organic layer was washed with brine , dried over na 2 so 4 , then concentrated under vacuum . the crude product was purified by flash chromatography using 7 % meoh in dcm to get n -( 4 -( 2 - methylpyridin - 4 - yl ) benzyl )- 2 - phenylpyrido [ 4 , 3 - b ] pyrazin - 5 - amine ( 61 mg , yield ˜ 72 %). ms m / z = 404 . 2 ( m + 1 ); 1 h nmr ( 400 mhz , dmso - d6 ) δ 9 . 53 ( s , 1h ), 8 . 77 ( d , j = 6 . 4 hz , 1h ), 8 . 35 - 8 . 39 ( m , 2h ), 8 . 21 ( s , 1h ), 8 . 11 ( d , j = 6 . 0 hz , 1h ), 8 . 07 ( d , j = 6 . 4 hz , 1h ), 7 . 96 ( d , j = 8 . 4 hz , 2h ), 7 . 60 - 7 . 65 ( m , 5h ), 7 . 14 ( d , j = 6 . 0 hz , 1h ), 5 . 76 ( s , 1h ), 4 . 90 ( d , j = 6 . 4 hz , 2h ), 2 . 71 ( s , 3h ). materials and methods : nih3t3 mouse fibroblast cells ( american type culture collection , manassas , va .) were transfected with a plasmid containing a luciferase gene driven by 5 copies of tcf elements . stale cells selected with 1 μg / ml of zeocin ( gibco / invitrogen , carlsbad , calif .) are cultured in dulbecco &# 39 ; s modified eagle &# 39 ; s medium ( invitrogen , carlsbad , calif .) supplemented with 10 % fbs ( invitrogen ), 50 unit / ml penicillin and 50 μg / ml of streptomycin ( invitrogen ) at 37 ° c . with 5 % co2 in air atmosphere . suspension hek293 cells ( atcc ) were transfected with a plasmid containing full - length human wnt - 3a cdna sequence driven by a cmv promoter , and stable cells were selected in freestyle 293 medium ( invitrogen ) supplemented with 100 ug / ml g418 . the nih3t3 tcf - luc cells and 293 wnt3a cells were co - cultured in a 96 - well plate with dmem medium supplemented with 0 . 5 % fbs . after 16 hours , the firefly luciferase activities are measured with the steady - glo ™ luciferase assay system ( promega ). the cells were treated with different concentrations of compounds of this invention during the co - culture . the ic50s were defined as the concentration when the compounds reduce the luminescence intensity by 50 %. to normalize for cell quantity and viability , celltiter glo assay is next performed in a duplicate plate . all compounds presented in the patent have ic 50 & lt ; 5 μm in wnt pathway reporter gene assay . selective examples were listed in table 2 below . compounds that inhibited the tcf reporter gene activity induced by the co - cultured wnt - 3a cells in the primary assay were followed up in a mechanistic study to identify the point of action of the compounds . two different of activators were assessed , one with purified recombinant wnt - 3a protein ( stemrd inc ., burlingame , calif . ), the other with a gsk - 3b inhibitor 6 - bromoindirubin - 3 ′- oxime ( stemrd inc ., burlingame , calif .). results of such mechanistic studies showed that some of the active compounds in this invention inhibit wnt pathway activation at a point before the wnt - 3a interaction with the receptors , as they did not inhibit the tcf reporter gene activation by recombinant wnt - 3a protein . the candidates of such action include , but are not limited to wntless / evenness interrupted ( wls / evi ), porcupine ( porcn ), and vps35p . the direct target of the active compounds is most likely to be porcn because transfection of porcn into wnt - 3a expressing cells abolished the inhibitory effect of the compounds model for myocardiac infarction ( mi ): a model for myocardial infarction was created in mice by left coronary artery ligation , which produced infarcts in the anterolateral wall of the left ventricle ( lv ). drug treatment : starting from 1 day prior to the ligation , 2 . 5 mg / kg cgx was given intraperitoneally once daily for 28 days . data in fig1 and 3 show that cardiac function measured by echocardiography as fractional shortening at day 14 or 28 after mi was significantly strengthened by cgx treatment . cgx treatment also improved animal survival after mi , likely through improved cardiac function and reduced the size of infarct area . histology examination of the heart tissue for collagen also indicated that cgx treatment significantly reduced myocardial fibrosis as compared to vehicle control after 28 days . animal model for lung fibrosis : mouse model of lung fibrosis was established in balb / c mice by intratracheal administration of bleomycin ( 10 mg / g body weight ). starting from 1 day prior to bleomycin administration , animal were treated with wnt inhibitor cgx compound orally at 10 mg / kg once daily or with the same volume of vehicle . treatment was repeated daily for 15 days . bronchoalveolar lavage fluid ( balf ) and lung tissues were harvested at day 15 for protein measurement and histology , respectively . collagen assay : the sircol collagen assay was performed following the manufacturer &# 39 ; s instructions . samples were from balf . histology analysis : lung tissues were formalin - fixed , dehydrated and then embedded with paraffin . the h . e . staining , masson trichrome staining and immnunohistochemical staining for alpha smooth muscle actin ( a - sma ) were performed on paraffin sections . data in fig5 , 7 , 8 and 9 show that cgx treatment improved animal survival after bleomycin - induced lung fibrosis . amounts of total protein and collagen in balf were significantly reduced by cgx treatment , indicating reduction of fibrogenic response . histology examination of the lung tissue of showed improved overall lung structure , reduced collagen deposition and decreased myofibroblast infiltration with cgx treatment . model for cardiac hypertrophy : a model for load - induced cardiac hypertrophy was created in mice by coarctation of the transverse aorta ( webpage : www . ncbi . nlm . nih . gov / pubmed / 18287666 ). drug treatment : 2 . 5 mg / kg cgx was given intraperitoneally once daily for 28 days . data in fig1 shows that the weight of the heart was reduced by cgx treatment compared with vehicle control . data in fig1 shows that cgx treatment also improved animal survival after coarctation of the transverse aorta , likely through improved cardiac function .